bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression and GTP Sensitivity of Peptide Histidine Isoleucine High‐Affinity‐Binding Sites in Rat
Authors: DEBAIGT COLIN , MEUNIER ANNIE‐CLAIRE , GOURSAUD STEPHANIE , MONTONI ALICIA , PINEAU NICOLAS , COUVINEAU ALAIN , LABURTHE MARC , MULLER JEAN‐MARC , JANET THIERRY
Published: August 2006

Abstract:  High‐affinity‐binding sites for the vasoactive intestinal peptide (VIP) analogs peptide histidine/isoleucine‐amide (PHI)/carboxyterminal methionine instead of isoleucine (PHM) are expressed in numerous tissues in the body but the nature of their receptors remains to be elucidated.
The data presented indicate that PHI discriminated a high‐affinity guanosine 5′‐triphosphate (GTP)‐insensitive‐binding subtype that represented the totality of the PHI‐binding sites in newborn rat tissues but was differentially expressed in adult animals. The GTP‐insensitive PHI/PHM‐binding sites were also observed in CHO cells over expressing the VPAC2 but not the VPAC1 VIP receptor.
PACAP, VIP, and PHI
Authors: DEJDA AGNIESZKA , JOZWIAK‐BEBENISTA MARTA , NOWAK JERZY Z.
Published: August 2006

Abstract: Pituitary adenylate cyclase‐activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), and peptide histidine‐isoleucine (PHI) are members of a superfamily of structurally related peptides widely distributed in the body and displaying pleiotropic biological activities. All these peptides are known to act via common receptors—VPAC1 and VPAC2. In addition, the effects of PACAP are mediated through its specific receptor named PAC1. The main signal transduction pathway of the mentioned receptors is adenylyl cyclase (AC)→cAMP system. PACAP and VIP may also signal through receptor‐linked phospholipase C (PLC)→IP3/DAG→PKC and phospholipase D (PLD)→phosphatidic acid (PA) pathways. In the present article, we have studied the effects of PACAP, VIP, and PHI (0.001–5000 nM) on the AC‐, PLC‐, and PLD‐driven signaling pathways in rat primary glial cell (astrocytes) cultures. All tested peptides dose‐dependently and strongly stimulated cyclic adenosine 3´,5´‐monophosphate (cAMP) production in this experimental model, displaying the following rank order of potency: PACAP >> VIP ≥ PHI. Their effects on PLC‐IP3/DAG were weaker, while only PACAP and VIP (0.1‐5 μM) significantly stimulated PLD activity. The obtained results showed that rat cerebral cortex‐derived astrocytes are responsive to PACAP, VIP and PHI/PHM and possess PAC1 and likely VPAC‐type receptors linked to activation of AC‐cAMP‐, PLC‐IP3/DAG‐, and PLD‐PA signaling systems.
Vasoactive Intestinal Peptide
Authors: DELGADO MARIO , GONZALEZ‐REY ELENA , GANEA DOINA
Published: August 2006

Abstract:  Tolerogenic dendritic cells (tDCs) play an important role in maintaining peripheral tolerance through the induction/activation of regulatory T cells (Treg). Endogenous factors contribute to the functional development of tDCs. In this article, we present evidence that two known immunosuppressive neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase‐activating polypeptide (PACAP), contribute to the development of bone marrow‐derived tDCs. The VIP/PACAP‐generated DCs are CD11clowCD45RBhigh, do not upregulate CD80, CD86, and CD40 following lipopolysaccharide (LPS) stimulation, and secrete high amounts of IL‐10.
The VIP/PACAP‐generated DCs induce functional Treg in vitro and in vivo. VIP/DCs induce antigen‐specific tolerance in vivo, suppress delayed‐type hypersensitivity (DTH), and T cells from VIP/DC‐inoculated mice transfer the suppression to naïve hosts. The effect of VIP/PACAP on the DC–Treg axis represents an additional mechanism for their general anti‐inflammatory role, particularly in anatomical sites that exhibit immune deviation or privilege.
The Effects of PACAP and VIP on the in Vitro Melatonin Secretion from the Embryonic Chicken Pineal Gland
Authors: FALUHELYI N. , REGL?DI D. , CSERNUS V.
Published: August 2006

Abstract:  The effects of in vitro VIP administration and those of in ovo pretreatment with PACAP antagonist (PACAP6‐38) on the development of the embryonic melatonin (MT) secretion were investigated. With dynamic in vitro bioassay we showed that (1) the development of the circadian MT secretion seems to be unaffected by VIP administrations or by PACAP6‐38 pretreatments; (2) exposure of the embryonic chicken pineal gland to VIP induces transitory increase in MT secretion at or before the 14th embryonic day in vitro.
C‐Type Natriuretic Peptide Is Specifically Augmented by Pituitary Adenylate Cyclase‐Activating Polypeptide in Rat Astrocytes
Authors: FUJIKAWA KOHSHO , NAGAYAMA TETSUYA , INOUE KAZUHIKO , MINAMINO NAOTO , KANGAWA KENJI , NIIRO MASAKI , MIYATA ATSURO
Published: August 2006

Abstract: In rat‐cultured astrocytes, pituitary adenylate cyclase‐activating polypeptide (PACAP) activates gene expression and secretion of C‐type natriuretic peptide (CNP) in a dose‐ and time‐dependent manner. These results suggest that PACAP might be involved in the regulation of CNP biosynthesis in astrocytes.
Modulation of Pituitary Adenylate Cyclase‐Activating Polypeptide (PACAP) Expression in Explant‐Cultured Guinea Pig Cardiac Neurons
Authors: GIRARD BEATRICE M. , YOUNG BETH A. , BUTTOLPH THOMAS R. , WHITE SHERYL L. , PARSONS RODNEY L.
Published: August 2006

