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Sample records for neuropeptides modulate compound

  1. The neuropeptide oxytocin modulates consumer brand relationships.

    PubMed

    Fürst, Andreas; Thron, Jesko; Scheele, Dirk; Marsh, Nina; Hurlemann, René

    2015-01-01

    Each year, companies invest billions of dollars into marketing activities to embellish brands as valuable relationship partners assuming that consumer brand relationships (CBRs) and interpersonal relationships rest upon the same neurobiological underpinnings. Given the crucial role of the neuropeptide oxytocin (OXT) in social bonding, this study tests whether OXT-based mechanisms also determine the bond between consumers and brands. We conducted a randomized, placebo-controlled study involving 101 subjects and analyzed the effect of intranasal OXT on consumers' attribution of relationship qualities to brands, brands paired with human celebrity endorsers, and familiar persons. OXT indeed promoted the attribution of relationship qualities not only in the case of social and semi-social stimuli, but also brands. Intriguingly, for subjects scoring high on autistic-like traits, the effect of OXT was completely reversed, evident in even lower relationship qualities across all stimulus categories. The importance of OXT in a CBR context is further corroborated by a three-fold increase in endogenous release of OXT following exposure to one's favorite brand and positive associations between baseline peripheral OXT concentrations and brand relationship qualities. Collectively, our findings indicate that OXT not only plays a fundamental role in developing interpersonal relationships, but also enables relationship formation with objects such as brands. PMID:26449882

  2. The neuropeptide oxytocin modulates consumer brand relationships

    PubMed Central

    Fürst, Andreas; Thron, Jesko; Scheele, Dirk; Marsh, Nina; Hurlemann, René

    2015-01-01

    Each year, companies invest billions of dollars into marketing activities to embellish brands as valuable relationship partners assuming that consumer brand relationships (CBRs) and interpersonal relationships rest upon the same neurobiological underpinnings. Given the crucial role of the neuropeptide oxytocin (OXT) in social bonding, this study tests whether OXT-based mechanisms also determine the bond between consumers and brands. We conducted a randomized, placebo-controlled study involving 101 subjects and analyzed the effect of intranasal OXT on consumers’ attribution of relationship qualities to brands, brands paired with human celebrity endorsers, and familiar persons. OXT indeed promoted the attribution of relationship qualities not only in the case of social and semi-social stimuli, but also brands. Intriguingly, for subjects scoring high on autistic-like traits, the effect of OXT was completely reversed, evident in even lower relationship qualities across all stimulus categories. The importance of OXT in a CBR context is further corroborated by a three-fold increase in endogenous release of OXT following exposure to one’s favorite brand and positive associations between baseline peripheral OXT concentrations and brand relationship qualities. Collectively, our findings indicate that OXT not only plays a fundamental role in developing interpersonal relationships, but also enables relationship formation with objects such as brands. PMID:26449882

  3. Neuropeptide-S (NPS) Receptor Genotype Modulates Basolateral Amygdala Responsiveness to Aversive Stimuli

    PubMed Central

    Dannlowski, Udo; Kugel, Harald; Franke, Friederike; Stuhrmann, Anja; Hohoff, Christa; Zwanzger, Peter; Lenzen, Thomas; Grotegerd, Dominik; Suslow, Thomas; Arolt, Volker; Heindel, Walter; Domschke, Katharina

    2011-01-01

    Recent studies point to a role of neuropeptide-S (NPS) in the etiology of anxiety disorders. In animal models, NPS and its receptor (NPSR) were shown to be highly expressed in the amygdala, a central structure in the fear circuit, also known to be hyper-responsive in anxiety disorders. Recently, a functional polymorphism in the NPSR gene (rs324981 A/T) has been associated with panic disorder and anxiety sensitivity. However, the role of NPSR gene variation in the modulation of fear-related amygdala responsiveness remains to be clarified. In 79 healthy subjects genotyped for NPSR rs324981, amygdala responses were assessed by means of fMRI. The participants were presented with fear-relevant faces in a robust emotion-processing paradigm frequently used to study amygdala responsiveness. We observed a strong association of NPSR T-alleles with right amygdala responsiveness to fear-relevant faces. The association peak was located in the BLA. Furthermore, responsiveness to aversive stimuli within this BLA cluster predicted a participant's self-reported harm avoidance but not depression level. We conclude that NPSR genotype is associated with increased amygdala responsiveness to fear-relevant stimuli. Thereby, NPSR rs324981 apparently causes an indirect effect on anxiety-related traits and potentially contributes to the pathogenesis of anxiety disorders by shaping fear-related limbic activity. PMID:21525857

  4. Neuropeptides Modulate Female Chemosensory Processing upon Mating in Drosophila.

    PubMed

    Hussain, Ashiq; Üçpunar, Habibe K; Zhang, Mo; Loschek, Laura F; Grunwald Kadow, Ilona C

    2016-05-01

    A female's reproductive state influences her perception of odors and tastes along with her changed behavioral state and physiological needs. The mechanism that modulates chemosensory processing, however, remains largely elusive. Using Drosophila, we have identified a behavioral, neuronal, and genetic mechanism that adapts the senses of smell and taste, the major modalities for food quality perception, to the physiological needs of a gravid female. Pungent smelling polyamines, such as putrescine and spermidine, are essential for cell proliferation, reproduction, and embryonic development in all animals. A polyamine-rich diet increases reproductive success in many species, including flies. Using a combination of behavioral analysis and in vivo physiology, we show that polyamine attraction is modulated in gravid females through a G-protein coupled receptor, the sex peptide receptor (SPR), and its neuropeptide ligands, MIPs (myoinhibitory peptides), which act directly in the polyamine-detecting olfactory and taste neurons. This modulation is triggered by an increase of SPR expression in chemosensory neurons, which is sufficient to convert virgin to mated female olfactory choice behavior. Together, our data show that neuropeptide-mediated modulation of peripheral chemosensory neurons increases a gravid female's preference for important nutrients, thereby ensuring optimal conditions for her growing progeny. PMID:27145127

  5. Neuropeptides Modulate Female Chemosensory Processing upon Mating in Drosophila

    PubMed Central

    Zhang, Mo; Loschek, Laura F.; Grunwald Kadow, Ilona C.

    2016-01-01

    A female’s reproductive state influences her perception of odors and tastes along with her changed behavioral state and physiological needs. The mechanism that modulates chemosensory processing, however, remains largely elusive. Using Drosophila, we have identified a behavioral, neuronal, and genetic mechanism that adapts the senses of smell and taste, the major modalities for food quality perception, to the physiological needs of a gravid female. Pungent smelling polyamines, such as putrescine and spermidine, are essential for cell proliferation, reproduction, and embryonic development in all animals. A polyamine-rich diet increases reproductive success in many species, including flies. Using a combination of behavioral analysis and in vivo physiology, we show that polyamine attraction is modulated in gravid females through a G-protein coupled receptor, the sex peptide receptor (SPR), and its neuropeptide ligands, MIPs (myoinhibitory peptides), which act directly in the polyamine-detecting olfactory and taste neurons. This modulation is triggered by an increase of SPR expression in chemosensory neurons, which is sufficient to convert virgin to mated female olfactory choice behavior. Together, our data show that neuropeptide-mediated modulation of peripheral chemosensory neurons increases a gravid female’s preference for important nutrients, thereby ensuring optimal conditions for her growing progeny. PMID:27145127

  6. Modulation of Locomotion and Reproduction by FLP Neuropeptides in the Nematode Caenorhabditis elegans.

    PubMed

    Chang, Yan-Jung; Burton, Tina; Ha, Lawrence; Huang, Zi; Olajubelo, Adewale; Li, Chris

    2015-01-01

    Neuropeptides function in animals to modulate most, if not all, complex behaviors. In invertebrates, neuropeptides can function as the primary neurotransmitter of a neuron, but more generally they co-localize with a small molecule neurotransmitter, as is commonly seen in vertebrates. Because a single neuron can express multiple neuropeptides and because neuropeptides can bind to multiple G protein-coupled receptors, neuropeptide actions increase the complexity by which the neural connectome can be activated or inhibited. Humans are estimated to have 90 plus neuropeptide genes; by contrast, nematodes, a relatively simple organism, have a slightly larger complement of neuropeptide genes. For instance, the nematode Caenorhabditis elegans has over 100 neuropeptide-encoding genes, of which at least 31 genes encode peptides of the FMRFamide family. To understand the function of this large FMRFamide peptide family, we isolated knockouts of different FMRFamide-encoding genes and generated transgenic animals in which the peptides are overexpressed. We assayed these animals on two basic behaviors: locomotion and reproduction. Modulating levels of different neuropeptides have strong as well as subtle effects on these behaviors. These data suggest that neuropeptides play critical roles in C. elegans to fine tune neural circuits controlling locomotion and reproduction. PMID:26406995

  7. Modulation of Locomotion and Reproduction by FLP Neuropeptides in the Nematode Caenorhabditis elegans

    PubMed Central

    Chang, Yan-Jung; Burton, Tina; Ha, Lawrence; Huang, Zi; Olajubelo, Adewale; Li, Chris

    2015-01-01

    Neuropeptides function in animals to modulate most, if not all, complex behaviors. In invertebrates, neuropeptides can function as the primary neurotransmitter of a neuron, but more generally they co-localize with a small molecule neurotransmitter, as is commonly seen in vertebrates. Because a single neuron can express multiple neuropeptides and because neuropeptides can bind to multiple G protein-coupled receptors, neuropeptide actions increase the complexity by which the neural connectome can be activated or inhibited. Humans are estimated to have 90 plus neuropeptide genes; by contrast, nematodes, a relatively simple organism, have a slightly larger complement of neuropeptide genes. For instance, the nematode Caenorhabditis elegans has over 100 neuropeptide-encoding genes, of which at least 31 genes encode peptides of the FMRFamide family. To understand the function of this large FMRFamide peptide family, we isolated knockouts of different FMRFamide-encoding genes and generated transgenic animals in which the peptides are overexpressed. We assayed these animals on two basic behaviors: locomotion and reproduction. Modulating levels of different neuropeptides have strong as well as subtle effects on these behaviors. These data suggest that neuropeptides play critical roles in C. elegans to fine tune neural circuits controlling locomotion and reproduction. PMID:26406995

  8. Short neuropeptide F is a sleep-promoting inhibitory modulator

    PubMed Central

    Shang, Yuhua; Donelson, Nathan C.; Vecsey, Christopher G.; Guo, Fang; Rosbash, Michael; Griffith, Leslie C.

    2013-01-01

    SUMMARY To advance the understanding of sleep regulation, we screened for sleep-promoting cells and identified neurons expressing neuropeptide Y-like short neuropeptide F (sNPF). Sleep-induction by sNPF meets all relevant criteria. Rebound sleep following sleep deprivation is reduced by activation of sNPF neurons and flies even experience negative sleep rebound upon cessation of sNPF neuronal stimulation, indicating that sNPF provides an important signal to the sleep homeostat. Only a subset of sNPF-expressing neurons, which includes the small ventrolateral clock neurons, is sleep-promoting. Their release of sNPF increases sleep consolidation in part by suppressing the activity of wake-promoting large ventrolateral clock neurons, and suppression of neuronal firing may be the general response to sNPF receptor activation. sNPF acutely increases sleep without altering feeding behavior, which it affects only on a much longer time scale. The profound effect of sNPF on sleep indicates that it is an important sleep-promoting molecule. PMID:24094110

  9. Neuropeptide F neurons modulate sugar reward during associative olfactory learning of Drosophila larvae.

    PubMed

    Rohwedder, Astrid; Selcho, Mareike; Chassot, Bérénice; Thum, Andreas S

    2015-12-15

    All organisms continuously have to adapt their behavior according to changes in the environment in order to survive. Experience-driven changes in behavior are usually mediated and maintained by modifications in signaling within defined brain circuits. Given the simplicity of the larval brain of Drosophila and its experimental accessibility on the genetic and behavioral level, we analyzed if Drosophila neuropeptide F (dNPF) neurons are involved in classical olfactory conditioning. dNPF is an ortholog of the mammalian neuropeptide Y, a highly conserved neuromodulator that stimulates food-seeking behavior. We provide a comprehensive anatomical analysis of the dNPF neurons on the single-cell level. We demonstrate that artificial activation of dNPF neurons inhibits appetitive olfactory learning by modulating the sugar reward signal during acquisition. No effect is detectable for the retrieval of an established appetitive olfactory memory. The modulatory effect is based on the joint action of three distinct cell types that, if tested on the single-cell level, inhibit and invert the conditioned behavior. Taken together, our work describes anatomically and functionally a new part of the sugar reinforcement signaling pathway for classical olfactory conditioning in Drosophila larvae. PMID:26234537

  10. Neuropeptide Substance-P-Conjugated Chitosan Nanofibers as an Active Modulator of Stem Cell Recruiting

    PubMed Central

    Kim, Min Sup; Park, Sang Jun; Cho, Wheemoon; Gu, Bon Kang; Kim, Chun-Ho

    2016-01-01

    The goal to successful wound healing is essentially to immobilize and recruit appropriate numbers of host stem or progenitor cells to the wound area. In this study, we developed a chitosan nanofiber-immobilized neuropeptide substance-P (SP), which mediates stem cell mobilization and migration, onto the surfaces of nanofibers using a peptide-coupling agent, and evaluated its biological effects on stem cells. The amount of immobilized SP on chitosan nanofibers was modulated over the range of 5.89 ± 3.27 to 75.29 ± 24.31 ng when reacted with 10 to 500 ng SP. In vitro migration assays showed that SP-incorporated nanofibers induced more rapid migration of human mesenchymal stem cells on nanofibers compared to pristine samples. Finally, the conjugated SP evoked a minimal foreign body reaction and recruited a larger number of CD29- and CD44-positive stem cells into nanofibers in a mouse subcutaneous pocket model. PMID:26751441

  11. Neuropeptide Substance-P-Conjugated Chitosan Nanofibers as an Active Modulator of Stem Cell Recruiting.

    PubMed

    Kim, Min Sup; Park, Sang Jun; Cho, Wheemoon; Gu, Bon Kang; Kim, Chun-Ho

    2016-01-01

    The goal to successful wound healing is essentially to immobilize and recruit appropriate numbers of host stem or progenitor cells to the wound area. In this study, we developed a chitosan nanofiber-immobilized neuropeptide substance-P (SP), which mediates stem cell mobilization and migration, onto the surfaces of nanofibers using a peptide-coupling agent, and evaluated its biological effects on stem cells. The amount of immobilized SP on chitosan nanofibers was modulated over the range of 5.89 ± 3.27 to 75.29 ± 24.31 ng when reacted with 10 to 500 ng SP. In vitro migration assays showed that SP-incorporated nanofibers induced more rapid migration of human mesenchymal stem cells on nanofibers compared to pristine samples. Finally, the conjugated SP evoked a minimal foreign body reaction and recruited a larger number of CD29- and CD44-positive stem cells into nanofibers in a mouse subcutaneous pocket model. PMID:26751441

  12. Neuropeptide S receptor gene variation modulates anterior cingulate cortex Glx levels during CCK-4 induced panic.

    PubMed

    Ruland, Tillmann; Domschke, Katharina; Schütte, Valerie; Zavorotnyy, Maxim; Kugel, Harald; Notzon, Swantje; Vennewald, Nadja; Ohrmann, Patricia; Arolt, Volker; Pfleiderer, Bettina; Zwanzger, Peter

    2015-10-01

    An excitatory-inhibitory neurotransmitter dysbalance has been suggested in pathogenesis of panic disorder. The neuropeptide S (NPS) system has been implicated in modulating GABA and glutamate neurotransmission in animal models and to genetically drive altered fear circuit function and an increased risk of panic disorder in humans. Probing a multi-level imaging genetic risk model of panic, in the present magnetic resonance spectroscopy (MRS) study brain glutamate+glutamine (Glx) levels in the bilateral anterior cingulate cortex (ACC) during a pharmacological cholecystokinin tetrapeptide (CCK-4) panic challenge were assessed depending on the functional neuropeptide S receptor gene (NPSR1) rs324981 A/T variant in a final sample of 35 healthy male subjects. The subjective panic response (Panic Symptom Scale; PSS) as well as cortisol and ACTH levels were ascertained throughout the experiment. CCK-4 injection was followed by a strong panic response. A significant time×genotype interaction was detected (p=.008), with significantly lower ACC Glx/Cr levels in T allele carriers as compared to AA homozygotes 5min after injection (p=.003). CCK-4 induced significant HPA axis stimulation, but no effect of genotype was discerned. The present pilot data suggests NPSR1 gene variation to modulate Glx levels in the ACC during acute states of stress and anxiety, with blunted, i.e. possibly maladaptive ACC glutamatergic reactivity in T risk allele carriers. Our results underline the notion of a genetically driven rapid and dynamic response mechanism in the neural regulation of human anxiety and further strengthen the emerging role of the NPS system in anxiety. PMID:26235955

  13. Activation of Neuropeptide Y Receptors Modulates Retinal Ganglion Cell Physiology and Exerts Neuroprotective Actions In Vitro

    PubMed Central

    Martins, João; Elvas, Filipe; Brudzewsky, Dan; Martins, Tânia; Kolomiets, Bogdan; Tralhão, Pedro; Gøtzsche, Casper R.; Cavadas, Cláudia; Castelo-Branco, Miguel; Woldbye, David P. D.; Picaud, Serge; Santiago, Ana R.

    2015-01-01

    Neuropeptide Y (NPY) is expressed in mammalian retina but the location and potential modulatory effects of NPY receptor activation remain largely unknown. Retinal ganglion cell (RGC) death is a hallmark of several retinal degenerative diseases, particularly glaucoma. Using purified RGCs and ex vivo rat retinal preparations, we have measured RGC intracellular free calcium concentration ([Ca2+]i) and RGC spiking activity, respectively. We found that NPY attenuated the increase in the [Ca2+]i triggered by glutamate mainly via Y1 receptor activation. Moreover, (Leu31, Pro34)−NPY, a Y1/Y5 receptor agonist, increased the initial burst response of OFF-type RGCs, although no effect was observed on RGC spontaneous spiking activity. The Y1 receptor activation was also able to directly modulate RGC responses by attenuating the NMDA-induced increase in RGC spiking activity. These results suggest that Y1 receptor activation, at the level of inner or outer plexiform layers, leads to modulation of RGC receptive field properties. Using in vitro cultures of rat retinal explants exposed to NMDA, we found that NPY pretreatment prevented NMDA-induced cell death. However, in an animal model of retinal ischemia-reperfusion injury, pretreatment with NPY or (Leu31, Pro34)−NPY was not able to prevent apoptosis or rescue RGCs. In conclusion, we found modulatory effects of NPY application that for the first time were detected at the level of RGCs. However, further studies are needed to evaluate whether NPY neuroprotective actions detected in retinal explants can be translated into animal models of retinal degenerative diseases. PMID:26311075

  14. Natural Compounds Modulating Mitochondrial Functions

    PubMed Central

    Gibellini, Lara; Bianchini, Elena; De Biasi, Sara; Nasi, Milena; Cossarizza, Andrea; Pinti, Marcello

    2015-01-01

    Mitochondria are organelles responsible for several crucial cell functions, including respiration, oxidative phosphorylation, and regulation of apoptosis; they are also the main intracellular source of reactive oxygen species (ROS). In the last years, a particular interest has been devoted to studying the effects on mitochondria of natural compounds of vegetal origin, quercetin (Qu), resveratrol (RSV), and curcumin (Cur) being the most studied molecules. All these natural compounds modulate mitochondrial functions by inhibiting organelle enzymes or metabolic pathways (such as oxidative phosphorylation), by altering the production of mitochondrial ROS and by modulating the activity of transcription factors which regulate the expression of mitochondrial proteins. While Qu displays both pro- and antioxidant activities, RSV and Cur are strong antioxidant, as they efficiently scavenge mitochondrial ROS and upregulate antioxidant transcriptional programmes in cells. All the three compounds display a proapoptotic activity, mediated by the capability to directly cause the release of cytochrome c from mitochondria or indirectly by upregulating the expression of proapoptotic proteins of Bcl-2 family and downregulating antiapoptotic proteins. Interestingly, these effects are particularly evident on proliferating cancer cells and can have important therapeutic implications. PMID:26167193

  15. Transgenic n-3 PUFAs enrichment leads to weight loss via modulating neuropeptides in hypothalamus.

    PubMed

    Ma, Shuangshuang; Ge, Yinlin; Gai, Xiaoying; Xue, Meilan; Li, Ning; Kang, Jingxuan; Wan, Jianbo; Zhang, Jinyu

    2016-01-12

    Body weight is related to fat mass, which is associated with obesity. Our study explored the effect of fat-1 gene on body weight in fat-1 transgenic mice. In present study, we observed that the weight/length ratio of fat-1 transgenic mice was lower than that of wild-type mice. The serum levels of triglycerides (TG), cholesterol (CT), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and blood glucose (BG) in fat-1 transgenic mice were all decreased. The weights of peri-bowels fat, perirenal fat and peri-testicular fat in fat-1 transgenic mice were reduced. We hypothesized that increase of n-3 PUFAs might alter the expression of hypothalamic neuropeptide genes and lead to loss of body weight in fat-1 transgenic mice. Therefore, we measured mRNA levels of appetite neuropeptides, Neuropeptide Y (NPY), Agouti-related peptides (AgRP), Proopiomelanocortin (POMC), Cocaine and amphetamine regulated transcript (CART), ghrelin and nesfatin-1 in hypothalamus by real-time PCR. Compared with wild-type mice, the mRNA levels of CART, POMC and ghrelin were higher, while the mRNA levels of NPY, AgRP and nesfatin-1 were lower in fat-1 transgenic mice. The results indicate that fat-1 gene or n-3 PUFAs participates in regulation of body weight, and the mechanism of this phenomenon involves the expression of appetite neuropeptides and lipoproteins in fat-1 transgenic mice. PMID:26610903

  16. Microglia-Induced Maladaptive Plasticity Can Be Modulated by Neuropeptides In Vivo

    PubMed Central

    Morara, Stefano; Colangelo, Anna Maria; Provini, Luciano

    2015-01-01

    Microglia-induced maladaptive plasticity is being recognized as a major cause of deleterious self-sustaining pathological processes that occur in neurodegenerative and neuroinflammatory diseases. Microglia, the primary homeostatic guardian of the central nervous system, exert critical functions both during development, in neural circuit reshaping, and during adult life, in the brain physiological and pathological surveillance. This delicate critical role can be disrupted by neural, but also peripheral, noxious stimuli that can prime microglia to become overreactive to a second noxious stimulus or worsen underlying pathological processes. Among regulators of microglia, neuropeptides can play a major role. Their receptors are widely expressed in microglial cells and neuropeptide challenge can potently influence microglial activity in vitro. More relevantly, this regulator activity has been assessed also in vivo, in experimental models of brain diseases. Neuropeptide action in the central nervous system has been associated with beneficial effects in neurodegenerative and neuroinflammatory pathological experimental models. This review describes some of the mechanisms of the microglia maladaptive plasticity in vivo and how neuropeptide activity can represent a useful therapeutical target in a variety of human brain pathologies. PMID:26273481

  17. Neuropeptide W

    PubMed Central

    Takenoya, Fumiko; Kageyama, Haruaki; Hirako, Satoshi; Ota, Eiji; Wada, Nobuhiro; Ryushi, Tomoo; Shioda, Seiji

    2012-01-01

    Neuropeptide W (NPW), which was first isolated from the porcine hypothalamus, exists in two forms, consisting of 23 (NPW23) or 30 (NPW30) amino acids. These neuropeptides bind to one of two NPW receptors, either NPBWR1 (otherwise known as GPR7) or NPBWR2 (GPR8), which belong to the G protein-coupled receptor family. GPR7 is expressed in the brain and peripheral organs of both humans and rodents, whereas GPR8 is not found in rodents. GPR7 mRNA in rodents is widely expressed in several hypothalamic regions, including the paraventricular, supraoptic, ventromedial, dorsomedial, suprachiasmatic, and arcuate nuclei. These observations suggest that GPR7 plays a crucial role in the modulation of neuroendocrine function. The intracerebroventricular infusion of NPW has been shown to suppress food intake and body weight and to increase both heat production and body temperature, suggesting that NPW functions as an endogenous catabolic signaling molecule. Here we summarize our current understanding of the distribution and function of NPW in the brain. PMID:23267349

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

    PubMed

    Sousa-Ferreira, Lígia; Garrido, Manuel; Nascimento-Ferreira, Isabel; Nobrega, Clévio; Santos-Carvalho, Ana; Alvaro, Ana Rita; Rosmaninho-Salgado, Joana; Kaster, Manuella; Kügler, Sebastian; de Almeida, Luís Pereira; Cavadas, Claudia

    2011-01-01

    Neuropeptide Y (NPY) produced by arcuate nucleus (ARC) neurons has a strong orexigenic effect on target neurons. Hypothalamic NPY levels undergo wide-ranging oscillations during the circadian cycle and in response to fasting and peripheral hormones (from 0.25 to 10-fold change). The aim of the present study was to evaluate the impact of a moderate long-term modulation of NPY within the ARC neurons on food consumption, body weight gain and hypothalamic neuropeptides. We achieved a physiological overexpression (3.6-fold increase) and down-regulation (0.5-fold decrease) of NPY in the rat ARC by injection of AAV vectors expressing NPY and synthetic microRNA that target the NPY, respectively. Our work shows that a moderate overexpression of NPY was sufficient to induce diurnal over-feeding, sustained body weight gain and severe obesity in adult rats. Additionally, the circulating levels of leptin were elevated but the immunoreactivity (ir) of ARC neuropeptides was not in accordance (POMC-ir was unchanged and AGRP-ir increased), suggesting a disruption in the ability of ARC neurons to response to peripheral metabolic alterations. Furthermore, a dysfunction in adipocytes phenotype was observed in these obese rats. In addition, moderate down-regulation of NPY did not affect basal feeding or normal body weight gain but the response to food deprivation was compromised since fasting-induced hyperphagia was inhibited and fasting-induced decrease in locomotor activity was absent.These results highlight the importance of the physiological ARC NPY levels oscillations on feeding regulation, fasting response and body weight preservation, and are important for the design of therapeutic interventions for obesity that include the NPY. PMID:21799827

  19. Effect of manganese treatment on the levels of neurotransmitters, hormones, and neuropeptides: modulation by stress

    SciTech Connect

    Hong, J.S.; Jung, C.R.; Seth, P.K.; Mason, G.; Bondy, S.C.

    1984-08-01

    Six weeks of daily intraperitoneal injection with manganese chloride (15 mg/kg body wt) reduced the normal weight gain of male Fischer-344 rats. This treatment depressed plasma testosterone and corticosterone levels, but prolactin levels were unaffected. The only significant changes in the levels of a variety of neuropeptides assayed in several regions were increases in the levels of hypothalamic substance P and pituitary neurotensin. Striatal serotonin, dopamine, and their metabolites were unchanged in manganese-exposed rats relative to saline-injected controls. However, the stress of injection combined with the effect of manganese appeared to significantly increase concentrations of striatal monoamines relative to uninjected controls.

  20. Modulation of leptin resistance by food compounds.

    PubMed

    Aragonès, Gerard; Ardid-Ruiz, Andrea; Ibars, Maria; Suárez, Manuel; Bladé, Cinta

    2016-08-01

    Leptin is mainly secreted by white adipose tissue and regulates energy homeostasis by inhibiting food intake and stimulating energy expenditure through its action in neuronal circuits in the brain, particularly in the hypothalamus. However, hyperleptinemia coexists with the loss of responsiveness to leptin in common obese conditions. This phenomenon has been defined as leptin resistance and the restoration of leptin sensitivity is considered to be a useful strategy to treat obesity. This review summarizes the existing literature on potentially valuable nutrients and food components to reverse leptin resistance. Notably, several food compounds, such as teasaponins, resveratrol, celastrol, caffeine, and taurine among others, are able to restore the leptin signaling in neurons by overexpressing anorexigenic peptides (proopiomelanocortin) and/or repressing orexigenic peptides (neuropeptide Y/agouti-related peptide), thus decreasing food intake. Additionally, some nutrients, such as vitamins A and D, can improve leptin transport through the blood-brain barrier. Therefore, food components can improve leptin resistance by acting at different levels of the leptin pathway; moreover, some compounds are able to target more than one feature of leptin resistance. However, systematic studies are necessary to define the actual effectiveness of each compound. PMID:26842874

  1. Neuropeptide Y Activity in the Nucleus Accumbens Modulates Feeding Behavior and Neuronal Activity

    PubMed Central

    van den Heuvel, José K.; Furman, Kara; Gumbs, Myrtille C.R.; Eggels, Leslie; Opland, Darren M.; Land, Benjamin B.; Kolk, Sharon M.; Narayanan, Nandakumar; Fliers, Eric; Kalsbeek, Andries; DiLeone, Ralph J.; la Fleur, Susanne E.

    2014-01-01

    Background Neuropeptide Y (NPY) is a hypothalamic neuropeptide that plays a prominent role in feeding and energy homeostasis. Expression of the NPY Y1 receptor (Y1R) is highly concentrated in the nucleus accumbens (Acb), a region important in the regulation of palatable feeding. In this study, we performed a number of experiments to investigate the actions of NPY in the Acb. Methods First, we determined caloric intake and food choice after bilateral administration of NPY in the Acb in rats on a free-choice diet of saturated fat, 30% sucrose solution, and standard chow and whether this was mediated by the Y1R. Second, we measured the effect of intra-Acb NPY on neuronal activity using in vivo electrophysiology. Third, we examined co-localization of Y1R with enkephalin and dynorphin neurons and the effect of NPY on preproenkephalin messenger RNA levels in the striatum using fluorescent and radioactive in situ hybridization. Finally, using retrograde tracing, we examined whether NPY neurons in the arcuate nucleus projected to the Acb. Results In rats on the free-choice, high-fat, high-sugar diet, intra-Acb NPY increased intake of fat, but not sugar or chow, and this was mediated by the Y1R. Intra-Acb NPY reduced neuronal firing, as well as preproenkephalin messenger RNA expression in the striatum. Moreover, Acb enkephalin neurons expressed Y1R and arcuate nucleus NPY neurons projected to the Acb. Conclusions NPY reduces neuronal firing in the Acb resulting in increased palatable food intake. Together, our neuroanatomical, pharmacologic, and neuronal activity data support a role and mechanism for intra-Acb NPY-induced fat intake. PMID:25109664

  2. Related neuropeptides use different balances of unitary mechanisms to modulate the cardiac neuromuscular system in the American lobster, Homarus americanus.

    PubMed

    Dickinson, Patsy S; Calkins, Andrew; Stevens, Jake S

    2015-02-01

    To produce flexible outputs, neural networks controlling rhythmic motor behaviors can be modulated at multiple levels, including the pattern generator itself, sensory feedback, and the response of the muscle to a given pattern of motor output. We examined the role of two related neuropeptides, GYSDRNYLRFamide (GYS) and SGRNFLRFamide (SGRN), in modulating the neurogenic lobster heartbeat, which is controlled by the cardiac ganglion (CG). When perfused though an isolated whole heart at low concentrations, both peptides elicited increases in contraction amplitude and frequency. At higher concentrations, both peptides continued to elicit increases in contraction amplitude, but GYS caused a decrease in contraction frequency, while SGRN did not alter frequency. To determine the sites at which these peptides induce their effects, we examined the effects of the peptides on the periphery and on the isolated CG. When we removed the CG and stimulated the motor nerve with constant bursts of stimuli, both GYS and SGRN increased contraction amplitude, indicating that each peptide modulates the muscle or the neuromuscular junction. When applied to the isolated CG, neither peptide altered burst frequency at low peptide concentrations; at higher concentrations, SGRN decreased burst frequency, whereas GYS continued to have no effect on frequency. Together, these data suggest that the two peptides elicit some of their effects using different mechanisms; in particular, given the known feedback pathways within this system, the importance of the negative (nitric oxide) relative to the positive (stretch) feedback pathways may differ in the presence of the two peptides. PMID:25392168

  3. Terminal-Nerve-Derived Neuropeptide Y Modulates Physiological Responses in the Olfactory Epithelium of Hungry Axolotls (Ambystoma mexicanum)

    PubMed Central

    Mousley, Angela; Polese, Gianluca; Marks, Nikki J.; Eisthen, Heather L.

    2007-01-01

    The vertebrate brain actively regulates incoming sensory information, effectively filtering input and focusing attention toward environmental stimuli that are most relevant to the animal's behavioral context or physiological state. Such centrifugal modulation has been shown to play an important role in processing in the retina and cochlea, but has received relatively little attention in olfaction. The terminal nerve, a cranial nerve that extends underneath the lamina propria surrounding the olfactory epithelium, displays anatomical and neurochemical characteristics that suggest that it modulates activity in the olfactory epithelium. Using immunocytochemical techniques, we demonstrate that neuropeptide Y (NPY) is abundantly present in the terminal nerve in the axolotl (Ambystoma mexicanum), an aquatic salamander. Because NPY plays an important role in regulating appetite and hunger in many vertebrates, we investigated the possibility that NPY modulates activity in the olfactory epithelium in relation to the animal's hunger level. We therefore characterized the full length NPY gene from axolotls to enable synthesis of authentic axolotl NPY for use in electrophysiological experiments. We find that axolotl NPY modulates olfactory epithelial responses evoked by L-glutamic acid, a food-related odorant, but only in hungry animals. Similarly, whole-cell patch-clamp recordings demonstrate that bath application of axolotl NPY enhances the magnitude of a tetrodotoxin-sensitive inward current, but only in hungry animals. These results suggest that expression or activity of NPY receptors in the olfactory epithelium may change with hunger level, and that terminal nerve-derived peptides modulate activity in the olfactory epithelium in response to an animal's changing behavioral and physiological circumstances. PMID:16855098

  4. Herbal Compounds and Toxins Modulating TRP Channels

    PubMed Central

    Vriens, Joris; Nilius, Bernd; Vennekens, Rudi

    2008-01-01

    Although the benefits are sometimes obvious, traditional or herbal medicine is regarded with skepticism, because the mechanism through which plant compounds exert their powers are largely elusive. Recent studies have shown however that many of these plant compounds interact with specific ion channels and thereby modulate the sensing mechanism of the human body. Especially members of the Transient Receptor Potential (TRP) channels have drawn large attention lately as the receptors for plant-derived compounds such as capsaicin and menthol. TRP channels constitute a large and diverse family of channel proteins that can serve as versatile sensors that allow individual cells and entire organisms to detect changes in their environment. For this family, a striking number of empirical views have turned into mechanism-based actions of natural compounds. In this review we will give an overview of herbal compounds and toxins, which modulate TRP channels. PMID:19305789

  5. Neuropeptide receptors provide a signalling pathway for trigeminal modulation of olfactory transduction.

    PubMed

    Daiber, Philipp; Genovese, Federica; Schriever, Valentin A; Hummel, Thomas; Möhrlen, Frank; Frings, Stephan

    2013-02-01

    The mammalian olfactory epithelium contains olfactory receptor neurons and trigeminal sensory endings. The former mediate odor detection, the latter the detection of irritants. The two apparently parallel chemosensory systems are in reality interdependent in various well-documented ways. Psychophysical studies have shown that virtually all odorants can act as irritants, and that most irritants have an odor. Thus, the sensory perception of odorants and irritants is based on simultaneous input from the two systems. Moreover, functional interactions between the olfactory system and the trigeminal system exist on both peripheral and central levels. Here we examine the impact of trigeminal stimulation on the odor response of olfactory receptor neurons. Using an odorant with low trigeminal potency (phenylethyl alcohol) and a non-odorous irritant (CO(2) ), we have explored this interaction in psychophysical experiments with human subjects and in electroolfactogram (EOG) recordings from rats. We have demonstrated that simultaneous activation of the trigeminal system attenuates the perception of odor intensity and distorts the EOG response. On the molecular level, we have identified a route for this cross-modal interaction. The neuropeptide calcitonin-gene related peptide (CGRP), which is released from trigeminal sensory fibres upon irritant stimulation, inhibits the odor response of olfactory receptor neurons. CGRP receptors expressed by these neurons mediate this neuromodulatory effect. This study demonstrates a site of trigeminal-olfactory interaction in the periphery. It reveals a pathway for trigeminal impact on olfactory signal processing that influences odor perception. PMID:23205840

  6. Neuropeptide Y input to the rat basolateral amygdala complex and modulation by conditioned fear.

    PubMed

    Leitermann, Randy J; Rostkowski, Amanda B; Urban, Janice H

    2016-08-15

    Within the basolateral amygdaloid complex (BLA), neuropeptide Y (NPY) buffers against protracted anxiety and fear. Although the importance of NPY's actions in the BLA is well documented, little is known about the source(s) of NPY fibers to this region. The current studies identified sources of NPY projections to the BLA by using a combination of anatomical and neurochemical approaches. NPY innervation of the BLA was assessed in rats by examining the degree of NPY coexpression within interneurons or catecholaminergic fibers with somatostatin and tyrosine hydroxylase (TH) or dopamine β-hydroxylase (DβH), respectively. Numerous NPY(+) /somatostatin(+) and NPY(+) /somatostatin(-) fibers were observed, suggesting at least two populations of NPY fibers within the BLA. No colocalization was noted between NPY and TH or DβH immunoreactivities. Additionally, Fluorogold (FG) retrograde tracing with immunohistochemistry was used to identify the precise origin of NPY projections to the BLA. FG(+) /NPY(+) cells were identified within the amygdalostriatal transition area (AStr) and stria terminalis and scattered throughout the bed nucleus of the stria terminalis. The subpopulation of NPY neurons in the AStr also coexpressed somatostatin. Subjecting animals to a conditioned fear paradigm increased NPY gene expression within the AStr, whereas no changes were observed within the BLA or stria terminalis. Overall, these studies identified limbic regions associated with stress circuits providing NPY input to the BLA and demonstrated that a unique NPY projection from the AStr may participate in the regulation of conditioned fear. J. Comp. Neurol. 524:2418-2439, 2016. © 2016 Wiley Periodicals, Inc. PMID:26779765

  7. The neuropeptide Y Y1 receptor knockdown modulates activator protein 1-involved feeding behavior in amphetamine-treated rats

    PubMed Central

    2013-01-01

    Background Hypothalamic neuropeptide Y (NPY) and two immediate early genes, c-fos and c-jun, have been found to be involved in regulating the appetite-suppressing effect of amphetamine (AMPH). The present study investigated whether cerebral catecholamine (CA) might regulate NPY and POMC expression and whether NPY Y1 receptor (Y1R) participated in activator protein-1 (AP-1)–mediated feeding. Methods Rats were given AMPH daily for 4 days. Changes in the expression of NPY, Y1R, c-Fos, c-Jun, and AP-1 were assessed and compared. Results Decreased CA could modulate NPY and melanocortin receptor 4 (MC4R) expressions. NPY and food intake decreased the most on Day 2, but Y1R, c-Fos, and c-Jun increased by approximately 350%, 280%, and 300%, respectively, on Day 2. Similarly, AP-1/DNA binding activity was increased by about 180% on Day 2. The expression patterns in Y1R, c-Fos, c-Jun, and AP-1/DNA binding were opposite to those in NPY during AMPH treatment. Y1R knockdown was found to modulate the opposite regulation between NPY and AP-1, revealing an involvement of Y1R in regulating NPY/AP-1–mediated feeding. Conclusions These results point to a molecular mechanism of CA/NPY/Y1R/AP-1 signaling in the control of AMPH-mediated anorexia and may advance the medical research of anorectic and anti-obesity drugs. PMID:24225225

  8. Singing modulates mood, stress, cortisol, cytokine and neuropeptide activity in cancer patients and carers.

    PubMed

    Fancourt, Daisy; Williamon, Aaron; Carvalho, Livia A; Steptoe, Andrew; Dow, Rosie; Lewis, Ian

    2016-01-01

    There is growing evidence that psychosocial interventions can have psychological benefits for people affected by cancer, including improved symptoms of mental health and wellbeing and optimised immune responses. However, despite growing numbers of music interventions, particularly singing, in cancer care, there is less research into their impact. We carried out a multicentre single-arm preliminary study to assess the impact of singing on mood, stress and immune response in three populations affected by cancer: carers (n = 72), bereaved carers (n = 66) and patients (n = 55). Participants were excluded if pregnant or if they were currently being treated with chemotherapy, radiotherapy or oral immunosuppressive drugs. Participants were regular participants in five choirs across South Wales and took part in one hour of group singing. Before and after singing, visual analogue mood scales, stress scales and saliva samples testing for cortisol, beta-endorphin, oxytocin and ten cytokines were taken. Across all five centres and in all four participant groups, singing was associated with significant reductions in negative affect and increases in positive affect (p < .01) alongside significant increases in cytokines including GM-CSF, IL17, IL2, IL4 and sIL-2rα (all p < .01). In addition, singing was associated with reductions in cortisol, beta-endorphin and oxytocin levels. This study provides preliminary evidence that singing improves mood state and modulates components of the immune system. Further work is needed to ascertain how this differs for more specific patient groups and whether repeat exposure could lead to meaningful, longitudinal effects. PMID:27170831

  9. Multiple neuropeptides in cholinergic motor neurons of Aplysia: evidence for modulation intrinsic to the motor circuit

    SciTech Connect

    Cropper, E.C.; Lloyd, P.E.; Reed, W.; Tenenbaum, R.; Kupfermann, I.; Weiss, K.R.

    1987-05-01

    Changes in Aplysia biting responses during food arousal are partially mediated by the serotonergic metacerebral cells (MCCs). The MCCs potentiate contractions of a muscle utilized in biting, the accessory radula closer (ARCM), when contractions are elicited by stimulation of either of the two cholinergic motor neurons B15 or B16 that innervate the muscle. The authors have now shown that ARCM contractions may also be potentiated by peptide cotransmitters in the ARCM motor neurons. They found that motor neuron B15 contains small cardioactive peptides A and B (SCP/sub A/ and SCP/sub B/) i.e., whole B15 neurons were bioactive on the SCP-sensitive Helix heart, as were reverse-phase HPLC fractions of B15 neurons that eluted like synthetic SCP/sub A/ and SCP/sub B/. Furthermore, (/sup 35/S)methionine-labeled B15 peptides precisely coeluted with synthetic SCP/sub A/ and SCP/sub B/. SCP/sub B/-like immunoreactivity was associated with dense-core vesicles in the soma of B15 and in neuritic varicosities and terminals in the ARCM. B16 motor neurons did not contain SCP/sub A/ or SCP/sub B/ but contained an unidentified bioactive peptide. RP-HPLC of (/sup 35/S)methionine-labeled B16s resulted in one major peak of radioactivity that did not coelute with either SCP and which, when subject to Edman degradation, yielded (/sup 35/S)methionine in positions where there is no methionine in the SCPs. Exogenously applied B16 peptide potentiated ARCM contractions elicited by stimulation of B15 or B16 neurons. Thus, in this system there appear to be two types of modulation; one type arises from the MCCs and is extrinsic to the motor system, whereas the second type arises from the motor neurons themselves and hence is intrinsic.

