1.
Endothelin system in intestinal villi: A possible role of endothelin-2/vasoactiveintestinal contractor in the maintenance of intestinal architecture.
Source
Microscopy Laboratory Applied to Cellular and Molecular Studies, Bioengineering and Bioinformatic School, National University of Entre Ríos, Ruta 11, Km 10, 3101 Oro Verde, Entre Ríos, Argentina.
Abstract
The endothelin system consists of three ligands (ET-1, ET-2 and ET-3) and at least two receptors (ETA and ETB). In mice ET-2 counterpart is a peptide originally called "vasoactive intestinal contractor" (VIC) for this reason, this peptide is frequently named ET-2/VIC. In intestinal villi, fibroblasts-like cells express endothelin's receptors and response to ET-1 and ET-3 peptides, changing their cellular shape. Several functions have been attributed to these peptides in the "architecture" maintenance of intestinal villi acting over sub-epithelial fibroblasts. Despite this, ET-2/VIC has not been analyzed in depth. In this work we show the intestine gene expression and immunolocalization of ET-1, ET-2 and the ETA and ETB receptors from duodenum to rectus and in the villus-crypt axis in mice, allowing a complete analysis of their functions. While ET-1 is expressed uniformly, ET-2 had a particular distribution, being higher at the bottom of the villi of duodenum, ileum and jejunum and reverting this pattern in the crypts of colon and rectus, where the higher expression was at the top. We postulated that ET-2 would act in a cooperative manner with ET-1, giving to the villus the straight enough to withstand mechanical stress.
Copyright © 2011 Elsevier Inc. All rights reserved.
Vasoactive Intestinal Peptide Enhances TNF-α-Induced IL-6 and IL-8 Synthesis in Human Proximal Renal Tubular Epithelial Cells by NF-κB-Dependent Mechanism.
Source
Division of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Abstract
Vasoactive intestinal polypeptide (VIP) is a 28-amino acid neuropeptide with vasodilator, bronchodilator, and anti-inflammatory effects. But little is known about its pro-inflammatory effects. We investigated the effect of VIP on the secretion of interleukin-6 (IL-6) and interleukin-8 (IL-8), two pro-inflammatory cytokines, in TNF-α-activated proximal renal tubular epithelial cell line (HK-2 cells). Cultured HK-2 cells were treated with TNF-α in the presence or absence of VIP with a dose range from 1 to 100 nM, followed by analysis of pro-inflammatory cytokines (IL-6 and IL-8) induction and their signal events including activation of the NF-κB pathway. We report here that tumor necrosis factor-α (TNF-α) increased IL-6 and IL-8 production, and that these effects were potentiated by VIP at 10 nM in HK-2 cells. However, VIP at 1 and 100 nM did not display this function. Consistent with these observations, we were able to show that VIP at 10 nM upregulated TNF-α-induced phosphorylation of IκB-α, leading to IκB-α degradation and the subsequent nuclear translocation of NF-κB. Furthermore, VIP-enhanced activation of NF-κB transcription activity was demonstrated using a NF-κB reporter construct upon transient transfection into HK-2 cells. These results strongly suggest that VIP synergistically enhances TNF-α-stimulated IL-6 and IL-8 synthesis via activating the NF-κB pathway in HK-2 cells.
Systemic and topical hormone therapies reduce vaginal innervation density in postmenopausal women.
Source
From the 1Department of Urology and The Landon Center on Aging, 2Institute for Neurological Disorders, 3Department of Molecular and Integrative Physiology, and 4Kansas Intellectual and Developmental Disabilities Research Center, University of Kansas Medical Center, Kansas City, KS.
Abstract
OBJECTIVE:
Menopause is often accompanied by vaginal discomfort including burning, itching, dryness, and spontaneous or provoked pain. Although the direct effects of estrogen withdrawal on vaginal cells are implicated, surgical menopause in rodents causes autonomic and sensory nerves to proliferate, suggesting that indirect effects mediated by changes in vaginal innervation may contribute. We assessed whether postmenopausal women display hormone-dependent changes in vaginal innervation.