Abstract: Pituitary adenylate cyclase‐activating polypeptide (PACAP) expression was quantified in explant‐cultured guinea pig cardiac ganglia neurons. In explant culture, both the percentage of PACAP‐immunoreactive neurons and pro‐PACAP transcript levels increased significantly. Treatment with neurturin or glial‐derived neurotrophic factor significantly suppressed the percentage of PACAP‐IR neurons, but not pro‐PACAP transcript levels.
VIP–PACAP System in Immunity
Authors: GOMARIZ R.P. , JUARRANZ Y. , ABAD C. , ARRANZ A. , LECETA J. , MARTINEZ C.
Published: August 2006

Abstract: Our research about VIP/PACAP and the immune system goes back to 1990 when our group described the expression of VIP on lymphocytes for the first time. Since this year, using three models of disease, septic shock, rheumathoid arthritis, and Crohn's disease, we are trying to contribute with new pieces to the puzzle of immunity to approach the use of VIP/PACAP system as a therapeutic agent. In 1999 we established that the first step in the beneficial effect of the VIP/PACAP system exerts consists in its potent anti‐inflammatory action. Thus, VIP and PACAP inhibit the expression and release of proinflammatory cytokines and chemokines, and enhance the production of the anti‐inflammatory factors. These effects were reported bothinvitroandinvivo, are mediated by the presence of PAC1, VPAC1, and VPAC2 receptors, in the three models of diseases used. The next step was that the system favors Th2 responses versus Th1 contributing to the remission of illness as rheumatoid arthritis or Crohn's disease by blocking the autoimmune component of these diseases. Because it appears that inflammatory processes requires more than blockade of a single mediator, new therapies blocking several components of both the infection‐ and the autoimmunity‐induced inflammation cascades should be an interesting focus of attention. In this sense, at present we are trying to dissect new aspects of the potential therapeutic of the VIP/PACAP system in the control of CC and CXC chemokine and their receptors, coagulation factors, adhesion molecules, acute phase proteins, and osteoclastogenesis mediators as well as in the modulation of the expression of Toll‐like receptors. Our more recent data open a hopeful door for the therapeutic use of VIP/PACAP in humans.
VIP: An Agent with License to Kill Infective Parasites
Authors: GONZALEZ‐REY ELENA , CHORNY ALEJO , DELGADO MARIO
Published: August 2006

Abstract: Antimicrobial peptides are small, cationic, and amphipathic peptides of variable length, sequence, and structure. They are effector molecules of innate immunity with microbicidal and both pro‐ or anti‐inflammatory activities. Vasoactive intestinal polypeptide (VIP) and the structurally related pituitary adenylate cyclase‐activating polypeptide (PACAP) are well‐known immunomodulators. On the basis of their cationic and amphipathic structures, resembling antimicrobial peptides, we propose that their immune role could also include a direct lethal effect against pathogens. We thus investigated the potential antiparasitic activities of VIP and PACAP against the African trypanosomeTrypanosoma brucei (T. brucei). Both peptides killed the bloodstream (infective) form but not the insect (noninfective) form of the parasite. VIP and PACAP caused complete destruction of the parasite integrity through a mechanism involving their entry and accumulation into the cytosol. These results provide the basis for further studies of these and other structurally related peptides as alternative treatments for parasitic diseases mainly with associated drug resistances.
New Nonradioactive Technique for Vasoactive Intestinal Peptide‐Receptor‐Ligand‐Binding Studies
Authors: HABERL INES , HABRINGER DANIELA SUSANNE , ANDREAE FRITZ , ARTL ANDREAS , MOSGOELLER WILHELM
Published: August 2006

Abstract:  We describe fluorescent‐labeled peptide (FLP) studies on living cells. The new technique is nonradioactive and it allows monitoring of the binding and internalization of Vasoactive Intestinal Peptide (VIP) in VIP receptor‐expressing cells. The technique is easy to perform and the observed reaction is peptide sequence specific.
New Insights into the Central PACAPergic System from the Phenotypes in PACAP‐ and PACAP Receptor‐Knockout Mice
Authors: HASHIMOTO HITOSHI , SHINTANI NORIHITO , BABA AKEMICHI
Published: August 2006

Abstract: Pituitary adenylate cyclase‐activating polypeptide (PACAP) is a structurally highly conserved neuropeptide and displays pleiotropic activity, including functioning as a neurotransmitter, neuromodulator, and neurotrophic factor. A series of recent experiments, including genetic manipulation of PACAP and its receptors, has led to better understanding of both normal and pathological processes in which PACAP has been proposed to play a role, and sheds light on previously uncharacterized functions of endogenous PACAP. The aim of this article is to briefly review the recent advances in understanding the role of PACAP in the central nervous system from PACAP‐ and PACAP receptor‐deficient mice, particularly with respect to behavioral and neurological features, including psychomotor behavior, feeding, stress responses, memory performance, ethanol sensitivity, chronic pain, and circadian rhythms. This article also discusses their potential involvement in human diseases.
Presence of PACAP and VIP in Embryonic Chicken Brain
Authors: JOZSA RITA , HOLLOSY TIBOR , NEMETH JOZSEF , TAMÁS ANDREA , LUBICS ANDREA , JAKAB BALAZS , OLAH ANDRAS , ARIMURA AKIRA , REGLÖDI DORA
Published: August 2006

Abstract: The aim of the present article was to investigate the occurrence and temporary changes of pituitary adenylate cyclase‐activating polypeptide (PACAP)‐38 and vasoactive intestinal peptide (VIP) in various brain areas of chicken embryos by means of radioimmunoassay. The highest concentrations of PACAP‐38 were measured in the brain stem followed by the hypothalamus, cerebellum, and telencephalon. PACAP‐38 levels were significantly higher than those of VIP in all examined brain areas. The levels of both PACAP‐38 and VIP showed a tendency to decrease until hatching during embryonic development of the chicken.
PACAP Enhances Mouse Urinary Bladder Contractility and Is Upregulated in Micturition Reflex Pathways after Cystitis
Authors: HERRERA GERALD M. , BRAAS KAREN M. , MAY VICTOR , VIZZARD MARGARET A.
Published: August 2006