  10. Singing modulates mood, stress, cortisol, cytokine and neuropeptide activity in cancer patients and carers

    PubMed Central

    Fancourt, Daisy; Williamon, Aaron; Carvalho, Livia A; Steptoe, Andrew; Dow, Rosie; Lewis, Ian

    2016-01-01

    There is growing evidence that psychosocial interventions can have psychological benefits for people affected by cancer, including improved symptoms of mental health and wellbeing and optimised immune responses. However, despite growing numbers of music interventions, particularly singing, in cancer care, there is less research into their impact. We carried out a multicentre single-arm preliminary study to assess the impact of singing on mood, stress and immune response in three populations affected by cancer: carers (n = 72), bereaved carers (n = 66) and patients (n = 55). Participants were excluded if pregnant or if they were currently being treated with chemotherapy, radiotherapy or oral immunosuppressive drugs. Participants were regular participants in five choirs across South Wales and took part in one hour of group singing. Before and after singing, visual analogue mood scales, stress scales and saliva samples testing for cortisol, beta-endorphin, oxytocin and ten cytokines were taken. Across all five centres and in all four participant groups, singing was associated with significant reductions in negative affect and increases in positive affect (p < .01) alongside significant increases in cytokines including GM-CSF, IL17, IL2, IL4 and sIL-2rα (all p < .01). In addition, singing was associated with reductions in cortisol, beta-endorphin and oxytocin levels. This study provides preliminary evidence that singing improves mood state and modulates components of the immune system. Further work is needed to ascertain how this differs for more specific patient groups and whether repeat exposure could lead to meaningful, longitudinal effects. PMID:27170831

  11. The Thioredoxin TRX-1 Modulates the Function of the Insulin-Like Neuropeptide DAF-28 during Dauer Formation in Caenorhabditis elegans

    PubMed Central

    Fierro-González, Juan Carlos; Cornils, Astrid; Alcedo, Joy

    2011-01-01

    Thioredoxins comprise a conserved family of redox regulators involved in many biological processes, including stress resistance and aging. We report that the C. elegans thioredoxin TRX-1 acts in ASJ head sensory neurons as a novel modulator of the insulin-like neuropeptide DAF-28 during dauer formation. We show that increased formation of stress-resistant, long-lived dauer larvae in mutants for the gene encoding the insulin-like neuropeptide DAF-28 requires TRX-1 acting in ASJ neurons, upstream of the insulin-like receptor DAF-2. Genetic rescue experiments demonstrate that redox-independent functions of TRX-1 specifically in ASJ neurons are needed for the dauer formation constitutive (Daf-c) phenotype of daf-28 mutants. GFP reporters of trx-1 and daf-28 show opposing expression patterns in dauers (i.e. trx-1 is up-regulated and daf-28 is down-regulated), an effect that is not observed in growing L2/L3 larvae. In addition, functional TRX-1 is required for the down-regulation of a GFP reporter of daf-28 during dauer formation, a process that is likely subject to DAF-28-mediated feedback regulation. Our findings demonstrate that TRX-1 modulates DAF-28 signaling by contributing to the down-regulation of daf-28 expression during dauer formation. We propose that TRX-1 acts as a fluctuating neuronal signaling modulator within ASJ neurons to monitor the adjustment of neuropeptide expression, including insulin-like proteins, during dauer formation in response to adverse environmental conditions. PMID:21304598

  12. Introduction: Invertebrate Neuropeptides IX

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Abstract This publication represents an introduction to the fifth in a series of special issues of the Peptides journal dedicated to invertebrate neuropeptides. The issue addresses a number of aspects of invertebrate neuropeptide research including identification of novel invertebrate neuropeptide ...

  13. Introduction: Invertebrate Neuropeptides XIII

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This publication represents an introduction to the thirteenth in a series of special issues of the Peptides journal dedicated to invertebrate neuropeptides. The issue addresses a number of aspects of invertebrate neuropeptide research including identification of novel invertebrate neuropeptide sequ...

  14. Introduction: Invertebrate Neuropeptides XV

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This publication represents an introduction to the fifteenth in a series of special issues of the Peptides journal dedicated to invertebrate neuropeptides. The issue addresses a number of aspects of invertebrate neuropeptide research including identification of novel invertebrate neuropeptide seque...

  15. Sensory neuropeptides and airway function.

    PubMed

    Solway, J; Leff, A R

    1991-12-01

    Sensory nerves synthesize tachykinins and calcitonin-gene related peptide and package these neuropeptides together in synaptic vesicles. Stimulation of these C-fibers by a range of chemical and physical factors results in afferent neuronal conduction that elicits central parasympathetic reflexes and in antidromic conduction that results in local release of neuropeptides through the axon reflex. In the airways, sensory neuropeptides act on bronchial smooth muscle, the mucosal vasculature, and submucosal glands to promote airflow obstruction, hyperemia, microvascular hyperpermeability, and mucus hypersecretion. In addition, tachykinins potentiate cholinergic neurotransmission. Proinflammatory effects of these peptides also promote the recruitment, adherence, and activation of granulocytes that may further exacerbate neurogenic inflammation (i.e., neuropeptide-induced plasma extravasation and vasodilation). Enzymatic degradation limits the physiological effects of tachykinins but may be impaired by respiratory infection or other factors. Given their sensitivity to noxious compounds and physical stimuli and their potent effects on airway function, it is possible that neuropeptide-containing sensory nerves play an important role in mediating airway responses in human disease. Supporting this view are the striking phenomenological similarities between hyperpnea-induced bronchoconstriction (HIB) in guinea pigs and HIB in patients with exercise-induced asthma. Endogenous tachykinins released from airway sensory nerves mediate HIB in guinea pigs and also cause hyperpnea-induced bronchovascular hyperpermeability in these animals. On the basis of these observations, it is reasonable to speculate that sensory neuropeptides participate in the pathogenesis of hyperpnea-induced airflow obstruction in human asthmatic subjects as well. PMID:1663932

  16. Spatial light modulation in compound semiconductor materials

    NASA Technical Reports Server (NTRS)

    Cheng, Li-Jen (Inventor); Gheen, Gregory O. (Inventor); Partovi, Afshin (Inventor)

    1990-01-01

    Spatial light modulation (22) in a III-V single crystal (12), e.g., gallium arsenide, is achieved using the photorefractive effect. Polarization rotation created by beam coupling is utilized in one embodiment. In particular, information (16)on a control beam (14) incident on the crystal is transferred to an input beam (10), also incident on the crystal. An output beam (18) modulated in intensity is obtained by passing the polarization-modulated input beam through a polarizer (20).

  17. Estrogen-related receptor β deletion modulates whole-body energy balance via estrogen-related receptor γ and attenuates neuropeptide Y gene expression.

    PubMed

    Byerly, Mardi S; Al Salayta, Muhannad; Swanson, Roy D; Kwon, Kiwook; Peterson, Jonathan M; Wei, Zhikui; Aja, Susan; Moran, Timothy H; Blackshaw, Seth; Wong, G William

    2013-04-01

    Estrogen-related receptors (ERRs) α, β and γ are orphan nuclear hormone receptors with no known ligands. Little is known concerning the role of ERRβ in energy homeostasis, as complete ERRβ-null mice die mid-gestation. We generated two viable conditional ERRβ-null mouse models to address its metabolic function. Whole-body deletion of ERRβ in Sox2-Cre:ERRβ(lox/lox) mice resulted in major alterations in body composition, metabolic rate, meal patterns and voluntary physical activity levels. Nestin-Cre:ERRβ(lox/lox) mice exhibited decreased expression of ERRβ in hindbrain neurons, the predominant site of expression, decreased neuropeptide Y (NPY) gene expression in the hindbrain, increased lean body mass, insulin sensitivity, increased energy expenditure, decreased satiety and decreased time between meals. In the absence of ERRβ, increased ERRγ signaling decreased satiety and the duration of time between meals, similar to meal patterns observed for both the Sox2-Cre:ERRβ(lox/lox) and Nestin-Cre:ERRβ(lox/lox) strains of mice. Central and/or peripheral ERRγ signaling may modulate these phenotypes by decreasing NPY gene expression. Overall, the relative expression ratio between ERRβ and ERRγ may be important in modulating ingestive behavior, specifically satiety, gene expression, as well as whole-body energy balance. PMID:23360481

  18. Effects of beta-endorphin on ornithine decarboxylase in tissues of developing rats: a potential role for this endogenous neuropeptide in the modulation of tissue growth.

    PubMed

    Bartolome, J V; Bartolome, M B; Daltner, L A; Evans, C J; Barchas, J D; Kuhn, C M; Schanberg, S M

    1986-06-23

    Ornithine decarboxlyase (ODC) catalyzes the initial step in the bio-synthesis of the polyamines spermidine and spermine, which are key regulators of cell growth, proliferation and differentiation. Intracisternal administration of beta-endorphin (1 microgram) to 6 day-old rats markedly decreased brain, liver, heart and kidney ODC activity. Conversely, subcutaneous administration of beta-endorphin increased ODC activity in the heart and liver. Thus, ODC inhibition in peripheral organs in rat pups given beta-endorphin intracisternally appears to reflect central effects of this neuropeptide. Experiments were also carried out to test whether opioid receptors are involved in these tissue ODC responses. Naloxone prevented the decreases in brain ODC indicating the participation of opioid receptors in that process. In contrast, naloxone did not alter ODC responses in peripheral organs in rat pups given beta-endorphin intracisternally, indicating that these effects are independent of its classical opioid character. These results support the view that endogenous beta-endorphin may play an important role in organogenesis by modulating the growth-related enzyme ODC. The data also suggest that the regulation of peripheral organ development by beta-endorphin may be mediated through the release of growth regulatory substances from the CNS. PMID:2941633

  19. Pulmonary neutrophil recruitment and bronchial reactivity in formaldehyde-exposed rats are modulated by mast cells and differentially by neuropeptides and nitric oxide

    SciTech Connect

    Lino dos Santos Franco, Adriana; Damazo, Amilcar Sabino; Beraldo de Souza, Hyula Regines; Domingos, Helory Vanni; Oliveira-Filho, Ricardo Martins; Oliani, Sonia Maria; Costa, Soraia Katia Pereira; Tavares de Lima, Wothan . E-mail: wtdelima@icb.usp.br

    2006-07-01

    We have used a pharmacological approach to study the mechanisms underlying the rat lung injury and the airway reactivity changes induced by inhalation of formaldehyde (FA) (1% formalin solution, 90 min once a day, 4 days). The reactivity of isolated tracheae and intrapulmonary bronchi were assessed in dose-response curves to methacholine (MCh). Local and systemic inflammatory phenomena were evaluated in terms of leukocyte countings in bronchoalveolar lavage (BAL) fluid, blood, bone marrow lavage and spleen. Whereas the tracheal reactivity to MCh did not change, a significant bronchial hyporesponsiveness (BHR) was found after FA inhalation as compared with naive rats. Also, FA exposure significantly increased the total cell numbers in BAL, in peripheral blood and in the spleen, but did not modify the counts in bone marrow. Capsaicin hindered the increase of leukocyte number recovered in BAL fluid after FA exposure. Both compound 48/80 and indomethacin were able to prevent the lung neutrophil influx after FA, but indomethacin had no effect on that of mononuclear cells. Following FA inhalation, the treatment with sodium cromoglycate (SCG), but not with the nitric oxide (NO) synthase inhibitor L-NAME, significantly reduced the total cell number in BAL. Compound 48/80, L-NAME and SCG significantly prevented BHR to MCh after FA inhalation, whereas capsaicin was inactive in this regard. On the other hand, indomethacin exacerbated BHR. These data suggest that after FA inhalation, the resulting lung leukocyte influx and BHR may involve nitric oxide, airway sensory fibers and mast cell-derived mediators. The effect of NO seemed to be largely restricted to the bronchial tonus, whereas neuropeptides appeared to be linked to the inflammatory response, therefore indicating that the mechanisms responsible for the changes of airway responsiveness caused by FA may be separate from those underlying its inflammatory lung effects.

  20. Introduction: Invertebrate Neuropeptides XI

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This publication represents an introduction to the eleventh in a series of special issues of the Peptides journal dedicated to invertebrate neuropeptides. The issue addresses a number of aspects of invertebrate neuropeptide research including identification of novel characterization of new biologic...

  1. Characterization of GdFFD, a d-Amino Acid-containing Neuropeptide That Functions as an Extrinsic Modulator of the Aplysia Feeding Circuit*

    PubMed Central

    Bai, Lu; Livnat, Itamar; Romanova, Elena V.; Alexeeva, Vera; Yau, Peter M.; Vilim, Ferdinand S.; Weiss, Klaudiusz R.; Jing, Jian; Sweedler, Jonathan V.

    2013-01-01

    During eukaryotic translation, peptides/proteins are created using l-amino acids. However, a d-amino acid-containing peptide (DAACP) can be produced through post-translational modification via an isomerase enzyme. General approaches to identify novel DAACPs and investigate their function, particularly in specific neural circuits, are lacking. This is primarily due to the difficulty in characterizing this modification and due to the limited information on neural circuits in most species. We describe a multipronged approach to overcome these limitations using the sea slug Aplysia californica. Based on bioinformatics and homology to known DAACPs in the land snail Achatina fulica, we targeted two predicted peptides in Aplysia, GFFD, similar to achatin-I (GdFAD versus GFAD, where dF stands for d-phenylalanine), and YAEFLa, identical to fulyal (YdAEFLa versus YAEFLa), using stereoselective analytical methods, i.e. MALDI MS fragmentation analysis and LC-MS/MS. Although YAEFLa in Aplysia was detected only in an all l-form, we found that both GFFD and GdFFD were present in the Aplysia CNS. In situ hybridization and immunolabeling of GFFD/GdFFD-positive neurons and fibers suggested that GFFD/GdFFD might act as an extrinsic modulator of the feeding circuit. Consistent with this hypothesis, we found that GdFFD induced robust activity in the feeding circuit and elicited egestive motor patterns. In contrast, the peptide consisting of all l-amino acids, GFFD, was not bioactive. Our data indicate that the modification of an l-amino acid-containing neuropeptide to a DAACP is essential for peptide bioactivity in a motor circuit, and thus it provides a functional significance to this modification. PMID:24078634

  2. Therapeutic Neuroendocrine Agonist and Antagonist Analogs of Hypothalamic Neuropeptides as Modulators of the Hypothalamic-Pituitary-Gonadal Axis.

    PubMed

    Newton, Claire L; Anderson, Ross C; Millar, Robert P

    2016-01-01

    Reproductive hormones play a role at all stages of life and affect most tissues of the body. Gonadotropin-releasing hormone (GnRH) synthesized in the hypothalamus stimulates the secretion of gonadotropins which in turn stimulate gonadal sex hormone production and gamete formation. This hypothalamic-pituitary-gonadal (HPG) axis has, therefore, been the target for the development of numerous drugs which regulate it at various points. These include sex steroid agonists and antagonists, inhibitors of sex steroid biosynthesis, and GnRH agonists and antagonists, which have found extensive applications in treating numerous conditions such as precocious puberty, delayed puberty, prostate cancer, benign prostatic hyperplasia, endometriosis, uterine fibroids and also in in vitro fertilization protocols. The novel neuroendocrine peptides, kisspeptin (KP) and neurokinin B (NKB), were recently discovered as upstream regulators of GnRH, and inactivating mutations of KP and NKB ligands or receptors result in a failure to progress through puberty. Agonists and antagonists of KP and NKB are being developed as more subtle modulators of the HPG axis. These new drugs offer additional and alternative therapeutic options in pediatric and adult hormone-dependent diseases. PMID:26684214

  3. Neuropeptides: conductors of the immune orchestra.

    PubMed

    Morley, J E; Kay, N E; Solomon, G F; Plotnikoff, N P

    1987-08-01

    There is increasing evidence for a bidirectional communications system between the immune system and the brain. Many of the substances involved in this communication appear to be neuropeptides. These findings have given biochemical validity to the clinical and epidemiological studies that have suggested that psychosocial factors can modulate the response to infections and neoplasms. PMID:3298913

  4. ASICs and neuropeptides.

    PubMed

    Vick, Jonathan S; Askwith, Candice C

    2015-07-01

    The acid sensing ion channels (ASICs) are proton-gated cation channels expressed throughout the nervous system. ASICs are activated during acidic pH fluctuations, and recent work suggests that they are involved in excitatory synaptic transmission. ASICs can also induce neuronal degeneration and death during pathological extracellular acidosis caused by ischemia, autoimmune inflammation, and traumatic injury. Many endogenous neuromodulators target ASICs to affect their biophysical characteristics and contributions to neuronal activity. One of the most unconventional types of modulation occurs with the interaction of ASICs and neuropeptides. Collectively, FMRFamide-related peptides and dynorphins potentiate ASIC activity by decreasing the proton-sensitivity of steady state desensitization independent of G protein-coupled receptor activation. By decreasing the proton-sensitivity of steady state desensitization, the FMRFamide-related peptides and dynorphins permit ASICs to remain active at more acidic basal pH. Unlike the dynorphins, some FMRFamide-related peptides also potentiate ASIC activity by slowing inactivation and increasing the sustained current. Through mechanistic studies, the modulation of ASICs by FMRFamide-related peptides and dynorphins appears to be through distinct interactions with the extracellular domain of ASICs. Dynorphins are expressed throughout the nervous system and can increase neuronal death during prolonged extracellular acidosis, suggesting that the interaction between dynorphins and ASICs may have important consequences for the prevention of neurological injury. The overlap in expression of FMRFamide-related peptides with ASICs in the dorsal horn of the spinal cord suggests that their interaction may have important consequences for the treatment of pain during injury and inflammation. This article is part of the Special Issue entitled 'Acid-Sensing Ion Channels in the Nervous System'. PMID:25592215

  5. ASICS AND NEUROPEPTIDES

    PubMed Central

    Vick, Jonathan S.; Askwith, Candice C.

    2015-01-01

    The acid sensing ion channels (ASICs) are proton-gated cation channels expressed throughout the nervous system. ASICs are activated during acidic pH fluctuations, and recent work suggests that they are involved in excitatory synaptic transmission. ASICs can also induce neuronal degeneration and death during pathological extracellular acidosis caused by ischemia, autoimmune inflammation, and traumatic injury. Many endogenous neuromodulators target ASICs to affect their biophysical characteristics and contributions to neuronal activity. One of the most unconventional types of modulation occurs with the interaction of ASICs and neuropeptides. Collectively, FMRFamide-related peptides and dynorphins potentiate ASIC activity by decreasing the proton-sensitivity of steady state desensitization independent of G protein-coupled receptor activation. By decreasing the proton-sensitivity of steady state desensitization, the FMRFamide-related peptides and dynorphins permit ASICs to remain active at more acidic basal pH. Unlike the dynorphins, some FMRFamide-related peptides also potentiate ASIC activity by slowing inactivation and increasing the sustained current. Through mechanistic studies, the modulation of ASICs by FMRFamide-related peptides and dynorphins appears to be through distinct interactions with the extracellular domain of ASICs. Dynorphins are expressed throughout the nervous system and can increase neuronal death during prolonged extracellular acidosis, suggesting that the interaction between dynorphins and ASICs may have important consequences for the prevention of neurological injury. The overlap in expression of FMRFamide-related peptides with ASICs in the dorsal horn of the spinal cord suggests that their interaction may have important consequences for the treatment of pain during injury and inflammation. PMID:25592215

  6. Neuropeptide physiology in helminths.

    PubMed

    Mousley, Angela; Novozhilova, Ekaterina; Kimber, Michael J; Day, Tim A

    2010-01-01

    Parasitic worms come from two distinct, distant phyla, Nematoda (roundworms) and Platyhelminthes (flatworms). The nervous systems of worms from both phyla are replete with neuropeptides and there is ample physiological evidence that these neuropeptides control vital aspects of worm biology. In each phyla, the physiological evidence for critical roles for helminth neuropeptides is derived from both parasitic and free-living members. In the nematodes, the intestinal parasite Ascaris suum and the free-living Caenorhabditis elegans have yielded most of the data; in the platyhelminths, the most physiological data has come from the blood fluke Schistosoma mansoni. FMRFamide-like peptides (FLPs) have many varied effects (excitation, relaxation, or a combination) on somatic musculature, reproductive musculature, the pharynx and motor neurons in nematodes. Insulin-like peptides (INSs) play an essential role in nematode dauer formation and other developmental processes. There is also some evidence for a role in somatic muscle control for the somewhat heterogeneous grouping ofpeptides known as neuropeptide-like proteins (NLPs). In platyhelminths, as in nematodes, FLPs have a central role in somatic muscle function. Reports of FLP physiological action in platyhelminths are limited to a potent excitation of the somatic musculature. Platyhelminths are also abundantly endowed with neuropeptide Fs (NPFs), which appear absent from nematodes. There is not yet any data linking platyhelminth NPF to any particular physiological outcome, but this neuropeptide does potently and specifically inhibit cAMP accumulation in schistosomes. In nematodes and platyhelminths, there is an abundance of physiological evidence demonstrating that neuropeptides play critical roles in the biology of both free-living and parasitic helminths. While it is certainly true that there remains a great deal to learn about the biology of neuropeptides in both phyla, physiological evidence presently available points

  7. Neuropeptide Regulation of Fear and Anxiety: Implications of Cholecystokinin, Endogenous Opioids, and Neuropeptide Y

    PubMed Central

    Bowers, Mallory E.; Choi, Dennis C.; Ressler, Kerry J.

    2012-01-01

    The neural circuitry of fear likely underlies anxiety and fear-related disorders such as specific and social phobia, panic disorder, and posttraumatic stress disorder. The primary pharmacological treatments currently utilized for these disorders include benzodiazepines, which act on the GABAergic receptor system, and antidepressants, which modulate the monamine systems. However, recent work on the regulation of fear neural circuitry suggests that specific neuropeptide modulation of this system is of critical importance. Recent reviews have examined the roles of the hypothalamic-pituitary-adrenal axis neuropeptides as well as the roles of neurotrophic factors in regulating fear. The present review, instead, will focus on three neuropeptide systems which have received less attention in recent years but which are clearly involved in regulating fear and its extinction. The endogenous opioid system, particularly activating the μ opioid receptors, has been demonstrated to regulate fear expression and extinction, possibly through functioning as an error signal within the amygdala to mark unreinforced conditioned stimuli. The cholecystokinin (CCK) system initially led to much excitement through its potential role in panic disorder. More recent work in the CCK neuropeptide pathway suggests that it may act in concordance with the endogenous cannabinoid system in the modulation of fear inhibition and extinction. Finally, older as well as very recent data suggests that neuropeptide Y (NPY) may play a very interesting role in counteracting stress effects, enhancing extinction, and enhancing resilience in fear and stress preclinical models. Future work in understanding the mechanisms of neuropeptide functioning, particularly within well-known behavioral circuits, are likely to provide fascinating new clues into the understanding of fear behavior as well as suggesting novel therapeutics for treating disorders of anxiety and fear dysregulation. PMID:22429904

  8. The corticotropin-releasing factor-like diuretic hormone 44 (DH44) and kinin neuropeptides modulate desiccation and starvation tolerance in Drosophila melanogaster.

    PubMed

    Cannell, Elizabeth; Dornan, Anthony J; Halberg, Kenneth A; Terhzaz, Selim; Dow, Julian A T; Davies, Shireen-A

    2016-06-01

    Malpighian tubules are critical organs for epithelial fluid transport and stress tolerance in insects, and are under neuroendocrine control by multiple neuropeptides secreted by identified neurons. Here, we demonstrate roles for CRF-like diuretic hormone 44 (DH44) and Drosophila melanogaster kinin (Drome-kinin, DK) in desiccation and starvation tolerance. Gene expression and labelled DH44 ligand binding data, as well as highly selective knockdowns and/or neuronal ablations of DH44 in neurons of the pars intercerebralis and DH44 receptor (DH44-R2) in Malpighian tubule principal cells, indicate that suppression of DH44 signalling improves desiccation tolerance of the intact fly. Drome-kinin receptor, encoded by the leucokinin receptor gene, LKR, is expressed in DH44 neurons as well as in stellate cells of the Malpighian tubules. LKR knockdown in DH44-expressing neurons reduces Malpighian tubule-specific LKR, suggesting interactions between DH44 and LK signalling pathways. Finally, although a role for DK in desiccation tolerance was not defined, we demonstrate a novel role for Malpighian tubule cell-specific LKR in starvation tolerance. Starvation increases gene expression of epithelial LKR. Also, Malpighian tubule stellate cell-specific knockdown of LKR significantly reduced starvation tolerance, demonstrating a role for neuropeptide signalling during starvation stress. PMID:26896569

  9. Neuropeptides controlling energy balance: orexins and neuromedins

    PubMed Central

    Nixon, Joshua P.; Kotz, Catherine M.; Novak, Colleen M.; Billington, Charles J.; Teske, Jennifer A.

    2016-01-01

    In this section we review the feeding and energy expenditure effects of orexin (also known as hypocretin) and neuromedin. Orexins are multifunctional neuropeptides that affect energy balance by participating in regulation of appetite, arousal, and spontaneous physical activity. Central orexin signaling for all functions originates in the lateral hypothalamus–perifornical area, and is likely functionally differentiated based on site of action and on interacting neural influences. The effect of orexin on feeding is likely related to arousal in some ways, but is nonetheless a separate neural process that depends on interactions with other feeding related neuropeptides. In a pattern distinct from other neuropeptides, orexin stimulates both feeding and energy expenditure. Orexin increases in energy expenditure are mainly by increasing spontaneous physical activity, and this energy expenditure effect is more potent than the effect on feeding. Global orexin manipulations, such as in transgenic models, produce energy balance changes consistent with a dominant energy expenditure effect of orexin. Neuromedins are gut-brain peptides that reduce appetite. There are gut sources of neuromedin, but likely the key appetite related neuromedin producing neurons are in hypothalamus and parallel other key anorectic neuropeptide expression in the arcuate to paraventricular hypothalamic projection. As with other hypothalamic feeding related peptides, hindbrain sites are likely also important sources and targets of neuromedin anorectic action. Neuromedin increases physical activity in addition to reducing appetite, thus producing a consistent negative energy balance effect. Together with the various other neuro-peptides, -transmitters, -modulators and –hormones, neuromedin and orexin act in the appetite network to produce changes in food intake and energy expenditure, which ultimately influences the regulation of body weight. PMID:22249811

  10. Neuropeptides and diabetic retinopathy

    PubMed Central

    Gábriel, Robert

    2013-01-01

    Diabetic retinopathy, a common complication of diabetes, develops in 75% of patients with type 1 and 50% of patients with type 2 diabetes, progressing to legal blindness in about 5%. In the recent years, considerable efforts have been put into finding treatments for this condition. It has been discovered that peptidergic mechanisms (neuropeptides and their analogues, activating a diverse array of signal transduction pathways through their multiple receptors) are potentially important for consideration in drug development strategies. A considerable amount of knowledge has been accumulated over the last three decades on human retinal neuropeptides and those elements in the pathomechanisms of diabetic retinopathy which might be related to peptidergic signal transduction. Here, human retinal neuropeptides and their receptors are reviewed, along with the theories relevant to the pathogenesis of diabetic retinopathy both in humans and in experimental models. By collating this information, the curative potential of certain neupeptides and their analogues/antagonists can also be discussed, along with the existing clinical treatments of diabetic retinopathy. The most promising peptidergic pathways for which treatment strategies may be developed at present are stimulation of the somatostatin-related pathway and the pituitary adenylyl cyclase-activating polypeptide-related pathway or inhibition of angiotensinergic mechanisms. These approaches may result in the inhibition of vascular endothelial growth factor production and neuronal apoptosis; therefore, both the optical quality of the image and the processing capability of the neural circuit in the retina may be saved. PMID:23043302

  11. Activations of c-fos/c-jun signaling are involved in the modulation of hypothalamic superoxide dismutase (SOD) and neuropeptide Y (NPY) gene expression in amphetamine-mediated appetite suppression

    SciTech Connect

    Hsieh, Y.-S.; Yang, S.-F.; Chiou, H.-L.; Kuo, D.-Y. . E-mail: dykuo@csmu.edu.tw

    2006-04-15

    Amphetamine (AMPH) is known as an anorectic agent. The mechanism underlying the anorectic action of AMPH has been attributed to its inhibitory action on hypothalamic neuropeptide Y (NPY), an appetite stimulant in the brain. This study was aimed to examine the molecular mechanisms behind the anorectic effect of AMPH. Results showed that AMPH treatment decreased food intake, which was correlated with changes of NPY mRNA level, but increased c-fos, c-jun and superoxide dismutase (SOD) mRNA levels in hypothalamus. To determine if c-fos or c-jun was involved in the anorectic response of AMPH, infusions of antisense oligonucleotide into the brain were performed at 1 h before daily AMPH treatment in freely moving rats, and the results showed that c-fos or c-jun knockdown could block this anorectic response and restore NPY mRNA level. Moreover, c-fos or c-jun knockdown could partially block SOD mRNA level that might involve in the modulation of NPY gene expression. It was suggested that c-fos/c-jun signaling might involve in the central regulation of AMPH-mediated feeding suppression via the modulation of NPY gene expression.

  12. Neuropeptides in depression: role of VGF

    PubMed Central

    Thakker-Varia, Smita; Alder, Janet

    2009-01-01

    The monoamine hypothesis of depression is increasingly called into question by newer theories that revolve around changes in neuronal plasticity, primarily in the hippocampus, at both the structural and functional levels. Chronic stress negatively regulates hippocampal function while antidepressants ameliorate the effects of stress on neuronal morphology and activity. Both stress and antidepressants have been shown to affect levels of brain-derived neurotrophic factor (BDNF) whose transcription is dependent on cAMP response element binding protein (CREB). BDNF itself has antidepressant-like actions and can induce transcription of a number of molecules. One class of genes regulated by both BDNF and serotonin (5-HT) are neuropeptides including VGF (non-acryonimic) which has a novel role in depression. Neuropeptides are important modulators of neuronal function but their role in affective disorders is just emerging. Recent studies demonstrate that VGF, which is also a CREB-dependent gene, is upregulated by antidepressant drugs and voluntary exercise and is reduced in animal models of depression. VGF enhances hippocampal synaptic plasticity as well as neurogenesis in the dentate gyrus but the mechanisms of antidepressant-like actions of VGF in behavioral paradigms are not known. We summarize experimental data describing the roles of BDNF, VGF and other neuropeptides in depression and how they may be acting through the generation of new neurons and altered synaptic activity. Understanding the molecular and cellular changes that underlie the actions of neuropeptides and how these adaptations result in antidepressant-like effects will aid in developing drugs that target novel pathways for major depressive disorders. PMID:18983874

  13. Countervailing Modulation of Ih by Neuropeptide Y and Corticotrophin-Releasing Factor in Basolateral Amygdala As a Possible Mechanism for Their Effects on Stress-Related Behaviors

    PubMed Central

    Giesbrecht, Chantelle J.; Mackay, James P.; Silveira, Heika B.; Urban, Janice H.; Colmers, William F.

    2012-01-01

    Stress and anxiety-related behaviors controlled by the basolateral amygdala (BLA) are regulated in vivo by neuropeptide Y (NPY) and corticotrophin-releasing factor (CRF): NPY produces anxiolytic effects, whereas CRF produces anxiogenic effects. These opposing actions are likely mediated via regulation of excitatory output from the BLA to afferent targets. In these studies, we examined mechanisms underlying the effects of NPY and CRF in the BLA using whole-cell patch-clamp electrophysiology in rat brain slices. NPY, even with tetrodotoxin present, caused a dose-dependent membrane hyperpolarization in BLA pyramidal neurons. The hyperpolarization resulted in the inhibition of pyramidal cells, despite arising from a reduction in a voltage-dependent membrane conductance. The Y1 receptor agonist, F 7P 34 NPY, produced a similar membrane hyperpolarization, whereas the Y1 antagonist, BIBO3304 [(R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N 2-(diphenylacetyl)-argininamide trifluoroacetate], blocked the effect of NPY. The NPY-inhibited current was identified as Ih, which is active at and hyperpolarized to rest. Responses to NPY were occluded by either Cs+ or ZD7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride), but unaffected by the GIRK-preferring blockers Ba 2+ and SCH23390 [(R)-(+)-7-chloro-8-hydroxy-3-methyl-l-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride]. Application of CRF, with or without TTX present, depolarized NPY-sensitive BLA pyramidal neurons, resulting from an increase in Ih. Electrophysiological and immunocytochemical data were consistent with a major role for the HCN1 subunit. Our results indicate that NPY, via Y1 receptors, directly inhibits BLA pyramidal neurons by suppressing a postsynaptic Ih, whereas CRF enhances resting Ih, causing an increased excitability of BLA pyramidal neurons. The opposing actions of these two peptides on the excitability of BLA output cells are consistent with the observed behavioral

  14. Neuropeptide GPCRs in C. elegans

    PubMed Central

    Frooninckx, Lotte; Van Rompay, Liesbeth; Temmerman, Liesbet; Van Sinay, Elien; Beets, Isabel; Janssen, Tom; Husson, Steven J.; Schoofs, Liliane

    2012-01-01

    Like most organisms, the nematode Caenorhabditis elegans relies heavily on neuropeptidergic signaling. This tiny animal represents a suitable model system to study neuropeptidergic signaling networks with single cell resolution due to the availability of powerful molecular and genetic tools. The availability of the worm’s complete genome sequence allows researchers to browse through it, uncovering putative neuropeptides and their cognate G protein-coupled receptors (GPCRs). Many predictions have been made about the number of C. elegans neuropeptide GPCRs. In this review, we report the state of the art of both verified as well as predicted C. elegans neuropeptide GPCRs. The predicted neuropeptide GPCRs are incorporated into the receptor classification system based on their resemblance to orthologous GPCRs in insects and vertebrates. Appointing the natural ligand(s) to each predicted neuropeptide GPCR (receptor deorphanization) is a crucial step during characterization. The development of deorphanization strategies resulted in a significant increase in the knowledge of neuropeptidergic signaling in C. elegans. Complementary localization and functional studies demonstrate that neuropeptides and their GPCRs represent a rich potential source of behavioral variability in C. elegans. Here, we review all neuropeptidergic signaling pathways that so far have been functionally characterized in C. elegans. PMID:23267347

  15. Flow-modulated targeted signal enhancement for volatile organic compounds.

    PubMed

    Hayward, Taylor; Gras, Ronda; Luong, Jim

    2016-06-01

    Comprehensive two-dimensional gas chromatography is a technique that is becoming more widespread within the analytical community, especially in the separation of complex mixtures. Modulation in comprehensive two-dimensional gas chromatography can be achieved by manipulating temperature or flow and offers many advantages such as increased separation power, but one underutilized advantage is increased detectability due to the reduction of peak width from the use of a modulator. A flow modulator was used to selectively target analytes for increased detectability with a standard flame ionization detector operated at 100 Hz, without the need for cryogens or advanced modulation software. By the collection of the entire peak volume followed by peak transfer rather than further separation, an increase of 12 times in peak height and detectability was realized for the analytes tested using an internal loop modulator configuration. An external loop flow modulator configuration allowed for more volatile analytes (with k < 5), and demonstrated an analyte detectability enhancement factor of at least 6. The collection loop size can be readily increased with an external loop configuration to accommodate for these naturally broader peaks. This novel flow modulated targeted signal enhancement approach was applied to industrially significant analyses like the analysis of methanol in a hydrocarbon streams. Methanol was detected at 7 ppb with a conventional flame ionization detector and without the need for pre-concentration. PMID:27120133

  16. Chronic Mild Cold Conditioning Modulates the Expression of Hypothalamic Neuropeptide and Intermediary Metabolic-Related Genes and Improves Growth Performances in Young Chicks

    PubMed Central

    Nguyen, Phuong; Greene, Elizabeth; Ishola, Peter; Huff, Geraldine; Donoghue, Annie; Bottje, Walter; Dridi, Sami

    2015-01-01

    Background Low environmental temperatures are among the most challenging stressors in poultry industries. Although landmark studies using acute severe cold exposure have been conducted, still the molecular mechanisms underlying cold-stress responses in birds are not completely defined. In the present study we determine the effect of chronic mild cold conditioning (CMCC) on growth performances and on the expression of key metabolic-related genes in three metabolically important tissues: brain (main site for feed intake control), liver (main site for lipogenesis) and muscle (main site for thermogenesis). Methods 80 one-day old male broiler chicks were divided into two weight-matched groups and maintained in two different temperature floor pen rooms (40 birds/room). The temperature of control room was 32°C, while the cold room temperature started at 26.7°C and gradually reduced every day (1°C/day) to reach 19.7°C at the seventh day of the experiment. At day 7, growth performances were recorded (from all birds) and blood samples and tissues were collected (n = 10). The rest of birds were maintained at the same standard environmental condition for two more weeks and growth performances were measured. Results Although feed intake remained unchanged, body weight gain was significantly increased in CMCC compared to the control chicks resulting in a significant low feed conversion ratio (FCR). Circulating cholesterol and creatine kinase levels were higher in CMCC chicks compared to the control group (P<0.05). CMCC significantly decreased the expression of both the hypothalamic orexigenic neuropeptide Y (NPY) and anorexigenic cocaine and amphetamine regulated transcript (CART) in chick brain which may explain the similar feed intake between the two groups. Compared to the control condition, CMCC increased the mRNA abundance of AMPKα1/α2 and decreased mTOR gene expression (P<0.05), the master energy and nutrient sensors, respectively. It also significantly decreased the

  17. Modulation of thermoreceptor TRPM8 by cooling compounds.

    PubMed

    Bharate, Sonali S; Bharate, Sandip B

    2012-04-18

    ThermoTRPs, a subset of the Transient Receptor Potential (TRP) family of cation channels, have been implicated in sensing temperature. TRPM8 and TRPA1 are both activated by cooling. TRPM8 is activated by innocuous cooling (<30 °C) and contributes to sensing unpleasant cold stimuli or mediating the effects of cold analgesia and is a receptor for menthol and icilin (mint-derived and synthetic cooling compounds, respectively). TRPA1 (Ankyrin family) is activated by noxious cold (<17 °C), icilin, and a variety of pungent compounds. Extensive amount of medicinal chemistry efforts have been published mainly in the form of patent literature on various classes of cooling compounds by various pharmaceutical companies; however, no prior comprehensive review has been published. When expressed in heterologous expression systems, such as Xenopus oocytes or mammalian cell lines, TRPM8 mediated currents are activated by a number of cooling compounds in addition to menthol and icilin. These include synthetic p-menthane carboxamides along with other class of compounds such as aliphatic/alicyclic alcohols/esters/amides, sulphones/sulphoxides/sulphonamides, heterocyclics, keto-enamines/lactams, and phosphine oxides. In the present review, the medicinal chemistry of various cooling compounds as activators of thermoTRPM8 channel will be discussed according to their chemical classes. The potential of these compounds to emerge as therapeutic agents is also discussed. PMID:22860192

  18. Modulation of Thermoreceptor TRPM8 by Cooling Compounds

    PubMed Central

    2012-01-01

    ThermoTRPs, a subset of the Transient Receptor Potential (TRP) family of cation channels, have been implicated in sensing temperature. TRPM8 and TRPA1 are both activated by cooling. TRPM8 is activated by innocuous cooling (<30 °C) and contributes to sensing unpleasant cold stimuli or mediating the effects of cold analgesia and is a receptor for menthol and icilin (mint-derived and synthetic cooling compounds, respectively). TRPA1 (Ankyrin family) is activated by noxious cold (<17 °C), icilin, and a variety of pungent compounds. Extensive amount of medicinal chemistry efforts have been published mainly in the form of patent literature on various classes of cooling compounds by various pharmaceutical companies; however, no prior comprehensive review has been published. When expressed in heterologous expression systems, such as Xenopus oocytes or mammalian cell lines, TRPM8 mediated currents are activated by a number of cooling compounds in addition to menthol and icilin. These include synthetic p-menthane carboxamides along with other class of compounds such as aliphatic/alicyclic alcohols/esters/amides, sulphones/sulphoxides/sulphonamides, heterocyclics, keto-enamines/lactams, and phosphine oxides. In the present review, the medicinal chemistry of various cooling compounds as activators of thermoTRPM8 channel will be discussed according to their chemical classes. The potential of these compounds to emerge as therapeutic agents is also discussed. PMID:22860192

  19. Modulation of signal transduction pathways by natural compounds in cancer.

    PubMed

    Ranjan, Alok; Fofaria, Neel M; Kim, Sung-Hoon; Srivastava, Sanjay K

    2015-10-01

    Cancer is generally regarded as the result of abnormal growth of cells. According to World Health Organization, cancer is the leading cause of mortality worldwide. Mother nature provides a large source of bioactive compounds with excellent therapeutic efficacy. Numerous phytochemicals from nature have been investigated for anticancer properties. In this review article, we discuss several natural compounds, which have shown anti-cancer activity. Natural compounds induce cell cycle arrest, activate intrinsic and extrinsic apoptosis pathways, generate Reactive Oxygen Species (ROS), and down-regulate activated signaling pathways, resulting in inhibition of cell proliferation, progression and metastasis of cancer. Several preclinical studies have suggested that natural compounds can also increase the sensitivity of resistant cancers to available chemotherapy agents. Furthermore, combining FDA approved anti-cancer drugs with natural compounds results in improved efficacy. On the basis of these exciting outcomes of natural compounds against several cancer types, several agents have already advanced to clinical trials. In conclusion, preclinical results and clinical outcomes against cancer suggest promising anticancer efficacy of agents from natural sources. PMID:26481373

  20. Modulation of Chloride Channel Functions by the Plant Lignan Compounds Kobusin and Eudesmin

    PubMed Central

    Jiang, Yu; Yu, Bo; Fang, Fang; Cao, Huanhuan; Ma, Tonghui; Yang, Hong

    2015-01-01

    Plant lignans are diphenolic compounds widely present in vegetables, fruits, and grains. These compounds have been demonstrated to have protective effect against cancer, hypertension and diabetes. In the present study, we showed that two lignan compounds, kobusin and eudesmin, isolated from Magnoliae Flos, could modulate intestinal chloride transport mediated by cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride channels (CaCCs). The compounds activated CFTR channel function in both FRT cells and in HT-29 cells. The modulating effects of kobusin and eudesmin on the activity of CaCCgie (CaCC expressed in gastrointestinal epithelial cells) were also investigated, and the result showed that both compounds could stimulate CaCCgie-mediated short-circuit currents and the stimulation was synergistic with ATP. In ex vivo studies, both compounds activated CFTR and CaCCgie chloride channel activities in mouse colonic epithelia. Remarkably, the compounds showed inhibitory effects toward ANO1/CaCC-mediated short-circuit currents in ANO1/CaCC-expressing FRT cells, with IC50 values of 100 μM for kobusin and 200 μM for eudesmin. In charcoal transit study, both compounds mildly reduced gastrointestinal motility in mice. Taken together, these results revealed a new kind of activity displayed by the lignan compounds, one that is concerned with the modulation of chloride channel function. PMID:26635857

  1. Evolutionary conservation of neuropeptide expression in the thymus of different species

    PubMed Central

    Silva, Alberto B; Aw, Danielle; Palmer, Donald B

    2006-01-01

    Evidence suggests that the immune and neuroendocrine systems cross talk by sharing ligands and receptors. Hormones and neuropeptides produced by the neuroendocrine system often modulate the function of lymphoid organs and immune cells. We have previously reported the intrathymic expression of somatostatin (SOM) in the mouse and that several neuropeptides, most notably calcitonin-gene-related peptide (CGRP), neuropeptide Y (NPY), SOM and substance P (SP), can modulate thymocyte development. However, little is known about the intrathymic expression of these neuropeptides either in the mouse or in other species. Moreover, a comparative analysis of the expression of these molecules would highlight the evolutionary importance of intrathymic neuroendocrine interactions in T-cell development. We have studied the expression of different neuropeptides in the thymus of zebrafish, Xenopus, avians, rodent, porcine, equine and human by immunohistochemistry and reverse transcription–polymerase chain reaction. We found that CGRP, NPY, SOM, SP and vasointestinal polypeptide (VIP) are expressed in the thymus of all species investigated. The thymic location of many of these neuropeptides was conserved and appears to be within the stromal compartments. Interestingly, in the avian thymus the expression of CGRP, SOM and SP appears to change depending on the age of the tissue. These findings suggest that neuropeptides may play an important role in T-cell development and provide further evidence of cross talk between the immune and neuroendocrine systems. PMID:16630030

  2. Hypothalamic neuropeptide signaling in alcohol addiction.

    PubMed

    Barson, Jessica R; Leibowitz, Sarah F

    2016-02-01

    The hypothalamus is now known to regulate alcohol intake in addition to its established role in food intake, in part through neuromodulatory neurochemicals termed neuropeptides. Certain orexigenic neuropeptides act in the hypothalamus to promote alcohol drinking, although they affect different aspects of the drinking response. These neuropeptides, which include galanin, the endogenous opioid enkephalin, and orexin/hypocretin, appear to stimulate alcohol intake not only through mechanisms that promote food intake but also by enhancing reward and reinforcement from alcohol. Moreover, these neuropeptides participate in a positive feedback relationship with alcohol, whereby they are upregulated by alcohol intake to promote even further consumption. They contrast with other orexigenic neuropeptides, such as melanin-concentrating hormone and neuropeptide Y, which promote alcohol intake under limited circumstances, are not consistently stimulated by alcohol, and do not enhance reward. They also contrast with neuropeptides that can be anorexigenic, including the endogenous opioid dynorphin, corticotropin-releasing factor, and melanocortins, which act in the hypothalamus to inhibit alcohol drinking as well as reward and therefore counter the ingestive drive promoted by orexigenic neuropeptides. Thus, while multiple hypothalamic neuropeptides may work together to regulate different aspects of the alcohol drinking response, excessive signaling from orexigenic neuropeptides or inadequate signaling from anorexigenic neuropeptides can therefore allow alcohol drinking to become dysregulated. PMID:25689818

  3. NEUROPEPTIDE MODULATION OF CHEMICALLY INDUCED SKIN IRRITATION

    EPA Science Inventory

    This study was designed to demonstrate that the early symptoms of chemically-induced skin irritation are neurally mediated. everal approaches were used to affect nerve transmission in adult Balb/c female mice. hese included general anesthesia (i.e., sodium pentobarbital), systemi...