METHODS:
Vaginal biopsies from 20 postmenopausal women undergoing surgery for stress urinary incontinence and pelvic organ prolapse were fixed and immunostained for the pan-neuronal marker protein gene product 9.5, sympathetic marker tyrosine hydroxylase, parasympathetic marker vasoactive intestinal polypeptide, and sensory nociceptor marker calcitonin gene-related peptide. Innervation density was measured as an apparent percentage of the section area occupied by immunofluorescent axons. Specimens were grouped according to whether participants received systemic hormone therapy (HT), topical (vaginal) HT, or no HT.
RESULTS:
Women not receiving HT showed relatively high levels of total innervation, with most axons expressing tyrosine hydroxylase or vasoactive intestinal polypeptide immunoreactivity. In women receiving systemic HT, overall innervation was reduced, as were presumptive parasympathetic, sympathetic, and sensory axon populations. Topical HT elicited more dramatic reductions in innervation than in systemic HT.
CONCLUSIONS:
Hormone therapy reduces autonomic and sensory vaginal innervation density, which may, in part, contribute to relief from vaginal discomfort. Moreover, topical therapy is more effective than systemic therapy, which may help explain the greater improvement reported with topical compared with systemic HT.
Venous leg ulcers.
Source
University of Leeds, Leeds, UK.
Abstract
INTRODUCTION:
Leg ulcers usually occur secondary to venous reflux or obstruction, but 20% of people with leg ulcers have arterial disease, with or without venous disorders. Between 1.5 and 3.0/1000 people have active leg ulcers. Prevalence increases with age to about 20/1000 in people aged over 80 years. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of standard treatments, adjuvant treatments, and organisational interventions for venous leg ulcers? What are the effects of advice about self-help interventions in people receiving usual care for venous leg ulcers? What are the effects of interventions to prevent recurrence of venous leg ulcers? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS:
We found 101 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS:
In this systematic review we present information relating to the effectiveness and safety of the following interventions: compression bandages and stockings, cultured allogenic (single or bilayer) skin replacement, debriding agents, dressings (cellulose, collagen, film, foam, hyaluronic acid-derived, semi-occlusive alginate), hydrocolloid (occlusive) dressings in the presence of compression, intermittent pneumatic compression, intravenous prostaglandin E1, larval therapy, laser treatment (low-level), leg ulcer clinics, multilayer elastic system, multilayer elastomeric (or non-elastomeric) high-compression regimens or bandages, oral treatments (aspirin, flavonoids, pentoxifylline, rutosides, stanozolol, sulodexide, thromboxane alpha(2) antagonists, zinc), peri-ulcer injection of granulocyte-macrophage colony-stimulating factor, self-help (advice to elevate leg, to keep leg active, to modify diet, to stop smoking, to reduce weight), short-stretch bandages, single-layer non-elastic system, skin grafting, superficial vein surgery, systemic mesoglycan, therapeutic ultrasound, and topical treatments (antimicrobial agents, autologous platelet lysate, calcitonin gene-relatedpeptide plus vasoactive intestinal polypeptide, freeze-dried keratinocyte lysate, mesoglycan, negative pressure, recombinant keratinocyte growth factor, platelet-derived growth factor).
High-frequency vagus nerve stimulation improves portal hypertension in cirrhotic rats.
Source
University Hospital Gasthuisberg, Leuven, Belgium.
Abstract
ObjectiveThe liver is innervated by the vagus nerve. Its efferent neurotransmitters acetylcholine (ACh) and vasoactive intestinal peptide (VIP) are both well-known vasodilators. A study was undertaken to determine whether electrical vagus nerve stimulation (STIM) influences portal vein pressure.MethodsThe left vagus nerve upstream of the hepatic branch was stimulated at 5 Hz (ACh release) and 10 Hz (VIP release) in normal and cirrhotic rats.ResultsSTIM at both frequencies decreased portal pressure in normal rats while, in cirrhotic rats, only 10 Hz STIM resulted in long-lasting reduction of portal pressure. Hepatic branch vagotomy prevented the STIM-induced decrease in pressure, proving that the effect is a direct hepatic effect. Deafferentation of the left vagus nerve by pretreatment with capsaicin did not change the effect of STIM, showing that the vagus efferents and not the afferents are responsible for the decrease in portal pressure. Injecting microspheres before and after STIM showed that STIM did not lead to redistribution of systemic blood flow but decreased portal pressure by lowering intrahepatic resistance. Using in situ liver perfusion to evaluate the intrahepatic effect of ACh and VIP, both neurotransmitters significantly decreased the perfusion pressure in normal rats. VIP also decreased portal pressure in cirrhotic rats, confirming the results of STIM. This VIP-induced decrease in pressure could be prevented by a VIP receptor 2 antagonist. L-NAME did not inhibit the VIP effect in cirrhotic rats, indicating that VIP does not act via nitric oxide.ConclusionHigh-frequency electrical vagus stimulation improves portal hypertension in cirrhotic rats, most likely through release of VIP, binding to VIP receptor 2. As the technology is already in use for other applications, vagus nerve stimulation might be an important new strategy in the treatment of portal hypertension.