Abstract:  Pituitary adenylate cyclase‐activating polypeptide (PACAP) elicits a transient contraction, sustained increase in the amplitude of spontaneous phasic contractions, and significantly increases the amplitude of nerve‐mediated contractions in mouse urinary bladder smooth muscle (UBSM) strips. PACAP immunoreactivity (IR) is increased in micturition reflex pathways following cystitis. PACAP may contribute to altered sensation and bladder overactivity in the chronic bladder inflammatory syndrome, interstitial cystitis.
Short‐Term Fasting Differentially Alters PACAP and VIP Levels in the Brains of Rat and Chicken
Authors: JOZSA RITA , NEMETH JOZSEF , TAMAS ANDREA , HOLLOSY TIBOR , LUBICS ANDREA , JAKAB BALAZS , OLAH ANDRAS , LENGVARI ISTVAN , ARIMURA AKIRA , REGLÖDI DORA
Published: August 2006

Abstract:  The present article investigated the levels of pituitary adenylate cyclase‐activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) in the brains of rats and chickens 12, 36, and 84 h after starvation. PACAP levels increased in both species, 12 h after food deprivation in rats, and with a 24‐h delay in chickens. VIP levels showed a more complex pattern: a gradual increase in the hypothalamus and telencephalon, and a significant decrease in the brain stem of rats. In chickens, a decrease was observed in every brain area after 36 h of starvation. These data show that PACAP and VIP are differentially regulated and are involved in the regulatory processes under a food‐restricted regimen, and are differentially altered in nocturnal and diurnal species.
VIP Decreases TLR4 Expression Induced by LPS and TNF‐α Treatment in Human Synovial Fibroblasts
Authors: JUARRANZ Y. , GUTIÉRREZ‐CAÑAS I. , ARRANZ A. , MARTÍNEZ C. , ABAD C. , LECETA J. , PABLOS J.L. , GOMARIZ R.P.
Published: August 2006

Abstract:  It has been demonstrated that VIP produces beneficial effects both in a murine model of rheumatoid arthritis and in human rheumatoid synovial fibroblasts through the modulation of proinflammatory mediators. Toll‐like receptors (TLRs) play a key role in the immediate recognition of microbial surface components by immune cells prior to the development of adaptative microbe‐specific immune responses. In this study, we demonstrate that VIP decreases lipopolysaccharide (LPS) and TNF‐α‐induced expression of TLR4 and its correlation with the production of CCL2 and CXCL8 chemokines in human synovial fibroblasts from patients with rheumatoid arthritis and osteoarthritis. Our results add a new step for the use of VIP, as a promising candidate, for the treatment of rheumatoid arthritis.
Differential Mechanisms for PACAP and GnRH cAMP Induction Contribute to Cross‐talk between both Hormones in the Gonadotrope LβT2 Cell Line
Authors: LARIVIÈRE SIGOLÈNE , GARREL GHISLAINE , ROBIN MARIE‐THÉRÈSE , COUNIS RAYMOND , COHEN‐TANNOUDJI JOËLLE
Published: August 2006

Abstract:  The effects and respective influence of pituitary adenylate cyclase‐activating polypeptide (PACAP) and gonadotropin‐releasing hormone (GnRH) on cyclic AMP (cAMP) production in pituitary gonadotropes were analyzed using the LβT2 cell line. Both hormones induced cAMP with, however, different intensity and time course. In addition, the GnRH effect was markedly reduced by PKC inhibitors. Despite its positive coupling to cAMP pathway, GnRH counteracted PACAP induction of cAMP and this effect was mimicked by the PKC activator phorbol 12‐myristate 13‐acetate (PMA). The data reveal major differences in the mechanisms by which PACAP and GnRH activate cAMP/PKA pathway in LβT2 cells and suggest that PKC activation serves GnRH not only to increase cAMP but also to counteract the PACAP stimulation of this signaling pathway.
Identification of Proteins Regulated by PACAP in PC12 Cells by 2D Gel Electrophoresis Coupled to Mass Spectrometry
Authors: LEBON ALEXIS , SEYER DAMIEN , COSETTE PASCAL , COQUET LAURENT , JOUENNE THIERRY , CHAN PHILIPPE , LEPRINCE JEROME , FOURNIER ALAIN , VAUDRY HUBERT , GONZALEZ BRUNO J , VAUDRY DAVID
Published: August 2006

Abstract: The rat pheochromocytoma PC12 cell line has been widely used as a model to study neuronal differentiation. In particular, after serum depletion, PC12 cells stop to proliferate and undergo apoptosis. Under such conditions, treatment with pituitary adenylate cyclase‐activating polypeptide (PACAP) promotes cell survival and induces neurite outgrowth. The identification of the proteins regulated by PACAP in PC12 cells under apoptotic conditions should provide valuable information concerning the mechanisms controlling neuronal cell survival and differentiation. To this aim, PC12 cells cultured in serum‐free medium were treated with PACAP (10−7M), proteins were extracted, separated by two‐dimensional gel electrophoresis (2‐DE), and identified by MALDI‐ToF mass spectrometry. The comparison between 16 2‐DE maps led to the characterization of 110 proteins regulated by PACAP among which 22 have been identified by automatic query of the Mascot, Aldente, and Profound servers with the ProGeR‐CDD database. Seventy‐six percent of these proteins, including the p17 subunit of caspase‐3, the heat shock protein hsp60, and the GTPase ran were found to be repressed whereas the others notably hsp27, tubulin β‐5, and calmodulin were overexpressed. Investigation of the putative functions indicated that some of the proteins regulated by PACAP and identified in the present article could control cell survival or differentiation.
Neuroendocrine Tumors Express PAC1 Receptors
Authors: LIEU SONG N. , OH DAVID S. , PISEGNA JOSEPH R. , GERMANO PATRICIA M.
Published: August 2006