  4. Neuropeptide Y bioavailability is suppressed in the hindlimb of female Sprague-Dawley rats

    PubMed Central

    Jackson, Dwayne N; Milne, Kevin J; Noble, Earl G; Shoemaker, J Kevin

    2005-01-01

    We recently reported that male, but not female, rats exhibit basal endogenous neuropeptide Y Y1-receptor modulation of hindlimb vasculature. The lack of baseline endo-genous Y1-receptor control in females was evident despite the expression of Y1-receptors and neuropeptide Y in hindlimb skeletal muscle tissue. The following study addressed the hypothesis that neuropeptide Y bioavailability is blunted in female rats under baseline conditions. It was further hypothesized that enhanced prejunctional autoinhibitory neuropeptide Y Y2-receptor expression and/or proteolytic processing of released neuropeptide Y may persist in female rats. Using western blot analysis, it was observed that females had greater overall neuropeptide Y Y2-receptor expression in skeletal muscle compared to males (P < 0.05). To address the prevalence/impact of baseline endogenous Y2-receptor activation on neuropeptide Y release in hindlimb vasculature, an arterial infusion of BIIE0246 (specific non-peptide Y2-receptor antagonist; 170 μg kg−1) was carried out on female and male rats. Y2-receptor blockade resulted in a decrease in hindlimb vascular conductance in females and males (P < 0.05). However, the BIIE0246-induced decrease in vascular conductance was Y1-receptor dependent in females, but not males (P < 0.05). In addition, compared to baseline, BIIE0246 infusion resulted in increased plasma neuropeptide Y concentration in females (P < 0.05), while there was no observable change in males. In a final experiment, systemic inhibition of proteolytic enzymes dipeptidylpeptidase IV (via 500 nm diprotin A) and aminopeptidase P (via 180 nm 2-mercaptoethanol) elicited a Y1-receptor-dependent decrease in hindlimb vascular conductance in females (P < 0.05). It was concluded that our previously reported lack of basal endogenous Y1-receptor activation in female hindlimb vasculature was (at least partially) due to prejunctional Y2-receptor autoinhibition and proteolytic processing of neuropeptide Y. PMID

  5. High-efficiency THz modulator based on phthalocyanine-compound organic films

    NASA Astrophysics Data System (ADS)

    He, Ting; Zhang, Bo; Shen, Jingling; Zang, Mengdi; Chen, Tianji; Hu, Yufeng; Hou, Yanbing

    2015-02-01

    We report a high efficiency, broadband terahertz (THz) modulator following a study of phthalocyanine-compound organic films irradiated with an external excitation laser. Both transmission and reflection modulations of each organic/silicon bilayers were measured using THz time-domain and continuous-wave systems. For very low intensities, the experimental results show that AlClPc/Si can achieve a high modulation factor for transmission and reflection, indicating that AlClPc/Si has a superior modulation efficiency compared with the other films (CuPc and SnCl2Pc). In contrast, the strong attenuation of the transmitted and reflected THz waves revealed that a nonlinear absorption process takes place at the organic/silicon interface.

  6. High-efficiency THz modulator based on phthalocyanine-compound organic films

    SciTech Connect

    He, Ting; Zhang, Bo E-mail: sjl-phy@cnu.edu.cn; Shen, Jingling E-mail: sjl-phy@cnu.edu.cn; Zang, Mengdi; Chen, Tianji; Hu, Yufeng; Hou, Yanbing

    2015-02-02

    We report a high efficiency, broadband terahertz (THz) modulator following a study of phthalocyanine-compound organic films irradiated with an external excitation laser. Both transmission and reflection modulations of each organic/silicon bilayers were measured using THz time-domain and continuous-wave systems. For very low intensities, the experimental results show that AlClPc/Si can achieve a high modulation factor for transmission and reflection, indicating that AlClPc/Si has a superior modulation efficiency compared with the other films (CuPc and SnCl{sub 2}Pc). In contrast, the strong attenuation of the transmitted and reflected THz waves revealed that a nonlinear absorption process takes place at the organic/silicon interface.

  7. Neuropeptides in experimental and degenerative arthritis.

    PubMed

    Niissalo, S; Hukkanen, M; Imai, S; Törnwall, J; Konttinen, Y T

    2002-06-01

    Classical symptoms of both inflammatory and degenerative arthritides may contribute to neurogenic responses like wheal, flare, edema, and pain. Rheumatoid arthritis (RA) is an autoimmune disease with an immunogenetic background. Neurogenic inflammation has been considered to play an essential role in RA, in part because of the symmetrical involvement (cross-spinal reflexes) and the predominant involvement of the most heavily innervated small joints of the hands and the feet (highly represented in the hominiculus). In contrast, osteoarthritis (OA) is considered to arise as a result of degeneration of the hyaline articular cartilage, which secondarily results in local inflammation and pain. However, it is possible that the age-related and predominant (compared to nociceptive nerves) degeneration of the proprioceptive, kinesthetic and vasoregulatory nerves can represent the primary pathogenic events. This leads to progressive damage of tissue with extremely poor capacity for self-regeneration. Inflammation, be it primary/autoimmune or secondary/degenerative, leads to peripheral sensitization and stimulation, which may further lead to central sensitization, neurogenic amplification of the inflammatory responses and activation of the neuro-endocrine axis. Neuropeptides serve as messengers, which modulate and mediate the actions in these cascades. Accordingly, many neuropeptides have been used successfully as experimental treatments, most recently VIP, which effectively controlled collagen-induced arthritis in mice. Therefore, it can safely be concluded that better treatment/control of disease activity and pain can be achieved by blocking the cascade leading to initiation and/or amplification of inflammatory process combined with effects on central nociceptive and neuroendocrine responses. PMID:12114296

  8. Probing Neuropeptide Signaling at the Organ and Cellular Domains via Imaging Mass Spectrometry

    PubMed Central

    Ye, Hui; Greer, Tyler; Li, Lingjun

    2012-01-01

    Imaging mass spectrometry (IMS) has evolved to be a promising technology due to its ability to detect a broad mass range of molecular species and create density maps for selected compounds. It is currently one of the most useful techniques to determine the spatial distribution of neuropeptides in cells and tissues. Although IMS is conceptually simple, sample preparation steps, mass analyzers, and software suites are just a few of the factors that contribute to the successful design of a neuropeptide IMS experiment. This review provides a brief overview of IMS sampling protocols, instrumentation, data analysis tools, technological advancements and applications to neuropeptide localization in neurons and endocrine tissues. Future perspectives in this field are also provided, concluding that neuropeptide IMS could revolutionize neuronal network and biomarker discovery studies. PMID:22465716

  9. Neuropeptide signaling remodels chemosensory circuit composition in Caenorhabditis elegans

    PubMed Central

    Leinwand, Sarah G.; Chalasani, Sreekanth H.

    2013-01-01

    Neural circuits detect environmental changes and drive behavior. The routes of information flow through dense neural networks are dynamic; however, the mechanisms underlying this circuit flexibility are poorly understood. Here, we define a novel, sensory context-dependent and neuropeptide-regulated switch in the composition of a C. elegans salt sensory circuit. The primary salt detectors, ASE sensory neurons, use BLI-4 endoprotease-dependent cleavage to release the insulin-like peptide INS-6 in response to large but not small changes in external salt stimuli. Insulins, signaling through the insulin receptor DAF-2, functionally switch the AWC olfactory sensory neuron into an interneuron in the salt circuit. Animals with disrupted insulin signaling have deficits in salt attraction, suggesting that peptidergic signaling potentiates responses to high salt stimuli, which may promote ion homeostasis. Our results show that sensory context and neuropeptide signaling modify neural networks and suggest general mechanisms for generating flexible behavioral outputs by modulating neural circuit composition. PMID:24013594

  10. Neuropeptide signaling remodels chemosensory circuit composition in Caenorhabditis elegans.

    PubMed

    Leinwand, Sarah G; Chalasani, Sreekanth H

    2013-10-01

    Neural circuits detect environmental changes and drive behavior. The routes of information flow through dense neural networks are dynamic, but the mechanisms underlying this circuit flexibility are poorly understood. Here, we define a sensory context-dependent and neuropeptide-regulated switch in the composition of a C. elegans salt sensory circuit. The primary salt detectors, ASE sensory neurons, used BLI-4 endoprotease-dependent cleavage to release the insulin-like peptide INS-6 in response to large, but not small, changes in external salt stimuli. Insulins, signaling through the insulin receptor DAF-2, functionally switched the AWC olfactory sensory neuron into an interneuron in the salt circuit. Worms with disrupted insulin signaling had deficits in salt attraction, suggesting that peptidergic signaling potentiates responses to high salt stimuli, which may promote ion homeostasis. Our results indicate that sensory context and neuropeptide signaling modify neural networks and suggest general mechanisms for generating flexible behavioral outputs by modulating neural circuit composition. PMID:24013594

  11. Screening and target identification of bioactive compounds that modulate cell migration and autophagy.

    PubMed

    Tashiro, Etsu; Imoto, Masaya

    2016-08-01

    Cell migration is a fundamental step for embryonic development, wound repair, immune responses, and tumor cell invasion and metastasis. It is well known that protrusive structures, namely filopodia and lamellipodia, can be observed at the leading edge of migrating cells. The formation of these structures is necessary for cell migration; however, the molecular mechanisms behind the formation of these structures remain largely unclear. Therefore, bioactive compounds that modulate protrusive structures are extremely powerful tools for studying the mechanisms behind the formation of these structures and subsequent cell migration. Therefore, we have screened for bioactive compounds that inhibit the formation of filopodia, lamellipodia, or cell migration from natural products, and attempted to identify the target molecules of our isolated compounds. Additionally, autophagy is a bulk, non-specific protein degradation system that is involved in the pathogenesis of cancer and neurodegenerative disorders. Recent extensive studies have revealed the molecular mechanisms of autophagy, however, they also remain largely unclear. Thus, we also have screened for bioactive compounds that modulate autophagy, and identified the target molecules. In the present article, we introduce the phenotypic screening system and target identification of four bioactive compounds. PMID:27094149

  12. Selected phenolic compounds in cultivated plants: ecologic functions, health implications, and modulation by pesticides.

    PubMed Central

    Daniel, O; Meier, M S; Schlatter, J; Frischknecht, P

    1999-01-01

    Phenolic compounds are widely distributed in the plant kingdom. Plant tissues may contain up to several grams per kilogram. External stimuli such as microbial infections, ultraviolet radiation, and chemical stressors induce their synthesis. The phenolic compounds resveratrol, flavonoids, and furanocoumarins have many ecologic functions and affect human health. Ecologic functions include defense against microbial pathogens and herbivorous animals. Phenolic compounds may have both beneficial and toxic effects on human health. Effects on low-density lipoproteins and aggregation of platelets are beneficial because they reduce the risk of coronary heart disease. Mutagenic, cancerogenic, and phototoxic effects are risk factors of human health. The synthesis of phenolic compounds in plants can be modulated by the application of herbicides and, to a lesser extent, insecticides and fungicides. The effects on ecosystem functioning and human health are complex and cannot be predicted with great certainty. The consequences of the combined natural and pesticide-induced modulating effects for ecologic functions and human health should be further evaluated. PMID:10229712

  13. Monitoring the apple polyphenol oxidase-modulated adduct formation of phenolic and amino compounds.

    PubMed

    Reinkensmeier, Annika; Steinbrenner, Katrin; Homann, Thomas; Bußler, Sara; Rohn, Sascha; Rawel, Hashadrai M

    2016-03-01

    Minimally processed fruit products such as smoothies are increasingly coming into demand. However, they are often combined with dairy ingredients. In this combination, phenolic compounds, polyphenoloxidases, and amino compounds could interact. In this work, a model approach is presented where apple serves as a source for a high polyphenoloxidase activity for modulating the reactions. The polyphenoloxidase activity ranged from 128 to 333nakt/mL in different apple varieties. From these, 'Braeburn' was found to provide the highest enzymatic activity. The formation and stability of resulting chromogenic conjugates was investigated. The results show that such adducts are not stable and possible degradation mechanisms leading to follow-up products formed are proposed. Finally, apple extracts were used to modify proteins and their functional properties characterized. There were retaining antioxidant properties inherent to phenolic compounds after adduct formation. Consequently, such interactions may also be utilized to improve the textural quality of food products. PMID:26471529

  14. Parasite neuropeptide biology: Seeding rational drug target selection?

    PubMed Central

    McVeigh, Paul; Atkinson, Louise; Marks, Nikki J.; Mousley, Angela; Dalzell, Johnathan J.; Sluder, Ann; Hammerland, Lance; Maule, Aaron G.

    2011-01-01

    The rationale for identifying drug targets within helminth neuromuscular signalling systems is based on the premise that adequate nerve and muscle function is essential for many of the key behavioural determinants of helminth parasitism, including sensory perception/host location, invasion, locomotion/orientation, attachment, feeding and reproduction. This premise is validated by the tendency of current anthelmintics to act on classical neurotransmitter-gated ion channels present on helminth nerve and/or muscle, yielding therapeutic endpoints associated with paralysis and/or death. Supplementary to classical neurotransmitters, helminth nervous systems are peptide-rich and encompass associated biosynthetic and signal transduction components – putative drug targets that remain to be exploited by anthelmintic chemotherapy. At this time, no neuropeptide system-targeting lead compounds have been reported, and given that our basic knowledge of neuropeptide biology in parasitic helminths remains inadequate, the short-term prospects for such drugs remain poor. Here, we review current knowledge of neuropeptide signalling in Nematoda and Platyhelminthes, and highlight a suite of 19 protein families that yield deleterious phenotypes in helminth reverse genetics screens. We suggest that orthologues of some of these peptidergic signalling components represent appealing therapeutic targets in parasitic helminths. PMID:24533265

  15. Performance Evaluation of the New Compound-Carrier-Modulated Signal for Future Navigation Signals.

    PubMed

    Luo, Ruidan; Xu, Ying; Yuan, Hong

    2016-01-01

    Navigation Signal based on Compound Carrier (NSCC), is proposed as the potential future global navigation satellite system (GNSS) signal modulation scheme. NSCC, a kind of multi-carrier (MC) signal, is generated by superposition and multi-parameter adjustment of sub-carriers. Therefore, a judious choice of parameter configation is needed. The main objective of this paper is to investigate the performance of the NSCC which is influenced by these parameters and to demonstrate its structure characteristics and superiority, employing a comprehensive evaluation system. The results show that the proposed NSCC signal processes full spectral efficiency and limited out of band (OOB) emissions, satisfying the demands of crowed frequency resources. It also presents better performance in terms of spectral separation coefficients (SSCs), tracking accuracy, multipath mitigation capability and anti-jamming reduction compared with the legacy navigation signals. NSCC modulation represents a serious candidate for navigation satellite augmentation systems, especially for signals applied in challenging environments. PMID:26828494

  16. Performance Evaluation of the New Compound-Carrier-Modulated Signal for Future Navigation Signals

    PubMed Central

    Luo, Ruidan; Xu, Ying; Yuan, Hong

    2016-01-01

    Navigation Signal based on Compound Carrier (NSCC), is proposed as the potential future global navigation satellite system (GNSS) signal modulation scheme. NSCC, a kind of multi-carrier (MC) signal, is generated by superposition and multi-parameter adjustment of sub-carriers. Therefore, a judious choice of parameter configation is needed. The main objective of this paper is to investigate the performance of the NSCC which is influenced by these parameters and to demonstrate its structure characteristics and superiority, employing a comprehensive evaluation system. The results show that the proposed NSCC signal processes full spectral efficiency and limited out of band (OOB) emissions, satisfying the demands of crowed frequency resources. It also presents better performance in terms of spectral separation coefficients (SSCs), tracking accuracy, multipath mitigation capability and anti-jamming reduction compared with the legacy navigation signals. NSCC modulation represents a serious candidate for navigation satellite augmentation systems, especially for signals applied in challenging environments. PMID:26828494

  17. Diarrhetic effect of okadaic acid could be related with its neuronal action: Changes in neuropeptide Y.

    PubMed

    Louzao, M Carmen; Fernández, Diego A; Abal, Paula; Fraga, Maria; Vilariño, Natalia; Vieytes, Mercedes R; Botana, Luis M

    2015-09-01

    Okadaic acid (OA) and dinophysistoxins (DTXs) are a group of marine toxins that cause diarrheic shellfish poisoning (DSP) in humans and animals. These compounds are produced by dinoflagellates of the Prorocentrum and Dinophysis genera and can accumulate in filter-feeding bivalves, posing a serious health risk for shellfish consumers. The enteric nervous system (ENS) plays a crucial role in the regulation of the gastrointestinal tract. In addition, neuropeptides produced by ENS affects the epithelial barrier functions. In the present work we used a two-compartment human coculture model containing the SH-SY5Y neuroblastoma cell line and polarized colonic epithelial monolayers (Caco-2) to study the OA intestinal permeability. First, we have determined OA cytotoxicity and we have found that OA reduces the viability of SH-SY5Y in a dose-dependent way, even though DTX1 is 4 to 5 times more potent than OA. Besides DTX1 is 15 to 18 orders of magnitude more potent than OA in decreasing transepithelial electrical resistance (TEER) of caco-2 cells without inducing cytotoxicity. Permeability assays indicate that OA cross the monolayer and modulates the neuropeptide Y (NPY) secretion by neuroblastoma cells. This NPY also affects the permeability of OA. This offers a novel approach to establish the influence of OA neuronal action on their diarrheic effects through a cross talk between ENS and intestine via OA induced NPY secretion. Therefore, the OA mechanisms of toxicity that were long attributed only to the inhibition of protein phosphatases, would require a reevaluation. PMID:26086426

  18. The Role of Neuropeptides in Mouse Models of Colitis.

    PubMed

    Padua, David; Vu, John P; Germano, Patrizia M; Pisegna, Joseph R

    2016-06-01

    Inflammatory bowel disease (IBD) constitutes an important clinically significant condition that results in morbidity and mortality. IBD can be generally classified into either ulcerative colitis (UC) or Crohn's disease (CD) that differs in the clinical and histopathology. The role of neuropeptides in the pathogenesis of these conditions is becoming increasingly recognized for their importance in modulating the inflammatory state. Animal models provide the greatest insight to better understand the pathophysiology of both disorders which will hopefully allow for improved treatment strategies. This review will provide a better understanding of the role of murine models for studying colitis. PMID:26646243

  19. Chiral separation of pharmaceutical compounds using electrochemically modulated liquid chromatography (EMLC)

    SciTech Connect

    Wang, S.

    1999-02-12

    This research explores the application of a new technique, termed electrochemically modulated liquid chromatography (EMLC), to the chiral separations of pharmaceutical compounds. The introduction section provides a literature review of the technique and its applications, as well as brief overview of the research described in each of the next two chapters. Chapter 2 investigates the EMLC-based enantiomeric separation of a group of chiral benzodiazepines with {beta}-cyclodextrin as a chiral mobile phase additive. Chapter 3 demonstrates the effects of several experimental parameters on the separation efficiency of drug enantiomers. The author concludes with a general summary and possible directions for future studies. Chapters 2 and 3 are processed separately.

  20. Dynamic combinatorial/covalent chemistry: a tool to read, generate and modulate the bioactivity of compounds and compound mixtures.

    PubMed

    Herrmann, Andreas

    2014-03-21

    Reversible covalent bond formation under thermodynamic control adds reactivity to self-assembled supramolecular systems, and is therefore an ideal tool to assess complexity of chemical and biological systems. Dynamic combinatorial/covalent chemistry (DCC) has been used to read structural information by selectively assembling receptors with the optimum molecular fit around a given template from a mixture of reversibly reacting building blocks. This technique allows access to efficient sensing devices and the generation of new biomolecules, such as small molecule receptor binders for drug discovery, but also larger biomimetic polymers and macromolecules with particular three-dimensional structural architectures. Adding a kinetic factor to a thermodynamically controlled equilibrium results in dynamic resolution and in self-sorting and self-replicating systems, all of which are of major importance in biological systems. Furthermore, the temporary modification of bioactive compounds by reversible combinatorial/covalent derivatisation allows control of their release and facilitates their transport across amphiphilic self-assembled systems such as artificial membranes or cell walls. The goal of this review is to give a conceptual overview of how the impact of DCC on supramolecular assemblies at different levels can allow us to understand, predict and modulate the complexity of biological systems. PMID:24296754

  1. The creation of modulated monoclinic aperiodic composites in n-alkane/urea compounds

    PubMed Central

    Mariette, Céline; Guérin, Laurent; Rabiller, Philippe; Chen, Yu-Sheng; Bosak, Alexei; Popov, Alexander; Hollingsworth, Mark D.

    2015-01-01

    n-Dodecane/urea is a member of the prototype series of n-alkane/urea inclusion compounds. At room temperature, it presents a quasi-one dimensional liquid-like state for the confined guest molecules within the rigid, hexagonal framework of the urea host. At lower temperatures, we report the existence of two other phases. Below Tc=248 K there appears a phase with rank four superspace group P6122(00γ), the one typically observed at room temperature in n-alkane/urea compounds with longer guest molecules. A misfit parameter, defined by the ratio γ=ch/cg (chost/cguest), is found to be 0.632±0.005. Below Tc1=123 K, a monoclinic modulated phase is created with a constant shift along c of the guest molecules in adjacent channels. The maximal monoclinic space group for this structure is P1211(α0γ). Analogies and differences with n-heptane/urea, which also presents a monoclinic, modulated low-temperature phase, are discussed. PMID:26213678

  2. The creation of modulated monoclinic aperiodic composites in n-alkane/urea compounds

    DOE PAGESBeta

    Mariette, Céline; Guérin, Laurent; Rabiller, Philippe; Chen, Yu-Sheng; Bosak, Alexei; Popov, Alexander; Hollingsworth, Mark D.; Toudic, Bertrand

    2014-09-12

    n-Dodecane/urea is a member of the prototype series of n-alkane/urea inclusion compounds. At room temperature, it presents a quasi-one dimensional liquid-like state for the confined guest molecules within the rigid, hexagonal framework of the urea host. At lower temperatures, we report the existence of two other phases. Below Tc=248 K there appears a phase with rank four superspace group P6122(00γ), the one typically observed at room temperature in n-alkane/urea compounds with longer guest molecules. A misfit parameter, defined by the ratio γ=ch/cg (chost/cguest), is found to be 0.632±0.005. Below Tc1=123 K, a monoclinic modulated phase is created with a constantmore » shift along c of the guest molecules in adjacent channels. The maximal monoclinic space group for this structure is P1211(α0γ). We discuss analogies and differences with n-heptane/urea, which also presents a monoclinic, modulated low-temperature phase.« less

  3. The creation of modulated monoclinic aperiodic composites in n-alkane/urea compounds

    SciTech Connect

    Mariette, Céline; Guérin, Laurent; Rabiller, Philippe; Chen, Yu-Sheng; Bosak, Alexei; Popov, Alexander; Hollingsworth, Mark D.; Toudic, Bertrand

    2014-09-12

    n-Dodecane/urea is a member of the prototype series of n-alkane/urea inclusion compounds. At room temperature, it presents a quasi-one dimensional liquid-like state for the confined guest molecules within the rigid, hexagonal framework of the urea host. At lower temperatures, we report the existence of two other phases. Below Tc=248 K there appears a phase with rank four superspace group P6122(00γ), the one typically observed at room temperature in n-alkane/urea compounds with longer guest molecules. A misfit parameter, defined by the ratio γ=ch/cg (chost/cguest), is found to be 0.632±0.005. Below Tc1=123 K, a monoclinic modulated phase is created with a constant shift along c of the guest molecules in adjacent channels. The maximal monoclinic space group for this structure is P1211(α0γ). We discuss analogies and differences with n-heptane/urea, which also presents a monoclinic, modulated low-temperature phase.

  4. Neuropeptide receptor transcriptome reveals unidentified neuroendocrine pathways.

    PubMed

    Yamanaka, Naoki; Yamamoto, Sachie; Zitnan, Dusan; Watanabe, Ken; Kawada, Tsuyoshi; Satake, Honoo; Kaneko, Yu; Hiruma, Kiyoshi; Tanaka, Yoshiaki; Shinoda, Tetsuro; Kataoka, Hiroshi

    2008-01-01

    Neuropeptides are an important class of molecules involved in diverse aspects of metazoan development and homeostasis. Insects are ideal model systems to investigate neuropeptide functions, and the major focus of insect neuropeptide research in the last decade has been on the identification of their receptors. Despite these vigorous efforts, receptors for some key neuropeptides in insect development such as prothoracicotropic hormone, eclosion hormone and allatotropin (AT), remain undefined. In this paper, we report the comprehensive cloning of neuropeptide G protein-coupled receptors from the silkworm, Bombyx mori, and systematic analyses of their expression. Based on the expression patterns of orphan receptors, we identified the long-sought receptor for AT, which is thought to stimulate juvenile hormone biosynthesis in the corpora allata (CA). Surprisingly, however, the AT receptor was not highly expressed in the CA, but instead was predominantly transcribed in the corpora cardiaca (CC), an organ adjacent to the CA. Indeed, by using a reverse-physiological approach, we purified and characterized novel allatoregulatory peptides produced in AT receptor-expressing CC cells, which may indirectly mediate AT activity on the CA. All of the above findings confirm the effectiveness of a systematic analysis of the receptor transcriptome, not only in characterizing orphan receptors, but also in identifying novel players and hidden mechanisms in important biological processes. This work illustrates how using a combinatorial approach employing bioinformatic, molecular, biochemical and physiological methods can help solve recalcitrant problems in neuropeptide research. PMID:18725956

  5. Second-generation compound for the modulation of utrophin in the therapy of DMD.

    PubMed

    Guiraud, Simon; Squire, Sarah E; Edwards, Benjamin; Chen, Huijia; Burns, David T; Shah, Nandini; Babbs, Arran; Davies, Stephen G; Wynne, Graham M; Russell, Angela J; Elsey, David; Wilson, Francis X; Tinsley, Jon M; Davies, Kay E

    2015-08-01

    Duchenne muscular dystrophy (DMD) is a lethal, X-linked muscle-wasting disease caused by lack of the cytoskeletal protein dystrophin. There is currently no cure for DMD although various promising approaches are progressing through human clinical trials. By pharmacologically modulating the expression of the dystrophin-related protein utrophin, we have previously demonstrated in dystrophin-deficient mdx studies, daily SMT C1100 treatment significantly reduced muscle degeneration leading to improved muscle function. This manuscript describes the significant disease modifying benefits associated with daily dosing of SMT022357, a second-generation compound in this drug series with improved physicochemical properties and a more robust metabolism profile. These studies in the mdx mouse demonstrate that oral administration of SMT022357 leads to increased utrophin expression in skeletal, respiratory and cardiac muscles. Significantly, utrophin expression is localized along the length of the muscle fibre, not just at the synapse, and is fibre-type independent, suggesting that drug treatment is modulating utrophin transcription in extra-synaptic myonuclei. This results in improved sarcolemmal stability and prevents dystrophic pathology through a significant reduction of regeneration, necrosis and fibrosis. All these improvements combine to protect the mdx muscle from contraction induced damage and enhance physiological function. This detailed evaluation of the SMT C1100 drug series strongly endorses the therapeutic potential of utrophin modulation as a disease modifying therapeutic strategy for all DMD patients irrespective of their dystrophin mutation. PMID:25935002

  6. Second-generation compound for the modulation of utrophin in the therapy of DMD

    PubMed Central

    Guiraud, Simon; Squire, Sarah E.; Edwards, Benjamin; Chen, Huijia; Burns, David T.; Shah, Nandini; Babbs, Arran; Davies, Stephen G.; Wynne, Graham M.; Russell, Angela J.; Elsey, David; Wilson, Francis X.; Tinsley, Jon M.; Davies, Kay E.

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a lethal, X-linked muscle-wasting disease caused by lack of the cytoskeletal protein dystrophin. There is currently no cure for DMD although various promising approaches are progressing through human clinical trials. By pharmacologically modulating the expression of the dystrophin-related protein utrophin, we have previously demonstrated in dystrophin-deficient mdx studies, daily SMT C1100 treatment significantly reduced muscle degeneration leading to improved muscle function. This manuscript describes the significant disease modifying benefits associated with daily dosing of SMT022357, a second-generation compound in this drug series with improved physicochemical properties and a more robust metabolism profile. These studies in the mdx mouse demonstrate that oral administration of SMT022357 leads to increased utrophin expression in skeletal, respiratory and cardiac muscles. Significantly, utrophin expression is localized along the length of the muscle fibre, not just at the synapse, and is fibre-type independent, suggesting that drug treatment is modulating utrophin transcription in extra-synaptic myonuclei. This results in improved sarcolemmal stability and prevents dystrophic pathology through a significant reduction of regeneration, necrosis and fibrosis. All these improvements combine to protect the mdx muscle from contraction induced damage and enhance physiological function. This detailed evaluation of the SMT C1100 drug series strongly endorses the therapeutic potential of utrophin modulation as a disease modifying therapeutic strategy for all DMD patients irrespective of their dystrophin mutation. PMID:25935002

  7. Neuropeptide evolution: Chelicerate neurohormone and neuropeptide genes may reflect one or more whole genome duplications.

    PubMed

    Veenstra, Jan A

    2016-04-01

    Four genomes and two transcriptomes from six Chelicerate species were analyzed for the presence of neuropeptide and neurohormone precursors and their GPCRs. The genome from the spider Stegodyphus mimosarum yielded 87 neuropeptide precursors and 120 neuropeptide GPCRs. Many neuropeptide transcripts were also found in the transcriptomes of three other spiders, Latrodectus hesperus, Parasteatoda tepidariorum and Acanthoscurria geniculata. For the scorpion Mesobuthus martensii the numbers are 79 and 93 respectively. The very small genome of the house dust mite, Dermatophagoides farinae, on the other hand contains a much smaller number of such genes. A few new putative Arthropod neuropeptide genes were discovered. Thus, both spiders and the scorpion have an achatin gene and in spiders there are two different genes encoding myosuppressin-like peptides while spiders also have two genes encoding novel LGamides. Another finding is the presence of trissin in spiders and scorpions, while neuropeptide genes that seem to be orthologs of Lottia LFRYamide and Platynereis CCRFamide were also found. Such genes were also found in various insect species, but seem to be lacking from the Holometabola. The Chelicerate neuropeptide and neuropeptide GPCR genes often have paralogs. As the large majority of these are probably not due to local gene duplications, is plausible that they reflect the effects of one or more ancient whole genome duplications. PMID:26928473

  8. Modulation of volatile organic compound formation in the Mycodiesel-producing endophyte Hypoxylon sp. CI-4.

    PubMed

    Ul-Hassan, Syed Riyaz; Strobel, Gary A; Booth, Eric; Knighton, Berk; Floerchinger, Cody; Sears, Joe

    2012-02-01

    An endophytic Hypoxylon sp. (strain CI-4) producing a wide spectrum of volatile organic compounds (VOCs), including 1,8-cineole, 1-methyl-1,4-cyclohexadiene and cyclohexane, 1,2,4-tris(methylene), was selected as a candidate for the modulation of VOC production. This was done in order to learn if the production of these and other VOCs can be affected by using agents that may modulate the epigenetics of the fungus. Many of the VOCs made by this organism are of interest because of their high energy densities and thus the potential they might have as Mycodiesel fuels. Strain CI-4 was exposed to the epigenetic modulators suberoylanilide hydroxamic acid (SAHA, a histone deacetylase) and 5-azacytidine (AZA, a DNA methyltransferase inhibitor). After these treatments the organism displayed striking cultural changes, including variations in pigmentation, growth rates and odour, in addition to significant differences in the bioactivities of the VOCs. The resulting variants were designated CI4-B, CI4-AZA and CI4-SAHA. GC/MS analyses of the VOCs produced by the variants showed considerable variation, with the emergence of several compounds not previously observed in the wild-type, particularly an array of tentatively identified terpenes such as α-thujene, sabinene, γ-terpinene, α-terpinolene and β-selinene, in addition to several primary and secondary alkanes, alkenes, organic acids and derivatives of benzene. Proton transfer reaction mass spectroscopic analyses showed a marked increase in the ratio of ethanol (mass 47) to the total mass of all other ionizable VOCs, from ~0.6 in the untreated strain CI-4 to ~0.8 in CI-4 grown in the presence of AZA. Strain CI4-B was created by exposure of the fungus to 100 µM SAHA; upon removal of the epigenetic modulator from the culture medium, it did not revert to the wild-type phenotype. Results of this study have implications for understanding why there may be a wide range of VOCs found in various isolates of this fungus in nature

  9. Neuropeptide action in insects and crustaceans.

    PubMed

    Mykles, Donald L; Adams, Michael E; Gäde, Gerd; Lange, Angela B; Marco, Heather G; Orchard, Ian

    2010-01-01

    Physiological processes are regulated by a diverse array of neuropeptides that coordinate organ systems. The neuropeptides, many of which act through G protein-coupled receptors, affect the levels of cyclic nucleotides (cAMP and cGMP) and Ca(2+) in target tissues. In this perspective, their roles in molting, osmoregulation, metabolite utilization, and cardiovascular function are highlighted. In decapod crustaceans, inhibitory neuropeptides (molt-inhibiting hormone and crustacean hyperglycemic hormone) suppress the molting gland through cAMP- and cGMP-mediated signaling. In insects, the complex movements during ecdysis are controlled by ecdysis-triggering hormone and a cascade of downstream neuropeptides. Adipokinetic/hypertrehalosemic/hyperprolinemic hormones mobilize energy stores in response to increased locomotory activity. Crustacean cardioacceleratory (cardioactive) peptide, proctolin, and FMRFamide-related peptides act on the heart, accessory pulsatile organs, and excurrent ostia to control hemolymph distribution to tissues. The osmoregulatory challenge of blood gorging in Rhodnius prolixus requires the coordinated release of serotonin and diuretic and antidiuretic hormones acting on the midgut and Malpighian tubules. These studies illustrate how multiple neuropeptides allow for flexibility in response to physiological challenges. PMID:20550437

  10. Neuropeptide Y: A stressful review

    PubMed Central

    Reichmann, Florian; Holzer, Peter

    2016-01-01

    Stress is defined as an adverse condition that disturbs the homeostasis of the body and activates adaptation responses. Among the many pathways and mediators involved, neuropeptide Y (NPY) stands out due to its unique stress-relieving, anxiolytic and neuroprotective properties. Stress exposure alters the biosynthesis of NPY in distinct brain regions, the magnitude and direction of this effect varying with the duration and type of stress. NPY is expressed in particular neurons of the brainstem, hypothalamus and limbic system, which explains why NPY has an impact on stress-related changes in emotional-affective behaviour and feeding as well as on stress coping. The biological actions of NPY in mammals are mediated by the Y1, Y2, Y4 and Y5 receptor, Y1 receptor stimulation being anxiolytic whereas Y2 receptor activation is anxiogenic. Emerging evidence attributes NPY a role in stress resilience, the ability to cope with stress. Thus there is a negative correlation between stress-induced behavioural disruption and cerebral NPY expression in animal models of post-traumatic stress disorder. Exogenous NPY prevents the negative consequences of stress, and polymorphisms of the NPY gene are predictive of impaired stress processing and increased risk of neuropsychiatric diseases. Stress is also a factor contributing to, and resulting from, neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease, in which NPY appears to play an important neuroprotective role. This review summarizes the evidence for an implication of NPY in stress-related and neurodegenerative pathologies and addresses the cerebral NPY system as a therapeutic target. PMID:26441327

  11. Neuropeptidomics: Mass Spectrometry-Based Identification and Quantitation of Neuropeptides.

    PubMed

    Lee, Ji Eun

    2016-03-01

    Neuropeptides produced from prohormones by selective action of endopeptidases are vital signaling molecules, playing a critical role in a variety of physiological processes, such as addiction, depression, pain, and circadian rhythms. Neuropeptides bind to post-synaptic receptors and elicit cellular effects like classical neurotransmitters. While each neuropeptide could have its own biological function, mass spectrometry (MS) allows for the identification of the precise molecular forms of each peptide without a priori knowledge of the peptide identity and for the quantitation of neuropeptides in different conditions of the samples. MS-based neuropeptidomics approaches have been applied to various animal models and conditions to characterize and quantify novel neuropeptides, as well as known neuropeptides, advancing our understanding of nervous system function over the past decade. Here, we will present an overview of neuropeptides and MS-based neuropeptidomic strategies for the identification and quantitation of neuropeptides. PMID:27103886

  12. Neuropeptidomics: Mass Spectrometry-Based Identification and Quantitation of Neuropeptides

    PubMed Central

    2016-01-01

    Neuropeptides produced from prohormones by selective action of endopeptidases are vital signaling molecules, playing a critical role in a variety of physiological processes, such as addiction, depression, pain, and circadian rhythms. Neuropeptides bind to post-synaptic receptors and elicit cellular effects like classical neurotransmitters. While each neuropeptide could have its own biological function, mass spectrometry (MS) allows for the identification of the precise molecular forms of each peptide without a priori knowledge of the peptide identity and for the quantitation of neuropeptides in different conditions of the samples. MS-based neuropeptidomics approaches have been applied to various animal models and conditions to characterize and quantify novel neuropeptides, as well as known neuropeptides, advancing our understanding of nervous system function over the past decade. Here, we will present an overview of neuropeptides and MS-based neuropeptidomic strategies for the identification and quantitation of neuropeptides. PMID:27103886

  13. Neuropeptidome of the Cephalopod Sepia officinalis: Identification, Tissue Mapping, and Expression Pattern of Neuropeptides and Neurohormones during Egg Laying.