The effect of active immunization against vasoactive intestinal peptide (VIP) and inhibin on reproductive performance of aging White Leghorn roosters.
Source
Department of Animal Sciences, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel;
Abstract
Decreasing fertility in aging domestic roosters is a well-known phenomenon. Aging is manifested by a decrease in plasma testosterone level, testis function, and spermatogenesis, resulting in a low level of fertility. The roles ofvasoactive intestinal peptide (VIP) and testicular inhibin in this aging process are not clear. The effects of active immunization against VIP, inhibin, or the combination of both hormones on the reproduction of aging White Leghorn (WL) roosters were assayed. In experiment 1a, 60 White Leghorn roosters (67 wk of age) were divided into 4 groups (n = 15/group). The first group was actively immunized against VIP, the second against inhibin, the third against VIP and inhibin, and the fourth served as a control. Active immunization against VIP decreased semen quality parameters, plasma steroid levels, and gene expression of gonadotropin-releasing hormone-I (GnRH-I), follicle-stimulating hormone (FSH), luteinizing hormone (LH), LH receptor, VIP, and prolactin (Prl). Immunization against inhibin increased some of the semen quality parameters and FSH mRNA gene expression but decreased inhibin gene expression. In experiment 1b, at 94 wk of age, we took the actively immunized against VIP group and the control group and divided them into 2 subgroups (n = 7 or 8): the first group was injected with 1 mg of ovine Prl (oPrl) daily for 7 d, and the second group served as a control. Administration of oPrl to previously VIP-immunized birds significantly elevated semen quality parameters. We suggest that VIP, Prl, and inhibin have an important effect on the reproductive axis in aging roosters. Active immunization against VIP-depressed reproductive activity and Prl administration restored their reproduction, indicating that both VIP and Prl are essential for reproduction in aging roosters. Immunization against inhibin improved FSH mRNA gene expression, suggesting a negative role of inhibin on FSH secretion in aging roosters. Not all semen quality parameters increased significantly after immunization against inhibin, even though FSH mRNA gene expression increased, suggesting interference in testicular function in aging roosters.
Gender-dependent association of type 2 diabetes with the vasoactive intestinal peptide receptor 1.
Source
Department of Biology and Biotechnology "Charles Darwin", Sapienza, University of Rome, Italy.
Abstract
Type 2 diabetes is characterized by an inadequate pancreatic beta-cell response to the progressive insulin resistance. Its pathogenesis is complex and has been connected with a state of preclinical chronic inflammation. Vasoactive intestinal peptide (VIP) and its receptors play a relevant role in the homeostasis of insulin secretion as well as in the control of inflammation. In particular, VIP receptor 1 (VPAC1) has been found to be down-modulated during inflammation, and to be associated with several diseases. The objective of this study was to compare the distribution of SNPs mapping in the VIP receptor 1 gene in cases with type 2 diabetes and matched controls. Seven hundred cases with type 2 diabetes (423 males and 277 females) and 830 random controls (419 males and 411 females) were analyzed for the distribution of three common SNPs mapping in the VPAC1 gene. The results show a significantly different genotype distribution of the SNP rs9677 in the 3'-UTR of VPAC1 in female cases with type 2 diabetes compared to gender-matched controls (ptrend=6×10(-4)). The rs9677 CC genotype confers the highest risk (OR: 2.1) and correlates with worse clinical parameters such as higher level of total cholesterol, higher LDL/HDL ratio and a higher HbA1c concentration. The genetic association reported here indicates that VIP/VPAC1 signaling can be a relevant pathway in the pathogenesis of type 2 diabetes in females suggesting that at least some aspects of the genetic predisposition to this disease can be gender-specific.
Copyright © 2011 Elsevier B.V. All rights reserved.
Lateralized hippocampal effects of vasoactive intestinal peptide on learning and memory in rats in a model of depression.