Abstract: Neuroendocrine tumors (NETs) of the gastrointestinal tract can be grossly divided into two general types: carcinoid and pancreatic endocrine tumors. The former develop in the luminal intestine whereas the latter occur within the pancreas. To ascertain whether pituitary adenylate cyclase‐activating polypeptide (PACAP) has a biological effect on the regulation of secretion or growth, we studied the well‐established NET cell line, BON. BON cells have been shown previously to contain chromogranin A, neurotensin, and serotonin. In response to mechanical stimulation, BON cells have been demonstrated to release serotonin. The current article demonstrates that the high‐affinity PAC1 receptor is expressed on the NET cell line BON. These results indicate that PACAP may regulate the biological release of peptides and serotonin from BON cells and that, like in solid tumors, PACAP could potentially stimulate the growth of BON cells.
Involvement of the Adenylyl Cyclase/Protein Kinase A Signaling Pathway in the Stimulatory Effect of PACAP on Frog Adrenocortical Cells
Authors: MONTERO‐HADJADJE MAITE , DELARUE CATHERINE , FOURNIER ALAIN , VAUDRY HUBERT , YON LAURENT
Published: August 2006

Abstract:  We have previously shown that PACAP stimulates in vitro the secretion of corticosteroids by frog adrenal explants and that PACAP increases cAMP formation and cytosolic calcium concentration (‘Ca2+’i) in adrenocortical cells. The aim of the present study was to investigate the involvement of cAMP and ‘Ca2+’i in the stimulatory effect of PACAP on steroid production. Incubation of adrenal explants with PACAP resulted in a significant increase in total inositol phosphate formation. Administration of the protein kinase A inhibitor, H89, markedly reduced the stimulatory effect of PACAP on corticosterone and aldosterone secretion by perifused adrenal slices. In contrast, chelation of intracellular or extracellular calcium, or incubation with calcium channel blockers, had no effect on PACAP‐evoked steroid secretion. Incubation of the cells with BAPTA or thapsigargin totally suppressed the stimulatory effect of PACAP on ‘Ca2+’i. In contrast, suppression of extracellular calcium with EGTA or blockage of voltage‐dependent Ca2+ channels did not impair PACAP‐induced Ca2+ response. These data indicate that, in frog adrenocortical cells, the stimulatory effect of PACAP on steroid secretion is mediated through activation of the cAMP/PKA pathway. Concurrently, PACAP causes calcium mobilization from IP3‐dependent intracellular stores through activation of a phospholipase C, while the calcium response is not involved in the stimulatory effect of PACAP on corticosteroid secretion.
PACAP and Type I PACAP Receptors in Human Prostate Cancer Tissue
Authors: MORETTI COSTANZO , MAMMI CATERINA , FRAJESE GIOVANNI VANNI , MARIANI STEFANIA , GNESSI LUCIO , ARIZZI MARIO , WANNENES FRANCESCA , FRAJESE GAETANO
Published: August 2006

Abstract: We characterized the expression and localization of pituitary adenylate cyclase‐activating polypeptide (PACAP) and its specific type I receptor variants in prostatic, hyperplastic, and carcinomatous tissue collected from patients undergoing prostate biopsy and surgery for benign prostatic hyperplasia (BPH) and prostate cancer (PCa). The immunohistochemical studies using an indirect immunoperoxidase technique evidenced positive immunostaining for PACAP in the cytoplasm of epithelial cells of hyperplastic and carcinomatous prostate specimens and in some scattered cells of the stroma. Type I PACAP receptors (PAC1 R) in healthy and BPH tissues were localized in all epithelial cells lining the lumen of the acini and in some stromal cells, while in specimens from PCa the anti‐PAC1 R antibody stained the apical portion of a large percentage of cells. Furthermore, our molecular studies provide evidence that several PAC1 R isoforms (null, SV1/SV2) are present in normal, hyperplastic, and neoplastic tissue, thenullvariant being the most intensely expressed in PCa. These observations provide additional evidence for a role of PACAP and PAC1 R in the events determining the outcome of PCa.
Expression of PACAP Receptor mRNAs by Neuropeptide Y Neurons in the Rat Arcuate Nucleus
Authors: MOUNIEN LOURDES , BIZET PATRICE , BOUTELET ISABELLE , GOURCEROL GUILLAUME , BASILLE MAGALI , GONZALEZ BRUNO , VAUDRY HUBERT , JEGOU SYLVIE
Published: August 2006

Abstract: Neuropeptide Y (NPY) and pituitary adenylate cyclase‐activating polypeptide (PACAP) exert opposite actions in energy homeostasis: NPY is a potent orexigenic peptide whereas PACAP reduces food intake. PAC1‐R and VPAC2‐R mRNAs are actively expressed in the arcuate nucleus of the hypothalamus which contains a prominent population of NPY neurons. By using a double‐labelingin situhybridization technique, we now show that a significant proportion of NPY neurons express PAC1‐R or VPAC2‐R mRNA. This observation indicates that PACAP may regulate the activity of NPY neurons, suggesting that the inhibitory effect of PACAP on food intake may be mediated, at least in part, through modulation of NPY neurotransmission.
Developmental Pattern of VIP Binding Sites in the Human Hypothalamus
Authors: NAJIMI MOHAMED , RACHIDI FATIMA , AFIF ABDELKRIM , CHIGR FATIHA
Published: August 2006

Abstract: We have studied the developmental patterns of vasoactive intestinal polypeptide (VIP) binding sites in the human hypothalamus. VIP recognition sites were widely distributed throughout the rostrocaudal extent of the hypothalamus. VIP binding was generally low in the fetal and neonatal periods and a tendency in increasing densities was observed during postnatal development. The age comparison of binding density indicates variations in several structures. Thus, the densities were higher in older infants in the preoptic area, lamina terminalis, and infundibular (IN) nucleus. These differences suggest the implication of VIP receptors in the development of this brain structure and the maintenance of its various functions.
The Vasoactive Intestinal Peptide Receptor Turnover in Pulmonary Arteries Indicates an Important Role for VIP in the Rat Lung Circulation
Authors: PETKOV VENTZISLAV , GENTSCHEVA TEMENUSCHKA , SCHAMBERGER CHANTAL , HABERL INES , ARTL ANDREAS , ANDREAE FRITZ , MOSGOELLER WILHELM
Published: August 2006