    PubMed

    Zatylny-Gaudin, Céline; Cornet, Valérie; Leduc, Alexandre; Zanuttini, Bruno; Corre, Erwan; Le Corguillé, Gildas; Bernay, Benoît; Garderes, Johan; Kraut, Alexandra; Couté, Yohan; Henry, Joël

    2016-01-01

    Cephalopods exhibit a wide variety of behaviors such as prey capture, communication, camouflage, and reproduction thanks to a complex central nervous system (CNS) divided into several functional lobes that express a wide range of neuropeptides involved in the modulation of behaviors and physiological mechanisms associated with the main stages of their life cycle. This work focuses on the neuropeptidome expressed during egg-laying through de novo construction of the CNS transcriptome using an RNAseq approach (Illumina sequencing). Then, we completed the in silico analysis of the transcriptome by characterizing and tissue-mapping neuropeptides by mass spectrometry. To identify neuropeptides involved in the egg-laying process, we determined (1) the neuropeptide contents of the neurohemal area, hemolymph (blood), and nerve endings in mature females and (2) the expression levels of these peptides. Among the 38 neuropeptide families identified from 55 transcripts, 30 were described for the first time in Sepia officinalis, 5 were described for the first time in the animal kingdom, and 14 were strongly overexpressed in egg-laying females as compared with mature males. Mass spectrometry screening of hemolymph and nerve ending contents allowed us to clarify the status of many neuropeptides, that is, to determine whether they were neuromodulators or neurohormones. PMID:26632866

  14. Polymorphic variation as a driver of differential neuropeptide gene expression.

    PubMed

    Quinn, John P; Warburton, Alix; Myers, Paul; Savage, Abigail L; Bubb, Vivien J

    2013-12-01

    The regulation of neuropeptide gene expression and their receptors in a tissue specific and stimulus inducible manner will determine in part behaviour and physiology. This can be a dynamic process resulting from short term changes in response to the environment or long term modulation imposed by epigenetically determined mechanisms established during life experiences. The latter underpins what is termed 'nature and nurture, or 'gene×environment interactions'. Dynamic gene expression of neuropeptides or their receptors is a key component of signalling in the CNS and their inappropriate regulation is therefore a predicted target underpinning psychiatric disorders and neuropathological processes. Finding the regulatory domains within our genome which have the potential to direct gene expression is a difficult challenge as 98% of our genome is non-coding and, with the exception of proximal promoter regions, such elements can be quite distant from the gene that they regulate. This review will deal with how we can find such domains by addressing both the most conserved non-exonic regions in the genome using comparative genomics and the most recent or constantly evolving DNA such as repetitive DNA or retrotransposons. We shall also explore how polymorphic changes in such domains can be associated with CNS disorders by altering the appropriate gene expression patterns which maintain normal physiology. PMID:24210140

  15. Neuropeptide FF receptors as novel targets for limbic seizure attenuation.

    PubMed

    Portelli, Jeanelle; Meurs, Alfred; Bihel, Frederic; Hammoud, Hassan; Schmitt, Martine; De Kock, Joery; Utard, Valerie; Humbert, Jean-Paul; Bertin, Isabelle; Buffel, Ine; Coppens, Jessica; Tourwe, Dirk; Maes, Veronique; De Prins, An; Vanhaecke, Tamara; Massie, Ann; Balasubramaniam, Ambikaipakan; Boon, Paul; Bourguignon, Jean-Jacques; Simonin, Frederic; Smolders, Ilse

    2015-08-01

    Neuropeptide Y (NPY) is a well established anticonvulsant and first-in-class antiepileptic neuropeptide. In this study, the controversial role of NPY1 receptors in epilepsy was reassessed by testing two highly selective NPY1 receptor ligands and a mixed NPY1/NPFF receptor antagonist BIBP3226 in a rat model for limbic seizures. While BIBP3226 significantly attenuated the pilocarpine-induced seizures, neither of the highly selective NPY1 receptor ligands altered the seizure severity. Administration of the NPFF1/NPFF2 receptor antagonist RF9 also significantly attenuated limbic seizure activity. To further prove the involvement of NPFF receptors in these seizure-modulating effects, low and high affinity antagonists for the NPFF receptors were tested. We observed that the low affinity ligand failed to exhibit anticonvulsant properties while the two high affinity ligands significantly attenuated the seizures. Continuous NPFF1 receptor agonist administration also inhibited limbic seizures whereas bolus administration of the NPFF1 receptor agonist was without effect. This suggests that continuous agonist perfusion could result in NPFF1 receptor desensitization and mimic NPFF1 receptor antagonist administration. Our data unveil for the first time the involvement of the NPFF system in the management of limbic seizures. PMID:25963417

  16. Neuromedin B and gastrin releasing peptide excite arcuate nucleus neuropeptide Y neurons in a novel transgenic mouse expressing strong renilla GFP in NPY neurons

    PubMed Central

    van den Pol, Anthony N.; Yao, Yang; Fu, Li-Ying; Foo, Kylie; Huang, Hao; Coppari, Roberto; Lowell, Brad; Broberger, Christian

    2009-01-01

    Neuropeptide Y (NPY) is one of the most widespread neuropeptides in the brain. Transgenic mice were generated that expressed bright renilla GFP in most or all of the known NPY cells in the brain, which otherwise were not identifiable. GFP expression in NPY cells was confirmed with immunocytochemistry and single cell RT-PCR. NPY neurons in the hypothalamic arcuate nucleus play an important role in energy homeostasis and endocrine control. Whole cell patch clamp recording was used to study identified arcuate NPY cells. Primary agents that regulate energy balance include melanocortin receptor agonists, AgRP, and cannabinoids; none of these substances substantially influenced electrical properties of NPY neurons. In striking contrast, neuropeptides of the bombesin family, including gastrin releasing peptide and neuromedin B which are found in axons in the arcuate nucleus and may also be released from the gut to signal the brain, showed strong direct excitatory actions at nanomolar levels on the NPY neurons, stronger than the actions of ghrelin and hypocretin/orexin. Bombesin-related peptides reduced input resistance and depolarized the membrane potential. The depolarization was attenuated by several factors: substitution of choline for sodium, extracellular Ni2+, inclusion of BAPTA in the pipette, KB-R7943 and SKF96365. Reduced extracellular calcium enhanced the current, which reversed around − 20 mV. Together, these data suggest two mechanisms, activation of non-selective cation channels and the sodium/calcium exchanger. Since both NPY and POMC neurons, which we also studied, are similarly directly excited by bombesin-like peptides, the peptides may function to initiate broad activation, rather than the cell-type selective activation or inhibition reported for many other compounds that modulate energy homeostasis. PMID:19357287

  17. Paraoxonase 1 (PON1) modulates the toxicity of mixed organophosphorus compounds

    SciTech Connect

    Jansen, Karen L.; Cole, Toby B.; Park, Sarah S.; Furlong, Clement E. Costa, Lucio G.

    2009-04-15

    A transgenic mouse model of the human hPON1{sub Q192R} polymorphism was used to address the role of paraoxonase (PON1) in modulating toxicity associated with exposure to mixtures of organophosphorus (OP) compounds. Chlorpyrifos oxon (CPO), diazoxon (DZO), and paraoxon (PO) are potent inhibitors of carboxylesterases (CaE). We hypothesized that a prior exposure to these OPs would increase sensitivity to malaoxon (MO), a CaE substrate, and the degree of the effect would vary among PON1 genotypes if the OP was a physiologically significant PON1 substrate in vivo. CPO and DZO are detoxified by PON1. For CPO hydrolysis, hPON1{sub R192} has a higher catalytic efficiency than hPON1{sub Q192}. For DZO hydrolysis, the two alloforms have nearly equal catalytic efficiencies. For PO hydrolysis, the catalytic efficiency of PON1 is too low to be physiologically relevant. When wild-type mice were exposed dermally to CPO, DZO, or PO followed 4-h later by increasing doses of MO, toxicity was increased compared to mice receiving MO alone, presumably due to CaE inhibition. Potentiation of MO toxicity by CPO and DZO was greater in PON1{sup -/-} mice, which have greatly reduced capacity to detoxify CPO or DZO. Potentiation by CPO was more pronounced in hPON1{sub Q192} mice than in hPON1{sub R192} mice due to the decreased efficiency of hPON1{sub Q192} for detoxifying CPO. Potentiation by DZO was similar in hPON1{sub Q192} and hPON1{sub R192} mice, which are equally efficient at hydrolyzing DZO. Potentiation by PO was equivalent among all four genotypes. These results indicate that PON1 status can have a major influence on CaE-mediated detoxication of OP compounds.

  18. A Low-Cost, Hands-on Module to Characterize Antimicrobial Compounds Using an Interdisciplinary, Biophysical Approach

    NASA Astrophysics Data System (ADS)

    Gordon, Vernita; Kaushik, Karishma; Kessel, Ashley; Ratnayeke, Nalin

    2015-03-01

    We have developed a hands-on, experimental module that combines biology experiments with a physics-based analytical model to characterize antimicrobial compounds. To understand antibiotic resistance, participants perform a disc diffusion assay to test the antimicrobial activity of different compounds, then apply a diffusion-based analytical model to gain insights into the behavior of the active antimicrobial component. In our experience, this module was robust, reproducible, and cost-effective, suggesting that it could be implemented in diverse settings such as undergraduate research, STEM camps, school programs, and laboratory training workshops. This module addresses the paucity of structured training or education programs that integrate diverse scientific fields by providing valuable, interdisciplinary research experience in science outreach and education initiatives. Its low cost requirements make it especially suitable for use in resource-limited settings.

  19. A Low-Cost, Hands-on Module to Characterize Antimicrobial Compounds Using an Interdisciplinary, Biophysical Approach

    PubMed Central

    Kaushik, Karishma S.; Kessel, Ashley; Ratnayeke, Nalin; Gordon, Vernita D.

    2015-01-01

    We have developed a hands-on experimental module that combines biology experiments with a physics-based analytical model in order to characterize antimicrobial compounds. To understand antibiotic resistance, participants perform a disc diffusion assay to test the antimicrobial activity of different compounds and then apply a diffusion-based analytical model to gain insights into the behavior of the active antimicrobial component. In our experience, this module was robust, reproducible, and cost-effective, suggesting that it could be implemented in diverse settings such as undergraduate research, STEM (science, technology, engineering, and math) camps, school programs, and laboratory training workshops. By providing valuable interdisciplinary research experience in science outreach and education initiatives, this module addresses the paucity of structured training or education programs that integrate diverse scientific fields. Its low-cost requirements make it especially suitable for use in resource-limited settings. PMID:25602254

  20. The neuropeptide bursicon acts in cuticle metabolism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bursicon is a heterodimeric neuropeptide formed of bursicon a (burs a) and bursicon B (burs B) that controls cuticle tanning and wing expansion in insects. Burs a-a and burs B-B homodimers are also formed; they act via an unknown receptor to induce expression of prophylactic immune and stress genes ...

  1. Evaluation of modulators and electron-capture detectors for comprehensive two-dimensional GC of halogenated organic compounds.

    PubMed

    Kristenson, E Maria; Korytár, Peter; Danielsson, Conny; Kallio, Minna; Brandt, Menno; Mäkelä, Jani; Vreuls, René J J; Beens, Jan; Brinkman, Udo A Th

    2003-11-26

    Different cryogenic and a heated GC x GC modulator(s) were evaluated and compared for the analysis of high-boiling halogenated compounds. The cryogenic modulators investigated were: (i) the longitudinally modulated cryogenic system; (ii) the liquid-nitrogen-cooled jet modulator (KT2001); (iii) a dual-jet CO2 modulator (made in-house); (iv) a semi-rotating cryogenic modulator (made in-house) and (v) a CO2 loop modulator (KT2003); the heated modulator was the slotted heater system (sweeper). Each modulator was optimised with respect to analyte peak widths at half height in the second-dimension. n-Alkanes, chlorinated alkanes, polychlorinated biphenyls (PCBs) and fluorinated polycyclic aromatic hydrocarbons (F-PAHs) were used as test analytes. The flow rate of the coolant was found to be an important parameter, i.e. the flow rate of the gaseous nitrogen in the KT2001, and of the liquid CO2 in the other cryogenic modulators. For the slotted heater the stroke velocity and pause time were important parameters. This modulator had a limited application range in terms of temperature due to a necessary 100 degrees C difference between sweeper and oven temperature. All cryogenic modulators were found to be suitable for the GC x GC analysis of high-boiling compounds, but the CO2 modulators are to be preferred to the KT2001 due to a wider application range and slightly narrower peaks. As regards the performance of three commercially available electron-capture detectors (ECDs), the aim was to obtain narrow peak widths in GC x GC, i.e. to avoid band broadening caused by the cell volume. The most important parameters were the flow rate of the make-up gas and the detector temperature which both should be as high as possible. Comparison of analyte peak widths obtained with ECD mode and flame ionisation detection (FID) showed that all ECDs exhibited band broadening compared to the FID. The narrowest peaks were obtained with the Agilent micro-ECD, which has a cell volume of only 150

  2. Rootin, a compound that inhibits root development through modulating PIN-mediated auxin distribution.

    PubMed

    Jeong, Suyeong; Kim, Jun-Young; Choi, Hyunmo; Kim, Hyunmin; Lee, Ilhwan; Soh, Moon-Soo; Nam, Hong Gil; Chang, Young-Tae; Lim, Pyung Ok; Woo, Hye Ryun

    2015-04-01

    Plant roots anchor the plant to the soil and absorb water and nutrients for growth. Understanding the molecular mechanisms regulating root development is essential for improving plant survival and agricultural productivity. Extensive molecular genetic studies have provided important information on crucial components for the root development control over the last few decades. However, it is becoming difficult to identify new regulatory components in root development due to the functional redundancy and lethality of genes involved in root development. In this study, we performed a chemical genetic screen to identify novel synthetic compounds that regulate root development in Arabidopsis seedlings. The screen yielded a root growth inhibitor designated as 'rootin', which inhibited Arabidopsis root development by modulating cell division and elongation, but did not significantly affect shoot development. Transcript analysis of phytohormone marker genes revealed that rootin preferentially altered the expression of auxin-regulated genes. Furthermore, rootin reduced the accumulation of PIN1, PIN3, and PIN7 proteins, and affected the auxin distribution in roots, which consequently may lead to the observed defects in root development. Our results suggest that rootin could be utilized to unravel the mechanisms underlying root development and to investigate dynamic changes in PIN-mediated auxin distribution. PMID:25711819

  3. Ultrasound window-modulated compounding Nakagami imaging: Resolution improvement and computational acceleration for liver characterization.

    PubMed

    Ma, Hsiang-Yang; Lin, Ying-Hsiu; Wang, Chiao-Yin; Chen, Chiung-Nien; Ho, Ming-Chih; Tsui, Po-Hsiang

    2016-08-01

    Ultrasound Nakagami imaging is an attractive method for visualizing changes in envelope statistics. Window-modulated compounding (WMC) Nakagami imaging was reported to improve image smoothness. The sliding window technique is typically used for constructing ultrasound parametric and Nakagami images. Using a large window overlap ratio may improve the WMC Nakagami image resolution but reduces computational efficiency. Therefore, the objectives of this study include: (i) exploring the effects of the window overlap ratio on the resolution and smoothness of WMC Nakagami images; (ii) proposing a fast algorithm that is based on the convolution operator (FACO) to accelerate WMC Nakagami imaging. Computer simulations and preliminary clinical tests on liver fibrosis samples (n=48) were performed to validate the FACO-based WMC Nakagami imaging. The results demonstrated that the width of the autocorrelation function and the parameter distribution of the WMC Nakagami image reduce with the increase in the window overlap ratio. One-pixel shifting (i.e., sliding the window on the image data in steps of one pixel for parametric imaging) as the maximum overlap ratio significantly improves the WMC Nakagami image quality. Concurrently, the proposed FACO method combined with a computational platform that optimizes the matrix computation can accelerate WMC Nakagami imaging, allowing the detection of liver fibrosis-induced changes in envelope statistics. FACO-accelerated WMC Nakagami imaging is a new-generation Nakagami imaging technique with an improved image quality and fast computation. PMID:27125557

  4. Sociality, pathogen avoidance, and the neuropeptides oxytocin and arginine vasopressin.

    PubMed

    Kavaliers, Martin; Choleris, Elena

    2011-11-01

    Both humans and nonhumans have evolved a variety of mechanisms to recognize pathogen threat and a variety of adaptive behavioral responses to minimize exposure to it. Because social interactions facilitate the spread of infection among individuals, the ability to recognize and avoid infected and potentially infected individuals is crucial. The neuropeptides oxytocin (OT) and arginine vasopressin (AVP) are involved in mediating various facets of social behavior, including social recognition and responses to salient social threats. Results of studies with rodents have revealed that OT and AVP are also associated with the olfactory-mediated recognition and avoidance of actually or potentially infected individuals. The evidence reviewed here suggests that OT and AVP likely play parallel roles in modulating the recognition and avoidance of socially relevant pathogen threat in both humans and rodents. PMID:21960250

  5. Peripheral site of action of levodropropizine in experimentally-induced cough: role of sensory neuropeptides.

    PubMed

    Lavezzo, A; Melillo, G; Clavenna, G; Omini, C

    1992-06-01

    The mechanism of action of levodropropizine has been investigated in different models of experimentally-induced cough in guinea-pigs. In particular it has been demonstrated that the antitussive drug has a peripheral site of action by injecting the drug intracerebroventricularly (i.c.v.). In these experiments levodropropizine (40 micrograms/50 microliters i.c.v.) did not prevent electrically-induced cough. On the other hand, codeine (5 micrograms/50 microliters i.c.v.) markedly prevented coughing. A difference in the potency ratio of levodropropizine and codeine has been demonstrated in capsaicin-induced cough; after oral administration, codeine was about two to three times more potent than levodropropizine. However, after aerosol administration the two compounds were equipotent. These data might suggest a peripheral site of action for levodropropizine which is related to sensory neuropeptides. Further support for the role of sensory neuropeptides in the mechanism of action of levodropropizine comes from the results obtained in capsaicin-desensitized animals. In this experimental model levodropropizine failed to prevent the vagally elicited cough in neuropeptide-depleted animals, whereas codeine did not differentiate between control and capsaicin-treated animals. In conclusion, our results support the suggestion that levodropropizine has a peripheral site of action. In addition, the interference with the sensory neuropeptide system may explain, at least in part, its activity in experimentally-induced cough. PMID:1611233

  6. Tick salivary compounds: their role in modulation of host defences and pathogen transmission

    PubMed Central

    Kazimírová, Mária; Štibrániová, Iveta

    2013-01-01

    Ticks require blood meal to complete development and reproduction. Multifunctional tick salivary glands play a pivotal role in tick feeding and transmission of pathogens. Tick salivary molecules injected into the host modulate host defence responses to the benefit of the feeding ticks. To colonize tick organs, tick-borne microorganisms must overcome several barriers, i.e., tick gut membrane, tick immunity, and moulting. Tick-borne pathogens co-evolved with their vectors and hosts and developed molecular adaptations to avoid adverse effects of tick and host defences. Large gaps exist in the knowledge of survival strategies of tick-borne microorganisms and on the molecular mechanisms of tick-host-pathogen interactions. Prior to transmission to a host, the microorganisms penetrate and multiply in tick salivary glands. As soon as the tick is attached to a host, gene expression and production of salivary molecules is upregulated, primarily to facilitate feeding and avoid tick rejection by the host. Pathogens exploit tick salivary molecules for their survival and multiplication in the vector and transmission to and establishment in the hosts. Promotion of pathogen transmission by bioactive molecules in tick saliva was described as saliva-assisted transmission (SAT). SAT candidates comprise compounds with anti-haemostatic, anti-inflammatory and immunomodulatory functions, but the molecular mechanisms by which they mediate pathogen transmission are largely unknown. To date only a few tick salivary molecules associated with specific pathogen transmission have been identified and their functions partially elucidated. Advanced molecular techniques are applied in studying tick-host-pathogen interactions and provide information on expression of vector and pathogen genes during pathogen acquisition, establishment and transmission. Understanding the molecular events on the tick-host-pathogen interface may lead to development of new strategies to control tick-borne diseases. PMID

  7. Sniffing human sex-steroid derived compounds modulates mood, memory and autonomic nervous system function in specific behavioral contexts.

    PubMed

    Bensafi, M; Brown, W M; Khan, R; Levenson, B; Sobel, N

    2004-06-01

    We asked whether the effects of exposure to two human sex-steroid derived compounds were context dependent. The effects of sniffing 4,16-androstadien-3-one (AND) and 1,3,5(10),16-estratetraen-3-ol (EST) on mood, memory, and autonomic nervous system responses were explored in 72 participants. Subjects were tested with AND, EST, or a Control compound within four mood contexts: neutral, sexually aroused, sad and happy. These moods were successfully induced using selected film segments (P < 0.0001). During the neutral context, none of the compounds affected mood or autonomic nervous system function. However, compound effects were significantly increased within arousing contexts. During the sexually arousing context, both compounds increased sexual arousal (P < 0.029). During the sad context, AND maintained positive mood in women (P< 0.050) and increased negative mood in men (P < 0.031). Memory for events during the sad context was impaired by AND in women (P < 0.047) but not in men. Finally, effects of AND on physiology were observed during the sexually arousing context whereby AND increased skin temperature in both sexes (P < 0.022) but reduced abdominal respiration rate in men only (P < 0.034). These results suggest that sex-steroidal compounds modulate mood, memory and autonomic nervous system responses and increase their significance within specific behavioral contexts. These findings lend support to a specific role for these compounds in chemical communication between humans. PMID:15135965

  8. Annotated compound data for modulators of detergent-solubilised or lipid-reconstituted respiratory type II NADH dehydrogenase activity obtained by compound library screening

    PubMed Central

    Dunn, Elyse A.; Cook, Gregory M.; Heikal, Adam

    2015-01-01

    The energy-generating membrane protein NADH dehydrogenase (NDH-2), a proposed antibacterial drug target (see “Inhibitors of type II NADH:menaquinone oxidoreductase represent a class of antitubercular drugs” Weinstein et al. 2005 [1]), was screened for modulators of activity in either detergent-solublised or lipid reconstituted (proteolipsome) form. Here we present an annotated list of compounds identified in a small-scale screen against NDH-2. The dataset contains information regarding the libraries screened, the identities of hit compounds and the physicochemical properties governing solubility and permeability. The implications of these data for future antibiotic discovery are discussed in our associated report, “Comparison of lipid and detergent enzyme environments for identifying inhibitors of membrane-bound energy-transducing proteins” [2]. PMID:26862571

  9. Frequency Effects in the Processing of Italian Nominal Compounds: Modulation of Headedness and Semantic Transparency

    ERIC Educational Resources Information Center

    Marelli, Marco; Luzzatti, Claudio

    2012-01-01

    There is a general debate as to whether constituent representations are accessed in compound processing. The present study addresses this issue, exploiting the properties of Italian compounds to test the role of headedness and semantic transparency in constituent access. In a first experiment, a lexical decision task was run on nominal compounds.…

  10. Relation between pulpal neuropeptides and dental caries

    PubMed Central

    Kangarlou Haghighi, Ali; Nafarzadeh, Shima; Shantiaee, Yazdan; Naseri, Mandana; Ahangari, Zohreh

    2010-01-01

    INTRODUCTION: Dental pulp has neural fibers that produce neuropeptides like Substance P (SP) and calcitonin gene-related peptide (CGRP). The inflammation of dental pulp can lead to an increase amount of SP and CGRP release, especially in symptomatic irreversible pulpitis. Therefore, it can be assumed that neuropeptides have some role in the progression of inflammation of the dental pulp. The aim of this study was to determine the relation between the presence and concentration of neuropeptides in dental pulps of carious teeth caries. MATERIALS AND METHODS: For this purpose, pulpal tissues were collected from 40 teeth (20 carious and 20 intact). Pulpal samples were cultured for 72 hours. ELISA reader was used for the detection of SP and CGRP in supernatant fluids. Statistical analysis was made by Mann-Whitney U and Chi square tests. RESULTS: SP and CGRP were present in 65% and 20% of inflamed pulpal samples, respectively and 40% and 5% of normal pulpal samples, respectively. Level of SP was significantly higher in inflamed pulp samples compared to intact pulps; however, there was no statistical difference when the other groups and neuropeptides were compared. The mean concentration of SP in normal pulps was 3.4 times greater than that of CGRP; interestingly in inflamed pulps the concentration of SP was 22.3 times greater than CGRP. CONCLUSION: We can conclude that in inflamed dental pulps, the concentration of SP is higher than CGRP. It can be hypothesized that CGRP has less effect on the inflammatory changes of dental pulps. PMID:24778684

  11. Characterization of Imidazopyridine Compounds as Negative Allosteric Modulators of Proton-Sensing GPR4 in Extracellular Acidification-Induced Responses

    PubMed Central

    Tobo, Ayaka; Tobo, Masayuki; Nakakura, Takashi; Ebara, Masashi; Tomura, Hideaki; Mogi, Chihiro; Im, Dong-Soon; Murata, Naoya; Kuwabara, Atsushi; Ito, Saki; Fukuda, Hayato; Arisawa, Mitsuhiro; Shuto, Satoshi; Nakaya, Michio; Kurose, Hitoshi; Sato, Koichi; Okajima, Fumikazu

    2015-01-01

    G protein-coupled receptor 4 (GPR4), previously proposed as the receptor for sphingosylphosphorylcholine, has recently been identified as the proton-sensing G protein-coupled receptor (GPCR) coupling to multiple intracellular signaling pathways, including the Gs protein/cAMP and G13 protein/Rho. In the present study, we characterized some imidazopyridine compounds as GPR4 modulators that modify GPR4 receptor function. In the cells that express proton-sensing GPCRs, including GPR4, OGR1, TDAG8, and G2A, extracellular acidification stimulates serum responsive element (SRE)-driven transcriptional activity, which has been shown to reflect Rho activity, with different proton sensitivities. Imidazopyridine compounds inhibited the moderately acidic pH-induced SRE activity only in GPR4-expressing cells. Acidic pH-stimulated cAMP accumulation, mRNA expression of inflammatory genes, and GPR4 internalization within GPR4-expressing cells were all inhibited by the GPR4 modulator. We further compared the inhibition property of the imidazopyridine compound with psychosine, which has been shown to selectively inhibit actions induced by proton-sensing GPCRs, including GPR4. In the GPR4 mutant, in which certain histidine residues were mutated to phenylalanine, proton sensitivity was significantly shifted to the right, and psychosine failed to further inhibit acidic pH-induced SRE activation. On the other hand, the imidazopyridine compound almost completely inhibited acidic pH-induced action in mutant GPR4. We conclude that some imidazopyridine compounds show specificity to GPR4 as negative allosteric modulators with a different action mode from psychosine, an antagonist susceptible to histidine residues, and are useful for characterizing GPR4-mediated acidic pH-induced biological actions. PMID:26070068

  12. p53 modulates the AMPK inhibitor compound C induced apoptosis in human skin cancer cells

    SciTech Connect

    Huang, Shi-Wei; Wu, Chun-Ying; Wang, Yen-Ting; Kao, Jun-Kai; Lin, Chi-Chen; Chang, Chia-Che; Mu, Szu-Wei; Chen, Yu-Yu; Chiu, Husan-Wen; Chang, Chuan-Hsun; Liang, Shu-Mei; Chen, Yi-Ju; Huang, Jau-Ling; Shieh, Jeng-Jer

    2013-02-15

    Compound C, a well-known inhibitor of the intracellular energy sensor AMP-activated protein kinase (AMPK), has been reported to cause apoptotic cell death in myeloma, breast cancer cells and glioma cells. In this study, we have demonstrated that compound C not only induced autophagy in all tested skin cancer cell lines but also caused more apoptosis in p53 wildtype skin cancer cells than in p53-mutant skin cancer cells. Compound C can induce upregulation, phosphorylation and nuclear translocalization of the p53 protein and upregulate expression of p53 target genes in wildtype p53-expressing skin basal cell carcinoma (BCC) cells. The changes of p53 status were dependent on DNA damage which was caused by compound C induced reactive oxygen species (ROS) generation and associated with activated ataxia-telangiectasia mutated (ATM) protein. Using the wildtype p53-expressing BCC cells versus stable p53-knockdown BCC sublines, we present evidence that p53-knockdown cancer cells were much less sensitive to compound C treatment with significant G2/M cell cycle arrest and attenuated the compound C-induced apoptosis but not autophagy. The compound C induced G2/M arrest in p53-knockdown BCC cells was associated with the sustained inactive Tyr15 phosphor-Cdc2 expression. Overall, our results established that compound C-induced apoptosis in skin cancer cells was dependent on the cell's p53 status. - Highlights: ► Compound C caused more apoptosis in p53 wildtype than p53-mutant skin cancer cells. ► Compound C can upregulate p53 expression and induce p53 activation. ► Compound C induced p53 effects were dependent on ROS induced DNA damage pathway. ► p53-knockdown attenuated compound C-induced apoptosis but not autophagy. ► Compound C-induced apoptosis in skin cancer cells was dependent on p53 status.

  13. Neuropeptides in the Gonads: From Evolution to Pharmacology

    PubMed Central

    McGuire, Nicolette L.; Bentley, George E.

    2010-01-01

    Vertebrate gonads are the sites of synthesis and binding of many peptides that were initially classified as neuropeptides. These gonadal neuropeptide systems are neither well understood in isolation, nor in their interactions with other neuropeptide systems. Further, our knowledge of the control of these gonadal neuropeptides by peripheral hormones that bind to the gonads, and which themselves are under regulation by true neuropeptide systems from the hypothalamus, is relatively meager. This review discusses the existence of a variety of neuropeptides and their receptors which have been discovered in vertebrate gonads, and the possible way in which such systems could have evolved. We then focus on two key neuropeptides for regulation of the hypothalamo-pituitary-gonadal axis: gonadotropin-releasing hormone (GnRH) and gonadotropin-inhibitory hormone (GnIH). Comparative studies have provided us with a degree of understanding as to how a gonadal GnRH system might have evolved, and they have been responsible for the discovery of GnIH and its gonadal counterpart. We attempt to highlight what is known about these two key gonadal neuropeptides, how their actions differ from their hypothalamic counterparts, and how we might learn from comparative studies of them and other gonadal neuropeptides in terms of pharmacology, reproductive physiology and evolutionary biology. PMID:21607065

  14. Amyloid-β / Neuropeptide Interactions Assessed by Ion Mobility-Mass Spectrometry

    PubMed Central

    Soper, Molly T.; DeToma, Alaina S.; Hyung, Suk-Joon; Lim, Mi Hee; Ruotolo, Brandon T.

    2013-01-01

    Recently, small peptides have been shown to modulate aggregation and toxicity of the amyloid-β protein (Aβ). As such, these new scaffolds may help discover a new class of biotherapeutics useful in the treatment of Alzheimer's disease. Many of these inhibitory peptide sequences have been derived from natural sources or from Aβ itself (e.g., C-terminal Aβ fragments). In addition, much earlier work indicates that tachykinins, a broad class of neuropeptides, display neurotrophic properties, presumably through direct interactions with either Aβ or its receptors. Based on this work, we undertook a limited screen of neuropeptides using ion mobility-mass spectrometry to search for similar such peptides with direct Aβ binding properties. Our results reveal that the neuropeptides leucine enkephalin (LE) and galanin interact with both the monomeric and small oligomeric forms of Aβ1-40 to create a range of complexes having diverse stoichiometries, while some tachyknins (i.e., substance P) do not. LE interacts with Aβ more strongly than galanin, and we utilized ion mobility-mass spectrometry, molecular dynamics simulations, gel electrophoresis/Western blot, and transmission electron microscopy to study the influence of this peptide on the structure of Aβ monomer, small Aβ oligomers, as well as the eventual formation of Aβ fibrils. We find that LE binds selectively within a region of Aβ between its N-terminal tail and hydrophobic core. Furthermore, our data indicate that LE modulates fibril generation, producing shorter fibrillar aggregates when added in stoichiometric excess relative to Aβ. PMID:23612608

  15. Identification of a new member of PBAN family of neuropeptides from the fire ant, Solenopsis invicta

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Neuropeptide hormones produced by neurosecretory cells in the central or peripheral nervous systems regulate various physiological and behavioral events during insect development and reproduction. Pyrokinin/Pheromone Biosynthesis Activating Neuropeptide (PBAN) is a major neuropeptide family, chara...

  16. Endogenous migration modulators as parent compounds for the development of novel cardiovascular and anti-inflammatory drugs

    PubMed Central

    Poller, Wolfgang; Rother, Madlen; Skurk, Carsten; Scheibenbogen, Carmen

    2012-01-01

    Development of novel cell migration modulators for anti-inflammatory and cardiovascular therapy is a complex task since any modulator will necessarily interfere with a balanced system of physiological regulators directing proper positioning of diverse immune cell types within the body. Whereas this shall serve efficient pathogen elimination, lack of proper control over these processes may result in counterproductive chronic inflammation and progressive tissue injury instead of healing. Prediction of the therapeutic potential or side effects of any migration modulator is not possible based on theoretical considerations alone but needs to be experimentally evaluated in preclinical disease models and by clinical studies. Here, we briefly summarize basic mechanism of cell migration, and groups of synthetic drugs currently in use for migration modulation. We then discuss one fundamental problem encountered with single-target approaches that arises from the complexity of any inflammation, with multiple interacting and often redundant factors being involved. This issue is likely to arise for any class of therapeutic agent (small molecules, peptides, antibodies, regulatory RNAs) addressing a single gene or protein. Against this background of studies on synthetic migration modulators addressing single targets, we then discuss the potential of endogenous proteins as therapeutic migration modulators, or as parent compounds for the development of mimetic drugs. Regulatory proteins of this type commonly address multiple receptors and signalling pathways and act upon the immune response in a phase-specific manner. Based on recent evidence, we suggest investigation of such endogenous migration modulators as novel starting points for anti-inflammatory and cardiovascular drug development. PMID:22035209

  17. A Flavonoid Compound Promotes Neuronal Differentiation of Embryonic Stem Cells via PPAR-β Modulating Mitochondrial Energy Metabolism

    PubMed Central

    Mei, Yu-qin; Pan, Zong-fu; Chen, Wen-teng; Xu, Min-hua; Zhu, Dan-yan; Yu, Yong-ping; Lou, Yi-jia

    2016-01-01

    Relatively little is known regarding mitochondrial metabolism in neuronal differentiation of embryonic stem (ES) cells. By using a small molecule, present research has investigated the pattern of cellular energy metabolism in neural progenitor cells derived from mouse ES cells. Flavonoid compound 4a faithfully facilitated ES cells to differentiate into neurons morphologically and functionally. The expression and localization of peroxisome proliferator-activated receptors (PPARs) were examined in neural progenitor cells. PPAR-β expression showed robust upregulation compared to solvent control. Treatment with PPAR-β agonist L165041 alone or together with compound 4a significantly promoted neuronal differentiation, while antagonist GSK0660 blocked the neurogenesis-promoting effect of compound 4a. Consistently, knockdown of PPAR-β in ES cells abolished compound 4a-induced neuronal differentiation. Interestingly, we found that mitochondrial fusion protein Mfn2 was also abolished by sh-PPAR-β, resulting in abnormal mitochondrial Ca2+ ([Ca2+]M) transients as well as impaired mitochondrial bioenergetics. In conclusion, we demonstrated that by modulating mitochondrial energy metabolism through Mfn2 and mitochondrial Ca2+, PPAR-β took an important role in neuronal differentiation induced by flavonoid compound 4a. PMID:27315062

  18. A Flavonoid Compound Promotes Neuronal Differentiation of Embryonic Stem Cells via PPAR-β Modulating Mitochondrial Energy Metabolism.

    PubMed

    Mei, Yu-Qin; Pan, Zong-Fu; Chen, Wen-Teng; Xu, Min-Hua; Zhu, Dan-Yan; Yu, Yong-Ping; Lou, Yi-Jia

    2016-01-01

    Relatively little is known regarding mitochondrial metabolism in neuronal differentiation of embryonic stem (ES) cells. By using a small molecule, present research has investigated the pattern of cellular energy metabolism in neural progenitor cells derived from mouse ES cells. Flavonoid compound 4a faithfully facilitated ES cells to differentiate into neurons morphologically and functionally. The expression and localization of peroxisome proliferator-activated receptors (PPARs) were examined in neural progenitor cells. PPAR-β expression showed robust upregulation compared to solvent control. Treatment with PPAR-β agonist L165041 alone or together with compound 4a significantly promoted neuronal differentiation, while antagonist GSK0660 blocked the neurogenesis-promoting effect of compound 4a. Consistently, knockdown of PPAR-β in ES cells abolished compound 4a-induced neuronal differentiation. Interestingly, we found that mitochondrial fusion protein Mfn2 was also abolished by sh-PPAR-β, resulting in abnormal mitochondrial Ca2+ ([Ca2+]M) transients as well as impaired mitochondrial bioenergetics. In conclusion, we demonstrated that by modulating mitochondrial energy metabolism through Mfn2 and mitochondrial Ca2+, PPAR-β took an important role in neuronal differentiation induced by flavonoid compound 4a. PMID:27315062

  19. DEMONSTRATION OF PILOT-SCALE PERVAPORATION SYSTEMS FOR VOLATILE ORGANIC COMPOUND REMOVAL FROM A SURFACTANT ENHANCED AQUIFER REMEDIATION FLUID. II. HOLLOW FIBER MEMBRANE MODULES

    EPA Science Inventory

    Pilot-scale demonstration of pervaporation-based removal of volatile organic compounds from a surfactant enhanced aquifer remediation (SEAR) fluid has been conducted at USEPA's Test & Evaluation Facility using hollow fiber membrane modules. The membranes consisted of microporous...

  20. Metabolic and Microbial Modulation of the Large Intestine Ecosystem by Non-Absorbed Diet Phenolic Compounds: A Review.

    PubMed

    Mosele, Juana I; Macià, Alba; Motilva, Maria-José

    2015-01-01

    Phenolic compounds represent a diverse group of phytochemicals whose intake is associated with a wide spectrum of health benefits. As consequence of their low bioavailability, most of them reach the large intestine where, mediated by the action of local microbiota, a series of related microbial metabolites are accumulated. In the present review, gut microbial transformations of non-absorbed phenolic compounds are summarized. Several studies have reached a general consensus that unbalanced diets are associated with undesirable changes in gut metabolism that could be detrimental to intestinal health. In terms of explaining the possible effects of non-absorbed phenolic compounds, we have also gathered information regarded their influence on the local metabolism. For this purpose, a number of issues are discussed. Firstly, we consider the possible implications of phenolic compounds in the metabolism of colonic products, such as short chain fatty acids (SCFA), sterols (cholesterol and bile acids), and microbial products of non-absorbed proteins. Due to their being recognized as affective antioxidant and anti-inflammatory agents, the ability of phenolic compounds to counteract or suppress pro-oxidant and/or pro-inflammatory responses, triggered by bowel diseases, is also presented. The modulation of gut microbiota through dietetic maneuvers including phenolic compounds is also commented on. Although the available data seems to assume positive effects in terms of gut health protection, it is still insufficient for solid conclusions to be extracted, basically due to the lack of human trials to confirm the results obtained by the in vitro and animal studies. We consider that more emphasis should be focused on the study of phenolic compounds, particularly in their microbial metabolites, and their power to influence different aspects of gut health. PMID:26393570

  1. Character Decomposition and Transposition Processes in Chinese Compound Words Modulates Attentional Blink

    PubMed Central

    Cao, Hongwen; Gao, Min; Yan, Hongmei

    2016-01-01

    The attentional blink (AB) is the phenomenon in which the identification of the second of two targets (T2) is attenuated if it is presented less than 500 ms after the first target (T1). Although the AB is eliminated in canonical word conditions, it remains unclear whether the character order in compound words affects the magnitude of the AB. Morpheme decomposition and transposition of Chinese two-character compound words can provide an effective means to examine AB priming and to assess combinations of the component representations inherent to visual word identification. In the present study, we examined the processing of consecutive targets in a rapid serial visual presentation (RSVP) paradigm using Chinese two-character compound words in which the two characters were transposed to form meaningful words or meaningless combinations (reversible, transposed, or canonical words). We found that when two Chinese characters that form a compound word, regardless of their order, are presented in an RSVP sequence, the likelihood of an AB for the second character is greatly reduced or eliminated compared to when the two characters constitute separate words rather than a compound word. Moreover, the order of the report for the two characters is more likely to be reversed when the normal order of the two characters in a compound word is reversed, especially when the interval between the presentation of the two characters is extremely short. These findings are more consistent with the cognitive strategy hypothesis than the resource-limited hypothesis during character decomposition and transposition of Chinese two-character compound words. These results suggest that compound characters are perceived as a unit, rather than two separate words. The data further suggest that readers could easily understand the text with character transpositions in compound words during Chinese reading. PMID:27379003

  2. Character Decomposition and Transposition Processes in Chinese Compound Words Modulates Attentional Blink.

    PubMed

    Cao, Hongwen; Gao, Min; Yan, Hongmei

    2016-01-01

    The attentional blink (AB) is the phenomenon in which the identification of the second of two targets (T2) is attenuated if it is presented less than 500 ms after the first target (T1). Although the AB is eliminated in canonical word conditions, it remains unclear whether the character order in compound words affects the magnitude of the AB. Morpheme decomposition and transposition of Chinese two-character compound words can provide an effective means to examine AB priming and to assess combinations of the component representations inherent to visual word identification. In the present study, we examined the processing of consecutive targets in a rapid serial visual presentation (RSVP) paradigm using Chinese two-character compound words in which the two characters were transposed to form meaningful words or meaningless combinations (reversible, transposed, or canonical words). We found that when two Chinese characters that form a compound word, regardless of their order, are presented in an RSVP sequence, the likelihood of an AB for the second character is greatly reduced or eliminated compared to when the two characters constitute separate words rather than a compound word. Moreover, the order of the report for the two characters is more likely to be reversed when the normal order of the two characters in a compound word is reversed, especially when the interval between the presentation of the two characters is extremely short. These findings are more consistent with the cognitive strategy hypothesis than the resource-limited hypothesis during character decomposition and transposition of Chinese two-character compound words. These results suggest that compound characters are perceived as a unit, rather than two separate words. The data further suggest that readers could easily understand the text with character transpositions in compound words during Chinese reading. PMID:27379003

  3. Transcriptomic identification of starfish neuropeptide precursors yields new insights into neuropeptide evolution.

    PubMed

    Semmens, Dean C; Mirabeau, Olivier; Moghul, Ismail; Pancholi, Mahesh R; Wurm, Yannick; Elphick, Maurice R

    2016-02-01

    Neuropeptides are evolutionarily ancient mediators of neuronal signalling in nervous systems. With recent advances in genomics/transcriptomics, an increasingly wide range of species has become accessible for molecular analysis. The deuterostomian invertebrates are of particular interest in this regard because they occupy an 'intermediate' position in animal phylogeny, bridging the gap between the well-studied model protostomian invertebrates (e.g. Drosophila melanogaster, Caenorhabditis elegans) and the vertebrates. Here we have identified 40 neuropeptide precursors in the starfish Asterias rubens, a deuterostomian invertebrate from the phylum Echinodermata. Importantly, these include kisspeptin-type and melanin-concentrating hormone-type precursors, which are the first to be discovered in a non-chordate species. Starfish tachykinin-type, somatostatin-type, pigment-dispersing factor-type and corticotropin-releasing hormone-type precursors are the first to be discovered in the echinoderm/ambulacrarian clade of the animal kingdom. Other precursors identified include vasopressin/oxytocin-type, gonadotropin-releasing hormone-type, thyrotropin-releasing hormone-type, calcitonin-type, cholecystokinin/gastrin-type, orexin-type, luqin-type, pedal peptide/orcokinin-type, glycoprotein hormone-type, bursicon-type, relaxin-type and insulin-like growth factor-type precursors. This is the most comprehensive identification of neuropeptide precursor proteins in an echinoderm to date, yielding new insights into the evolution of neuropeptide signalling systems. Furthermore, these data provide a basis for experimental analysis of neuropeptide function in the unique context of the decentralized, pentaradial echinoderm bauplan. PMID:26865025

  4. Transcriptomic identification of starfish neuropeptide precursors yields new insights into neuropeptide evolution

    PubMed Central

    Semmens, Dean C.; Mirabeau, Olivier; Moghul, Ismail; Pancholi, Mahesh R.; Wurm, Yannick; Elphick, Maurice R.

    2016-01-01

    Neuropeptides are evolutionarily ancient mediators of neuronal signalling in nervous systems. With recent advances in genomics/transcriptomics, an increasingly wide range of species has become accessible for molecular analysis. The deuterostomian invertebrates are of particular interest in this regard because they occupy an ‘intermediate' position in animal phylogeny, bridging the gap between the well-studied model protostomian invertebrates (e.g. Drosophila melanogaster, Caenorhabditis elegans) and the vertebrates. Here we have identified 40 neuropeptide precursors in the starfish Asterias rubens, a deuterostomian invertebrate from the phylum Echinodermata. Importantly, these include kisspeptin-type and melanin-concentrating hormone-type precursors, which are the first to be discovered in a non-chordate species. Starfish tachykinin-type, somatostatin-type, pigment-dispersing factor-type and corticotropin-releasing hormone-type precursors are the first to be discovered in the echinoderm/ambulacrarian clade of the animal kingdom. Other precursors identified include vasopressin/oxytocin-type, gonadotropin-releasing hormone-type, thyrotropin-releasing hormone-type, calcitonin-type, cholecystokinin/gastrin-type, orexin-type, luqin-type, pedal peptide/orcokinin-type, glycoprotein hormone-type, bursicon-type, relaxin-type and insulin-like growth factor-type precursors. This is the most comprehensive identification of neuropeptide precursor proteins in an echinoderm to date, yielding new insights into the evolution of neuropeptide signalling systems. Furthermore, these data provide a basis for experimental analysis of neuropeptide function in the unique context of the decentralized, pentaradial echinoderm bauplan. PMID:26865025

  5. Mimetic analogs of three insect neuropeptide classes for pest management

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Neuropeptides are potent regulators of critical life processes in insects, but are subjected to rapid degradation by peptidases in the hemolymph (blood), tissues and gut. This limitation can be overcome via replacement of peptidase susceptible portions of the insect neuropeptides to create analogs w...

  6. Mimetic analogs of pyrokinin neuropeptides for pest management

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Neuropeptides are potent regulators of critical life processes in insects, but are subjected to rapid degradation by peptidases in the hemolymph (blood), tissues and gut. This limitation can be overcome via replacement of peptidase susceptible portions of the insect neuropeptides to create analogs ...