Source
Department of Physiology and Pathophysiology, Medical University Varna, 55 Marin Drinov St., 9000, Varna, Bulgaria, mvelikova@yahoo.com.
Abstract
RATIONALE:
Findings of pharmacological studies revealed that vasoactive intestinal peptide (VIP) plays a modulatory role in learning and memory. A role of the peptide in the neurobiological mechanisms of affective disorders was also suggested.
OBJECTIVE:
The objectives are to study the involvement of VIP in learning and memory processes after unilateral and bilateral local application into hippocampal CA1 area in rats with a model of depression (bilateral olfactory bulbectomy-OBX) and to test whether VIP receptors could affect cognition.
RESULTS:
VIP (50 ng) and combination (VIP(6-28) 10 ng + VIP 50 ng) microinjected bilaterally or into the right CA1 area improved the learning and memory of OBX rats in shuttle-box and step-through behavioral tests as compared to the saline-treated OBX controls. Left-side VIP microinjections did not affect the number of avoidances (shuttle box) and learning criteria (step through) as compared to the left-side saline-treated OBX controls. The administration of the combination into left CA1 influenced positively the performance in the step-through task. VIP antagonist (VIP(6-28), 10 ng) did not affect learning and memory of OBX rats. These findings suggest asymmetric effect of VIP on cognitive processes in hippocampus of rats with OBX model of depression.
CONCLUSION:
Our results point to a lateralized modulatory effect of VIP injected in the hippocampal CA1 area on the avoidance deficits in OBX rats. The right CA1 area was predominantly involved in the positive effect of VIP on learning and memory. A possible role of the PAC1 receptors is suggested.
Epithelial Expression of Vasoactive Intestinal Peptide in Ulcerative Colitis: Down-Regulation in Markedly Inflamed Colon.
Source
Department of Clinical and Experimental Medicine, Medical Microbiology, Linköping University, 58183, Linköping, Sweden, maria.jonsson@liu.se.
Abstract
BACKGROUND:
Vasoactive intestinal peptide (VIP) has a number of important effects in intestinal physiology and pathology, including in ulcerative colitis (UC). The expression patterns of the predominant VIP receptor in the mucosa (the VPAC1 receptor) are unknown for the mucosa in UC. It is assumed that the sources of VIP in the intestine are the innervation and the inflammatory cells.
AIMS:
The VIP and VPAC1 receptor expression patterns in the epithelial layer of UC and non-UC patients were examined in the present study. The influence of marked inflammation of the mucosa was evaluated.
METHODS:
Specimens of the human colon, including the colon of UC patients, were examined concerning expressions of VIP and VPAC1 receptor, focusing on the epithelial layer. Immunohistochemistry and in situ hybridization were utilized.
RESULTS:
There were VIP mRNA reactions and also marked VPAC1 receptor immunoreactions in the normal and slightly/moderately affected epithelium. VIP mRNA reactions were not detected and VPAC1 immunoreactions were minimal in response to marked mucosal derangement.
CONCLUSIONS:
The findings suggest that there is a local production of VIP in the epithelial cells in normal and slightly/moderately inflamed mucosa but not in severely inflamed mucosa. Furthermore, a marked downregulation in VPAC1 receptor expressions occurs in the epithelium in severe UC. Based on the knowledge that VIP can have trophic, healing and anti-inflammatory effects, it is likely that the decrease in VIP mRNA and VPAC1 receptor reactions seen in severely affected mucosa in UC may be associated with adverse effects on intestinal function.
Pharmacogenomics in pulmonary arterial hypertension: Toward a mechanistic, target-based approach to therapy.
Source
Department of Medicine, State University of New York at Stony Brook, and Department of Veterans Affairs Medical Center, Northport, New York, USA.