Abstract:  Vasoactive intestinal peptide (VIP) is a potent vasorelaxing peptide that plays a role in lung physiology and possibly in pulmonary hypertension. We investigated the turnover of the VIP receptors on rat pulmonary arteries ex vivo. There was evidence for a fast receptor turnover in pulmonary arteries, which underlines the important role of VIP for the regulation of pulmonary circulation and pulmonary pathology.
A Splice Variant to PACAP Receptor That Is Involved in Spermatogenesis Is Expressed in Astrocytes
Authors: PILZER INBAR , GOZES ILLANA
Published: August 2006

Abstract: The pituitary adenylate cyclase‐activating polypeptide (PACAP) receptor, PAC1, recognizes PACAP with a higher affinity than it recognizes vasoactive intestinal peptide (VIP) and belongs to the subfamily G protein–coupled receptors. So far, more than 10 different splice variants of PAC1 have been cloned from rat tissue. Interestingly, the various PAC1 splice variants exhibit different signaling pathways. These splice variants are suggested to play a functional role mostly in the brain as well as in the testes. The present article introduces PAC1(3a) that was originally discovered in testes as another potential regulator in rat astrocytes.
NAP, a Peptide Derived from the Activity‐Dependent Neuroprotective Protein, Modulates Macrophage Function
Authors: QUINTANA FRANCISCO J. , ZALTZMAN ROY , FERNANDEZ‐MONTESINOS RAFAEL , HERRERA JUAN LUIS , GOZES ILLANA , COHEN IRUN R. , POZO DAVID
Published: August 2006

Abstract: NAP is an eight‐amino acid neuroprotective peptide NAPVSIPQ; it is the smallest active element derived from the recently cloned activity‐dependent neuroprotective protein (ADNP). NAP readily enters the brain from the blood. It will be important to learn whether NAP, in addition to its neuroprotective activity, also might influence immune‐mediated inflammation. Here, we report that: (a) macrophages express ADNP; (b) expression of ADNP in macrophages responds to VIP; and (c) NAP downregulates the key inflammatory cytokines tumor necrosis factor (TNF‐α), interleukin‐16 (IL‐16), and IL‐12 in macrophages. These findings indicate that ADNP/NAP can play an important role in immune regulation as well as in neuroprotection, which may be mutually related processes.
Mechanisms of VIP‐Induced Neuroprotection against Neonatal Excitotoxicity
Authors: RANGON CLAIRE‐MARIE , DICOU ELENI , GOURSAUD STÉPHANIE , MOUNIEN LOURDES , JÉGOU SYLVIE , JANET THIERRY , MULLER JEAN‐MARC , LELIÈVRE VINCENT , GRESSENS PIERRE
Published: August 2006

Abstract: Two VIP receptors, shared with a similar affinity by pituitary adenylate cyclase‐activating polypeptide (PACAP), have been cloned: VPAC1 and VPAC2. PHI binds to these receptors with a lower affinity. We previously showed that VIP protects against excitotoxic white matter damage in newborn mice. This article aimed to determine the receptor involved in VIP‐induced neuroprotection. VIP effects were mimicked with a similar potency by VPAC2 agonists and PHI but not by VPAC1 agonists, PACAP 27 or PACAP 38. VIP neuroprotective effects were lost in mice lacking VPAC2 receptor.In situhybridization confirmed the presence of VPAC2 mRNA. These data suggest that, in this model, VIP‐induced neuroprotection is mediated by VPAC2 receptors. The pharmacology of this VPAC2 receptor seems unconventional as PACAP does not mimic VIP effects and PHI acts with a comparable potency.
Comparative Study of the Effects of PACAP in Young, Aging, and Castrated Males in a Rat Model of Parkinson's Disease
Authors: REGLÓDI D. , TAMÁS A. , LENGVÁRI I. , TOTH G. , SZALONTAY L. , LUBICS A.
Published: August 2006

Abstract:  We have previously shown that PACAP ameliorates the neurological symptoms and reduces the dopaminergic cell loss in young male rats, in a 6‐hydroxydopamine (6‐OHDA)‐induced lesion of the substantia nigra, a model of Parkinson's disease. In the present study, we compared the effects of PACAP in young, aging, and castrated males. Our results show that PACAP significantly reduced the dopaminergic cell loss in young and aging males. In castrated males, 6‐OHDA did not induce such a severe cell loss, and it was not altered by PACAP. However, PACAP effectively ameliorated behavioral symptoms in all groups, with a degree of recovery depending on age and endocrine status.
Neuroprotective Effect of PACAP against Kainic Acid‐Induced Neurotoxicity in Rat Retina
Authors: SEKI TAMOTSU , NAKATANI MASAYOSHI , TAKI CHISATO , SHINOHARA YUKO , OZAWA MOTOKI , NISHIMURA SHIGERU , ITO HIROYUKI , SHIODA SEIJI
Published: August 2006

Abstract: Pituitary adenylate cyclase‐activating polypeptide (PACAP) is well known to protect delayed neuronal cell death in the brain of rodents. In order to investigate the neuroprotective action of PACAP in the retina, we examined the effects of PACAP on kainic acid (KA)‐induced neurotoxicity in the rat retina. Many ganglion cells in the retina died after KA injection in the control group and PACAP treatment significantly promoted cell survival. These findings strongly suggest that PACAP plays very important roles in preventing cell death in the retina.
Serotonergic Inhibition of Intense Jumping Behavior in Mice Lacking PACAP (Adcyap1−/−)
Authors: SHINTANI NORIHITO , HASHIMOTO HITOSHI , TANAKA KAZUHIRO , KAWAGISHI NAOFUMI , KAWAGUCHI CHIHIRO , HATANAKA MICHIYOSHI , AGO YUKIO , MATSUDA TOSHIO , BABA AKEMICHI
Published: August 2006