  7. METABOLISM OF AN INSECT NEUROPEPTIDE BY THE NEMATODE C. ELEGANS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We are interested in neuropeptides in nematodes as leads to new control agents for parasitic nematodes. This includes physiological aspects of neuropeptide action and metabolic regulation of these peptides. The free-living nematode Caenorhabditis elegans, with its mapped genome, offers unique opport...

  8. ACTP: A webserver for predicting potential targets and relevant pathways of autophagy-modulating compounds

    PubMed Central

    Ouyang, Liang; Cai, Haoyang; Liu, Bo

    2016-01-01

    Autophagy (macroautophagy) is well known as an evolutionarily conserved lysosomal degradation process for long-lived proteins and damaged organelles. Recently, accumulating evidence has revealed a series of small-molecule compounds that may activate or inhibit autophagy for therapeutic potential on human diseases. However, targeting autophagy for drug discovery still remains in its infancy. In this study, we developed a webserver called Autophagic Compound-Target Prediction (ACTP) (http://actp.liu-lab.com/) that could predict autophagic targets and relevant pathways for a given compound. The flexible docking of submitted small-molecule compound (s) to potential autophagic targets could be performed by backend reverse docking. The webpage would return structure-based scores and relevant pathways for each predicted target. Thus, these results provide a basis for the rapid prediction of potential targets/pathways of possible autophagy-activating or autophagy-inhibiting compounds without labor-intensive experiments. Moreover, ACTP will be helpful to shed light on identifying more novel autophagy-activating or autophagy-inhibiting compounds for future therapeutic implications. PMID:26824420

  9. Mini-review: the evolution of neuropeptide signaling.

    PubMed

    Grimmelikhuijzen, Cornelis J P; Hauser, Frank

    2012-08-10

    Neuropeptides and their G protein-coupled receptors (GPCRs) have an early evolutionary origin and are already abundant in basal animals with primitive nervous systems such as cnidarians (Hydra, jellyfishes, corals, and sea anemones). Most animals emerging after the Cnidaria belong to two evolutionary lineages, the Protostomia (to which the majority of invertebrates belong) and Deuterostomia (to which some minor groups of invertebrates, and all vertebrates belong). These two lineages split about 700 million years (Myr) ago. Many mammalian neuropeptide GPCRs have orthologues in the Protostomia and this is also true for some of the mammalian neuropeptides. Examples are oxytocin/vasopressin, GnRH, gastrin/CCK, and neuropeptide Y and their GPCRs. These results implicate that protostomes (for example insects and nematodes) can be used as models to study the biology of neuropeptide signaling. PMID:22726357

  10. Neuropeptides: metabolism to bioactive fragments and the pharmacology of their receptors.

    PubMed

    Hallberg, Mathias

    2015-05-01

    The proteolytic processing of neuropeptides has an important regulatory function and the peptide fragments resulting from the enzymatic degradation often exert essential physiological roles. The proteolytic processing generates, not only biologically inactive fragments, but also bioactive fragments that modulate or even counteract the response of their parent peptides. Frequently, these peptide fragments interact with receptors that are not recognized by the parent peptides. This review discusses tachykinins, opioid peptides, angiotensins, bradykinins, and neuropeptide Y that are present in the central nervous system and their processing to bioactive degradation products. These well-known neuropeptide systems have been selected since they provide illustrative examples that proteolytic degradation of parent peptides can lead to bioactive metabolites with different biological activities as compared to their parent peptides. For example, substance P, dynorphin A, angiotensin I and II, bradykinin, and neuropeptide Y are all degraded to bioactive fragments with pharmacological profiles that differ considerably from those of the parent peptides. The review discusses a selection of the large number of drug-like molecules that act as agonists or antagonists at receptors of neuropeptides. It focuses in particular on the efforts to identify selective drug-like agonists and antagonists mimicking the effects of the endogenous peptide fragments formed. As exemplified in this review, many common neuropeptides are degraded to a variety of smaller fragments but many of the fragments generated have not yet been examined in detail with regard to their potential biological activities. Since these bioactive fragments contain a small number of amino acid residues, they provide an ideal starting point for the development of drug-like substances with ability to mimic the effects of the degradation products. Thus, these substances could provide a rich source of new pharmaceuticals

  11. Neuropeptides as lung cancer growth factors.

    PubMed

    Moody, Terry W; Moreno, Paola; Jensen, Robert T

    2015-10-01

    This manuscript is written in honor of the Festschrift for Abba Kastin. I met Abba at a Society for Neuroscience meeting and learned that he was Editor-in-Chief of the Journal Peptides. I submitted manuscripts to the journal on "Neuropeptides as Growth Factors in Cancer" and subsequently was named to the Editorial Advisory Board. Over the past 30 years I have published dozens of manuscripts in Peptides and reviewed hundreds of submitted manuscripts. It was always rewarding to interact with Abba, a consummate professional. When I attended meetings in New Orleans I would sometimes go out to dinner with him at the restaurant "Commanders Palace". When I chaired the Summer Neuropeptide Conference we were honored to have him receive the Fleur Strand Award one year in Israel. I think that his biggest editorial contribution has been the "Handbook of Biologically Active Peptides." I served as a Section Editor on "Cancer/Anticancer Peptides" and again found that it was a pleasure working with him. This review focuses on the mechanisms by which bombesin-like peptides, neurotensin and vasoactive intestinal peptide regulate the growth of lung cancer. PMID:25836991

  12. Neuropeptide Y and posttraumatic stress disorder

    PubMed Central

    Sah, R; Geracioti, TD

    2016-01-01

    Resiliency to the adverse effects of extraordinary emotional trauma on the brain varies within the human population. Accordingly, some people cope better than others with traumatic stress. Neuropeptide Y (NPY) is a 36-amino-acid peptide transmitter abundantly expressed in forebrain limbic and brain stem areas that regulate stress and emotional behaviors. Studies largely in rodents demonstrate a role for NPY in promoting coping with stress. Moreover, accruing data from the genetic to the physiological implicate NPY as a potential ‘resilience-to-stress’ factor in humans. Here, we consolidate findings from preclinical and clinical studies of NPY that are of relevance to stress-associated syndromes, most prototypically posttraumatic stress disorder (PTSD). Collectively, these data suggest that reduced central nervous system (CNS) NPY concentrations or function may be associated with PTSD. We also link specific symptoms of human PTSD with extant findings in the NPY field to reveal potential physiological contributions of the neuropeptide to the disorder. In pursuit of understanding the physiological basis and treatment of PTSD, the NPY system is an attractive target. PMID:22801411

  13. Aplysia californica neurons express microinjected neuropeptide genes.

    PubMed Central

    DesGroseillers, L; Cowan, D; Miles, M; Sweet, A; Scheller, R H

    1987-01-01

    Neuropeptide genes are expressed in specific subsets of large polyploid neurons in Aplysia californica. We have defined the transcription initiation sites of three of these neuropeptide genes (the R14, L11, and ELH genes) and determined the nucleotide sequence of the promoter regions. The genes contain the usual eucaryotic promoter signals as well as other structures of potential regulatory importance, including inverted and direct repeats. The L11 and ELH genes, which are otherwise unrelated, have homology in the promoter regions, while the R14 promoter was distinct. When cloned plasmids were microinjected into Aplysia neurons in organ culture, transitions between supercoiled, relaxed circular, and linear DNAs occurred along with ligation into high-molecular-weight species. About 20% of the microinjected neurons expressed the genes. The promoter region of the R14 gene functioned in expression of the microinjected DNA in all cells studied. When both additional 5' and 3' sequences were included, the gene was specifically expressed only in R14, suggesting that the specificity of expression is generated by a multicomponent repression system. Finally, the R14 peptide could be expressed in L11, demonstrating that it is possible to alter the transmitter phenotype of these neurons by introduction of cloned genes. Images PMID:3670293

  14. Modulation of alternative splicing with chemical compounds in new therapeutics for human diseases.

    PubMed

    Ohe, Kenji; Hagiwara, Masatoshi

    2015-04-17

    Alternative splicing is a critical step where a limited number of human genes generate a complex and diverse proteome. Various diseases, including inherited diseases with abnormalities in the "genome code," have been found to result in an aberrant mis-spliced "transcript code" with correlation to the resulting phenotype. Chemical compound-based and nucleic acid-based strategies are trying to target this mis-spliced "transcript code". We will briefly mention about how to obtain splicing-modifying-compounds by high-throughput screening and overview of what is known about compounds that modify splicing pathways. The main focus will be on RNA-binding protein kinase inhibitors. In the main text, we will refer to diseases where splicing-modifying-compounds have been intensively investigated, with comparison to nucleic acid-based strategies. The information on their involvement in mis-splicing as well as nonsplicing events will be helpful in finding better compounds with less off-target effects for future implications in mis-splicing therapy. PMID:25560473

  15. Avicholic Acid: A Lead Compound from Birds on the Route to Potent TGR5 Modulators

    PubMed Central

    2012-01-01

    Grounding on our former 3D QSAR studies, a knowledge-based screen of natural bile acids from diverse animal species has led to the identification of avicholic acid as a selective but weak TGR5 agonist. Chemical modifications of this compound resulted in the disclosure of 6α-ethyl-16-epi-avicholic acid that shows enhanced potency at TGR5 and FXR receptors. The synthesis, biological appraisals, and structure–activity relationships of this series of compounds are herein described. Moreover, a thorough physicochemical characterization of 6α-ethyl-16-epi-avicholic acid as compared to naturally occurring bile acids is reported and discussed. PMID:24900463

  16. Seminalplasmin: recent evolution of another member of the neuropeptide Y gene family.

    PubMed Central

    Herzog, H; Hort, Y; Schneider, R; Shine, J

    1995-01-01

    Seminalplasmin, the major basic protein of bull semen, an important regulator of calcium transport in bovine sperm and a positive modulator of the zona pellucida-induced acrosome reaction, is shown to be a recently created member of the neuropeptide Y gene family. Sequence analysis of the bovine peptide YY-pancreatic polypeptide gene cluster reveals an unexpected and extensive homology between seminalplasmin and the neuropeptide Y gene family, at the level of both gene structure and primary amino acid and nucleotide sequences. The extremely high degree of homology to the peptide YY gene, in both coding and especially noncoding regions, suggests that the seminalplasmin gene has arisen by a very recent gene duplication of the bovine peptide YY gene. Despite the more than 95% nucleotide sequence identity, a few specific mutations in the seminalplasmin gene have resulted in both the loss of the amino- and carboxyl-terminal cleavage sites characteristic of all other members of the neuropeptide Y family and the acquisition of a function apparently unrelated to the neurotransmitter/endocrine role of peptide YY. PMID:7831336

  17. The role of Neuropeptide Y in fear conditioning and extinction.

    PubMed

    Tasan, R O; Verma, D; Wood, J; Lach, G; Hörmer, B; de Lima, T C M; Herzog, H; Sperk, G

    2016-02-01

    While anxiety disorders are the brain disorders with the highest prevalence and constitute a major burden for society, a considerable number of affected people are still treated insufficiently. Thus, in an attempt to identify potential new anxiolytic drug targets, neuropeptides have gained considerable attention in recent years. Compared to classical neurotransmitters they often have a regionally restricted distribution and may bind to several distinct receptor subtypes. Neuropeptide Y (NPY) is a highly conserved neuropeptide that is specifically concentrated in limbic brain areas and signals via at least 5 different G-protein-coupled receptors. It is involved in a variety of physiological processes including the modulation of emotional-affective behaviors. An anxiolytic and stress-reducing property of NPY is supported by many preclinical studies. Whether NPY may also interact with processing of learned fear and fear extinction is comparatively unknown. However, this has considerable relevance since pathological, inappropriate and generalized fear expression and impaired fear extinction are hallmarks of human post-traumatic stress disorder and a major reason for its treatment-resistance. Recent evidence from different laboratories emphasizes a fear-reducing role of NPY, predominantly mediated by exogenous NPY acting on Y1 receptors. Since a reduction of fear expression was also observed in Y1 receptor knockout mice, other Y receptors may be equally important. By acting on Y2 receptors, NPY promotes fear extinction and generates a long-term suppression of fear, two important preconditions that could support cognitive behavioral therapies in human patients. A similar effect has been demonstrated for the closely related pancreatic polypeptide (PP) when acting on Y4 receptors. Preliminary evidence suggests that NPY modulates fear in particular by activation of Y1 and Y2 receptors in the basolateral and central amygdala, respectively. In the basolateral amygdala, NPY

  18. Neuropeptide Signaling in Crustaceans Probed by Mass Spectrometry

    NASA Astrophysics Data System (ADS)

    Liang, Zhidan

    Neuropeptides are one of the most diverse classes of signaling molecules whose identities and functions are not yet fully understood. They have been implicated in the regulation of a wide range of physiological processes, including feeding-related and motivated behaviors, and also environmental adaptations. In this work, improved mass spectrometry-based analytical platforms were developed and applied to the crustacean systems to characterize signaling molecules. This dissertation begins with a review of mass spectrometry-based neuropeptide studies from both temporal- and spatial-domains. This review is then followed by several chapters detailing a few research projects related to the crustacean neuropeptidomic characterization and comparative analysis. The neuropeptidome of crayfish, Orconectes rusticus is characterized for the first time using mass spectrometry-based tools. In vivo microdialysis sampling technique offers the capability of direct sampling from extracellular space in a time-resolved manner. It is used to investigate the secreted neuropeptide and neurotransmitter content in Jonah crab, Cancer borealis, in this work. A new quantitation strategy using alternative mass spectrometry data acquisition approach is developed and applied for the first time to quantify neuropeptides. Coupling of this method with microdialysis enables the study of neuropeptide dynamics concurrent with different behaviors. Proof-of-principle experiments validating this approach have been carried out in Jonah crab, Cancer borealis to study feeding- and circadian rhythm-related neuropeptide changes using micoridialysis in a time-resolved manner. This permits a close correlation between behavioral and neurochemical changes, providing potential candidates for future validation of regulatory roles. In addition to providing spatial information, mass spectrometry imaging (MSI) technique enables the characterization of signaling molecules while preserving the temporal resolution. A

  19. Control of sleep-to-wake transitions via fast aminoacid and slow neuropeptide transmission

    PubMed Central

    Mosqueiro, Thiago; de Lecea, Luis; Huerta, Ramon

    2014-01-01

    The Locus Coeruleus (LC) modulates cortical, subcortical, cerebellar, brainstem and spinal cord circuits and it expresses receptors for neuromodulators that operate in a time scale of several seconds. Evidences from anatomical, electrophysiological and optogenetic experiments have shown that LC neurons receive input from a group of neurons called Hypocretins (HCRTs) that release a neuropeptide called hypocretin. It is less known how these two groups of neurons can be coregulated using GABAergic neurons. Since the time scales of GABAA inhibition is several orders of magnitude faster than the hypocretin neuropeptide effect, we investigate the limits of circuit activity regulation using a realistic model of neurons. Our investigation shows that GABAA inhibition is insufficient to control the activity levels of the LCs. Despite slower forms of GABAA can in principle work, there is not much plausibility due to the low probability of the presence of slow GABAA and lack of robust stability at the maximum firing frequencies. The best possible control mechanism predicted by our modeling analysis is the presence of inhibitory neuropeptides that exert effects in a similar time scale as the hypocretin/orexin. Although the nature of these inhibitory neuropeptides has not been identified yet, it provides the most efficient mechanism in the modeling analysis. Finally, we present a reduced mean-field model that perfectly captures the dynamics and the phenomena generated by this circuit. This investigation shows that brain communication involving multiple time scales can be better controlled by employing orthogonal mechanisms of neural transmission to decrease interference between cognitive processes and hypothalamic functions. PMID:25598695

  20. Compound cavity theory of resonant phase modulation in laser self-mixing ultrasonic vibration measurement

    NASA Astrophysics Data System (ADS)

    Tao, Yufeng; Wang, Ming; Guo, Dongmei

    2016-07-01

    The theoretical basis of self-mixing interference (SMI) employing a resonant phase modulator is explored to prove its tempting advantages. The adopted method induces a pure phase carrier without increasing system complexity. A simple time-domain signal process is used to estimate modulation depth and precisely track vibrating trail, which promises the flexibility of measuring ultrasonic vibration regardless of the constraint of the Bessel functions. The broad bandwidth, low speckle noise, compact, safe, and easy operating SMI system obtains the best resolution of a poor reflection environment. Numerical simulation discusses the spectrum broadening and errors due to multiple reflections. Experimental results agree with theory coherently and are compared with laser Doppler vibration meter showing a dynamical error better than 20 nm in ultrasonic vibration measurement.

  1. Control of arousal through neuropeptide afferents of the locus coeruleus.

    PubMed

    Zitnik, Gerard A

    2016-06-15

    The locus coeruleus-norepinephine (LC-NE) system is implicated in mediating several aspects of arousal. Alterations in LC neuronal discharge is associated with distinct changes in behavior, cognition, sensory processing and regulation of the sleep-wake cycle. Changes in LC output and subsequent release of NE in target brain regions help adjust arousal state to respond appropriately to environmental conditions and behavioral circumstances. One way in which LC activity is controlled is through release of endogenous neuropeptides. Based on the sleep-wake cycle and environmental cues specific neuropeptide afferent systems are activated, innervating the LC. These neuropeptides include: corticotropin releasing factor (CRF), orexin (ORX), endogenous opioids, substance P (SP), melanin-concentrating hormone (MCH), neuropeptide Y (NPY) and somatostatin (SS). This review summarizes studies examining the neuroanatomical projections of these neuropeptides, their receptors in the LC, the actions on LC neurons and downstream NE release, as well as the behavioral and cognitive effects associated individual neuropeptide-mediated innervation of the LC. Finally, the relationship between individual neuropeptides, the LC-NE system and various clinical disorders is discussed, providing evidence for possible therapeutic targets for treatment of several arousal- and stress-related disorders. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID:26688115

  2. NeuroPep: a comprehensive resource of neuropeptides.

    PubMed

    Wang, Yan; Wang, Mingxia; Yin, Sanwen; Jang, Richard; Wang, Jian; Xue, Zhidong; Xu, Tao

    2015-01-01

    Neuropeptides play a variety of roles in many physiological processes and serve as potential therapeutic targets for the treatment of some nervous-system disorders. In recent years, there has been a tremendous increase in the number of identified neuropeptides. Therefore, we have developed NeuroPep, a comprehensive resource of neuropeptides, which holds 5949 non-redundant neuropeptide entries originating from 493 organisms belonging to 65 neuropeptide families. In NeuroPep, the number of neuropeptides in invertebrates and vertebrates is 3455 and 2406, respectively. It is currently the most complete neuropeptide database. We extracted entries deposited in UniProt, the database (www.neuropeptides.nl) and NeuroPedia, and used text mining methods to retrieve entries from the MEDLINE abstracts and full text articles. All the entries in NeuroPep have been manually checked. 2069 of the 5949 (35%) neuropeptide sequences were collected from the scientific literature. Moreover, NeuroPep contains detailed annotations for each entry, including source organisms, tissue specificity, families, names, post-translational modifications, 3D structures (if available) and literature references. Information derived from these peptide sequences such as amino acid compositions, isoelectric points, molecular weight and other physicochemical properties of peptides are also provided. A quick search feature allows users to search the database with keywords such as sequence, name, family, etc., and an advanced search page helps users to combine queries with logical operators like AND/OR. In addition, user-friendly web tools like browsing, sequence alignment and mapping are also integrated into the NeuroPep database. Database URL: http://isyslab.info/NeuroPep PMID:25931458

  3. NeuroPep: a comprehensive resource of neuropeptides

    PubMed Central

    Wang, Yan; Wang, Mingxia; Yin, Sanwen; Jang, Richard; Wang, Jian; Xue, Zhidong; Xu, Tao

    2015-01-01

    Neuropeptides play a variety of roles in many physiological processes and serve as potential therapeutic targets for the treatment of some nervous-system disorders. In recent years, there has been a tremendous increase in the number of identified neuropeptides. Therefore, we have developed NeuroPep, a comprehensive resource of neuropeptides, which holds 5949 non-redundant neuropeptide entries originating from 493 organisms belonging to 65 neuropeptide families. In NeuroPep, the number of neuropeptides in invertebrates and vertebrates is 3455 and 2406, respectively. It is currently the most complete neuropeptide database. We extracted entries deposited in UniProt, the database (www.neuropeptides.nl) and NeuroPedia, and used text mining methods to retrieve entries from the MEDLINE abstracts and full text articles. All the entries in NeuroPep have been manually checked. 2069 of the 5949 (35%) neuropeptide sequences were collected from the scientific literature. Moreover, NeuroPep contains detailed annotations for each entry, including source organisms, tissue specificity, families, names, post-translational modifications, 3D structures (if available) and literature references. Information derived from these peptide sequences such as amino acid compositions, isoelectric points, molecular weight and other physicochemical properties of peptides are also provided. A quick search feature allows users to search the database with keywords such as sequence, name, family, etc., and an advanced search page helps users to combine queries with logical operators like AND/OR. In addition, user-friendly web tools like browsing, sequence alignment and mapping are also integrated into the NeuroPep database. Database URL: http://isyslab.info/NeuroPep PMID:25931458

  4. Stress-related neuropeptides and alcoholism: CRH, NPY, and beyond.

    PubMed

    Ciccocioppo, Roberto; Gehlert, Donald R; Ryabinin, Andrey; Kaur, Simranjit; Cippitelli, Andrea; Thorsell, Annika; Lê, Anh D; Hipskind, Philip A; Hamdouchi, Chafiq; Lu, Jianliang; Hembre, Erik J; Cramer, Jeffrey; Song, Min; McKinzie, David; Morin, Michelle; Economidou, Daina; Stopponi, Serena; Cannella, Nazzareno; Braconi, Simone; Kallupi, Marsida; de Guglielmo, Giordano; Massi, Maurizio; George, David T; Gilman, Jody; Hersh, Jacqueline; Tauscher, Johannes T; Hunt, Stephen P; Hommer, Daniel; Heilig, Markus

    2009-11-01

    This article summarizes the proceedings of a symposium held at the conference on "Alcoholism and Stress: A Framework for Future Treatment Strategies" in Volterra, Italy, May 6-9, 2008. Chaired by Markus Heilig and Roberto Ciccocioppo, this symposium offered a forum for the presentation of recent data linking neuropetidergic neurotransmission to the regulation of different alcohol-related behaviors in animals and in humans. Dr. Donald Gehlert described the development of a new corticotrophin-releasing factor receptor 1 antagonist and showed its efficacy in reducing alcohol consumption and stress-induced relapse in different animal models of alcohol abuse. Dr. Andrey Ryabinin reviewed recent findings in his laboratory, indicating a role of the urocortin 1 receptor system in the regulation of alcohol intake. Dr. Annika Thorsell showed data supporting the significance of the neuropeptide Y receptor system in the modulation of behaviors associated with a history of ethanol intoxication. Dr. Roberto Ciccocioppo focused his presentation on the nociceptin/orphanin FQ (N/OFQ) receptors as treatment targets for alcoholism. Finally, Dr. Markus Heilig showed recent preclinical and clinical evidence suggesting that neurokinin 1 antagonism may represent a promising new treatment for alcoholism. Collectively, these investigators highlighted the significance of neuropeptidergic neurotransmission in the regulation of neurobiological mechanisms of alcohol addiction. Data also revealed the importance of these systems as treatment targets for the development of new medication for alcoholism. PMID:19913192

  5. The effect of tachykinin neuropeptides on amyloid {beta} aggregation

    SciTech Connect

    Flashner, Efrat; Raviv, Uri; Friedler, Assaf

    2011-04-01

    Research highlights: {yields} Mechanistic explanation of how tachykinin neuropeptides reduce A{beta}-induced neurotoxicity. {yields} Biophysical studies suggest that tachykinins do not modulate the distribution of A{beta} oligomeric states, but rather may incorporate into the fibrils. {yields} A possible strategy to inhibit toxicity of amyloid fibrils. -- Abstract: A hallmark of Alzheimer's disease is production of amyloid {beta} peptides resulting from aberrant cleavage of the amyloid precursor protein. Amyloid {beta} assembles into fibrils under physiological conditions, through formation of neurotoxic intermediate oligomers. Tachykinin peptides are known to affect amyloid {beta} neurotoxicity in cells. To understand the mechanism of this effect, we studied how tachykinins affect A{beta}(1-40) aggregation in vitro. Fibrils grown in the presence of tachykinins exhibited reduced thioflavin T (ThT) fluorescence, while their morphology, observed in transmission electron microscopy (TEM), did not alter. Cross linking studies revealed that the distribution of low molecular weight species was not affected by tachykinins. Our results suggest that there may be a specific interaction between tachykinins and A{beta}(1-40) that allows them to co-assemble. This effect may explain the reduction of A{beta}(1-40) neurotoxicity in cells treated with tachykinins.

  6. Identification of compounds that modulate retinol signaling using a cell-based qHTS assay.

    PubMed

    Chen, Yanling; Sakamuru, Srilatha; Huang, Ruili; Reese, David H; Xia, Menghang

    2016-04-01

    In vertebrates, the retinol (vitamin A) signaling pathway (RSP) controls the biosynthesis and catabolism of all-trans retinoic acid (atRA), which regulates transcription of genes essential for embryonic development. Chemicals that interfere with the RSP to cause abnormal intracellular levels of atRA are potential developmental toxicants. To assess chemicals for the ability to interfere with retinol signaling, we have developed a cell-based RARE (Retinoic Acid Response Element) reporter gene assay to identify RSP disruptors. To validate this assay in a quantitative high-throughput screening (qHTS) platform, we screened the Library of Pharmacologically Active Compounds (LOPAC) in both agonist and antagonist modes. The screens detected known RSP agonists, demonstrating assay reliability, and also identified novel RSP agonists including kenpaullone, niclosamide, PD98059 and SU4312, and RSP antagonists including Bay 11-7085, LY294002, 3,4-Methylenedioxy-β-nitrostyrene, and topoisomerase inhibitors (camptothecin, topotecan, amsacrine hydrochloride, and idarubicin). When evaluated in the P19 pluripotent cell, these compounds were found to affect the expression of the Hoxa1 gene that is essential for embryo body patterning. These results show that the RARE assay is an effective qHTS approach for screening large compound libraries to identify chemicals that have the potential to adversely affect embryonic development through interference with retinol signaling. PMID:26820057

  7. The dual function of nitrite under stomach conditions is modulated by reducing compounds.

    PubMed

    Volk, J; Gorelik, S; Granit, R; Kohen, R; Kanner, J

    2009-09-01

    Salivary nitrite plays a role in the lipid peroxidation process of muscle tissue in simulated gastric fluid. The objectives of our study were to elucidate the fate of nitrite in the presence of reducing compounds and to evaluate its effect on lipid peroxidation during digestion. Nitrite at pH 3 (possibly NO(2.), not NO.) can oxidize beta-carotene, but the addition of reducing compounds, ascorbic acid or polyphenols, alters its effect. Ascorbic acid alone promoted the formation of NO. from nitrite only up to pH 3, but the addition of iron ions facilitated the formation of NO. up to pH 5.5. NO prevented membranal lipid peroxidation under stomach conditions. Nitrite, only in the presence of reducing compounds, achieved the same goal but at much higher concentrations. Addition of polyphenols to nitrite synergistically improved its antioxidant effect. Therefore, to promote NO. production and to achieve better control of the lipid peroxidation process in the stomach, a nitrite-rich meal should be consumed simultaneously with food rich in polyphenols. PMID:19375499

  8. Block of the Mevalonate Pathway Triggers Oxidative and Inflammatory Molecular Mechanisms Modulated by Exogenous Isoprenoid Compounds

    PubMed Central

    Tricarico, Paola Maura; Kleiner, Giulio; Valencic, Erica; Campisciano, Giuseppina; Girardelli, Martina; Crovella, Sergio; Knowles, Alessandra; Marcuzzi, Annalisa

    2014-01-01

    Deregulation of the mevalonate pathway is known to be involved in a number of diseases that exhibit a systemic inflammatory phenotype and often neurological involvements, as seen in patients suffering from a rare disease called mevalonate kinase deficiency (MKD). One of the molecular mechanisms underlying this pathology could depend on the shortage of isoprenoid compounds and the subsequent mitochondrial damage, leading to oxidative stress and pro-inflammatory cytokines’ release. Moreover, it has been demonstrated that cellular death results from the balance between apoptosis and pyroptosis, both driven by mitochondrial damage and the molecular platform inflammasome. In order to rescue the deregulated pathway and decrease inflammatory markers, exogenous isoprenoid compounds were administered to a biochemical model of MKD obtained treating a murine monocytic cell line with a compound able to block the mevalonate pathway, plus an inflammatory stimulus. Our results show that isoprenoids acted in different ways, mainly increasing the expression of the evaluated markers [apoptosis, mitochondrial dysfunction, nucleotide-binding oligomerization-domain protein-like receptors 3 (NALP3), cytokines and nitric oxide (NO)]. Our findings confirm the hypothesis that inflammation is triggered, at least partially, by the shortage of isoprenoids. Moreover, although further studies are necessary, the achieved results suggest a possible role for exogenous isoprenoids in the treatment of MKD. PMID:24758928

  9. Transcriptome analysis of neuropeptides and G-protein coupled receptors (GPCRs) for neuropeptides in the brown planthopper Nilaparvata lugens.

    PubMed

    Tanaka, Yoshiaki; Suetsugu, Yoshitaka; Yamamoto, Kimiko; Noda, Hiroaki; Shinoda, Tetsuro

    2014-03-01

    The genes encoding neuropeptides, neurohormones and their putative G-protein coupled receptors were identified in the brown planthopper (BPH), Nilaparvata lugens (Stål) by transcriptome analysis (RNA-seq). Forty-eight candidate genes were found to encode neuropeptides or peptide hormones. These include all known insect neuropeptides and neurohormones, with the exception of neuropeptide-like precursor 2 (NPLP2) and trissin. The gene coding for prothoracicotropic hormone (PTTH) was first identified from hemimetabolous insect. A total of 57 putative neuropeptide GPCR genes were identified and phylogenetic analysis showed most of them to be closely related to insect GPCRs. A notable finding was the occurrence of vertebrate hormone receptors, thyrotropin-releasing hormone receptor (TRHR)-like GPCR and parathyroid hormone receptor (PTHR)-like GPCRs. These results suggest that N. lugens possesses the most comprehensive neuropeptide system yet found in insects. Moreover, our findings demonstrate the power of RNA-seq as a tool for analyzing the neuropeptide-related genes in the absence of whole genome sequence information. PMID:23932938

  10. Modulation of PPAR Expression and Activity in Response to Polyphenolic Compounds in High Fat Diets

    PubMed Central

    Domínguez-Avila, J. Abraham; González-Aguilar, Gustavo A.; Alvarez-Parrilla, Emilio; de la Rosa, Laura A.

    2016-01-01

    Peroxisome proliferator-activated receptors (PPAR) are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD) can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP) found in vegetable foodstuffs are capable of positively modulating this pathway. We therefore focused this review on the possible effects that PP can have on PPAR when administered together with HFD. We found that PP from diverse sources, such as coffee, olives, rice, berries and others, are capable of inducing the expression of genes involved in a decrease of adipose mass, liver and serum lipids and lipid biosynthesis in animal and cell models of HFD. Since cells or gut bacteria can transform PP into different metabolites, it is possible that a synergistic or antagonistic effect ultimately occurs. PP molecules from vegetable sources are an interesting option to maintain or return to a state of energy homeostasis, possibly due to an adequate PPAR expression and activity. PMID:27367676

  11. Modulation of PPAR Expression and Activity in Response to Polyphenolic Compounds in High Fat Diets.

    PubMed

    Domínguez-Avila, J Abraham; González-Aguilar, Gustavo A; Alvarez-Parrilla, Emilio; de la Rosa, Laura A

    2016-01-01

    Peroxisome proliferator-activated receptors (PPAR) are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD) can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP) found in vegetable foodstuffs are capable of positively modulating this pathway. We therefore focused this review on the possible effects that PP can have on PPAR when administered together with HFD. We found that PP from diverse sources, such as coffee, olives, rice, berries and others, are capable of inducing the expression of genes involved in a decrease of adipose mass, liver and serum lipids and lipid biosynthesis in animal and cell models of HFD. Since cells or gut bacteria can transform PP into different metabolites, it is possible that a synergistic or antagonistic effect ultimately occurs. PP molecules from vegetable sources are an interesting option to maintain or return to a state of energy homeostasis, possibly due to an adequate PPAR expression and activity. PMID:27367676

  12. Nav1.1 Modulation by a Novel Triazole Compound Attenuates Epileptic Seizures in Rodents

    PubMed Central

    2015-01-01

    Here, we report the discovery of a novel anticonvulsant drug with a molecular organization based on the unique scaffold of rufinamide, an anti-epileptic compound used in a clinical setting to treat severe epilepsy disorders such as Lennox-Gastaut syndrome. Although accumulating evidence supports a working mechanism through voltage-gated sodium (Nav) channels, we found that a clinically relevant rufinamide concentration inhibits human (h)Nav1.1 activation, a distinct working mechanism among anticonvulsants and a feature worth exploring for treating a growing number of debilitating disorders involving hNav1.1. Subsequent structure–activity relationship experiments with related N-benzyl triazole compounds on four brain hNav channel isoforms revealed a novel drug variant that (1) shifts hNav1.1 opening to more depolarized voltages without further alterations in the gating properties of hNav1.1, hNav1.2, hNav1.3, and hNav1.6; (2) increases the threshold to action potential initiation in hippocampal neurons; and (3) greatly reduces the frequency of seizures in three animal models. Altogether, our results provide novel molecular insights into the rational development of Nav channel-targeting molecules based on the unique rufinamide scaffold, an outcome that may be exploited to design drugs for treating disorders involving particular Nav channel isoforms while limiting adverse effects. PMID:24635129

  13. South Asian Medicinal Compounds as Modulators of Resistance to Chemotherapy and Radiotherapy

    PubMed Central

    Prasad, N. Rajendra; Muthusamy, Ganesan; Shanmugam, Mohana; Ambudkar, Suresh V.

    2016-01-01

    Cancer is a hyperproliferative disorder that involves transformation, dysregulation of apoptosis, proliferation, invasion, angiogenesis and metastasis. During the last 30 years, extensive research has revealed much about the biology of cancer. Chemotherapy and radiotherapy are the mainstays of cancer treatment, particularly for patients who do not respond to surgical resection. However, cancer treatment with drugs or radiation is seriously limited by chemoresistance and radioresistance. Various approaches and strategies are employed to overcome resistance to chemotherapy and radiation treatment. Many plant-derived phytochemicals have been investigated for their chemo- and radio-sensitizing properties. The peoples of South Asian countries such as India, Pakistan, Sri Lanka, Nepal, Bangladesh and Bhutan have a large number of medicinal plants from which they produce various pharmacologically potent secondary metabolites. The medicinal properties of these compounds have been extensively investigated and many of them have been found to sensitize cancer cells to chemo- and radio-therapy. This review focuses on the role of South Asian medicinal compounds in chemo- and radio-sensitizing properties in drug- and radio-resistant cancer cells. Also discussed is the role of South Asian medicinal plants in protecting normal cells from radiation, which may be useful during radiotherapy of tumors to spare surrounding normal cells. PMID:26959063

  14. Challenges for the in vivo quantification of brain neuropeptides using microdialysis sampling and LC-MS.

    PubMed

    Van Wanseele, Yannick; De Prins, An; De Bundel, Dimitri; Smolders, Ilse; Van Eeckhaut, Ann

    2016-09-01

    In recent years, neuropeptides and their receptors have received an increased interest in neuropharmacological research. Although these molecules are considered relatively small compared with proteins, their in vivo quantification using microdialysis is more challenging than for small molecules. Low microdialysis recoveries, aspecific adsorption and the presence of various multiply charged precursor ions during ESI-MS/MS detection hampers the in vivo quantification of these low abundant biomolecules. Every step in the workflow, from sampling until analysis, has to be optimized to enable the sensitive analysis of these compounds in microdialysates. PMID:27554986

  15. Polar/apolar compounds induce leukemia cell differentiation by modulating cell-surface potential.

    PubMed Central

    Arcangeli, A; Carlà, M; Del Bene, M R; Becchetti, A; Wanke, E; Olivotto, M

    1993-01-01

    The mechanism of action of polar/apolar inducers of cell differentiation, such as dimethyl sulfoxide and hexamethylene-bisacetamide, is still obscure. In this paper evidence is provided that their effects on murine erythroleukemia cells are modulated by various extracellular cations as a precise function of the cation effects on membrane surface potential. The interfacial effects of the inducers were directly measured on the charged electrode, showing that both dimethyl sulfoxide and hexamethylene-bisacetamide, at the effective concentrations for cell differentiation and within the physiological range of charge density, adsorb at the charged surface and produce a potential shift. A linear correlation was found between this shift and the inducer effects on cell differentiation. Besides offering a different interpretation of the mechanism of action of the inducers, these findings indicate that surface potential has a signaling function. They may also be relevant to cancer treatments based on tumor-cell commitment to terminal differentiation. Images Fig. 1 PMID:8516337

  16. Pituitary adenylate cyclase-activating polypeptide-like compounds could modulate the activity of coelomocytes in the earthworm.

    PubMed

    Somogyi, Ildiko; Boros, Akos; Engelmann, Peter; Varhalmi, Eszter; Nemeth, Jozsef; Lubics, Andrea; Tamas, Andrea; Kiss, Peter; Reglodi, Dora; Pollak, Edit; Molnar, Laszlo

    2009-04-01

    By means of radioimmunoassay, we studied the concentration of pituitary adenylate cyclase-activating polypeptide (PACAP)-like proteins in intact and regenerating earthworms. Transection of animals increased the concentration of PACAP-like compounds in coelomocytes, and a decreasing rostrocaudal gradient was detected in the regenerating animals. Western blot analysis revealed a range of PAC1-receptor proteins with molecular weights from 40 to 80 kDa. Electron microscopic immunocytochemistry showed that PAC1 receptors were located on distinct sets of coelomocytes (mainly on amebocytes and on some granulocytes). Based on our results we hypothesize a link between PACAP and coelomocytes, suggesting that PACAP modulates the function of amebocytes and certain granulocytes that play a role in tissue remodeling of regenerating earthworms. PMID:19456404

  17. Use of a flor velum yeast for modulating colour, ethanol and major aroma compound contents in red wine.

    PubMed

    Moreno, Juan; Moreno-García, Jaime; López-Muñoz, Beatriz; Mauricio, Juan Carlos; García-Martínez, Teresa

    2016-12-15

    The most important and negative effect of the global warming for winemakers in warm and sunny regions is the observed lag between industrial and phenolic grape ripeness, so only it is possible to obtain an acceptable colour when the ethanol content of wine is high. By contrast, the actual market trends are to low ethanol content wines. Flor yeast growing a short time under velum conditions, decreases the ethanol and volatile acidity contents, has a favorable effect on the colour and astringency and significantly changes the wine content in 1-propanol, isobutanol, acetaldehyde, 1,1-diethoxiethane and ethyl lactate. The Principal Component Analysis of six enological parameters or five aroma compounds allows to classify the wines subjected to different velum formation conditions. The obtained results in two tasting sessions suggest that the flor yeast helps to modulate the ethanol, astringency and colour and supports a new biotechnological perspective for red winemakers. PMID:27451159

  18. The Role of Hypothalamic Neuropeptides in Neurogenesis and Neuritogenesis

    PubMed Central

    Bakos, Jan; Zatkova, Martina; Bacova, Zuzana; Ostatnikova, Daniela

    2016-01-01

    The hypothalamus is a source of neural progenitor cells which give rise to different populations of specialized and differentiated cells during brain development. Newly formed neurons in the hypothalamus can synthesize and release various neuropeptides. Although term neuropeptide recently undergoes redefinition, small-size hypothalamic neuropeptides remain major signaling molecules mediating short- and long-term effects on brain development. They represent important factors in neurite growth and formation of neural circuits. There is evidence suggesting that the newly generated hypothalamic neurons may be involved in regulation of metabolism, energy balance, body weight, and social behavior as well. Here we review recent data on the role of hypothalamic neuropeptides in adult neurogenesis and neuritogenesis with special emphasis on the development of food intake and social behavior related brain circuits. PMID:26881105

  19. High-speed guided-wave electro-optic modulators and polarization converters in III-V compound semiconductors

    NASA Astrophysics Data System (ADS)

    Rahmatian, Farnoosh

    In the last few decades, the need for electronic communication has increased by several orders of magnitude. Due to the rapid growth of the demand for transmission bandwidth, development of very high-speed communication systems is crucial. This thesis describes integrated-optic electro-optic modulators using travelling-wave electrodes in compound semiconductors for ultra-high-speed guided-wave optical communications. Both Mach-Zehnder (MZ) interferometric modulators and polarization converters (PC) have been studied with particular emphasis on the latter ones. Slow-wave travelling-wave electrodes in compound semiconductors have previously been proposed and demonstrated. Here, a study of slow-wave, travelling-wave electrodes on compound semiconductors has been performed in order to significantly improve their use in ultra-wide-band guided-wave electro-optic devices. The most important factors limiting the high frequency performance of such devices, in general, are the microwave-lightwave velocity mismatch and the microwave loss on the electrodes. Based on the deeper understanding acquired through our study, we have designed, fabricated, and tested low-loss, slow-wave, travelling-wave electrodes on semi- insulating GaAs (SI-GaAs) and AlGaAs/GaAs substrates. Microwave-to-lightwave velocity matching within 1% was achieved using slow-wave coplanar strip electrodes; many of the electrodes had effective microwave indices in the range 3.3 to 3.4 (measured at frequencies up to 40 GHz). For the electrodes fabricated on SI-GaAs substrates, microwave losses of 0.22 Np/cm and 0.34 Np/cm (average values at 40 GHz) were measured for the slow-wave coplanar strip and the slow-wave coplanar waveguide electrodes, respectively. For the electrodes fabricated on the AlGaAs/GaAs substrates containing the modulators, the corresponding losses were, on average, 0.17 Np/cm higher at 40 GHz. For the first time, ultra-wide-band polarization converters using slow-wave electrodes have been

  20. A zebrafish compound screen reveals modulation of neutrophil reverse migration as an anti-inflammatory mechanism.

    PubMed

    Robertson, Anne L; Holmes, Geoffrey R; Bojarczuk, Aleksandra N; Burgon, Joseph; Loynes, Catherine A; Chimen, Myriam; Sawtell, Amy K; Hamza, Bashar; Willson, Joseph; Walmsley, Sarah R; Anderson, Sean R; Coles, Mark C; Farrow, Stuart N; Solari, Roberto; Jones, Simon; Prince, Lynne R; Irimia, Daniel; Rainger, G Ed; Kadirkamanathan, Visakan; Whyte, Moira K B; Renshaw, Stephen A

    2014-02-26

    Diseases of failed inflammation resolution are common and largely incurable. Therapeutic induction of inflammation resolution is an attractive strategy to bring about healing without increasing susceptibility to infection. However, therapeutic targeting of inflammation resolution has been hampered by a lack of understanding of the underlying molecular controls. To address this drug development challenge, we developed an in vivo screen for proresolution therapeutics in a transgenic zebrafish model. Inflammation induced by sterile tissue injury was assessed for accelerated resolution in the presence of a library of known compounds. Of the molecules with proresolution activity, tanshinone IIA, derived from a Chinese medicinal herb, potently induced inflammation resolution in vivo both by induction of neutrophil apoptosis and by promoting reverse migration of neutrophils. Tanshinone IIA blocked proinflammatory signals in vivo, and its effects are conserved in human neutrophils, supporting a potential role in treating human inflammation and providing compelling evidence of the translational potential of this screening strategy. PMID:24574340

  1. Modulating intracellular acidification by regulating the incubation time of proton caged compounds.

    PubMed

    Carbone, Marilena; Sabbatella, Gianfranco; Antonaroli, Simonetta; Orlando, Viviana; Biagioni, Stefano; Nucara, Alessandro

    2016-09-01

    A proton caged compound, the 1-(2-nitrophenyl)- ethylhexadecyl sulfonate (HDNS), was dosed into HEK-293 at different incubation times. Samples were irradiated with filtered UV light for inducing photolysis of the HDNS and then probed by infrared spectroscopy. The intracellular acidification reaction can be followed by monitoring the consequent CO2 peak intensity variation. The total CO2 produced is similar for all the samples, hence it is only a function of the initial HDNS concentration. The way it is achieved, though, is different for the different incubation times and follows kinetics, which results in a combination of a linear CO2 increase and a steep CO2 increase followed by a decay. This is interpreted in terms of confinement of the HDNS into intracellular vesicles of variable average size and sensitive to UV light when they reach critical dimensions. PMID:27017356

  2. Volatile Organic Compounds Identified in Post-Flight Air Analysis of the Multipurpose Logistics Module from International Space Station

    NASA Astrophysics Data System (ADS)

    Peterson, B.; Wheeler, R.