Abstract
Pharmacogenomics is the study of how genetic variations influence the response to drugs, by correlating gene expression with the drug's efficacy and toxicity. This concept has recently been successfully applied in oncology. To test its applicability to PAH, we examined two experimental models of the disease: mice with deletion of the Vasoactive Intestinal Peptide gene (VIP(- /-)); and rats injected with monocrotaline (MCT). Since the two models express comparable phenotypic features, we analyzed their particular gene alterations, with special reference to genes related to pulmonary vasoconstriction, vascular remodeling, and inflammation. We then compared the phenotypic and genotypic responses in each model to treatment with the same drug, VIP. In untreated VIP(-/-) mice there was over-expression of almost all genes promoting vasoconstriction/ proliferation, as well as inflammation, and under-expression of all vasodilator/anti-proliferative genes. As expected, treatment with VIP fully corrected both the key PAH features, and all gene expression alterations. MCT-treated rats showed two distinct sets of alterations. One, similar to that in VIP(- /-) mice, i.e., tended to promote vascular remodeling and inflammation, e.g., up-regulation of myosin polypeptides, procollagen, and some inflammatory genes. The other was a set of opposite alterations that suggested an effort to modulate the PAH, e.g., up-regulation of the VIP and NOS3 genes. In this model, VIP treatment failed to correct many of the genotypic abnormalities, and, in parallel, incompletely corrected the phenotypic changes as well. This preliminary proof-of-concept study demonstrates the importance of genomic information in determining therapeutic outcome, and thus in selecting personalized therapy. Full validation of the merits of pharmacogenomics must await studies of lungs from patients with different forms of PAH.
Physical activity and natural anti-VIP antibodies: potential role in breast and prostate cancer therapy.
Source
Sveti Sava Hospital, Belgrade, Serbia.
Abstract
BACKGROUND:
There is convincing evidence from numerous clinical and epidemiological studies that physical activity can reduce the risk for breast and prostate cancer. The biological mechanisms underlying this phenomenon remain elusive. Herein we suggest a role for naturally produced antibodies reactive with the vasoactive intestinal peptide (VIP) in the suppression of breast and prostate cancer, which we believe could offer a possible molecular mechanism underlying control of these cancers by physical exercise.
METHODOLOGY AND RESULTS:
We found that sera from individuals having breast and prostate cancers have decreased titers of VIP natural antibodies as demonstrated by a lower reactivity against peptide NTM1, having similar informational and structural properties as VIP. In contrast, sera collected from elite athletes, exhibited titers of natural NTM1-reactive antibodies that are significantly increased, suggesting that physical activity boosts production of these antibodies.
SIGNIFICANCE:
Presented results suggest that physical exercise stimulates production of natural anti-VIP antibodies and likely results in suppression of VIP. This, in turn, may play a protective role against breast and prostate cancers. Physical exercise should be further investigated as a potential tool in the treatment of these diseases.
Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions.
Source
Instituto de Parasitologia y Biomedicina, IPBLN-CSIC, Granada, Spain.
Abstract
Vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide/neurotransmitter, is widely distributed in both the central and peripheral nervous system. VIP is released by both neurons and immune cells. Various cell types, including immune cells, express VIP receptors. VIP has pleiotropic effects as a neurotransmitter, immune regulator, vasodilator and secretagogue. This review is focused on VIP production and effects on immune cells, VIP receptor signaling as related to immune functions, and the involvement of VIP in inflammatory and autoimmune disorders. The review addresses present clinical use of VIP and future therapeutic directions.
Origin and convergent evolution of exendin genes.
Source
Department of Laboratory Medicine and Pathobiology, 1 King's College Circle, University of Toronto, Toronto, Ont., Canada M5S 1A8; Banting and Best Diabetes Centre University of Toronto, Toronto, Ont., Canada M5S 1A8.
Abstract
Exendins are secretin hormone-like peptides that are components of the toxins from two venomous lizards, Heloderma suspectum (Gila monster) and Heloderma horridium (Mexican bearded lizard). Exendins-1 and -2 are vasoactive intestinal peptide (VIP)-like, both in sequence and function, while exendins-3 and -4 are glucagon-like peptide-1 (GLP-1)-like. The evolutionary origin of these peptides, and the genes that encode them, has been unclear. Recently, genes orthologous to exendin have been identified in reptiles, birds and amphibians. Analysis of the orthologous sequences demonstrates that the Heloderma exendins diversified by gene duplication from a common exendin ancestor on the Heloderma lineage after divergence from other reptiles, including the anole lizard and Burmese python. In addition, the exendin toxin peptide sequences, but not their pro or signal peptides, have evolved very rapidly on the Heloderma lineage, likely as they adapted to their new function as toxins. Exendins-1 and -2 not only evolved rapidly but their sequences have evolved convergently upon that of VIP, resulting in a doubling of its identity with VIP, while exendins-3 and -4 have retained an ancestral property of being more GLP-1-like sequences. These results suggest that the ancestral role of exendin, which is potentially still retained in some species, had greater similarity with proglucagon-derived peptides or GIP.