Abstract: Genetic manipulation of pituitary adenylate cyclase‐activating polypeptide (PACAP) in mice has uncovered its involvement in psychomotor function. We previously observed that mice lacking theAdcyap1gene encoding the neuropeptide PACAP (Adcyap1−/−) displayed intense jumping behavior when placed in a novel environment such as an open field. Here, we show thatAdcyap1−/−mice manifest jumping behavior as early as at least 6 weeks of age when compared with wild‐type mice and that the selective serotonin (5‐HT) reuptake inhibitor, fluoxetine, as well as the serotonin precursor, 5‐hydroxytryptophan, suppress jumping behavior. Our previous study showed a slight decrease in 5‐HT metabolite, 5‐hydroxyindoleacetic acid (5‐HIAA) inAdcyap1−/−mouse brain. Taken together, these results suggest that there is a developmental aspect to the jumping behavior seen inAdcyap1−/−mice, and that jumping behaviour may involve the serotonergic system.
Cyclic AMP Formation in C6 Glioma Cells
Authors: SOKOLOWSKA PAULINA , NOWAK JERZY Z.
Published: August 2006

Abstract: Pituitary adenylate cyclase‐activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) exert their actions via common receptors, VPAC1 and VPAC2, which are equally sensitive to both peptides, while PACAP stimulates its specific PAC1‐type receptors. Both peptides potently stimulate cAMP production in different biological systems. In the present article, we examined the effects of PACAP and VIP on cAMP formation in C6 rat glioma cells used between passages 12‐28 (early) and 120‐136 (late). In the presence of the PDE inhibitor IBMX (0.1 mM), PACAP (0.1 μM) and VIP (1 μM) strongly stimulated cAMP synthesis in C6 cells in early passages, but not in C6 cells in late passages. In contrast, forskolin (10 μM), a direct activator of adenylyl cyclase, and isoprenaline (10 μM), a β‐adrenergic receptor agonist, strongly stimulated cAMP production in both early and late C6 cell passages. Concentration‐dependent studies carried out in early passages with PACAP‐38, PACAP‐27, mammalian and chicken VIPs, and PHI/PHM peptides (1–5 μM) revealed that both forms of PACAP produced strong cAMP accumulation, VIP peptides were less effective than PACAP, while the cAMP effects of PHI/PHM peptides were noticeable only at the highest doses tested. These results suggest that C6 glioma cells in early passages possess functional PAC1 and possibly VPAC‐type receptors, but either the density of PACAP/VIP receptors progressively declines or the PACAP/VIP receptor‐Gs protein coupling becomes less effective through culture passages.
Protective Effects of PACAP in Excitotoxic Striatal Lesion
Authors: TAMÁS A. , LUBICS A. , LENGVÁRI I. , REGLÓDI D.
Published: August 2006

Abstract: The present article investigated the effects of pituitary adenylate cyclase‐activating polypeptide (PACAP) treatment in a quinolinic acid (QA)‐induced unilateral lesion of the striatum, a model of Huntington`s disease (HD). PACAP was given locally, preceding the lesion. Behavioral analysis was performed after 1, 10, and 30 days, when motor activity and asymmetrical signs were evaluated. Three weeks after the treatment, a catalepsy test was performed by haloperidol administration, and finally histological assessment of the striatum was done. Our results show that PACAP treatment attenuated the behavioral deficits and reduced the number of lesioned neurons in the striatum.
Characterization of the PAC1 Variants Expressed in the Mouse Heart
Authors: USHIYAMA MINA , SUGAWARA HIDEKI , INOUE KAZUHIKO , KANGAWA KENJI , YAMADA KATSUSHI , MIYATA ATSURO
Published: August 2006

Abstract: Pituitary adenylate cyclase‐activating polypeptide (PACAP), a pleiotropic neuropeptide, exerts a variety of physiological functions through three types of G protein–coupled receptors, PAC1, VPAC1, and VAPC2. Characterization of the molecular forms of PAC1 in mouse heart revealed the presence of four types of variant receptors harboring the N or S variant in the first extracellular domain (EC1 domain) with or without the HOP1 insert in the third intracellular cytoplasmic loop (IC3 loop). Then, we assessed the binding affinity and ability to stimulate adenylyl cyclase of the PCA1 variant‐expressing cells for PACAP. Adenylyl cyclase activation by PACAP was markedly influenced with the variant in the EC1 domain as well as that in the IC3 loop, in spite of a little difference in their binding properties. These data suggest that the combination of EC1 domain variants and IC3 loop variants might account for the diversity of intracellular signaling, which might contribute to multiple functions of PACAP including a role in the cardiovascular system.
Distribution of PACAP in the Brain of the Cartilaginous FishTorpedo Marmorata
Authors: VALIANTE SALUATORE , PRISCO MARINA , RICCHIARI LOREDANA , LAFORGIA VINCENZA , VARANO LORENZO , ANDREUCCETTI PIERO
Published: August 2006

Abstract: In this article, we investigated the distribution of pituitary adenylate cyclase‐activating polypeptide (PACAP) and its mRNA by immunohistochemistry,in situhybridization, and RT‐PCR techniques, in the central nervous system of the elasmobranchTorpedo marmorata. RT‐PCR analysis showed that the CNS ofT. marmorataexpresses a messenger encoding PACAP. The immunohistochemistry andin situhybridization patterns were partly overlapping, with a major expression in the hypothalamo–pituitary region and, surprisingly, in the saccus vasculosus. Our results show that, inT. marmorata, PACAP is synthesized and widely distributed in the CNS, suggesting an as yet unidentified role for this peptide in elasmobranch brain physiology.
Hedgehog Signaling
Authors: WASCHEK JAMES A. , DICICCO‐BLOOM EMANUEL , NICOT ARNAUD , LELIEVRE VINCENT
Published: August 2006