    Bioregenerative systems involve storing and processing waste along with atmospheric management. The MPLM, Multipurpose Logistics Module, is a reusable logistics carrier and primary delivery system used to resupply the International Space Station (ISS) and return Station cargo that requires a pressurized environment. The cylindrical module is approximately 6.4 meters long, 4.6 meters in diameter, and weighs almost 4,082kg. The module provides storage and additional workspace for up to two astronauts when docked to the ISS. It can carry up to 9,072 kg of supplies, science experiments, spare parts and other logistical components for ISS. There is concern for a potentially hazardous condition caused by contamination of the atmosphere in the MPLM upon return from orbit. This would be largely due to unforeseen spills or container leakage. This has led to the need for special care in handling the returned module prior to processing the module for its next flight. Prior to opening the MPLM, atmospheric samples are analyzed for trace volatile organic compounds, VOC's. It is noted that our analyses also reflect the atmosphere in the ISS on that day of closure. With the re turn of STS-108, 12th ISS Flight (UF1), the analysis showed 24 PPM of methane. This corresponds to the high levels on space station during a time period when the air filtration system was shut off. Chemical characterization of atmospheres on the ISS and MPLM provide useful information for concerns with plant growth experiments on ISS. Work with closed plant growth chambers show potential for VOC's to accumulate to toxic levels for plants. The ethylene levels for 4 MPLM analyses over the course on one year were measured at, 0.070, 0.017, 0.012 and 0.007 PPM. Phytochemical such as ethylene are detected with natural plant physiological events such as flowering and as a result of plant damage or from decaying food. A build up of VOC's may contribute to phytotoxic effects for the plant growth experiments or

  3. [Effects of neuropeptides on interferon production in vitro].

    PubMed

    Kul'chikov, A E; Makarenko, A N

    2008-01-01

    The study of an interferon-inducing action of neuropeptides (a cerebrolysin model) on production of interferons by human blood leukocytes has shown that neuropeptides induce gamma-interferon production in the titer 267 IU/ml that determines one of the mechanisms of a neuroimmunocorrecting effect of cerebrolysin (Ebewe, Austria) in many neurological diseases (acute stroke, brain traumas and different neuroinfectious diseases). PMID:18720720

  4. The pollen enigma: modulation of the allergic immune response by non-allergenic, pollen-derived compounds.

    PubMed

    Gilles, Stefanie; Behrendt, Heidrun; Ring, Johannes; Traidl-Hoffmann, Claudia

    2012-01-01

    The question what makes an allergen an allergen puzzled generations of researchers. Pollen grains of anemophilous plants are the most important allergen carriers in ambient air, and pollinosis is a highly prevalent multi-organ disease in civilized countries. In the past, research on the allergenicity of pollen has mainly focused on elucidating genetic predisposing factors and on defining certain structural characteristics of pollen derived allergens. Recently, studies extended to the analysis of non-allergenic, adjuvant mediators co-released from pollen. Besides active proteases and oxidases, extracts of pollen contain low molecular weight molecules like pollen-associated lipid mediators or adenosine exhibiting a potential to stimulate and modulate cultured human immune cells. This article reviews our current knowledge on non-allergenic, protein and non-protein compounds from pollen and their in vitro and in vivo effects on the allergic immune response. To ultimately judge the physiological relevance of these compounds, a systematic approach will be needed comparing their releasability, content and activity in different, allergenic and non-allergenic, pollen species. System biology such as proteome and metabolome analysis will be a useful future approach to better understand pollen biology. PMID:22390694

  5. Natural compounds regulate energy metabolism by the modulating the activity of lipid-sensing nuclear receptors.

    PubMed

    Goto, Tsuyoshi; Kim, Young-Il; Takahashi, Nobuyuki; Kawada, Teruo

    2013-01-01

    Obesity causes excess fat accumulation in various tissues, most notoriously in the adipose tissue, along with other insulin-responsive organs such as skeletal muscle and the liver, which predisposes an individual to the development of metabolic abnormalities. The molecular mechanisms underlying obesity-induced metabolic abnormalities have not been completely elucidated; however, in recent years, the search for therapies to prevent the development of obesity and obesity-associated metabolic disorders has increased. It is known that several nuclear receptors, when activated by specific ligands, regulate carbohydrate and lipid metabolism at the transcriptional level. The expression of lipid metabolism-related enzymes is directly regulated by the activity of various nuclear receptors via their interaction with specific response elements in promoters of those genes. Many natural compounds act as ligands of nuclear receptors and regulate carbohydrate and lipid metabolism by regulating the activities of these nuclear receptors. In this review, we describe our current knowledge of obesity, the role of lipid-sensing nuclear receptors in energy metabolism, and several examples of food factors that act as agonists or antagonists of nuclear receptors, which may be useful for the management of obesity and the accompanying energy metabolism abnormalities. PMID:23180608

  6. Neuropeptide Y in the olfactory microvillar cells.

    PubMed

    Montani, Giorgia; Tonelli, Simone; Elsaesser, Rebecca; Paysan, Jacques; Tirindelli, Roberto

    2006-07-01

    This paper examines a possible role of microvillar cells in coordinating cell death and regeneration of olfactory epithelial neurons. The olfactory neuroepithelium of mammals is a highly dynamic organ. Olfactory neurons periodically degenerate by apoptosis and as a consequence of chemical or physical damage. To compensate for this loss of cells, the olfactory epithelium maintains a lifelong ability to regenerate from a pool of resident multipotent stem cells. To assure functional continuity and histological integrity of the olfactory epithelium over a period of many decades, apoptosis and regeneration require to be precisely coordinated. Among the factors that have been implicated in mediating this regulation is the neuropeptide Y (NPY). Knockout mice that lack functional expression of this neurogenic peptide show defects in embryonic development of the olfactory epithelium and in its ability to regenerate in the adult. Here we show that, in postnatal olfactory epithelia, NPY is exclusively expressed by a specific population of microvillar cells. We previously characterized these cells as a novel type of putative chemosensory cells, which are provided with a phosphatidyl-inositol-mediated signal transduction cascade. Our findings allow for the first time to suggest that microvillar cells are involved in connecting apoptosis to neuronal regeneration by stimulus-induced release of NPY. PMID:16800866

  7. Neuropeptides and alcohol addiction in monkeys.

    PubMed

    van Ree, J M; Kornet, M; Goosen, C

    1994-01-01

    Neuropeptides have been implicated in experimental drug addiction. Desglycinamide (Arg8) vasopressin (DGAVP) attenuates heroin and cocaine intake during initiation of drug self-administration in rats. beta-Endorphin is self-administered in rats and a role of endogenous opioids in cocaine reward has been proposed. The present studies deal with voluntary alcohol consumption in monkeys under free choice conditions. Monkeys initiated alcohol drinking within a few days and after a stable drinking pattern was acquired increased their ethanol consumption during a short period following interruption of the alcohol supply (relapse). The alcohol drinking behavior seems under the control of reinforcement principles. DGAVP reduced the acquisition of alcohol drinking in the majority of treated monkeys. Initiation of alcohol drinking induced modifications in neuroendocrine homeostasis e.g. an increased plasma beta-endorphin. Both the opioid antagonist naltrexone and the opioid agonist morphine dose-dependently decreased alcohol intake during continuous supply and after imposed abstinence. The monkeys were more sensitive to both drugs after imposed abstinence. The effects are interpreted in the context of the endorphin compensation hypothesis of addictive behavior. It is suggested that endorphins may be particularly implicated in craving for addictive drugs and in relapse of addictive behavior. PMID:8032147

  8. Iii-V Compound Multiple Quantum Well Based Modulator and Switching Devices.

    NASA Astrophysics Data System (ADS)

    Hong, Songcheol

    A general formalism to study the absorption and photocurrent in multiple quantum well is provided with detailed consideration of quantum confined Stark shift, exciton binding energy, line broadening, tunneling, polarization, and strain effects. Results on variation of exciton size, binding energies and transition energies as a function electric field and well size have been presented. Inhomogeneous line broadening of exciton lines due to interface roughness, alloy disorder and well to well size fluctuation is calculated. The potential of material tailoring by introducing strain for specific optical response is discussed. Theoretical and experimental results on excitonic and band-to-band absorption spectra in strained multi-quantum well structures are shown. I also report on polarization dependent optical absorption for excitonic and interband transitions in lattice matched and strained multiquantum well structures in presence of transverse electric field. Photocurrent in a p-i(MQW)-n diode with monochromatic light is examined with respect to different temperatures and intensities. The negative resistance of I-V characteristic of the p-i-n diode is based on the quantum confined Stark effect of the heavy hole excitonic transition in a multiquantum well. This exciton based photocurrent characteristic allows efficient switching. A general purpose low power optical logic device using the controller-modulator concept bas been proposed and realized. The controller is a heterojunction phototransistor with multiquantum wells in the base-collector depletion region. This allows an amplified photocurrent controlled voltage feedback with low light intensity levels. Detailed analysis of the sensitivity of this device in various modes of operation is studied. Studies are also presented on the cascadability of the device as well as its integrating -thresholding properties. A multiquantum well heterojunction bipolar transistor (MHBT), which has N^+ -p^+-i(MQW)-N structure has been

  9. Modulation of growth performance in disease: reactive nitrogen compounds and their impact on cell proteins.

    PubMed

    Elsasser, T H; Kahl, S; Rumsey, T S; Blum, J W

    2000-08-01

    During life, all animals encounter situations that challenge their capability for optimal growth. In reacting to immune challenges in the form of disease, homeostatic mechanisms attempt to overcome disharmony of the body's internal environment, or simply put, stress. The overall impact of stress revolves around a dynamic relationship between the level of challenge imparted on physiological systems and the degree of host response that is mounted in the process of detecting and reacting to the stress. In growing animals, the majority of milder stress encounters are manifest in terms of energetic inefficiencies and periods of reduced anabolism. In contrast, severe stress is often characterized by frank catabolism and tissue wasting. In some instances a level of stress (that might be termed a "stress breakpoint") is reached at which time the host response itself contributes to the cascade of negative effectors that further cause illness. These "breakpoint" responses are characterized by more intense acute responses to stress or a much more protracted duration of the response than would be expected given the nature of the stress. Key to understanding how growth in the young animal responds to infectious stresses is the recognition that (a) when immune responses that normally maintain health go awry, the reporters and effectors of the immune system (cytokines and the nitric oxide cascade) can contribute to stress disease processes and (b) reactive nitrogen compounds derived from the nitric oxide, as well as super oxide anion can modify intracellular proteins and block otherwise normal biochemical processes that regulate cell function. A key example of this is the loss of regulation of IGF-I by GH. As animals react more severely to disease stress, IGF-I concentrations in plasma decline progressively. Recent data derived from (LPS) challenges performed on young calves suggest that the prolonged decline in IGF-I is associated with the development of hepatic cytotoxicity

  10. Neuropeptide Y inhibits cholangiocarcinoma cell growth and invasion

    PubMed Central

    DeMorrow, Sharon; Onori, Paolo; Venter, Julie; Invernizzi, Pietro; Frampton, Gabriel; White, Mellanie; Franchitto, Antonio; Kopriva, Shelley; Bernuzzi, Francesca; Francis, Heather; Coufal, Monique; Glaser, Shannon; Fava, Giammarco; Meng, Fanyin; Alvaro, Domenico; Carpino, Guido; Gaudio, Eugenio

    2011-01-01

    No information exists on the role of neuropeptide Y (NPY) in cholangiocarcinoma growth. Therefore, we evaluated the expression and secretion of NPY and its subsequent effects on cholangiocarcinoma growth and invasion. Cholangiocarcinoma cell lines and nonmalignant cholangiocytes were used to assess NPY mRNA expression and protein secretion. NPY expression was assessed by immunohistochemistry in human liver biopsies. Cell proliferation and migration were evaluated in vitro by MTS assays and matrigel invasion chambers, respectively, after treatment with NPY or a neutralizing NPY antibody. The effect of NPY or NPY depletion on tumor growth was assessed in vivo after treatment with NPY or the neutralizing NPY antibody in a xenograft model of cholangiocarcinoma. NPY secretion was upregulated in cholangiocarcinoma compared with normal cholangiocytes. Administration of exogenous NPY decreased proliferation and cell invasion in all cholangiocarcinoma cell lines studied and reduced tumor cell growth in vivo. In vitro, the effects of NPY on proliferation were blocked by specific inhibitors for NPY receptor Y2, but not Y1 or Y5, and were associated with an increase in intracellular d-myo-inositol 1,4,5-trisphosphate and PKCα activation. Blocking of NPY activity using a neutralizing antibody promoted cholangiocarcinoma growth in vitro and in vivo and increased the invasiveness of cholangiocarcinoma in vitro. Increased NPY immunoreactivity in human tumor tissue occurred predominantly in the center of the tumor, with less expression toward the invasion front of the tumor. We demonstrated that NPY expression is upregulated in cholangiocarcinoma, which exerts local control on tumor cell proliferation and invasion. Modulation of NPY secretion may be important for the management of cholangiocarcinoma. PMID:21270292

  11. Neuropeptide Regulation of Signaling and Behavior in the BNST

    PubMed Central

    Kash, Thomas L.; Pleil, Kristen E.; Marcinkiewcz, Catherine A.; Lowery-Gionta, Emily G.; Crowley, Nicole; Mazzone, Christopher; Sugam, Jonathan; Hardaway, J. Andrew; McElligott, Zoe A.

    2015-01-01

    Recent technical developments have transformed how neuroscientists can probe brain function. What was once thought to be difficult and perhaps impossible, stimulating a single set of long range inputs among many, is now relatively straight-forward using optogenetic approaches. This has provided an avalanche of data demonstrating causal roles for circuits in a variety of behaviors. However, despite the critical role that neuropeptide signaling plays in the regulation of behavior and physiology of the brain, there have been remarkably few studies demonstrating how peptide release is causally linked to behaviors. This is likely due to both the different time scale by which peptides act on and the modulatory nature of their actions. For example, while glutamate release can effectively transmit information between synapses in milliseconds, peptide release is potentially slower [See the excellent review by Van Den Pol on the time scales and mechanisms of release (van den Pol, 2012)] and it can only tune the existing signals via modulation. And while there have been some studies exploring mechanisms of release, it is still not as clearly known what is required for efficient peptide release. Furthermore, this analysis could be complicated by the fact that there are multiple peptides released, some of which may act in contrast. Despite these limitations, there are a number of groups making progress in this area. The goal of this review is to explore the role of peptide signaling in one specific structure, the bed nucleus of the stria terminalis, that has proven to be a fertile ground for peptide action. PMID:25475545

  12. Dietary phenolic compounds selectively inhibit the individual subunits of maltase-glucoamylase and sucrase-isomaltase with the potential of modulating glucose release

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this study, it was hypothesized that dietary phenolic compounds selectively inhibit the individual C- and N-terminal (Ct, Nt) subunits of the two small intestinal alpha-glucosidases, maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI), for a modulated glycemic carbohydrate digestion. The inhi...

  13. Specific antioxidant compounds differentially modulate cytotoxic activity of doxorubicin and cisplatin: in vitro and in vivo study

    PubMed Central

    Panchuk, Rostyslav; Skorokhyd, Nadia; Chumak, Vira; Lehka, Lilya; Omelyanchik, Sofya; Gurinovich, Valery; Moiseenok, Andrey; Heffeter, Petra; Berger, Walter; Stoika, Rostyslav

    2014-01-01

    Aim To use the antioxidant compounds (sodium selenite, selenomethionine, D-pantethine) for modulation of cytotoxic effect of doxorubicin and cisplatin toward wild type and drug-resistant mutants of several human tumor cells. Similar treatments were applied in vivo toward adult male Wistar rats. Methods Human tumor cells of different lines (HCT-116, Jurkat and HL-60) with various mechanisms of drug-resistance were treated with doxorubicin or cisplatin, alone or in combination with sodium selenite, selenomethionine, or D-pantethine. Cell viability, induction of apoptosis, and production of O2- radicals were measured. Activity of redox potential modulating enzymes was measured in the liver and blood plasma of adult male Wistar rats subjected to similar treatments. Results All antioxidants used in physiologically harmless concentration inhibited cytotoxic action of doxorubicin toward tumor cells sensitive to chemotherapy treatment by 15%-30%, and slightly enhanced cytotoxic effect of this medicine toward drug-resistant malignant cells. At the same time, there was no significant effect of these antioxidants on cisplatin action. Such effects were accompanied by a complete inhibition of production of superoxide radicals induced by doxorubicin. The results of in vivo study in adult male Wistar rats were in agreement with the results of in vitro study of human tumor cells. Conclusion Protective effect of specific antioxidant agents during cytotoxic action of doxorubicin was demonstrated in vitro in drug-sensitive human tumor cells and in adult male Wistar rats, while there was no protective effect in drug-resistant sub-lines of these tumor cells during action of doxorubicin and cisplatin. PMID:24891279

  14. Bioactive compounds or metabolites from black raspberries modulate T lymphocyte proliferation, myeloid cell differentiation and Jak/STAT signaling

    PubMed Central

    Mace, Thomas A.; King, Samantha A.; Ameen, Zeenath; Elnaggar, Omar; Young, Gregory; Riedl, Kenneth M.; Schwartz, Steven J.; Clinton, Steven K.; Knobloch, Thomas J.; Weghorst, Christopher M.; Lesinski, Gregory B.

    2014-01-01

    Bioactive phyotochemicals from natural products, such as black raspberries (BRB; Rubus occidentalis) have direct anti-cancer properties on malignant cells in culture and in xenograft models. BRB components inhibit cancer progression in more complex rodent carcinogenesis models. Although mechanistic targets for BRB phytochemicals in cancer cells are beginning to emerge, the potential role in modulating host immune processes impacting cancer have not been systematically examined. We hypothesized that BRB contain compounds capable of eliciting potent immunomodulatory properties that impact cellular mediators relevant to chronic inflammation and tumor progression. We studied both an ethanol extract from black raspberries (BRB-E) containing a diverse mixture of phytochemicals and two abundant phytochemical metabolites of BRB produced upon ingestion (Cyanidin-3-Rutinoside, C3R; Quercitin-3-Rutinoside, Q3R). BRB-E inhibited proliferation and viability of CD3/CD28 activated human CD4+ and CD8+ T lymphocytes. BRB-E also limited in vitro expansion of myeloid-derived suppressor cells (MDSC) and their suppressive capacity. Pre-treatment of immune cells with BRB-E attenuated IL-6-mediated phosphorylation of signal transducer and activator of transcription-3 (STAT3) and IL-2 induced STAT5 phosphorylation. In contrast, pre-treatment of immune cells with the C3R and Q3R metabolites inhibited MDSC expansion, IL-6-mediated STAT3 signaling, but not IL-2 induced STAT5 phosphorylation and were less potent inhibitors of T cell viability. Together these data indicate that BRB extracts and their physiologically-relevant metabolites contain phytochemicals that affect immune processes relevant to carcinogenesis and immunotherapy. Furthermore, specific BRB components and their metabolites may be a source of lead compounds for drug development that exhibit targeted immunological outcomes or inhibition of specific STAT-regulated signaling pathways. PMID:24893859

  15. Bioactive compounds or metabolites from black raspberries modulate T lymphocyte proliferation, myeloid cell differentiation and Jak/STAT signaling.

    PubMed

    Mace, Thomas A; King, Samantha A; Ameen, Zeenath; Elnaggar, Omar; Young, Gregory; Riedl, Kenneth M; Schwartz, Steven J; Clinton, Steven K; Knobloch, Thomas J; Weghorst, Christopher M; Lesinski, Gregory B

    2014-09-01

    Bioactive phytochemicals from natural products, such as black raspberries (BRB; Rubus occidentalis), have direct anticancer properties on malignant cells in culture and in xenograft models. BRB components inhibit cancer progression in more complex rodent carcinogenesis models. Although mechanistic targets for BRB phytochemicals in cancer cells are beginning to emerge, the potential role in modulating host immune processes impacting cancer have not been systematically examined. We hypothesized that BRB contain compounds capable of eliciting potent immunomodulatory properties that impact cellular mediators relevant to chronic inflammation and tumor progression. We studied both an ethanol extract from black raspberries (BRB-E) containing a diverse mixture of phytochemicals and two abundant phytochemical metabolites of BRB produced upon ingestion (Cyanidin-3-Rutinoside, C3R; Quercitin-3-Rutinoside, Q3R). BRB-E inhibited proliferation, and viability of CD3/CD28 activated human CD4(+) and CD8(+) T lymphocytes. BRB-E also limited in vitro expansion of myeloid-derived suppressor cells (MDSC) and their suppressive capacity. Pre-treatment of immune cells with BRB-E attenuated IL-6-mediated phosphorylation of signal transducer and activator of transcription-3 (STAT3) and IL-2-induced STAT5 phosphorylation. In contrast, pre-treatment of immune cells with the C3R and Q3R metabolites inhibited MDSC expansion, IL-6-mediated STAT3 signaling, but not IL-2-induced STAT5 phosphorylation and were less potent inhibitors of T cell viability. Together these data indicate that BRB extracts and their physiologically relevant metabolites contain phytochemicals that affect immune processes relevant to carcinogenesis and immunotherapy. Furthermore, specific BRB components and their metabolites may be a source of lead compounds for drug development that exhibits targeted immunological outcomes or inhibition of specific STAT-regulated signaling pathways. PMID:24893859

  16. Multiple Neuropeptide-Coding Genes Involved in Planarian Pharynx Extension.

    PubMed

    Shimoyama, Seira; Inoue, Takeshi; Kashima, Makoto; Agata, Kiyokazu

    2016-06-01

    Planarian feeding behavior involves three steps: moving toward food, extending the pharynx from their planarian's ventral side after arriving at the food, and ingesting the food through the pharynx. Although pharynx extension is a remarkable behavior, it remains unknown what neuronal cell types are involved in its regulation. To identify neurons involved in regulating pharynx extension, we quantitatively analyzed pharynx extension and sought to identify these neurons by RNA interference (RNAi) and in situ hybridization. This assay, when performed using planarians with amputation of various body parts, clearly showed that the head portion is indispensable for inducing pharynx extension. We thus tested the effects of knockdown of brain neurons such as serotonergic, GABAergic, and dopaminergic neurons by RNAi, but did not observe any effects on pharynx extension behavior. However, animals with RNAi of the Prohormone Convertase 2 (PC2, a neuropeptide processing enzyme) gene did not perform the pharynx extension behavior, suggesting the possible involvement of neuropeptide(s in the regulation of pharynx extension. We screened 24 neuropeptide-coding genes, analyzed their functions by RNAi using the pharynx extension assay system, and identified at least five neuropeptide genes involved in pharynx extension. These was expressed in different cells or neurons, and some of them were expressed in the brain, suggesting complex regulation of planarian feeding behavior by the nervous system. PMID:27268986

  17. The neuropeptide bursicon acts in cuticle metabolism.

    PubMed

    Dong, Shengzhang; Zhang, Hongwei; Chen, Xi; Stanley, David; Yu, Xiaoping; Song, Qisheng

    2015-06-01

    Bursicon is a heterodimeric neuropeptide formed of bursicon α (burs α) and bursicon β (burs β) that controls cuticle tanning and wing expansion in insects. Burs α-α and burs β-β homodimers are also formed; they act via an unknown receptor to induce expression of prophylactic immune and stress genes during molting. Based on the hypothesis that burs β-β and/or bursicon influence expression of additional genes acting after the molt, we prepared and sequenced six Drosophila cDNA libraries from groups of flies separately injected with burs β-β, bursicon, or blank control. Compared to the control, the burs β-β treatments led to upregulation (by at least 1.5-fold) of 262 genes at 0.5 h postinjection (PI) and 298 genes at 1 h PI; 323 genes at 0.5 h PI and 269 genes at 1h PI were downregulated (by at least 0.67). Similar changes were recorded following bursicon injections. Of these genes, expression of seven transcripts encoding cuticle proteins was upregulated and three downregulated by burs β-β; expression of nine transcripts encoding cuticle proteins were upregulated and four downregulated following bursicon treatments. Expression of dozens of genes involved in chitin metabolism was altered by the experimental treatments. We recorded parallel changes in expression of selected genes by transcriptome and qPCR analysis. These findings support our hypothesis that burs β-β and bursicon influence expression of additional genes acting after the molt. We report that burs β-β and bursicon act in cuticle synthesis and degradation by regulating the expression of cuticular protein and chitin metabolizing related genes. PMID:25821138

  18. Neuropeptide-Driven Cross-Modal Plasticity following Sensory Loss in Caenorhabditis elegans

    PubMed Central

    Rabinowitch, Ithai; Laurent, Patrick; Zhao, Buyun; Walker, Denise; Beets, Isabel; Schoofs, Liliane; Bai, Jihong; Schafer, William R.; Treinin, Millet

    2016-01-01

    Sensory loss induces cross-modal plasticity, often resulting in altered performance in remaining sensory modalities. Whereas much is known about the macroscopic mechanisms underlying cross-modal plasticity, only scant information exists about its cellular and molecular underpinnings. We found that Caenorhabditis elegans nematodes deprived of a sense of body touch exhibit various changes in behavior, associated with other unimpaired senses. We focused on one such behavioral alteration, enhanced odor sensation, and sought to reveal the neuronal and molecular mechanisms that translate mechanosensory loss into improved olfactory acuity. To this end, we analyzed in mechanosensory mutants food-dependent locomotion patterns that are associated with olfactory responses and found changes that are consistent with enhanced olfaction. The altered locomotion could be reversed in adults by optogenetic stimulation of the touch receptor (mechanosensory) neurons. Furthermore, we revealed that the enhanced odor response is related to a strengthening of inhibitory AWC→AIY synaptic transmission in the olfactory circuit. Consistently, inserting in this circuit an engineered electrical synapse that diminishes AWC inhibition of AIY counteracted the locomotion changes in touch-deficient mutants. We found that this cross-modal signaling between the mechanosensory and olfactory circuits is mediated by neuropeptides, one of which we identified as FLP-20. Our results indicate that under normal function, ongoing touch receptor neuron activation evokes FLP-20 release, suppressing synaptic communication and thus dampening odor sensation. In contrast, in the absence of mechanosensory input, FLP-20 signaling is reduced, synaptic suppression is released, and this enables enhanced olfactory acuity; these changes are long lasting and do not represent ongoing modulation, as revealed by optogenetic experiments. Our work adds to a growing literature on the roles of neuropeptides in cross

  19. Identification and RNA Interference of the Pheromone Biosynthesis Activating Neuropeptide (PBAN) in the Common Cutworm Moth Spodoptera litura (Lepidoptera: Noctuidae).

    PubMed

    Lu, Qin; Huang, Ling-Yan; Chen, Peng; Yu, Jin-Feng; Xu, Jin; Deng, Jian-Yu; Ye, Hui

    2015-06-01

    Spodoptera litura F. is one of the most destructive insect pests of many agricultural crops and notorious for developing insecticide resistance. Developing environmental friendly control methods such as novel pheromone and RNAi-related control strategies is imperative to control this pest. In the present study, the full-length cDNA encoding the diapause hormone and pheromone biosynthesis activating neuropeptide (DH-PBAN) was identified and characterized in S. litura. This 809-bp transcript contains a 573-nucleotide ORF encoding a 191-amino acid protein, from which five putative neuropeptides, including PBAN, DH, and α-, β-, and γ-subesophageal ganglion neuropeptides, were derived. Phylogenetic analysis showed that both the whole protein and each of the five neuropeptides have high similarities to those of DH-PBANs from other insect orders particularly Lepidoptera. Females treated with TKYFSPRLamide (the active core fragment of PBAN) produced significantly more four types of pheromone compounds (A; B; C; D) than controls. RNA interference by injection of PBAN dsRNA significantly reduced the relative expression levels of this gene in adult females (approximately reduced by 60%). As a consequence, females treated with PBAN dsRNA produced significantly less four types of pheromone compounds (A; B; C; D) than controls. These results suggest that PBAN function in activating sex pheromone biosynthesis and the RNAi of DH-PBAN gene can be induced by the injection of dsRNA into the body cavity in S. litura. This study suggests the possibility of novel pheromone-related pest control strategies based on RNAi techniques. PMID:26470263

  20. Acrolein depletes the neuropeptides CGRP and substance P in sensory nerves in rat respiratory tract.

    PubMed Central

    Springall, D R; Edginton, J A; Price, P N; Swanston, D W; Noel, C; Bloom, S R; Polak, J M

    1990-01-01

    The mammalian respiratory tract is densely innervated by autonomic and sensory nerves around airways and blood vessels. Subsets of these nerves contain a number of putative neurotransmitter peptides, such as substance P and calcitonin gene-related peptide (CGRP) in sensory nerves and vasoactive intestinal polypeptide (VIP), possibly serving autonomic functions. CGRP is also found in endocrine cells in rat airway epithelium. These peptides are all pharmacologically potent effectors of bronchial and vascular smooth muscle and bronchial secretion. Their functions in vivo are less well established. We have therefore examined the effects of inhaled acrolein, a sensory irritant, on three pulmonary neuropeptides: CGRP, substance P, and VIP. Groups of rats (n = 3 each) were exposed for 10 min to acrolein in air (Ct = 510, 1858, and 5693 mg.min/m3) or to air alone. Fifteen minutes later they were killed (pentabarbitone IP) and their respiratory tracts were dissected and fixed in 0.4% p-benzoquinone solution. Cryostat sections were stained by indirect immunofluorescence for a general nerve marker (PGP 9.5) and neuropeptides. The acrolein-treated animals had a dose-related decrease in tracheal substance P- and CGRP-immunoreactive nerve fibers compared with controls. No change was seen in total nerve fiber distribution and number (PGP 9.5) or VIP immunoreactivity, nor in CGRP-immunoreactive epithelial endocrine cells. It is concluded that the rat tracheal peptidergic nerves are a sensitive indicator of inhaled irritant substances. Their reduced immunoreactivity may be because of a release of sensory neuropeptides that could play a role in the physiological response to irritant or toxic compounds. Images FIGURE 4. a FIGURE 4. b FIGURE 5. a FIGURE 5. b FIGURE 6. a FIGURE 6. b FIGURE 7. a FIGURE 7. b FIGURE 7. c FIGURE 8. a FIGURE 8. b PMID:1696540

  1. Atlas of Central Nervous System and the first Neuropeptide from Fire Ant

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In some insects, especially lepidopteran species, regulation of pheromone biosynthesis and production is under hormonal control. The neuropeptide hormone responsible, PBAN (Pheromone Biosynthesis Activating Neuropeptide), is synthesized in the subesophageal ganglion (SG) and released into the hemoly...

  2. Job Stress and Neuropeptide Response Contributing to Food Intake Regulation

    PubMed Central

    Kim, Ki-Woong; Won, Yong Lim; Ko, Kyung Sun

    2015-01-01

    The purpose of the present study is to investigate the correlations between food intake behavior and job stress level and neuropeptide hormone concentrations. Job strain and food intake behavior were first identified using a self-reported questionnaire, concentrations of neuropeptide hormones (adiponectin, brain derived neurotrophic factor [BDNF], leptin, and ghrelin) were determined, and the correlations were analyzed. In the results, job strain showed significant correlations with adiponectin (odds ratio [OR], 1.220; 95% confidence interval [CI], 1.001~1.498; p < 0.05) and BDNF (OR, 0.793; 95% CI, 0.646~0.974; p < 0.05), and ghrelin exhibited a significant correlation with food intake score (OR, 0.911; 95% CI, 0.842~0.985, p < 0.05). These results suggest that job stress affects food intake regulation by altering the physiological concentrations of neuropeptide hormones as well as emotional status. PMID:26877843

  3. Brain neuropeptides in central ventilatory and cardiovascular regulation in trout

    PubMed Central

    Le Mével, Jean-Claude; Lancien, Frédéric; Mimassi, Nagi; Conlon, J. Michael

    2012-01-01

    Many neuropeptides and their G-protein coupled receptors (GPCRs) are present within the brain area involved in ventilatory and cardiovascular regulation but only a few mammalian studies have focused on the integrative physiological actions of neuropeptides on these vital cardio-respiratory regulations. Because both the central neuroanatomical substrates that govern motor ventilatory and cardiovascular output and the primary sequence of regulatory peptides and their receptors have been mostly conserved through evolution, we have developed a trout model to study the central action of native neuropeptides on cardio-ventilatory regulation. In the present review, we summarize the most recent results obtained using this non-mammalian model with a focus on PACAP, VIP, tachykinins, CRF, urotensin-1, CGRP, angiotensin-related peptides, urotensin-II, NPY, and PYY. We propose hypotheses regarding the physiological relevance of the results obtained. PMID:23115556

  4. Peptidomics for the discovery and characterization of neuropeptides and hormones

    PubMed Central

    Romanova, Elena V.; Sweedler, Jonathan V.

    2015-01-01

    The discovery of neuropeptides as signaling molecules with paracrine or hormonal regulatory functions has led to trailblazing advances in physiology and fostered the characterization of numerous neuropeptide-binding G-protein coupled receptors (GPCRs) as potential drug targets. The impact on human health has been tremendous: approximately 30% of commercial drugs act via the GPCR pathway. However, about 25% of the GPCRs encoded by the mammalian genome still lack their pharmacological identity. Searching for the orphan GPCR endogenous ligands that likely are neuropeptides has proved to be a formidable task. Here we describe the mass spectrometry-based technologies and experimental strategies that have been successful in achieving high throughput characterization of endogenous peptides in nervous and endocrine systems. PMID:26143240

  5. Mass spectrometric map of neuropeptide expression in Ascaris suum.

    PubMed

    Yew, Joanne Y; Kutz, Kimberly K; Dikler, Sergei; Messinger, Lynn; Li, Lingjun; Stretton, Antony O

    2005-08-01

    A mass spectrometric method was used for the localization and sequence characterization of peptides in the nervous system of the parasitic nematode Ascaris suum. Mass spectrometric techniques utilizing MALDI-TOF, MALDI-TOF/TOF, and MALDI-FT instruments were combined with in situ chemical derivatization to examine the expression of known and putative neuropeptides in the A. suum nervous system. This first attempt at peptidomic characterization in A. suum mapped the expression of 39 neuropeptides, 17 of which are considered to be novel and whose expression has not been previously reported. These analyses also revealed that the peptide expression profile is unique to each nervous structure and that the majority of peptides observed belong to the RFamide family of neuropeptides. In addition, four new peptide sequences with a shared C-terminal PNFLRFamide motif are proposed based on in situ sequencing with mass spectrometry. PMID:15973679

  6. Neuropeptides and the Microbiota-Gut-Brain Axis

    PubMed Central

    Holzer, Peter; Farzi, Aitak

    2015-01-01

    Neuropeptides are important mediators both within the nervous system and between neurons and other cell types. Neuropeptides such as substance P, calcitonin gene-related peptide and neuropeptide Y (NPY), vasoactive intestinal polypeptide, somatostatin and corticotropin-releasing factor are also likely to play a role in the bidirectional gut-brain communication. In this capacity they may influence the activity of the gastrointestinal microbiota and its interaction with the gut-brain axis. Current efforts in elucidating the implication of neuropeptides in the microbiota-gut-brain axis address 4 information carriers from the gut to the brain (vagal and spinal afferent neurons; immune mediators such as cytokines; gut hormones; gut microbiota-derived signalling molecules) and 4 information carriers from the central nervous system to the gut (sympathetic efferent neurons; parasympathetic efferent neurons; neuroendocrine factors involving the adrenal medulla; neuroendocrine factors involving the adrenal cortex). Apart from operating as neurotransmitters, many biologically active peptides also function as gut hormones. Given that neuropeptides and gut hormones target the same cell membrane receptors (typically G protein-coupled receptors), the two messenger roles often converge in the same or similar biological implications. This is exemplified by NPY and peptide YY (PYY), two members of the PP-fold peptide family. While PYY is almost exclusively expressed by enteroendocrine cells, NPY is found at all levels of the gut-brain and brain-gut axis. The function of PYY-releasing enteroendocrine cells is directly influenced by short chain fatty acids generated by the intestinal microbiota from indigestible fibre, while NPY may control the impact of the gut microbiota on inflammatory processes, pain, brain function and behaviour. Although the impact of neuropeptides on the interaction between the gut microbiota and brain awaits to be analysed, biologically active peptides are

  7. Neurotoxin-induced neuropeptide perturbations in striatum of neonatal rats.

    PubMed

    Karlsson, Oskar; Kultima, Kim; Wadensten, Henrik; Nilsson, Anna; Roman, Erika; Andrén, Per E; Brittebo, Eva B

    2013-04-01

    The cyanobacterial toxin β-N-methylamino-l-alanine (BMAA) is suggested to play a role in neurodegenerative disease. We have previously shown that although the selective uptake of BMAA in the rodent neonatal striatum does not cause neuronal cell death, exposure during the neonatal development leads to cognitive impairments in adult rats. The aim of the present study was to characterize the changes in the striatal neuropeptide systems of male and female rat pups treated neonatally (postnatal days 9-10) with BMAA (40-460 mg/kg). The label-free quantification of the relative levels of endogenous neuropeptides using mass spectrometry revealed that 25 peptides from 13 neuropeptide precursors were significantly changed in the rat neonatal striatum. The exposure to noncytotoxic doses of BMAA induced a dose-dependent increase of neurosecretory protein VGF-derived peptides, and changes in the relative levels of cholecystokinin, chromogranin, secretogranin, MCH, somatostatin and cortistatin-derived peptides were observed at the highest dose. In addition, the results revealed a sex-dependent increase in the relative level of peptides derived from the proenkephalin-A and protachykinin-1 precursors, including substance P and neurokinin A, in female pups. Because several of these peptides play a critical role in the development and survival of neurons, the observed neuropeptide changes might be possible mediators of BMAA-induced behavioral changes. Moreover, some neuropeptide changes suggest potential sex-related differences in susceptibility toward this neurotoxin. The present study also suggests that neuropeptide profiling might provide a sensitive characterization of the BMAA-induced noncytotoxic effects on the developing brain. PMID:23410195

  8. Functional Module Connectivity Map (FMCM): A Framework for Searching Repurposed Drug Compounds for Systems Treatment of Cancer and an Application to Colorectal Adenocarcinoma

    PubMed Central

    Chung, Feng-Hsiang; Chiang, Yun-Ru; Tseng, Ai-Lun; Sung, Yung-Chuan; Lu, Jean; Huang, Min-Chang; Ma, Nianhan; Lee, Hoong-Chien

    2014-01-01

    Drug repurposing has become an increasingly attractive approach to drug development owing to the ever-growing cost of new drug discovery and frequent withdrawal of successful drugs caused by side effect issues. Here, we devised Functional Module Connectivity Map (FMCM) for the discovery of repurposed drug compounds for systems treatment of complex diseases, and applied it to colorectal adenocarcinoma. FMCM used multiple functional gene modules to query the Connectivity Map (CMap). The functional modules were built around hub genes identified, through a gene selection by trend-of-disease-progression (GSToP) procedure, from condition-specific gene-gene interaction networks constructed from sets of cohort gene expression microarrays. The candidate drug compounds were restricted to drugs exhibiting predicted minimal intracellular harmful side effects. We tested FMCM against the common practice of selecting drugs using a genomic signature represented by a single set of individual genes to query CMap (IGCM), and found FMCM to have higher robustness, accuracy, specificity, and reproducibility in identifying known anti-cancer agents. Among the 46 drug candidates selected by FMCM for colorectal adenocarcinoma treatment, 65% had literature support for association with anti-cancer activities, and 60% of the drugs predicted to have harmful effects on cancer had been reported to be associated with carcinogens/immune suppressors. Compounds were formed from the selected drug candidates where in each compound the component drugs collectively were beneficial to all the functional modules while no single component drug was harmful to any of the modules. In cell viability tests, we identified four candidate drugs: GW-8510, etacrynic acid, ginkgolide A, and 6-azathymine, as having high inhibitory activities against cancer cells. Through microarray experiments we confirmed the novel functional links predicted for three candidate drugs: phenoxybenzamine (broad effects), GW-8510 (cell

  9. Tailless and Atrophin control Drosophila aggression by regulating neuropeptide signalling in the pars intercerebralis

    NASA Astrophysics Data System (ADS)

    Davis, Shaun M.; Thomas, Amanda L.; Nomie, Krystle J.; Huang, Longwen; Dierick, Herman A.

    2014-02-01

    Aggressive behaviour is widespread throughout the animal kingdom. However, its mechanisms are poorly understood, and the degree of molecular conservation between distantly related species is unknown. Here we show that knockdown of tailless (tll) increases aggression in Drosophila, similar to the effect of its mouse orthologue Nr2e1. Tll localizes to the adult pars intercerebralis (PI), which shows similarity to the mammalian hypothalamus. Knockdown of tll in the PI is sufficient to increase aggression and is rescued by co-expressing human NR2E1. Knockdown of Atrophin, a Tll co-repressor, also increases aggression, and both proteins physically interact in the PI. tll knockdown-induced aggression is fully suppressed by blocking neuropeptide processing or release from the PI. In addition, genetically activating PI neurons increases aggression, mimicking the aggression-inducing effect of hypothalamic stimulation. Together, our results suggest that a transcriptional control module regulates neuropeptide signalling from the neurosecretory cells of the brain to control aggressive behaviour.

  10. Discovery of Defense- and Neuropeptides in Social Ants by Genome-Mining

    PubMed Central

    Gruber, Christian W.; Muttenthaler, Markus

    2012-01-01

    Natural peptides of great number and diversity occur in all organisms, but analyzing their peptidome is often difficult. With natural product drug discovery in mind, we devised a genome-mining approach to identify defense- and neuropeptides in the genomes of social ants from Atta cephalotes (leaf-cutter ant), Camponotus floridanus (carpenter ant) and Harpegnathos saltator (basal genus). Numerous peptide-encoding genes of defense peptides, in particular defensins, and neuropeptides or regulatory peptide hormones, such as allatostatins and tachykinins, were identified and analyzed. Most interestingly we annotated genes that encode oxytocin/vasopressin-related peptides (inotocins) and their putative receptors. This is the first piece of evidence for the existence of this nonapeptide hormone system in ants (Formicidae) and supports recent findings in Tribolium castaneum (red flour beetle) and Nasonia vitripennis (parasitoid wasp), and therefore its confinement to some basal holometabolous insects. By contrast, the absence of the inotocin hormone system in Apis mellifera (honeybee), another closely-related member of the eusocial Hymenoptera clade, establishes the basis for future studies on the molecular evolution and physiological function of oxytocin/vasopressin-related peptides (vasotocin nonapeptide family) and their receptors in social insects. Particularly the identification of ant inotocin and defensin peptide sequences will provide a basis for future pharmacological characterization in the quest for potent and selective lead compounds of therapeutic value. PMID:22448224

  11. Discovery of defense- and neuropeptides in social ants by genome-mining.

    PubMed

    Gruber, Christian W; Muttenthaler, Markus

    2012-01-01

    Natural peptides of great number and diversity occur in all organisms, but analyzing their peptidome is often difficult. With natural product drug discovery in mind, we devised a genome-mining approach to identify defense- and neuropeptides in the genomes of social ants from Atta cephalotes (leaf-cutter ant), Camponotus floridanus (carpenter ant) and Harpegnathos saltator (basal genus). Numerous peptide-encoding genes of defense peptides, in particular defensins, and neuropeptides or regulatory peptide hormones, such as allatostatins and tachykinins, were identified and analyzed. Most interestingly we annotated genes that encode oxytocin/vasopressin-related peptides (inotocins) and their putative receptors. This is the first piece of evidence for the existence of this nonapeptide hormone system in ants (Formicidae) and supports recent findings in Tribolium castaneum (red flour beetle) and Nasonia vitripennis (parasitoid wasp), and therefore its confinement to some basal holometabolous insects. By contrast, the absence of the inotocin hormone system in Apis mellifera (honeybee), another closely-related member of the eusocial Hymenoptera clade, establishes the basis for future studies on the molecular evolution and physiological function of oxytocin/vasopressin-related peptides (vasotocin nonapeptide family) and their receptors in social insects. Particularly the identification of ant inotocin and defensin peptide sequences will provide a basis for future pharmacological characterization in the quest for potent and selective lead compounds of therapeutic value. PMID:22448224

  12. A role for amontillado, the Drosophila homolog of the neuropeptide precursor processing protease PC2, in triggering hatching behavior.

    PubMed

    Siekhaus, D E; Fuller, R S

    1999-08-15

    Accurate proteolytic processing of neuropeptide and peptide hormone precursors by members of the kexin/furin family of proteases is key to determining both the identities and activities of signaling peptides. Here we identify amontillado (amon), the Drosophila melanogaster homolog of the mammalian neuropeptide processing protease PC2, and show that in contrast to vertebrate PC2, amontillado expression undergoes extensive regulation in the nervous system during development. In situ hybridization reveals that expression of amontillado is restricted to the final stages of embryogenesis when it is found in anterior sensory structures and in only 168 cells in the brain and ventral nerve cord. After larvae hatch from their egg shells, the sensory structures and most cells in the CNS turn off or substantially reduce amontillado expression, suggesting that amontillado plays a specific role late in embryogenesis. Larvae lacking the chromosomal region containing amontillado show no gross anatomical defects and respond to touch. However, such larvae show a greatly reduced frequency of a hatching behavior of wild-type Drosophila in which larvae swing their heads, scraping through the eggshell with their mouth hooks. Ubiquitous expression of amontillado can restore near wild-type levels of this behavior, whereas expression of amontillado with an alanine substitution for the catalytic histidine cannot. These results suggest that amontillado expression is regulated as part of a programmed modulation of neural signaling that controls hatching behavior by producing specific neuropeptides in particular neurons at an appropriate developmental time. PMID:10436051

  13. Neuropeptide Y Enhances Olfactory Mucosa Responses to Odorant in Hungry Rats

    PubMed Central

    Negroni, Julia; Meunier, Nicolas; Monnerie, Régine; Salesse, Roland; Baly, Christine; Caillol, Monique; Congar, Patrice

    2012-01-01

    Neuropeptide Y (NPY) plays an important role in regulating appetite and hunger in vertebrates. In the hypothalamus, NPY stimulates food intake under the control of the nutritional status. Previous studies have shown the presence of NPY and receptors in rodent olfactory system, and suggested a neuroproliferative role. Interestingly, NPY was also shown to directly modulate olfactory responses evoked by a food-related odorant in hungry axolotls. We have recently demonstrated that another nutritional cue, insulin, modulates the odorant responses of the rat olfactory mucosa (OM). Therefore, the aim of the present study was to investigate the potential effect of NPY on rat OM responses to odorants, in relation to the animal's nutritional state. We measured the potential NPY modulation of OM responses to odorant, using electro-olfactogram (EOG) recordings, in fed and fasted adult rats. NPY application significantly and transiently increased EOG amplitudes in fasted but not in fed rats. The effects of specific NPY-receptor agonists were similarly quantified, showing that NPY operated mainly through Y1 receptors. These receptors appeared as heterogeneously expressed by olfactory neurons in the OM, and western blot analysis showed that they were overexpressed in fasted rats. These data provide the first evidence that NPY modulates the initial events of odorant detection in the rat OM. Because this modulation depends on the nutritional status of the animal, and is ascribed to NPY, the most potent orexigenic peptide in the central nervous system, it evidences a strong supplementary physiological link between olfaction and nutritional processes. PMID:23024812

  14. Development and first application of an Aerosol Collection Module (ACM) for quasi online compound specific aerosol measurements

    NASA Astrophysics Data System (ADS)

    Hohaus, Thorsten; Kiendler-Scharr, Astrid; Trimborn, Dagmar; Jayne, John; Wahner, Andreas; Worsnop, Doug

    2010-05-01

    Atmospheric aerosols influence climate and human health on regional and global scales (IPCC, 2007). In many environments organics are a major fraction of the aerosol influencing its properties. Due to the huge variety of organic compounds present in atmospheric aerosol current measurement techniques are far from providing a full speciation of organic aerosol (Hallquist et al., 2009). The development of new techniques for compound specific measurements with high time resolution is a timely issue in organic aerosol research. Here we present first laboratory characterisations of an aerosol collection module (ACM) which was developed to allow for the sampling and transfer of atmospheric PM1 aerosol. The system consists of an aerodynamic lens system focussing particles on a beam. This beam is directed to a 3.4 mm in diameter surface which is cooled to -30 °C with liquid nitrogen. After collection the aerosol sample can be evaporated from the surface by heating it to up to 270 °C. The sample is transferred through a 60cm long line with a carrier gas. In order to test the ACM for linearity and sensitivity we combined it with a GC-MS system. The tests were performed with octadecane aerosol. The octadecane mass as measured with the ACM-GC-MS was compared versus the mass as calculated from SMPS derived total volume. The data correlate well (R2 0.99, slope of linear fit 1.1) indicating 100 % collection efficiency. From 150 °C to 270 °C no effect of desorption temperature on transfer efficiency could be observed. The ACM-GC-MS system was proven to be linear over the mass range 2-100 ng and has a detection limit of ~ 2 ng. First experiments applying the ACM-GC-MS system were conducted at the Jülich Aerosol Chamber. Secondary organic aerosol (SOA) was formed from ozonolysis of 600 ppbv of b-pinene. The major oxidation product nopinone was detected in the aerosol and could be shown to decrease from 2 % of the total aerosol to 0.5 % of the aerosol over the 48 hours of

  15. Insight into the Molecular and Functional Diversity of Cnidarian Neuropeptides

    PubMed Central

    Takahashi, Toshio; Takeda, Noriyo

    2015-01-01

    Cnidarians are the most primitive animals to possess a nervous system. This phylum is composed of the classes Scyphozoa (jellyfish), Cubozoa (box jellyfish), and Hydrozoa (e.g., Hydra, Hydractinia), which make up the subphylum Medusozoa, as well as the class Anthozoa (sea anemones and corals). Neuropeptides have an early evolutionary origin and are already abundant in cnidarians. For example, from the cnidarian Hydra, a key model system for studying the peptides involved in developmental and physiological processes, we identified a wide variety of novel neuropeptides from Hydra magnipapillata (the Hydra Peptide Project). Most of these peptides act directly on muscle cells and induce contraction and relaxation. Some peptides are involved in cell differentiation and morphogenesis. In this review, we describe FMRFamide-like peptides (FLPs), GLWamide-family peptides, and the neuropeptide Hym-355; FPQSFLPRGamide. Several hundred FLPs have been isolated from invertebrate animals such as cnidarians. GLWamide-family peptides function as signaling molecules in muscle contraction, metamorphosis, and settlement in cnidarians. Hym-355; FPQSFLPRGamide enhances neuronal differentiation in Hydra. Recently, GLWamide-family peptides and Hym-355; FPQSFLPRGamide were shown to trigger oocyte maturation and subsequent spawning in the hydrozoan jellyfish Cytaeis uchidae. These findings suggest the importance of these neuropeptides in both developmental and physiological processes. PMID:25625515

  16. The insect capa neuropeptides impact desiccation and cold stress responses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Insects are so successful because of great resistance to environmental stress, yet little is known about how such responses may be mediated by the neuroendocrine system. Results: We provide evidence that the capability (capa) neuropeptide gene and peptide are critical mediators of desic...

  17. Neutral endopeptidase modulates neurogenic inflammation.

    PubMed

    Nadel, J A

    1991-06-01

    A noncholinergic, nonadrenergic nervous system has been described, involving the sensory nerves in the airways. Chemicals, dusts and other irritants stimulate these sensory nerves to release substance P and related neuropeptides. These neuropeptides have the remarkable ability to affect multiple cells in the airways and to provoke many responses including cough, mucus secretion, smooth muscle contraction, plasma extravasation and neutrophil adhesion. This series of effects is termed "neurogenic inflammation." An enzyme exists on the surfaces of all lung cells that contain receptors for these neuropeptides. This enzyme, neutral endopeptidase (NEP), by cleaving and thus inactivating the neuropeptides, limits the concentration of the neuropeptide that reaches the receptor on the cell surface. Thus, neurogenic inflammatory responses are normally mild and presumably protective in nature. However, when NEP is inhibited pharmacologically (with NEP inhibitors) or by cigarette smoke, respiratory viral infection, or by inhalation of the industrial pollutant toluene diisocyanate, neurogenic inflammatory responses are exaggerated. Delivery of exogenous human recombinant NEP inhibits neurogenic inflammation. Finally, evidence is provided that corticosteroids suppress neurogenic plasma extravasation and that this drug can upregulate NEP in human airway tissue. Neutral endopeptidase cleaves multiple peptides. Thus, its selectivity resides, at least in part, on its fixed location on the surfaces of specific cells where it can modulate effects of peptides exposed to the cells' surfaces. PMID:1889501

  18. Mass Spectrometric Analysis of Spatio-Temporal Dynamics of Crustacean Neuropeptides

    PubMed Central

    OuYang, Chuanzi; Liang, Zhidan; Li, Lingjun

    2014-01-01

    Neuropeptides represent one of the largest classes of signaling molecules used by nervous systems to regulate a wide range of physiological processes. Over the past several years, mass spectrometry (MS)-based strategies have revolutionized the discovery of neuropeptides in numerous model organisms, especially in decapod crustaceans. Here, we focus our discussion on recent advances in the use of MS-based techniques to map neuropeptides in spatial domain and monitoring their dynamic changes in temporal domain. These MS-enabled investigations provide valuable information about the distribution, secretion and potential function of neuropeptides with high molecular specificity and sensitivity. In situ MS imaging and in vivo microdialysis are highlighted as key technologies for probing spatio-temporal dynamics of neuropeptides in the crustacean nervous system. This review summarizes the latest advancement in MS-based methodologies for neuropeptide analysis including typical workflow and sample preparation strategies as well as major neuropeptide families discovered in decapod crustaceans. PMID:25448012

  19. Enkephalin levels and the number of neuropeptide Y-containing interneurons in the hippocampus are decreased in female cannabinoid-receptor 1 knock-out mice.

    PubMed

    Rogers, Sophie A; Kempen, Tracey A Van; Pickel, Virginia M; Milner, Teresa A

    2016-05-01

    Drug addiction requires learning and memory processes that are facilitated by activation of cannabinoid-1 (CB1) and opioid receptors in the hippocampus. This involves activity-dependent synaptic plasticity that is partially regulated by endogenous opioid (enkephalin and dynorphin) and non-opioid peptides, specifically cholecystokinin, parvalbumin and neuropeptide Y, the neuropeptides present in inhibitory interneurons that co-express CB1 or selective opioid receptors. We tested the hypothesis that CB1 receptor expression is a determinant of the availability of one or more of these peptide modulators in the hippocampus. This was achieved by quantitatively analyzing the immunoperoxidase labeling for each of these neuropeptide in the dorsal hippocampus of female wild-type (CB1+/+) and cannabinoid receptor 1 knockout (CB1-/-) C57/BL6 mice. The levels of Leu(5)-enkephalin-immunoreactivity were significantly reduced in the hilus of the dentate gyrus and in stratum lucidum of CA3 in CB1-/- mice. Moreover, the numbers of neuropeptide Y-immunoreactive interneurons in the dentate hilus were significantly lower in the CB1-/- compared to wild-type mice. However, CB1+/+ and CB1-/- mice did not significantly differ in expression levels of either dynorphin or cholecystokinin, and showed no differences in numbers of parvalbumin-containing interneurons. These findings suggest that the cannabinoid and opioid systems have a nuanced, regulatory relationship that could affect the balance of excitation and inhibition in the hippocampus and thus processes such as learning that rely on this balance. PMID:27012427

  20. Discovery of sea urchin NGFFFamide receptor unites a bilaterian neuropeptide family

    PubMed Central

    Semmens, Dean C.; Beets, Isabel; Rowe, Matthew L.; Blowes, Liisa M.; Oliveri, Paola; Elphick, Maurice R.

    2015-01-01

    Neuropeptides are ancient regulators of physiology and behaviour, but reconstruction of neuropeptide evolution is often difficult owing to lack of sequence conservation. Here, we report that the receptor for the neuropeptide NGFFFamide in the sea urchin Strongylocentrotus purpuratus (phylum Echinodermata) is an orthologue of vertebrate neuropeptide-S (NPS) receptors and crustacean cardioactive peptide (CCAP) receptors. Importantly, this has facilitated reconstruction of the evolution of two bilaterian neuropeptide signalling systems. Genes encoding the precursor of a vasopressin/oxytocin-type neuropeptide and its receptor duplicated in a common ancestor of the Bilateria. One copy of the precursor retained ancestral features, as seen in highly conserved vasopressin/oxytocin–neurophysin-type precursors. The other copy diverged, but this took different courses in protostomes and deuterostomes. In protostomes, the occurrence of a disulfide bridge in neuropeptide product(s) of the precursor was retained, as in CCAP, but with loss of the neurophysin domain. In deuterostomes, we see the opposite scenario—the neuropeptides lost the disulfide bridge, and neurophysin was retained (as in the NGFFFamide precursor) but was subsequently lost in vertebrate NPS precursors. Thus, the sea urchin NGFFFamide precursor and receptor are ‘missing links’ in the evolutionary history of neuropeptides that control ecdysis in arthropods (CCAP) and regulate anxiety in humans (NPS). PMID:25904544

  1. Molecular characterization and expression profiles of neuropeptide precursors in the migratory locust.

    PubMed

    Hou, Li; Jiang, Feng; Yang, Pengcheng; Wang, Xianhui; Kang, Le

    2015-08-01

    Neuropeptides serve as the most important regulatory signals in insects. Many neuropeptides and their precursors have been identified in terms of the contig sequences of whole genome information of the migratory locust (Locusta migratoria), which exhibits a typical phenotypic plasticity in morphology, behavior and physiology. However, functions of these locust neuropeptides are largely unknown. In this study, we first revised the 23 reported neuropeptide precursor genes and identified almost all the neuropeptide precursors and corresponding products in L. migratoria. We further revealed the significant expansion profiles (such as AKH) and alternative splicing of neuropeptide genes (Lom-ITP, Lom-OK and Lom-NPF1). Transcriptomic analysis indicated that several neuropeptides, such as Lom-ACP and Lom-OK, displayed development-specific expression patterns. qRT-PCR data confirmed that most neuropeptide precursors were strongly expressed in the central nervous system. Fifteen neuropeptide genes displayed different expression levels between solitarious and gregarious locusts. These findings provide valuable clues to understand neuropeptide evolution and their functional roles in basic biology and phase transition in locusts. PMID:26036749

  2. Relationship of the Chemokine, CXCL12, to Effects of Dietary Fat on Feeding-Related Behaviors and Hypothalamic Neuropeptide Systems

    PubMed Central

    Poon, Kinning; Barson, Jessica R.; Ho, Hui T.; Leibowitz, Sarah F.

    2016-01-01

    The intake of a high fat diet (HFD), in addition to stimulating orexigenic neuropeptides in the hypothalamus while promoting overeating and reducing locomotor behavior, is known to increase inflammatory mediators that modulate neuronal systems in the brain. To understand the involvement of chemokines in the effects of a HFD, we examined in rats whether HFD intake affects a specific chemokine, CXCL12, and its receptors, CXCR4 and CXCR7, in the hypothalamus together with the neuropeptides and whether CXCL12 itself acts similarly to a HFD in stimulating the neuropeptides and altering ingestion and locomotor behavior. Compared to low-fat chow, a HFD for 5 days significantly increased the expression of CXCL12 and its receptors, in both the paraventricular nucleus (PVN) where the neuropeptides enkephalin (ENK) and galanin were also stimulated and the perifornical lateral hypothalamus (PFLH) where orexin (OX) and melanin-concentrating hormone (MCH) were increased. In contrast, the HFD had no impact on expression of CXCL12 or its receptors in the arcuate nucleus (ARC) where the carbohydrate-related peptide, neuropeptide Y (NPY), was suppressed. Analysis of protein levels revealed a similar stimulatory effect of a HFD on CXCL12 levels in the PVN and PFLH, as well as in blood, and an increase in the number of CXCR4-positive cells in the PVN. In the ARC, in contrast, levels of CXCL12 and number of CXCR4-positive cells were too low to measure. When centrally administered, CXCL12 was found to have similar effects to a HFD. Injection of CXCL12 into the third cerebral ventricle immediately anterior to the hypothalamus significantly stimulated the ingestion of a HFD, reduced novelty-induced locomotor activity, and increased expression of ENK in the PVN where the CXCR4 receptors were dense. It had no impact, however, on NPY in the ARC or on OX and MCH in the PFLH where the CXCR4 receptors were not detected. These results, showing CXCL12 in the hypothalamus to be stimulated by a HFD

  3. Three novel Cu6S6 cluster-based coordination compounds: synthesis, framework modulation and the sensing of small molecules and Fe(3+) ions.

    PubMed

    Song, Jiang-Feng; Li, Si-Zhe; Zhou, Rui-Sha; Shao, Jia; Qiu, Xiao-Min; Jia, Ying-Ying; Wang, Jun; Zhang, Xiao

    2016-08-01

    Three novel Cu6S6 cluster-based coordination compounds formulated as [Cu(mpymt)3]2 (1), {(CuBr4)[Cu(mpymt)6]}n (2), and {(CuI6)[Cu(mpymt)6]}n (3) (Hmpymt = 4-methylpyrimidine-2-thione), have been synthesized under solvothermal conditions and characterized by elemental analysis, infrared (IR) spectroscopy, thermal gravimetric analysis, powder X-ray diffraction and single-crystal X-ray diffraction. Structural analysis reveals that compound 1 shows a distorted octahedral core of six copper atoms (Cu6S6) constructed from four α and two β type N[double bond, length as m-dash]C-SH parts from six mpymt(-) anions. Compound 2 displays an interesting 3D framework constructed from Cu6S6 and Cu4Br4 Cu(i) clusters simultaneously, interestingly, six mpymt(-) with α type N[double bond, length as m-dash]C-SH parts are involved in the formation of Cu6S6. Compound 3 displays an infinite 1D framework constructed from Cu6S6 and Cu6I6 Cu(i) clusters, notably, four α and two β type N[double bond, length as m-dash]C-SH parts are involved in the formation of the Cu6S6 cluster, however, only mpymt(-) ligands containing α type N[double bond, length as m-dash]C-SH parts form the bridged Cu6I6 cluster. The experimental results reveal that halogen ions finely modulate the structural features of compounds 1-3. The fluorescent properties of compounds 1-3 in the solid state and in various solvent emulsions were investigated in detail, the results of which indicate that compounds 1-3 are all highly sensitive naked eye colorimetric sensors for NB, 2-NT and Fe(3+) (NB = nitrobenzene and 2-NT = 2-nitrotoluene). PMID:27377475

  4. Brain clock driven by neuropeptides and second messengers.

    PubMed

    Miro-Bueno, Jesus; Sosík, Petr

    2014-09-01

    The master circadian pacemaker in mammals is localized in a small portion of the brain called the suprachiasmatic nucleus (SCN). It is unclear how the SCN produces circadian rhythms. A common interpretation is that the SCN produces oscillations through the coupling of genetic oscillators in the neurons. The coupling is effected by a network of neuropeptides and second messengers. This network is crucial for the correct function of the SCN. However, models that study a possible oscillatory behavior of the network itself have received little attention. Here we propose and analyze a model to examine this oscillatory potential. We show that an intercellular oscillator emerges in the SCN as a result of the neuropeptide and second messenger dynamics. We find that this intercellular clock can produce circadian rhythms by itself with and without genetic clocks. We also found that the model is robust to perturbation of parameters and can be entrained by light-dark cycles. PMID:25314471

  5. Brain clock driven by neuropeptides and second messengers

    NASA Astrophysics Data System (ADS)

    Miro-Bueno, Jesus; Sosík, Petr

    2014-09-01

    The master circadian pacemaker in mammals is localized in a small portion of the brain called the suprachiasmatic nucleus (SCN). It is unclear how the SCN produces circadian rhythms. A common interpretation is that the SCN produces oscillations through the coupling of genetic oscillators in the neurons. The coupling is effected by a network of neuropeptides and second messengers. This network is crucial for the correct function of the SCN. However, models that study a possible oscillatory behavior of the network itself have received little attention. Here we propose and analyze a model to examine this oscillatory potential. We show that an intercellular oscillator emerges in the SCN as a result of the neuropeptide and second messenger dynamics. We find that this intercellular clock can produce circadian rhythms by itself with and without genetic clocks. We also found that the model is robust to perturbation of parameters and can be entrained by light-dark cycles.

  6. Neuropeptide S- and Neuropeptide S receptor-expressing neuron populations in the human pons

    PubMed Central

    Adori, Csaba; Barde, Swapnali; Bogdanovic, Nenad; Uhlén, Mathias; Reinscheid, Rainer R.; Kovacs, Gabor G.; Hökfelt, Tomas

    2015-01-01

    Neuropeptide S (NPS) is a regulatory peptide with potent pharmacological effects. In rodents, NPS is expressed in a few pontine cell clusters. Its receptor (NPSR1) is, however, widely distributed in the brain. The anxiolytic and arousal-promoting effects of NPS make the NPS–NPSR1 system an interesting potential drug target in mood-related disorders. However, so far possible disease-related mechanisms involving NPS have only been studied in rodents. To validate the relevance of these animal studies for i.a. drug development, we have explored the distribution of NPS-expressing neurons in the human pons using in situ hybridization and stereological methods and we compared the distribution of NPS mRNA expressing neurons in the human and rat brain. The calculation revealed a total number of 22,317 ± 2411 NPS mRNA-positive neurons in human, bilaterally. The majority of cells (84%) were located in the parabrachial area in human: in the extension of the medial and lateral parabrachial nuclei, in the Kölliker-Fuse nucleus and around the adjacent lateral lemniscus. In human, in sharp contrast to the rodents, only very few NPS-positive cells (5%) were found close to the locus coeruleus. In addition, we identified a smaller cell cluster (11% of all NPS cells) in the pontine central gray matter both in human and rat, which has not been described previously even in rodents. We also examined the distribution of NPSR1 mRNA-expressing neurons in the human pons. These cells were mainly located in the rostral laterodorsal tegmental nucleus, the cuneiform nucleus, the microcellular tegmental nucleus region and in the periaqueductal gray. Our results show that both NPS and NPSR1 in the human pons are preferentially localized in regions of importance for integration of visceral autonomic information and emotional behavior. The reported interspecies differences must, however, be considered when looking for targets for new pharmacotherapeutical interventions. PMID:26441556

  7. Possible role of neuropeptides in obsessive compulsive disorder.

    PubMed

    McDougle, C J; Barr, L C; Goodman, W K; Price, L H

    1999-01-01

    The most consistent finding in clinical research of obsessive compulsive disorder (OCD) is the significant treatment advantage of potent serotonin uptake inhibitors (SUIs) over other classes of antidepressant and antianxiety drugs. Clinical neurobiological studies of OCD, however, have yielded limited and inconsistent evidence for significant fundamental abnormalities in monoamine systems including serotonin, norepinephrine and dopamine. Furthermore, one-third to one-half of OCD patients do not experience a clinically meaningful improvement with SUI treatment. Investigation beyond the monoamine systems may be necessary in order to more fully understand the pathophysiology of obsessive-compulsive symptoms and develop improved treatments. Evidence from preclinical studies suggests that neuropeptides may have important influences on memory acquisition, maintenance and retrieval; grooming, maternal, sexual and aggressive behavior; fixed action patterns; and stereotyped behavior; these phenomena may relate to some features of OCD. In addition, extensive interactions have been identified in the brain between neuropeptidergic and monoaminergic systems, including co-localization among specific populations of neurons. The purpose of this review is to present the current knowledge of the role of neuropeptides in the clinical neurobiology of children, adolescents and adults with OCD focusing primarily on results from pharmacological challenge and cerebrospinal fluid studies. Where evidence exists, developmentally regulated differences in neuropeptide function between children and adolescents versus adults with OCD will be emphasized; these data are intended to underscore the potential importance of establishing the age of symptom onset (childhood versus adult) in individual patients with OCD participating in clinical neurobiological investigations. Likewise, where information is available, differences in measures of neuropeptides between patients with non-tic-related OCD

  8. Mesolimbic neuropeptide W coordinates stress responses under novel environments.

    PubMed

    Motoike, Toshiyuki; Long, Jeffrey M; Tanaka, Hirokazu; Sinton, Christopher M; Skach, Amber; Williams, S Clay; Hammer, Robert E; Sakurai, Takeshi; Yanagisawa, Masashi

    2016-05-24

    Neuropeptide B (NPB) and neuropeptide W (NPW) are endogenous neuropeptide ligands for the G protein-coupled receptors NPBWR1 and NPBWR2. Here we report that the majority of NPW neurons in the mesolimbic region possess tyrosine hydroxylase immunoreactivity, indicating that a small subset of dopaminergic neurons coexpress NPW. These NPW-containing neurons densely and exclusively innervate two limbic system nuclei in adult mouse brain: the lateral bed nucleus of the stria terminalis and the lateral part of the central amygdala nucleus (CeAL). In the CeAL of wild-type mice, restraint stress resulted in an inhibition of cellular activity, but this stress-induced inhibition was attenuated in the CeAL neurons of NPW(-/-) mice. Moreover, the response of NPW(-/-) mice to either formalin-induced pain stimuli or a live rat (i.e., a potential predator) was abnormal only when they were placed in a novel environment: The mice failed to show the normal species-specific self-protective and aversive reactions. In contrast, the behavior of NPW(-/-) mice in a habituated environment was indistinguishable from that of wild-type mice. These results indicate that the NPW/NPBWR1 system could play a critical role in the gating of stressful stimuli during exposure to novel environments. PMID:27140610

  9. Insect capa neuropeptides impact desiccation and cold tolerance

    PubMed Central

    Terhzaz, Selim; Teets, Nicholas M.; Cabrero, Pablo; Henderson, Louise; Ritchie, Michael G.; Nachman, Ronald J.; Dow, Julian A. T.; Denlinger, David L.; Davies, Shireen-A.

    2015-01-01

    The success of insects is linked to their impressive tolerance to environmental stress, but little is known about how such responses are mediated by the neuroendocrine system. Here we show that the capability (capa) neuropeptide gene is a desiccation- and cold stress-responsive gene in diverse dipteran species. Using targeted in vivo gene silencing, physiological manipulations, stress-tolerance assays, and rationally designed neuropeptide analogs, we demonstrate that the Drosophila melanogaster capa neuropeptide gene and its encoded peptides alter desiccation and cold tolerance. Knockdown of the capa gene increases desiccation tolerance but lengthens chill coma recovery time, and injection of capa peptide analogs can reverse both phenotypes. Immunohistochemical staining suggests that capa accumulates in the capa-expressing Va neurons during desiccation and nonlethal cold stress but is not released until recovery from each stress. Our results also suggest that regulation of cellular ion and water homeostasis mediated by capa peptide signaling in the insect Malpighian (renal) tubules is a key physiological mechanism during recovery from desiccation and cold stress. This work augments our understanding of how stress tolerance is mediated by neuroendocrine signaling and illustrates the use of rationally designed peptide analogs as agents for disrupting protective stress tolerance. PMID:25730885

  10. Toward a consensus nomenclature for insect neuropeptides and peptide hormones.

    PubMed

    Coast, Geoffrey M; Schooley, David A

    2011-03-01

    The nomenclature currently in use for insect neuropeptide and peptide hormone families is reviewed and suggestions are made as to how it can be rationalized. Based upon this review, a number of conventions are advanced as a guide to a more rationale nomenclature. The scheme that is put forward builds upon the binomial nomenclature scheme proposed by Raina and Gäde in 1988, when just over 20 insect neuropeptides had been identified. Known neuropeptides and peptide hormones are assigned to 32 structurally distinct families, frequently with overlapping functions. The names given to these families are those that are currently in use, and describe a biological function, homology to known invertebrate/vertebrate peptides, or a conserved structural motif. Interspecific isoforms are identified using a five-letter code to indicate genus and species names, and intraspecific isoforms are identified by Roman or Arabic numerals, with the latter used to signify the order in which sequences are encoded on a prepropeptide. The proposed scheme is sufficiently flexible to allow the incorporation of novel peptides, and could be extended to other arthropods and non-arthropod invertebrates. PMID:21093513

  11. Can neuropeptides treat obesity? A review of neuropeptides and their potential role in the treatment of obesity

    PubMed Central

    Boughton, C K; Murphy, K G

    2013-01-01

    Obesity is a major worldwide public health issue. The physiological systems that regulate body weight are thus of great interest as targets for anti-obesity agents. Peptidergic systems are critical to the regulation of energy homeostasis by key regions in the hypothalamus and brainstem. A number of neuropeptide systems have therefore been investigated as potential treatments for obesity. Blocking orexigenic peptide signals such as neuropeptide Y, melanin-concentrating hormone, orexins, relaxin-3 and galanin-like peptide or stimulating anorectic signalling pathways used by peptides such as the melanocortins, ciliary neurotrophic factor and brain-derived neurotrophic factor, are approaches that have shown some promise, but which have also highlighted possible concerns. Manipulation of central peptidergic systems poses a number of therapeutic problems, including brain access and side effects. Given that the homeostatic defence of body weight may limit the effectiveness of any single-target therapy developed, a combination therapy approach may offer the best hope for the effective prevention and treatment of obesity. LINKED ARTICLES This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7 PMID:23121386

  12. Support for involvement of glutamate decarboxylase 1 and neuropeptide Y in anxiety susceptibility.

    PubMed

    Donner, Jonas; Sipilä, Tessa; Ripatti, Samuli; Kananen, Laura; Chen, Xiangning; Kendler, Kenneth S; Lönnqvist, Jouko; Pirkola, Sami; Hettema, John M; Hovatta, Iiris

    2012-04-01

    Genetic mapping efforts have identified putative susceptibility genes for human anxiety disorders. The most intensively studied genes are involved in neurotransmitter metabolism and signaling or stress response. In addition, neuropeptides and targets of anxiolytics have been examined. It has become apparent that gene × environment interactions may explain individual variation in stress resilience and predisposition to mental disorders. We aimed to replicate previous genetic findings in 16 putative anxiety susceptibility genes and further test whether they modulate the risk for developing an anxiety disorder in adulthood after childhood stress exposure. We tested 93 single-nucleotide polymorphisms (SNPs) for genetic association to anxiety disorders in the Finnish population-based Health 2000 sample (282 cases and 575 matched controls). In addition, we examined by logistic regression modeling whether the SNP genotypes modified the effect of the number of self-reported childhood adversities on anxiety disorder risk. The most significant evidence for association was observed in glutamate decarboxylase 1 (GAD1) with phobias (P = 0.0005). A subsequent meta-analysis (N = 1985) incorporating previously published findings supported involvement of a single GAD1 risk haplotype in determining susceptibility to a broad range of internalizing disorders (P = 0.0009). We additionally found that SNPs and haplotypes in neuropeptide Y (NPY) modified the effect of childhood adversities on anxiety susceptibility (P = 0.003). In conclusion, we provide further support for involvement of mainly GAD1, but also NPY in determining predisposition to anxiety disorders. PMID:22328461

  13. Increase in sensory neuropeptides surrounding the Achilles tendon in rats with adjuvant arthritis.

    PubMed

    Bring, Daniel K-I; Heidgren, Marie-Louise; Kreicbergs, Andris; Ackermann, Paul W

    2005-03-01

    The Achilles tendon in rats with adjuvant arthritis was analyzed by radioimmunoassay (RIA) and semi-quantitative immunohistochemistry for the occurrence of two sensory neuropeptides, substance P (SP) and calcitonin gene related peptide (CGRP), and a sensory modulating peptide, galanin (GAL). The tissue concentration of SP and CGRP in the Achilles tendon and its envelope, i.e. the paratenon and bony insertion, as assessed by RIA was increased by 22% and 71%, respectively, compared to normal controls, whereas the level of GAL was unchanged. Semi-quantitative immunohistochemistry applied to different regions of the tendon in arthritic rats disclosed an increased occurrence of SP and CGRP positive nerve fibers in the paratenon and bone tendinous junction, whereas GAL fibers were only increased at the bone tendinous junction. Notably, neither neuropeptides nor inflammatory cells were seen in the tendon proper. The increased occurrence of SP and CGRP in the tendon envelope presumably reflects inflammatory actions, whereas that of GAL implies an endogenous anti-inflammatory response. The observed SP and CGRP upregulation in the paratenon and bony insertion suggests a pathophysiological role in paratenonitis and enthesitis often seen in patients with rheumatoid arthritis. Presumably Achillodynia originates in the tendon envelope rather than the tendon proper. The observations could be used to define new pharmacological targets for mitigating symptoms from tendons in rheumatoid arthritis and possibly also in other disorders. Whether a neuronal pathogenic mechanism underlies tendon overuse disorders in non-arthritic tendinopathies and the development of degeneration, i.e. tendinosis, remains to be studied. PMID:15734239

  14. The Evolution and Variety of RFamide-Type Neuropeptides: Insights from Deuterostomian Invertebrates

    PubMed Central

    Elphick, Maurice R.; Mirabeau, Olivier

    2014-01-01

    Five families of neuropeptides that have a C-terminal RFamide motif have been identified in vertebrates: (1) gonadotropin-inhibitory hormone (GnIH), (2) neuropeptide FF (NPFF), (3) pyroglutamylated RFamide peptide (QRFP), (4) prolactin-releasing peptide (PrRP), and (5) Kisspeptin. Experimental demonstration of neuropeptide–receptor pairings combined with comprehensive analysis of genomic and/or transcriptomic sequence data indicate that, with the exception of the deuterostomian PrRP system, the evolutionary origins of these neuropeptides can be traced back to the common ancestor of bilaterians. Here, we review the occurrence of homologs of vertebrate RFamide-type neuropeptides and their receptors in deuterostomian invertebrates – urochordates, cephalochordates, hemichordates, and echinoderms. Extending analysis of the occurrence of the RFamide motif in other bilaterian neuropeptide families reveals RFamide-type peptides that have acquired modified C-terminal characteristics in the vertebrate lineage (e.g., NPY/NPF), neuropeptide families where the RFamide motif is unique to protostomian members (e.g., CCK/sulfakinins), and RFamide-type peptides that have been lost in the vertebrate lineage (e.g., luqins). Furthermore, the RFamide motif is also a feature of neuropeptide families with a more restricted phylogenetic distribution (e.g., the prototypical FMRFamide-related neuropeptides in protostomes). Thus, the RFamide motif is both an ancient and a convergent feature of neuropeptides, with conservation, acquisition, or loss of this motif occurring in different branches of the animal kingdom. PMID:24994999

  15. Biology-oriented synthesis of a withanolide-inspired compound collection reveals novel modulators of hedgehog signaling.

    PubMed

    Švenda, Jakub; Sheremet, Michael; Kremer, Lea; Maier, Lukáš; Bauer, Jonathan O; Strohmann, Carsten; Ziegler, Slava; Kumar, Kamal; Waldmann, Herbert

    2015-05-01

    Biology-oriented synthesis employs the structural information encoded in complex natural products to guide the synthesis of compound collections enriched in bioactivity. The trans-hydrindane dehydro-δ-lactone motif defines the characteristic scaffold of the steroid-like withanolides, a plant-derived natural product class with a diverse pattern of bioactivity. A withanolide-inspired compound collection was synthesized by making use of three key intermediates that contain this characteristic framework derivatized with different reactive functional groups. Biological evaluation of the compound collection in cell-based assays that monitored biological signal-transduction processes revealed a novel class of Hedgehog signaling inhibitors that target the protein Smoothened. PMID:25736574

  16. Differential modulation of retinal ganglion cell light responses by orthosteric and allosteric metabotropic glutamate receptor 8 compounds

    PubMed Central

    Reed, Brian T.; Morgans, Catherine W.; Duvoisin, Robert M.

    2012-01-01

    To investigate the role of mGluR8 in modulating the synaptic responses of retinal ganglion cells, we used a recently identified positive allosteric modulator of mGluR8, AZ12216052 (AZ) and the mGluR8-specific orthosteric agonist (S)-3,4-dicarboxyphenylglycine (DCPG). These agents were applied to whole-cell voltage-clamped ganglion cells from an isolated, superfused mouse retina preparation. DCPG reduced OFF-ganglion cell excitatory currents, whereas AZ enhanced the peak excitatory currents in ON-, OFF-, and ON-OFF-ganglion cells. The effects on ganglion cell inhibitory currents were more varied. The effects of the allosteric modulator were stronger for bright stimuli than for dim stimuli, consistent with receptor stimulation by endogenous glutamate being stronger during bright light stimulation and with mGluR8 receptors mainly being localized away from glutamate release sites, immuno-labeled with VGLUT1. The differential sensitivity of ganglion cell light responses to DCPG and AZ supports multiple sites where mGluR8 modulates the light responses of ganglion cells. PMID:23164615

  17. Epithelial-mesenchymal transition: focus on metastatic cascade, alternative splicing, non-coding RNAs and modulating compounds

    PubMed Central

    2013-01-01

    Epithelial-mesenchymal transition (EMT) is a key process in embryonic development and metastases formation during malignant progression. This review focuses on transcriptional regulation, non-coding RNAs, alternative splicing events and cell adhesion molecules regulation during EMT. Additionally, we summarize the knowledge with regard to the small potentially druggable molecules capable of modulating EMT for cancer therapy. PMID:24053443

  18. Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake.

    PubMed

    Wardman, Jonathan H; Gomes, Ivone; Bobeck, Erin N; Stockert, Jennifer A; Kapoor, Abhijeet; Bisignano, Paola; Gupta, Achla; Mezei, Mihaly; Kumar, Sanjai; Filizola, Marta; Devi, Lakshmi A

    2016-01-01

    Several neuropeptide systems in the hypothalamus, including neuropeptide Y and agouti-related protein (AgRP), control food intake. Peptides derived from proSAAS, a precursor implicated in the regulation of body weight, also control food intake. GPR171 is a heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) for BigLEN (b-LEN), a peptide derived from proSAAS. To facilitate studies exploring the physiological role of GPR171, we sought to identify small-molecule ligands for this receptor by performing a virtual screen of a compound library for interaction with a homology model of GPR171. We identified MS0015203 as an agonist of GPR171 and demonstrated the selectivity of MS0015203 for GPR171 by testing the binding of this compound to 80 other membrane proteins, including family A GPCRs. Reducing the expression of GPR171 by shRNA (short hairpin RNA)-mediated knockdown blunted the cellular and tissue response to MS0015203. Peripheral injection of MS0015203 into mice increased food intake and body weight, and these responses were significantly attenuated in mice with decreased expression of GPR171 in the hypothalamus. Together, these results suggest that MS0015203 is a useful tool to probe the pharmacological and functional properties of GPR171 and that ligands targeting GPR171 may eventually lead to therapeutics for food-related disorders. PMID:27245612

  19. Peptidergic modulation of serotonin and nerve elicited responses of the salivary duct muscle in the snail, Helix pomatia.

    PubMed

    Kiss, T; Hernádi, L; László, Z; Fekete, Zs N; Elekes, K

    2010-06-01

    In the present study, the ability of a range of endogenous neuropeptides to modulate neuromuscular transmission was examined in the salivary duct neuromuscular preparation of the terrestrial snail, Helix pomatia. Immunohistochemical and physiological techniques were used to localize the neuropeptides (GSPYFVamide, CARP, FMRFamide and APGWamide) and to investigate whether contractions elicited by the stimulation of the salivary nerve or by exogenously applied 5-HT are subject to peptidergic modulation. All of the neuropeptides studied decreased the tonus by a direct action on the muscle fibers in a concentration dependent manner in a range of 10(-9) to 10(-6)M. Neuropeptides distinctly affected the 5-HT evoked contraction or relaxation and GSPYFVa and APGWa decreased also the amplitude of contractions elicited by the stimulation of the salivary nerve. All four neuropeptides facilitated the relaxation phase providing further evidence for the postsynaptic action of neuropeptides. Low Ca(2+)/high Mg(2+) saline abolished the nerve-elicited contractions, however the denervated muscle retained the ability to contract due to the mobilization of the Ca(2+) from intracellular stores. It was concluded, that peptides belonging to different peptide families exerted their effects through pre- and postsynaptic mechanisms. The modulatory effect of neuropeptides can be assigned to the partial co-localization of 5-HT and neuropeptides in the nerves innervating muscles of the salivary duct, as it was demonstrated by double-labeling immunohistochemistry. A double origin of the 5-HTergic innervation was demonstrated, including efferents originating from both the cerebral and visceral ganglia. PMID:20307609

  20. Compound A, a Dissociated Glucocorticoid Receptor Modulator, Inhibits T-bet (Th1) and Induces GATA-3 (Th2) Activity in Immune Cells

    PubMed Central

    Ferraz-de-Paula, Viviane; Palermo-Neto, Joao; Castro, Carla N.; Druker, Jimena; Holsboer, Florian; Perone, Marcelo J.; Gerlo, Sarah; De Bosscher, Karolien; Haegeman, Guy; Arzt, Eduardo

    2012-01-01

    Background Compound A (CpdA) is a dissociating non-steroidal glucocorticoid receptor (GR) ligand which has anti-inflammatory properties exerted by down-modulating proinflammatory gene expression. By favouring GR monomer formation, CpdA does not enhance glucocorticoid (GC) response element-driven gene expression, resulting in a reduced side effect profile as compared to GCs. Considering the importance of Th1/Th2 balance in the final outcome of immune and inflammatory responses, we analyzed how selective GR modulation differentially regulates the activity of T-bet and GATA-3, master drivers of Th1 and Th2 differentiation, respectively. Results Using Western analysis and reporter gene assays, we show in murine T cells that, similar to GCs, CpdA inhibits T-bet activity via a transrepressive mechanism. Different from GCs, CpdA induces GATA-3 activity by p38 MAPK-induction of GATA-3 phosphorylation and nuclear translocation. CpdA effects are reversed by the GR antagonist RU38486, proving the involvement of GR in these actions. ELISA assays demonstrate that modulation of T-bet and GATA-3 impacts on cytokine production shown by a decrease in IFN-γ and an increase in IL-5 production, respectively. Conclusions Taken together, through their effect favoring Th2 over Th1 responses, particular dissociated GR ligands, for which CpdA represents a paradigm, hold potential for the application in Th1-mediated immune disorders. PMID:22496903

  1. Increased prepubertal body weight enhances leptin sensitivity in proopiomelanocortin and neuropeptide y neurons before puberty onset in female rats.