Abstract:  Hedgehog (HH) is a secreted protein named for the bristle phenotype observed in Drosophila embryos that lack the corresponding gene. Three homologs have been characterized in vertebrates, all which have critical roles in the development of multiple organ systems. Moreover, these proteins regulate stem cell production and activation during tissue repair after injury, and appear to drive proliferation in a variety of type of tumors, including those arising in the brain, foregut, lung, breast, pancreas, stomach, and prostate. Early evidence from Drosophila, and later work in vertebrates established the cAMP/protein kinase A (PKA) pathway as a major pathway which opposes HH signaling, doing so by phosphorylating intracellular signaling mediators and targeting them for degradation. Thus, it seems possible that ligands which activate G protein–coupled receptors (GPCR) may act in some cases to oppose or enhance HH signaling. We studied a possible interaction of pituitary adenylyl cyclase‐activating peptide (PACAP) with sonic hedgehog (SHH) in the developing cerebellum, where both PACAP and SHH are know to act. PACAP and the PAC1‐specific agonist, maxadilan, were found to completely block the proliferative action of SHH on developing cerebellar granule neurons. It remains to be determined if HH/GPCR antagonistic interactions play additional important roles in development, plasticity, tissue repair, cancer, and other processes.
PACAP Stimulates Biosynthesis and Release of Endozepines from Rat Astrocytes
Authors: MASMOUDI‐KOUKI OLFA , GANDOLFO PIERRICK , LEPRINCE JEROME , VAUDRY DAVID , PELLETIER GEORGES , FOURNIER ALAIN , VAUDRY HUBERT , TONON MARIE‐CHRISTINE
Published: August 2006

Abstract: Astrocytes synthesize and release endozepines, a family of neuropeptides related to diazepam‐binding inhibitor (DBI). Astroglial cells also express the receptors of pituitary adenylate cyclase‐activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP). In the present article, we show that PACAP dose dependently increases DBI gene expression and stimulates endozepine release through activation of PAC1‐R. PACAP increases cAMP formation, enhances polyphosphoinositide turnover, and evokes calcium mobilization from intracellular Ca2+pools. The effect of PACAP on endozepine release is mediated through the adenylyl cyclase/PKA pathway while the downregulation of astrocyte response to PACAP can be ascribed to activation of the PLC/PKC pathway.
Immunocytochemical Distribution of VIP and PACAP in the Rat Brain Stem
Authors: AHNAOU ABDEL , YON LAURENT , ARLUISON MICHEL , VAUDRY HUBERT , HANNIBAL JENS , HAMON MICHEL , ADRIEN JOELLE , BOURGIN PATRICE
Published: August 2006

Abstract: Recent evidence indicates that pituitary adenylate cyclase‐activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) might play an important role in rapid eye movement sleep (REMS) generation at the pontine level in rats. We have thus examined the immunohistochemical distribution of VIP and PACAP in the pontine and mesencephalic areas known to be involved in REMS control in rats. A dense network of VIP‐immunoreactive cell bodies and fibers was found in the dorsal raphe nucleus. A large number of PACAP‐positive perikarya and nerve fibers was observed in the area known as the REMS induction zone within the pontine reticular formation (PRF). The present results provide an anatomical basis to our previous functional data, and suggest that PACAPergic mechanisms within the PRF play a critical role in long‐term regulation of REMS.
Electrocardiogram Differentiation of Benign Early Repolarization Versus Acute Myocardial Infarction by Emergency Physicians and Cardiologists
Authors: Turnipseed Samuel D. , Bair Aaron E. , Kirk J. Douglas , Diercks Deborah B. , Tabar Poroshat , Amsterdam Ezra A.
Published: August 2006

Objectives:
ST‐segment elevation (STE) related to benign early repolarization (BER), a common normal variant, can be difficult to distinguish from acute myocardial infarction (AMI). The authors compared the electrocardiogram (ECG) interpretations of these two entities by emergency physicians (EPs) and cardiologists.

Methods:
Twenty‐five cases (13 BER, 12 AMI) of patients presenting to the emergency department with chest pain were identified. Criteria for BER required four of the following: 1) widespread STE (precordial greater than limb leads), 2) J‐point elevation, 3) concavity of initial up‐sloping portion of ST segment, 4) notching or irregular contour of J point, and 5) prominent, concordant T waves. Additional BER criteria were 1) stable ECG pattern, 2) negative cardiac injury markers, and 3) normal cardiac stress test or angiography. AMI criteria were 1) regional STE, 2) positive cardiac injury markers, and 3) identification of culprit coronary artery by angiography in less than eight hours of presentation. The 25 ECGs were distributed to 12 EPs and 12 cardiologists (four in academic medicine, four in community practice, and four in community academics [health maintenance organization] in each physician group). The physicians were informed of the patients' age, gender, and race, and they then interpreted the ECGs as BER or AMI. Undercalls (AMI misdiagnosed as BER) and overcalls (BER misdiagnosed as AMI) were calculated for each physician group.

Results:
Cardiologists correctly interpreted 90% of ECGs, and EPs correctly interpreted 81% of ECGs. The proportion of undercalls (missed AMI/total AMI) was 2.8% for cardiologists (95% confidence interval [CI] = 0.09% to 5.5%) compared with 9.7% for EPs (95% CI = 4.8% to 14.6%) (p = 0.02). The proportion of overcalls (missed BER/total BER) was 17.3% for cardiologists (95% CI = 11.4% to 23.3%) versus 27.6% for EPs (95% CI = 20.6% to 34.6%) (p = 0.03). The mean number of years in practice was 19.8 for cardiologists (95% CI = 19 to 20.5) and 11 years for EPs (95% CI = 10.5 to 12.0) (p < 0.001).

Conclusions:
Although correct interpretation was high in both groups, cardiologists, who had significantly more years of practice, had fewer misinterpretations than EPs in distinguishing BER from AMI electrocardiographically.
A Single Ventilator for Multiple Simulated Patients to Meet Disaster Surge
Authors: Neyman Greg , Irvin Charlene Babcock
Published: August 2006

Objectives

To determine if a ventilator available in an emergency department could quickly be modified to provide ventilation for four adults simultaneously.