    PubMed

    Castro-González, David; Fuente-Martín, Esther; Sánchez-Garrido, Miguel A; Argente-Arizón, Pilar; Tena-Sempere, Manuel; Barrios, Vicente; Chowen, Julie A; Argente, Jesús

    2015-04-01

    Pubertal onset may be advanced by obesity, with leptin potentially acting as a permissive factor. We hypothesized that having increased body weight (BW) prepubertally affects the ability of leptin to activate intracellular signaling pathways and modulate the expression of hypothalamic neuropeptides involved in reproduction and metabolism. Because being raised in small litters (SLs) tends to increase BW at weaning, female rats were raised in litters of 4 or large litters (LLs) of 12 pups. Leptin (3 μg/g BW) or vehicle (saline) was injected sc at postnatal day (PND) 21 and 30. Rats raised in SLs weighed more at both ages, but relative visceral and subcutaneous fat was increased only on PND21. Serum leptin levels were not different at PND21 or PND30. At PND21, key elements of intracellular leptin signaling (phosphorylated signal transducer and activator of transcription 3 and phosphorylated Akt [p-Akt]) were lower in SL than in LL rats. Leptin injection stimulated phosphorylated signal transducer and activator of transcription 3 in both groups, with a greater increase in LL, whereas p-Akt rose only in SL rats. At PND30, basal leptin signaling did not differ between LL and SL rats. Leptin activation of Akt was similar at 45 minutes, but at 2 hours p-AKT levels were higher in SL than in LL rats, as was the decrease in neuropeptide Y mRNA and increase in pro-opiomelanocortin mRNA levels. No change in the reproductive axis was found. Thus, being raised in SLs increases BW and visceral body fat content, fails to increase plasma leptin concentrations, and increases the leptin responsiveness of both neuropeptide Y and pro-opiomelanocortin cells in the prepubertal hypothalamus. PMID:25574789

  2. Reproductive neuropeptides: prevalence of GnRH and KNDy neural signalling components in a model avian, gallus gallus.

    PubMed

    Joseph, Nerine T; Tello, Javier A; Bedecarrats, Gregoy Y; Millar, Robert P

    2013-09-01

    Diverse external and internal environmental factors are integrated in the hypothalamus to regulate the reproductive system. This is mediated through the pulsatile secretion of GnRH into the portal system to stimulate pituitary gonadotrophin secretion, which in turn regulates gonadal function. A single subpopulation of neurones termed 'KNDy neurones' located in the hypothalamic arcuate nucleus co-localise kisspeptin (Kiss), neurokinin B (NKB) and dynorphin (Dyn) and are responsive to negative feedback effects of sex steroids. The co-ordinated secretion from KNDy neurones appears to modulate the pulsatile release of GnRH, acting as a proximate pacemaker. This review briefly describes the neuropeptidergic control of reproduction in the avian class, highlighting the status of reproductive neuropeptide signalling systems homologous to those found in mammalian genomes. Genes encoding the GnRH system are complete in the chicken with similar roles to the mammalian counterparts, whereas genes encoding Kiss signalling components appear missing in the avian lineage, indicating a differing set of hypothalamic signals controlling avian reproduction. Gene sequences encoding both NKB and Dyn signalling components are present in the chicken genome, but expression analysis and functional studies remain to be completed. The focus of this article is to describe the avian complement of neuropeptidergic reproductive hormones and provide insights into the putative mechanisms that regulate reproduction in birds. These postulations highlight differences in reproductive strategies of birds in terms of gonadal steroid feedback systems, integration of metabolic signals and seasonality. Also included are propositions of KNDy neuropeptide gene silencing and plasticity in utilisation of these neuropeptides during avian evolution. PMID:23756151

  3. The orexin neuropeptide system: physical activity and hypothalamic function throughout the aging process

    PubMed Central

    Zink, Anastasia N.; Perez-Leighton, Claudio Esteban; Kotz, Catherine M.

    2014-01-01

    There is a rising medical need for novel therapeutic targets of physical activity. Physical activity spans from spontaneous, low intensity movements to voluntary, high-intensity exercise. Regulation of spontaneous and voluntary movement is distributed over many brain areas and neural substrates, but the specific cellular and molecular mechanisms responsible for mediating overall activity levels are not well understood. The hypothalamus plays a central role in the control of physical activity, which is executed through coordination of multiple signaling systems, including the orexin neuropeptides. Orexin producing neurons integrate physiological and metabolic information to coordinate multiple behavioral states and modulate physical activity in response to the environment. This review is organized around three questions: (1) How do orexin peptides modulate physical activity? (2) What are the effects of aging and lifestyle choices on physical activity? (3) What are the effects of aging on hypothalamic function and the orexin peptides? Discussion of these questions will provide a summary of the current state of knowledge regarding hypothalamic orexin regulation of physical activity during aging and provide a platform on which to develop improved clinical outcomes in age-associated obesity and metabolic syndromes. PMID:25408639

  4. In the proper context: Neuropeptide regulation of behavioral transitions during food searching

    PubMed Central

    Bhattacharya, Raja; Francis, Michael M

    2015-01-01

    Neuromodulation enables transient restructuring of anatomically fixed neural circuits, generating alternate outputs and distinct states that allow for flexible organismal responses to changing conditions. We recently identified a requirement for the neuropeptide-like protein NLP-12, a Caenorhabditis elegans homolog of mammalian Cholecystokinin (CCK), in the control of behavioral responses to altered food availability. We showed that deletion of nlp-12 impairs turning during local food searching while nlp-12 overexpression is sufficient to induce deep body bends and enhance turning. nlp-12 is solely expressed in the DVA interneuron that is located postsynaptic to the dopaminergic PDE neurons and presynaptic to premotor and motor neurons, well-positioned for modulating sensorimotor tasks. Interestingly, DVA was previously implicated in a NLP-12 mediated proprioceptive feedback loop during C. elegans locomotion. Here, we discuss the modulatory effects of NLP-12 with an emphasis on the potential for circuit level integration with olfactory information about food availability. In addition, we propose potential mechanisms by which DVA may integrate distinct forms of sensory information to regulate NLP-12 signaling and mediate context-dependent modulation of the motor circuit. PMID:26430569

  5. In the proper context: Neuropeptide regulation of behavioral transitions during food searching.

    PubMed

    Bhattacharya, Raja; Francis, Michael M

    2015-01-01

    Neuromodulation enables transient restructuring of anatomically fixed neural circuits, generating alternate outputs and distinct states that allow for flexible organismal responses to changing conditions. We recently identified a requirement for the neuropeptide-like protein NLP-12, a Caenorhabditis elegans homolog of mammalian Cholecystokinin (CCK), in the control of behavioral responses to altered food availability. We showed that deletion of nlp-12 impairs turning during local food searching while nlp-12 overexpression is sufficient to induce deep body bends and enhance turning. nlp-12 is solely expressed in the DVA interneuron that is located postsynaptic to the dopaminergic PDE neurons and presynaptic to premotor and motor neurons, well-positioned for modulating sensorimotor tasks. Interestingly, DVA was previously implicated in a NLP-12 mediated proprioceptive feedback loop during C. elegans locomotion. Here, we discuss the modulatory effects of NLP-12 with an emphasis on the potential for circuit level integration with olfactory information about food availability. In addition, we propose potential mechanisms by which DVA may integrate distinct forms of sensory information to regulate NLP-12 signaling and mediate context-dependent modulation of the motor circuit. PMID:26430569

  6. The stress response neuropeptide CRF increases amyloid-β production by regulating γ-secretase activity

    PubMed Central

    Park, Hyo-Jin; Ran, Yong; Jung, Joo In; Holmes, Oliver; Price, Ashleigh R; Smithson, Lisa; Ceballos-Diaz, Carolina; Han, Chul; Wolfe, Michael S; Daaka, Yehia; Ryabinin, Andrey E; Kim, Seong-Hun; Hauger, Richard L; Golde, Todd E; Felsenstein, Kevin M

    2015-01-01

    The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid-β (Aβ) production. In cells, CRF treatment increases Aβ production and triggers CRF receptor 1 (CRFR1) and γ-secretase internalization. Co-immunoprecipitation studies establish that γ-secretase associates with CRFR1; this is mediated by β-arrestin binding motifs. Additionally, CRFR1 and γ-secretase co-localize in lipid raft fractions, with increased γ-secretase accumulation upon CRF treatment. CRF treatment also increases γ-secretase activityin vitro, revealing a second, receptor-independent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate γ-secretase activity. Unexpectedly, CRFR1 antagonists also increased Aβ. These data collectively link CRF to increased Aβ through γ-secretase and provide mechanistic insight into how stress may increase AD risk. They also suggest that direct targeting of CRF might be necessary to effectively modulate this pathway for therapeutic benefit in AD, as CRFR1 antagonists increase Aβ and in some cases preferentially increase Aβ42 via complex effects on γ-secretase. PMID:25964433

  7. Intranasally Administered Neuropeptide S (NPS) Exerts Anxiolytic Effects Following Internalization Into NPS Receptor-Expressing Neurons

    PubMed Central

    Ionescu, Irina A; Dine, Julien; Yen, Yi-Chun; Buell, Dominik R; Herrmann, Leonie; Holsboer, Florian; Eder, Matthias; Landgraf, Rainer; Schmidt, Ulrike

    2012-01-01

    Experiments in rodents revealed neuropeptide S (NPS) to constitute a potential novel treatment option for anxiety diseases such as panic and post-traumatic stress disorder. However, both its cerebral target sites and the molecular underpinnings of NPS-mediated effects still remain elusive. By administration of fluorophore-conjugated NPS, we pinpointed NPS target neurons in distinct regions throughout the entire brain. We demonstrated their functional relevance in the hippocampus. In the CA1 region, NPS modulates synaptic transmission and plasticity. NPS is taken up into NPS receptor-expressing neurons by internalization of the receptor–ligand complex as we confirmed by subsequent cell culture studies. Furthermore, we tracked internalization of intranasally applied NPS at the single-neuron level and additionally demonstrate that it is delivered into the mouse brain without losing its anxiolytic properties. Finally, we show that NPS differentially modulates the expression of proteins of the glutamatergic system involved inter alia in synaptic plasticity. These results not only enlighten the path of NPS in the brain, but also establish a non-invasive method for NPS administration in mice, thus strongly encouraging translation into a novel therapeutic approach for pathological anxiety in humans. PMID:22278093

  8. The neuropeptide tachykinin is essential for pheromone detection in a gustatory neural circuit

    PubMed Central

    Shankar, Shruti; Chua, Jia Yi; Tan, Kah Junn; Calvert, Meredith EK; Weng, Ruifen; Ng, Wan Chin; Mori, Kenji; Yew, Joanne Y

    2015-01-01

    Gustatory pheromones play an essential role in shaping the behavior of many organisms. However, little is known about the processing of taste pheromones in higher order brain centers. Here, we describe a male-specific gustatory circuit in Drosophila that underlies the detection of the anti-aphrodisiac pheromone (3R,11Z,19Z)-3-acetoxy-11,19-octacosadien-1-ol (CH503). Using behavioral analysis, genetic manipulation, and live calcium imaging, we show that Gr68a-expressing neurons on the forelegs of male flies exhibit a sexually dimorphic physiological response to the pheromone and relay information to the central brain via peptidergic neurons. The release of tachykinin from 8 to 10 cells within the subesophageal zone is required for the pheromone-triggered courtship suppression. Taken together, this work describes a neuropeptide-modulated central brain circuit that underlies the programmed behavioral response to a gustatory sex pheromone. These results will allow further examination of the molecular basis by which innate behaviors are modulated by gustatory cues and physiological state. DOI: http://dx.doi.org/10.7554/eLife.06914.001 PMID:26083710

  9. Chrysotoxine, a novel bibenzyl compound, inhibits 6-hydroxydopamine induced apoptosis in SH-SY5Y cells via mitochondria protection and NF-κB modulation.

    PubMed

    Song, Ju-Xian; Shaw, Pang-Chui; Sze, Cho-Wing; Tong, Yao; Yao, Xin-Sheng; Ng, Tzi-Bun; Zhang, Yan-Bo

    2010-11-01

    Some naturally occurring bibenzyl compounds have been reported as free radical scavengers. The present study tested our hypothesis that bibenzyl compounds may be neuroprotective against apoptosis induced by the neurotoxins. Five structurally similar bibenzyl derivatives were tested for their protective effect against 6-hydroxydopamine (6-OHDA) induced toxicity in the human neuroblastoma cell line SH-SY5Y. The results showed that one bibenzyl compound, namely chrysotoxine, significantly attenuated 6-OHDA-induced cell death. The subsequent mechanism study demonstrated that chrysotoxine significantly attenuated 6-OHDA-induced apoptosis characterized by DNA fragmentation and nuclear condensation in a dose-dependent manner. 6-OHDA-induced intracellular generation of reactive oxygen species (ROS), activation of p38 MAPK and ERK1/2, and mitochondrial dysfunctions, including the decrease of membrane potential, increase of intracellular free Ca2+, release of cytochrome c, imbalance of Bax/Bcl-2 ratio and activation of caspase-3 were strikingly attenuated by chrysotoxine pretreatment. Meanwhile, chrysotoxine counteracted NF-κB activation by blocking its translocation to the nucleus, thereby preventing up-regulation of inducible nitric oxide synthase (iNOS) and intracellular NO release. The data provide the first evidence that chrysotoxine protects SH-SY5Y cells against 6-OHDA toxicity possibly through mitochondria protection and NF-κB modulation. Chrysotoxine is thus a candidate for further evaluation of its protection against neurodegeneration in Parkinson's disease. PMID:20708055

  10. Lilium compounds kaempferol and jatropham can modulate cytotoxic and genotoxic effects of radiomimetic zeocin in plants and human lymphocytes In vitro.

    PubMed

    Jovtchev, Gabriele; Gateva, Svetla; Stankov, Alexander

    2016-06-01

    Organisms are constantly exposed to the detrimental effect of environmental DNA-damaging agents. The harmful effects of environmental genotoxins could be decreased in a viable way by antimutagenesis. One of the modern approaches to reduce the mutagenic burden is based on exogenous natural and synthetic compounds that possess protective and antimutagenic potential against genotoxins. The natural compounds kaempferol and jatropham isolated from Lilium candidum were tested with respect to their potential to protect cells against the radiomimetic zeocin, as well as to their cytotoxic and genotoxic activities in two types of experimental eukaryotic test systems: Hordeum vulgare and human lymphocytes in vitro. Mitotic index (MI) was used as an endpoint for cytotoxicity; the frequency of chromosome aberrations (MwA) and the number of induced micronuclei (MN), as endpoints for genotoxicity/clastogenicity. Formation of aberration "hot spots" was also used as an indicator for genotoxicity in H. vulgare. Both kaempferol and jatropham were shown to possess a potential to modulate and decrease the cytotoxic and genotoxic/clastogenic effect of zeocin depending on the experimental design and the test system. Our data could be useful for health research programs, particularly in clarifying the pharmacological potential and activity of natural plant compounds. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 751-764, 2016. PMID:25504804

  11. Ligand modulation of a dinuclear platinum compound leads to mechanistic differences in cell cycle progression and arrest

    PubMed Central

    Menon, Vijay R.; Peterson, Erica J.; Valerie, Kristoffer; Farrell, Nicholas P.; Povirk, Lawrence F.

    2013-01-01

    Despite similar structures and DNA binding profiles, two recently synthesized dinuclear platinum compounds are shown to elicit highly divergent effects on cell cycle progression. In colorectal HCT116 cells, BBR3610 shows a classical G2/M arrest with initial accumulation in S phase, but the derivative compound BBR3610-DACH, formed by introduction of the 1,2-diaminocyclohexane (DACH) as carrier ligand, results in severe G1/S as well as G2/M phase arrest, with nearly complete S phase depletion. The origin of this unique effect was studied. Cellular interstrand crosslinking as assayed by comet analysis was similar for both compounds, confirming previous in vitro results obtained on plasmid DNA. Immunoblotting revealed a stabilization of p53 and concomitant transient increases in p21 and p27 proteins after treatment with BBR3610-DACH. Cell viability assays and cytometric analysis of p53 and p21 null cells indicated that BBR3610-DACH-induced cell cycle arrest was p21-dependent and partially p53-dependent. However, an increase in the levels of cyclin E was observed with steady state levels of CDK2 and Cdc25A, suggesting that the G1 block occurs downstream of CDK/cyclin complex formation. The G2/M block was corroborated with decreased levels of cyclin A and cyclin B1. Surprisingly, BBR3610-DACH-induced G1 block was independent of ATM and ATR. Finally, both compounds induced apoptosis, with BBR3610-DACH showing a robust PARP-1 cleavage that was not associated with caspase-3/7 cleavage. In summary, BBR3610-DACH is a DNA binding platinum agent with unique inhibitory effects on cell cycle progression that could be further developed as a chemotherapeutic agent complementary to cisplatin and oxaliplatin. PMID:24161784

  12. Natural thioallyl compounds increase oxidative stress resistance and lifespan in Caenorhabditis elegans by modulating SKN-1/Nrf.

    PubMed

    Ogawa, Takahiro; Kodera, Yukihiro; Hirata, Dai; Blackwell, T Keith; Mizunuma, Masaki

    2016-01-01

    Identification of biologically active natural compounds that promote health and longevity, and understanding how they act, will provide insights into aging and metabolism, and strategies for developing agents that prevent chronic disease. The garlic-derived thioallyl compounds S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC) have been shown to have multiple biological activities. Here we show that SAC and SAMC increase lifespan and stress resistance in Caenorhabditis elegans and reduce accumulation of reactive oxygen species (ROS). These compounds do not appear to activate DAF-16 (FOXO orthologue) or mimic dietary restriction (DR) effects, but selectively induce SKN-1 (Nrf1/2/3 orthologue) targets involved in oxidative stress defense. Interestingly, their treatments do not facilitate SKN-1 nuclear accumulation, but slightly increased intracellular SKN-1 levels. Our data also indicate that thioallyl structure and the number of sulfur atoms are important for SKN-1 target induction. Our results indicate that SAC and SAMC may serve as potential agents that slow aging. PMID:26899496

  13. Rhodomycin A, a novel Src-targeted compound, can suppress lung cancer cell progression via modulating Src-related pathways

    PubMed Central

    Lin, Sih-Yin; Lin, Sheng-Yi; Wong, Yung-Hao; Yu, Sung-Liang; Chen, Huei-Wen; Yang, Chih-Hsin; Chang, Gee-Chen; Chen, Jeremy J.W.

    2015-01-01

    Src activation is involved in cancer progression and the interplay with EGFR. Inhibition of Src activity also represses the signalling pathways regulated by EGFR. Therefore, Src has been considered a target molecule for drug development. This study aimed to identify the compounds that target Src to suppress lung cancer tumourigenesis and metastasis and investigate their underlying molecular mechanisms. Using a molecular docking approach and the National Cancer Institute (NCI) compound dataset, eight candidate compounds were selected, and we evaluated their efficacy. Among them, rhodomycin A was the most efficient at reducing the activity and expression of Src in a dose-dependent manner, which was also the case for Src-associated proteins, including EGFR, STAT3, and FAK. Furthermore, rhodomycin A significantly suppressed cancer cell proliferation, migration, invasion, and clonogenicity in vitro and tumour growth in vivo. In addition, rhodomycin A rendered gefitinib-resistant lung adenocarcinoma cells more sensitive to gefitinib treatment, implying a synergistic effect of the combination therapy. Our data also reveal that the inhibitory effect of rhodomycin A on lung cancer progression may act through suppressing the Src-related multiple signalling pathways, including PI3K, JNK, Paxillin, and p130cas. These findings will assist the development of anti-tumour drugs to treat lung cancer. PMID:26312766

  14. Natural thioallyl compounds increase oxidative stress resistance and lifespan in Caenorhabditis elegans by modulating SKN-1/Nrf

    PubMed Central

    Ogawa, Takahiro; Kodera, Yukihiro; Hirata, Dai; Blackwell, T. Keith; Mizunuma, Masaki

    2016-01-01

    Identification of biologically active natural compounds that promote health and longevity, and understanding how they act, will provide insights into aging and metabolism, and strategies for developing agents that prevent chronic disease. The garlic-derived thioallyl compounds S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC) have been shown to have multiple biological activities. Here we show that SAC and SAMC increase lifespan and stress resistance in Caenorhabditis elegans and reduce accumulation of reactive oxygen species (ROS). These compounds do not appear to activate DAF-16 (FOXO orthologue) or mimic dietary restriction (DR) effects, but selectively induce SKN-1 (Nrf1/2/3 orthologue) targets involved in oxidative stress defense. Interestingly, their treatments do not facilitate SKN-1 nuclear accumulation, but slightly increased intracellular SKN-1 levels. Our data also indicate that thioallyl structure and the number of sulfur atoms are important for SKN-1 target induction. Our results indicate that SAC and SAMC may serve as potential agents that slow aging. PMID:26899496

  15. Neuropeptide Y directly affects ovarian cell proliferation and apoptosis.

    PubMed

    Sirotkin, Alexander V; Kardošová, Diana; Alwasel, Saleh Hamad; Harrath, Abdel Halim

    2015-12-01

    The effects of neuropeptide Y (NPY; 0, 10, 100 and 1000 ng/mL) on the expression of PCNA, bax and p53 were examined by immunocytochemistry in porcine luteinized granulosa cells. NPY inhibited proliferation as well as promoted apoptosis and accumulation of p53 in the cells. This is the first report to demonstrate the direct action of NPY on ovarian cell proliferation and apoptosis. The results of the study suggest that the effect is mediated by transcription factor p53. PMID:26679167

  16. CGRP as a neuropeptide in migraine: lessons from mice

    PubMed Central

    Russo, Andrew F

    2015-01-01

    Migraine is a neurological disorder that is far more than just a bad headache. A hallmark of migraine is altered sensory perception. A likely contributor to this altered perception is the neuropeptide calcitonin gene-related peptide (CGRP). Over the past decade, CGRP has become firmly established as a key player in migraine. Although the mechanisms and sites of action by which CGRP might trigger migraine remain speculative, recent advances with mouse models provide some hints. This brief review focuses on how CGRP might act as both a central and peripheral neuromodulator to contribute to the migraine-like symptom of light aversive behaviour in mice. PMID:26032833

  17. Biostable analogs of insect kinin and insectatachykinin neuropeptides: Novel antifeedants and aphicides

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Neuropeptides are potent regulators of critical life processes in insects, but are subject to rapid degradation by peptidases in the hemolymph (blood), tissues and gut. This limitation can be overcome via replacement of peptidase susceptible portions of the insect neuropeptides with non-natural resi...

  18. Vesicle capture, not delivery, scales up neuropeptide storage in neuroendocrine terminals

    PubMed Central

    Bulgari, Dinara; Zhou, Chaoming; Hewes, Randall S.; Deitcher, David L.; Levitan, Edwin S.

    2014-01-01

    Neurons vary in their capacity to produce, store, and release neuropeptides packaged in dense-core vesicles (DCVs). Specifically, neurons used for cotransmission have terminals that contain few DCVs and many small synaptic vesicles, whereas neuroendocrine neuron terminals contain many DCVs. Although the mechanistic basis for presynaptic variation is unknown, past research demonstrated transcriptional control of neuropeptide synthesis suggesting that supply from the soma limits presynaptic neuropeptide accumulation. Here neuropeptide release is shown to scale with presynaptic neuropeptide stores in identified Drosophila cotransmitting and neuroendocrine terminals. However, the dramatic difference in DCV number in these terminals occurs with similar anterograde axonal transport and DCV half-lives. Thus, differences in presynaptic neuropeptide stores are not explained by DCV delivery from the soma or turnover. Instead, greater neuropeptide accumulation in neuroendocrine terminals is promoted by dramatically more efficient presynaptic DCV capture. Greater capture comes with tradeoffs, however, as fewer uncaptured DCVs are available to populate distal boutons and replenish neuropeptide stores following release. Finally, expression of the Dimmed transcription factor in cotransmitting neurons increases presynaptic DCV capture. Therefore, DCV capture in the terminal is genetically controlled and determines neuron-specific variation in peptidergic function. PMID:24550480

  19. Reproductive neuropeptides that stimulate spawning in the Sydney Rock Oyster (Saccostrea glomerata).

    PubMed

    In, Vu Van; Ntalamagka, Nikoleta; O'Connor, Wayne; Wang, Tianfang; Powell, Daniel; Cummins, Scott F; Elizur, Abigail

    2016-08-01

    The Sydney Rock Oyster, Saccostrea glomerata, is a socioeconomically important species in Australia, yet little is known about the molecular mechanism that regulates its reproduction. To address this gap, we have performed a combination of high throughput transcriptomic and peptidomic analysis, to identify genes and neuropeptides that are expressed in the key regulatory tissues of S. glomerata; the visceral ganglia and gonads. Neuropeptides are known to encompass a diverse class of peptide messengers that play functional roles in many aspects of an animal's life, including reproduction. Approximately 28 neuropeptide genes were identified, primarily within the visceral ganglia transcriptome, that encode precursor proteins containing numerous neuropeptides; some were confirmed through mass spectral peptidomics analysis of the visceral ganglia. Of those, 28 bioactive neuropeptides were synthesized, and then tested for their capacity to induce gonad development and spawning in S. glomerata. Egg laying hormone, gonadotropin-releasing hormone, APGWamide, buccalin, CCAP and LFRFamide were neuropeptides found to trigger spawning in ripe animals. Additional testing of APGWa and buccalin demonstrated their capacity to advance conditioning and gonadal maturation. In summary, our analysis of S. glomerata has identified neuropeptides that can influence the reproductive cycle of this species, specifically by accelerating gonadal maturation and triggering spawning. Other molluscan neuropeptides identified in this study will enable further research into understanding the neuroendocrinology of oysters, which may benefit their cultivation. PMID:27328253

  20. Discovery of Small-Molecule Modulators of the Human Y4 Receptor

    PubMed Central

    Weaver, David; Beck-Sickinger, Annette G.; Meiler, Jens

    2016-01-01

    The human neuropeptide Y4 receptor (Y4R) and its native ligand, pancreatic polypeptide, are critically involved in the regulation of human metabolism by signaling satiety and regulating food intake, as well as increasing energy expenditure. Thus, this receptor represents a putative target for treatment of obesity. With respect to new approaches to treat complex metabolic disorders, especially in multi-receptor systems, small molecule allosteric modulators have been in the focus of research in the last years. However, no positive allosteric modulators or agonists of the Y4R have been described so far. In this study, small molecule compounds derived from the Niclosamide scaffold were identified by high-throughput screening to increase Y4R activity. Compounds were characterized for their potency and their effects at the human Y4R and as well as their selectivity towards Y1R, Y2R and Y5R. These compounds provide a structure-activity relationship profile around this common scaffold and lay the groundwork for hit-to-lead optimization and characterization of positive allosteric modulators of the Y4R. PMID:27294784

  1. Discovery of Small-Molecule Modulators of the Human Y4 Receptor.

    PubMed

    Sliwoski, Gregory; Schubert, Mario; Stichel, Jan; Weaver, David; Beck-Sickinger, Annette G; Meiler, Jens

    2016-01-01

    The human neuropeptide Y4 receptor (Y4R) and its native ligand, pancreatic polypeptide, are critically involved in the regulation of human metabolism by signaling satiety and regulating food intake, as well as increasing energy expenditure. Thus, this receptor represents a putative target for treatment of obesity. With respect to new approaches to treat complex metabolic disorders, especially in multi-receptor systems, small molecule allosteric modulators have been in the focus of research in the last years. However, no positive allosteric modulators or agonists of the Y4R have been described so far. In this study, small molecule compounds derived from the Niclosamide scaffold were identified by high-throughput screening to increase Y4R activity. Compounds were characterized for their potency and their effects at the human Y4R and as well as their selectivity towards Y1R, Y2R and Y5R. These compounds provide a structure-activity relationship profile around this common scaffold and lay the groundwork for hit-to-lead optimization and characterization of positive allosteric modulators of the Y4R. PMID:27294784

  2. Modulation of population density and size of silver nanoparticles embedded in bacterial cellulose via ammonia exposure: visual detection of volatile compounds in a piece of plasmonic nanopaper

    NASA Astrophysics Data System (ADS)

    Heli, B.; Morales-Narváez, E.; Golmohammadi, H.; Ajji, A.; Merkoçi, A.

    2016-04-01

    The localized surface plasmon resonance exhibited by noble metal nanoparticles can be sensitively tuned by varying their size and interparticle distances. We report that corrosive vapour (ammonia) exposure dramatically reduces the population density of silver nanoparticles (AgNPs) embedded within bacterial cellulose, leading to a larger distance between the remaining nanoparticles and a decrease in the UV-Vis absorbance associated with the AgNP plasmonic properties. We also found that the size distribution of AgNPs embedded in bacterial cellulose undergoes a reduction in the presence of volatile compounds released during food spoilage, modulating the studied nanoplasmonic properties. In fact, such a plasmonic nanopaper exhibits a change in colour from amber to light amber upon the explored corrosive vapour exposure and from amber to a grey or taupe colour upon fish or meat spoilage exposure. These phenomena are proposed as a simple visual detection of volatile compounds in a flexible, transparent, permeable and stable single-use nanoplasmonic membrane, which opens the way to innovative approaches and capabilities in gas sensing and smart packaging.The localized surface plasmon resonance exhibited by noble metal nanoparticles can be sensitively tuned by varying their size and interparticle distances. We report that corrosive vapour (ammonia) exposure dramatically reduces the population density of silver nanoparticles (AgNPs) embedded within bacterial cellulose, leading to a larger distance between the remaining nanoparticles and a decrease in the UV-Vis absorbance associated with the AgNP plasmonic properties. We also found that the size distribution of AgNPs embedded in bacterial cellulose undergoes a reduction in the presence of volatile compounds released during food spoilage, modulating the studied nanoplasmonic properties. In fact, such a plasmonic nanopaper exhibits a change in colour from amber to light amber upon the explored corrosive vapour exposure and

  3. Neuropeptide Y is an angiogenic factor in cardiovascular regeneration.

    PubMed

    Saraf, Rabya; Mahmood, Feroze; Amir, Rabia; Matyal, Robina

    2016-04-01

    In diabetic cardiomyopathy, there is altered angiogenic signaling and increased oxidative stress. As a result, anti-angiogenic and pro-inflammatory pathways are activated. These disrupt cellular metabolism and cause fibrosis and apoptosis, leading to pathological remodeling. The autonomic nervous system and neurotransmitters play an important role in angiogenesis. Therapies that promote angiogenesis may be able to relieve the pathology in these disease states. Neuropeptide Y (NPY) is the most abundantly produced and expressed neuropeptide in the central and peripheral nervous systems in mammals and plays an important role in promoting angiogenesis and cardiomyocyte remodeling. It produces effects through G-protein-coupled Y receptors that are widely distributed and also present on the myocardium. Some of these receptors are also involved in diseased states of the heart. NPY has been implicated as a potent growth factor, causing cell proliferation in multiple systems while the NPY3-36 fragment is selective in stimulating angiogenesis and cardiomyocyte remodeling. Current research is focusing on developing a drug delivery mechanism for NPY to prolong therapy without having significant systemic consequences. This could be a promising innovation in the treatment of diabetic cardiomyopathy and ischemic heart disease. PMID:26875634

  4. Inflammation and Neuropeptides: The Connection in Diabetic Wound Healing

    PubMed Central

    Pradhan, Leena; Nabzdyk, Christoph; Andersen, Nicholas D; LoGerfo, Frank W; Veves, Aristidis

    2013-01-01

    This article provides a broad overview of the interaction between neuropeptides and inflammatory mediators as it pertains to diabetic wound healing. Abnormal wound healing is a major complication of both type I and type II diabetes and is the most frequent cause of non-traumatic lower limb amputation. Wound healing requires the orchestrated integration of complex biological and molecular events. Inflammation, proliferation and migration of cells followed by angiogenesis and re-epithelization are essential phases of wound healing. The link between wound healing and the nervous system is clinically apparent as peripheral neuropathy is reported in 30–50% of diabetic patients and is the most common and sensitive predictor of foot ulceration. The bidirectional connection between the nervous and the immune systems and the role it plays in wound healing has emerged as one of the focal features of the wound healing dogma. The mediators of this connection include neuropeptides and the cytokines released from different cells including immune and cutaneous cells. Therefore, to develop successful wound healing therapies, it is vital to understand in depth the signaling pathways in the neuro-immune axis and their implication in diabetic wound healing. PMID:19138453

  5. Allatotropin: An Ancestral Myotropic Neuropeptide Involved in Feeding

    PubMed Central

    Alzugaray, María Eugenia; Adami, Mariana Laura; Diambra, Luis Anibal; Hernandez-Martinez, Salvador; Damborenea, Cristina; Noriega, Fernando Gabriel; Ronderos, Jorge Rafael

    2013-01-01

    Background Cell-cell interactions are a basic principle for the organization of tissues and organs allowing them to perform integrated functions and to organize themselves spatially and temporally. Peptidic molecules secreted by neurons and epithelial cells play fundamental roles in cell-cell interactions, acting as local neuromodulators, neurohormones, as well as endocrine and paracrine messengers. Allatotropin (AT) is a neuropeptide originally described as a regulator of Juvenile Hormone synthesis, which plays multiple neural, endocrine and myoactive roles in insects and other organisms. Methods A combination of immunohistochemistry using AT-antibodies and AT-Qdot nanocrystal conjugates was used to identify immunoreactive nerve cells containing the peptide and epithelial-muscular cells targeted by AT in Hydra plagiodesmica. Physiological assays using AT and AT- antibodies revealed that while AT stimulated the extrusion of the hypostome in a dose-response fashion in starved hydroids, the activity of hypostome in hydroids challenged with food was blocked by treatments with different doses of AT-antibodies. Conclusions AT antibodies immunolabeled nerve cells in the stalk, pedal disc, tentacles and hypostome. AT-Qdot conjugates recognized epithelial-muscular cell in the same tissues, suggesting the existence of anatomical and functional relationships between these two cell populations. Physiological assays indicated that the AT-like peptide is facilitating food ingestion. Significance Immunochemical, physiological and bioinformatics evidence advocates that AT is an ancestral neuropeptide involved in myoregulatory activities associated with meal ingestion and digestion. PMID:24143240

  6. Neuropeptides and peptide hormones in syncope and orthostatic intolerance.

    PubMed

    Krishnan, Balaji; Benditt, David G

    2014-01-01

    Syncope and orthostatic intolerance (OI) are common clinical syndromes often requiring medical attention. The former is defined as transient loss of consciousness and postural tone due to self-limited cerebral hypoperfusion, while the latter consists of inappropriate cardiovascular responses to upright posture such as occur with orthostatic hypotension (OH) or postural orthostatic tachycardia syndrome. The most frequent causes of syncope and OI are conditions that temporarily disrupt essential moment-to-moment interaction between the autonomic nervous system and cardiovascular system. In this regard, many neuropeptides (NPs) or peptide hormones (PH) exert cardioactive effects that might contribute to the pathophysiology of certain forms of syncope or OI. To date, the principal peptides that have been studied in this context are: atrial and B-type-neuropeptides, adrenomedullin, endothelin-1 (ET-1), galanin, and vasopressin. While definitive conclusions cannot yet be drawn, the intrinsic vasoconstrictor ET-1 appears to be elevated in OH, presumably to compensate for vasodilation and hypotension of other etiologies. As such elevated ET-1 may become a marker for OH. Further, elevated NT-proBNP may play a role in causing vasodilation and hypotension in some forms of OH of previously unknown cause, and may be a marker in other patients of a cardiovascular cause of syncope and OI. In the end, the study of the role of NPs and PHs in syncope and OI syndromes is at an early stage, and considerable further future effort is needed. PMID:25299506

  7. Modulation of Histone Deacetylase Activity by Dietary Isothiocyanates and Allyl Sulfides: Studies with Sulforaphane and Garlic Organosulfur Compounds

    PubMed Central

    Nian, Hui; Delage, Barbara; Ho, Emily; Dashwood, Roderick H.

    2009-01-01

    Histone deacetylase (HDAC) inhibitors reactivate epigenetically-silenced genes in cancer cells, triggering cell cycle arrest and apoptosis. Recent evidence suggests that dietary constituents can act as HDAC inhibitors, such as the isothiocyanates found in cruciferous vegetables and the allyl compounds present in garlic. Broccoli sprouts are a rich source of sulforaphane (SFN), an isothiocyanate that is metabolized via the mercapturic acid pathway and inhibits HDAC activity in human colon, prostate, and breast cancer cells. In mouse preclinical models, SFN inhibited HDAC activity and induced histone hyperacetylation coincident with tumor suppression. Inhibition of HDAC activity also was observed in circulating peripheral blood mononuclear cells obtained from people who consumed a single serving of broccoli sprouts. Garlic organosulfur compounds can be metabolized to allyl mercaptan (AM), a competitive HDAC inhibitor that induced rapid and sustained histone hyperacetylation in human colon cancer cells. Inhibition of HDAC activity by AM was associated with increased histone acetylation and Sp3 transcription factor binding to the promoter region of the P21WAF1 gene, resulting in elevated p21 protein expression and cell cycle arrest. Collectively, the results from these studies, and others reviewed herein, provide new insights into the relationships between reversible histone modifications, diet, and cancer chemoprevention. PMID:19197985

  8. Media effects in modulating the conformational equilibrium of a model compound for tumor necrosis factor converting enzyme inhibition

    NASA Astrophysics Data System (ADS)

    Banchelli, Martina; Guardiani, Carlo; Sandberg, Robert B.; Menichetti, Stefano; Procacci, Piero; Caminati, Gabriella

    2015-07-01

    Small-molecule inhibitors of Tumor Necrosis Factor α Converting Enzyme (TACE) are a promising therapeutic tool for Rheumatoid Arthritis, Multiple Sclerosis and other autoimmune diseases. Here we report on an extensive chemical-physical analysis of the media effects in modulating the conformational landscape of MBET306, the common scaffold and a synthetic precursor of a family of recently discovered tartrate-based TACE inhibitors. The structural features of this molecule with potential pharmaceutical applications have been disclosed by interpreting extensive photophysical measurements in various solvents with the aid of enhanced sampling molecular dynamics simulations and time dependent density functional calculations. Using a combination of experimental and computational techniques, the paper provides a general protocol for studying the structure in solution of molecular systems characterized by the existence of conformational metastable states.

  9. Modulation of Sweet Taste by Umami Compounds via Sweet Taste Receptor Subunit hT1R2

    PubMed Central

    Kim, Yiseul; Kim, Ki Hwa; Kim, Jung Tae; Moon, Hana; Kim, Min Jung; Misaka, Takumi; Rhyu, Mee-Ra

    2015-01-01

    Although the five basic taste qualities—sweet, sour, bitter, salty and umami—can be recognized by the respective gustatory system, interactions between these taste qualities are often experienced when food is consumed. Specifically, the umami taste has been investigated in terms of whether it enhances or reduces the other taste modalities. These studies, however, are based on individual perception and not on a molecular level. In this study we investigated umami-sweet taste interactions using umami compounds including monosodium glutamate (MSG), 5’-mononucleotides and glutamyl-dipeptides, glutamate-glutamate (Glu-Glu) and glutamate-aspartic acid (Glu-Asp), in human sweet taste receptor hT1R2/hT1R3-expressing cells. The sensitivity of sucrose to hT1R2/hT1R3 was significantly attenuated by MSG and umami active peptides but not by umami active nucleotides. Inhibition of sweet receptor activation by MSG and glutamyl peptides is obvious when sweet receptors are activated by sweeteners that target the extracellular domain (ECD) of T1R2, such as sucrose and acesulfame K, but not by cyclamate, which interact with the T1R3 transmembrane domain (TMD). Application of umami compounds with lactisole, inhibitory drugs that target T1R3, exerted a more severe inhibitory effect. The inhibition was also observed with F778A sweet receptor mutant, which have the defect in function of T1R3 TMD. These results suggest that umami peptides affect sweet taste receptors and this interaction prevents sweet receptor agonists from binding to the T1R2 ECD in an allosteric manner, not to the T1R3. This is the first report to define the interaction between umami and sweet taste receptors. PMID:25853419

  10. Antioxidative Dietary Compounds Modulate Gene Expression Associated with Apoptosis, DNA Repair, Inhibition of Cell Proliferation and Migration

    PubMed Central

    Wang, Likui; Gao, Shijuan; Jiang, Wei; Luo, Cheng; Xu, Maonian; Bohlin, Lars; Rosendahl, Markus; Huang, Wenlin

    2014-01-01

    Many dietary compounds are known to have health benefits owing to their antioxidative and anti-inflammatory properties. To determine the molecular mechanism of these food-derived compounds, we analyzed their effect on various genes related to cell apoptosis, DNA damage and repair, oxidation and inflammation using in vitro cell culture assays. This review further tests the hypothesis proposed previously that downstream products of COX-2 (cyclooxygenase-2) called electrophilic oxo-derivatives induce antioxidant responsive elements (ARE), which leads to cell proliferation under antioxidative conditions. Our findings support this hypothesis and show that cell proliferation was inhibited when COX-2 was down-regulated by polyphenols and polysaccharides. Flattened macrophage morphology was also observed following the induction of cytokine production by polysaccharides extracted from viili, a traditional Nordic fermented dairy product. Coix lacryma-jobi (coix) polysaccharides were found to reduce mitochondrial membrane potential and induce caspase-3- and 9-mediated apoptosis. In contrast, polyphenols from blueberries were involved in the ultraviolet-activated p53/Gadd45/MDM2 DNA repair system by restoring the cell membrane potential. Inhibition of hypoxia-inducible factor-1 by saponin extracts of ginsenoside (Ginsen) and Gynostemma and inhibition of S100A4 by coix polysaccharides inhibited cancer cell migration and invasion. These observations suggest that antioxidants and changes in cell membrane potential are the major driving forces that transfer signals through the cell membrane into the cytosol and nucleus, triggering gene expression, changes in cell proliferation and the induction of apoptosis or DNA repair. PMID:25226533