Methods

Using lung simulators, readily available plastic tubing, and ventilators (840 Series Ventilator; Puritan‐Bennett), human lung simulators were added in parallel until the ventilator was ventilating the equivalent of four adults. Data collected included peak pressure, positive end‐expiratory pressure, total tidal volume, and total minute ventilation. Any obvious asymmetry in the delivery of gas to the lung simulators was also documented. The ventilator was run for almost 12 consecutive hours (5.5 hours of pressure control and more than six hours of volume control).

Results

Using readily available plastic tubing set up to minimize dead space volume, the four lung simulators were easily ventilated for 12 hours using one ventilator. In pressure control (set at 25 mm H2O), the mean tidal volume was 1,884 mL (approximately 471 mL/lung simulator) with an average minute ventilation of 30.2 L/min (or 7.5 L/min/lung simulator). In volume control (set at 2 L), the mean peak pressure was 28 cm H2O and the minute ventilation was 32.5 L/min total (8.1 L/min/lung simulator).

Conclusions

A single ventilator may be quickly modified to ventilate four simulated adults for a limited time. The volumes delivered in this simulation should be able to sustain four 70‐kg individuals. While further study is necessary, this pilot study suggests significant potential for the expanded use of a single ventilator during cases of disaster surge involving multiple casualties with respiratory failure.
Age determination in individual wild-caughtDrosophila serratausing pteridine concentration
Authors: Robson Simon K. A. , Vickers Mathew , Blows Mark W. , Crozier Ross H.
Published: August 2006

Fluorescence spectrophotometry can reliably detect levels of the pteridine 6-biopterin in the heads of individual Drosophila serrata Malloch 1927. Pteridine content in both laboratory and field captured flies is typically a level of magnitude higher than the minimally detectable level(meanlab=0.54 units, meanfield=0.44 units, minimum detectable level=0.01 units) and can be used to predict individual age in laboratory populations with high certainty (r2=57%). Laboratory studies of individuals of known age (from 1 to 48 days old)indicate that while pteridine level increases linearly with age, they also increase in a linear manner with rearing temperature and ambient light levels,but are independent of sex. As expected, the longevity of laboratory-reared males (at least 48 days) is higher than the range of predicted ages of wild-caught males based on individual pteridine levels (40 days). However, the predictive equation based on pteridine level alone suggested that a number of wild-caught males were less than 0 days old, and the 95% confidence limits for these predictions based on the inverse regression are broad. The age of the oldest wild-caught male is predicted to fall within the range of 2 to 50 days. The significant effects of temperature and light intensity determined in the laboratory study (effect sizes ω2=14.3 and 20.4%,respectively) suggests that the calibration of the age prediction equation for field populations would be significantly improved when combined with fine-scaled studies of habitat temperature and light conditions. The ability to determine relative age in individual wild-caught D. serratapresents great opportunities for a variety of evolutionary studies on the dynamics of natural populations.
Unraveling the mechanical properties of composite silk threads spun by cribellate orb-weaving spiders
Authors: Blackledge Todd A. , Hayashi Cheryl Y.
Published: August 2006

Orb-web weaving spiders depend upon the mechanical performance of capture threads to absorb the energy of flying prey. Most orb-weavers spin wet capture threads with core fibers of flagelliform silk. These threads are extremely compliant and extensible due to the folding of their constituent proteins into molecular nanosprings and hydration by a surrounding coating of aqueous glue. In contrast, other orb-weavers use cribellate capture threads, which are composite structures consisting of core fibers of pseudoflagelliform silk surrounded by a matrix of fine dry cribellar fibrils. Based on phylogenetic evidence, cribellate capture threads predate the use of viscid capture threads. To better characterize how pseudoflagelliform and cribellar fibrils function, we investigated the mechanical performance of cribellate capture threads for three genera of spiders (Deinopis, Hyptiotes and Uloborus). These taxa spin very diverse web architectures, ranging from complete orbs to evolutionarily reduced triangle webs and cast nets. We found that the pseudoflagelliform core fibers of these webs were stiffer and stronger, but also less extensible, than flagelliform silk. However,cribellate capture threads achieved overall high extensibilities because the surrounding cribellar fibrils contributed substantially to the tensile performance of threads long after the core pseudoflagelliform fibers ruptured. In the case of Deinopis capture threads, up to 90% of the total work performed could be attributed to these fibrils. These findings yield insight into the evolutionary transition from cribellate to viscid capture threads.
Effect of parental age and associated size on fecundity, growth and survival in the yellow seahorseHippocampus kuda
Authors: Dzyuba Borys , Van Look Katrien J. W. , Cliffe Alex , Koldewey Heather J. , Holt William V.
Published: August 2006

Seahorses, together with the pipefishes (Family Syngnathidae), are the only vertebrates in which embryonic development takes place within a specialised body compartment, the brood pouch, of the male instead of the female. Embryos develop in close association with the brood pouch epithelium in a manner that bears some resemblance to embryo-placental relationships in mammals. We have explored the hypothesis that parental body size and age should affect offspring postnatal growth and survival if brood pouch quality impacts upon prenatal embryonic nutrition or respiration. Using an aquarium population of the yellow seahorse, Hippocampus kuda, we show here that large parents produce offspring whose initial postnatal growth rates (weeks one to three) were significantly higher than those of the offspring of younger and smaller parents. Whereas 90% of offspring from the larger parents survived for the duration of the study (7 weeks), less that 50% of offspring from smaller parents survived for the same period. For the offspring of large parents,growth rates from individual males were negatively correlated with the number of offspring in the cohort (r=-0.82; P<0.05); this was not the case for offspring from small parents (r=0.048; P>0.9). Observations of embryos within the pouch suggested that when relatively few embryos are present they may attach to functionally advantageous sites and thus gain physiological support during gestation. These results suggest that male body size, and pouch size and function, may influence the future fitness and survival of their offspring.