Copyright © 2011 Elsevier Inc. All rights reserved.
CD4+ T cell derived novel peptide Thp5 induces IL-4 production in CD4+ T cells to direct T helper 2 cell differentiation.
Source
International Center for Genetic Engineering and Biotechnology, India;
Abstract
The differentiation of naive CD4+ T cells into T helper 2 (Th2) cells requires production of the cytokine IL-4 in the local microenvironment. It is evident that naive/quiescently activated CD4+ T cells produce the IL-4 that drives Th2 cell differentiation. Because early production of IL-4 in naive T cells leads to preferential Th2 cell differentiation, this process needs to be tightly regulated so as to avoid catastrophic and misdirected Th2 cell differentiation. Here, we show that Thp5, a novel peptide with structural similarity to vasoactive intestinal peptide (VIP), regulates production of early IL-4 in newly activated CD4+ T cells. Induction of IL-4 in CD4+ T cells by Thp5 is independent of the transcription factor STAT6 but dependent on Erk-1/2 signaling. Furthermore, cytokines (IL-12 and TGF-β) that promote the differentiation of Th1 or Th17 cells inhibit Thp5 induction, thus suppressing Th2 cell differentiation. We further showed that Thp5 enhances Th2 responses and exacerbates allergic airway inflammation (AAI) in mice. Taken together, our findings reveal that early-activated CD4+ T cells produce Thp5, which plays a critical role as a molecular switch in the differentiation of Th cells, biasing the response towards the Th2 cell phenotype.
Age-related changes in myosin-V myenteric neurons, CGRP and VIP immunoreactivity in the ileum of rats supplemented with ascorbic acid.
Source
Department of Morphological Sciences, Statal University of Maringá, PR, Brazil.
Abstract
We examined the effects of ascorbic acid supplementation on myosin-V, calcitonin gene-related peptide (CGRP) andvasoactive intestinal polypeptide (VIP) immunoractivities in the myenteric neurons in aging rats. Male rats were divided into groups: young 90-day-old rats (E90), 345-day-old control rats (E345), 428-day-old control rats (E428), 90- to 345-day-old rats treated with ascorbic acid (1 g/L) (EA345), and 90- to 428-day-old rats treated with ascorbic acid (1g/L) (EA428). The quantitative results showed that aging reduced the number of myosin-V-immunoreactive neurons compared with young animals (E90). Ascorbic acid supplementation in the EA345 and EA428 groups increased the average area of myosin-V neurons by 24.6% and 24.1% compared with the E345 and E428 groups, respectively. When all groups were compared, we observed significant differences for the CGRP- and VIP-immunoractive varicosities of nerve fibers from myenteric neurons. Ascorbic acid supplementation had a neurotrophic effect on all neurons studied, suggesting a neuroprotective role.
Endothelin-2, the Forgotten Isoform: Emerging Role in the Cardiovascular System, Ovarian Development, Immunology and Cancer.
Abstract
Endothelin-2 (ET-2, also known as vasoactive intestinal contractor or VIC, in rodents) differs from endothelin-1 (ET-1) by only two amino acids, and unlike the third isoform, endothelin-3 (ET-3), it has the same affinity as ET-1 for both ET(A) and ET(B) receptors. It is often assumed that ET-2 would mimic the actions of the more abundant ET-1 and current pharmacological interventions used to inhibit the ET system would also block the actions of ET-2. These assumptions have focused research on ET-1 with ET-2 studied in much less detail. Recent research suggests that our understanding of the ET family requires re-evaluation. Although ET-2 is very similar in structure as well as pharmacology to ET-1, and may co-exist in the same tissue compartments, there is converging evidence for an important and distinct ET-2 pathway. Specifically is has been demonstrated that ET-2 has a key role in ovarian physiology, with ET-2 mediated contraction proposed as a final signal facilitating ovulation. Furthermore, ET-2 may also have a pathophysiological role in heart failure, immunology and cancer. Comparison of ET-2 versus ET-1 mRNA expression suggests this may be accomplished at the level of gene expression but differences may also exist in peptide synthesis by enzymes such as endothelin converting enzymes (ECE) and chymase which may allow the two pathways to be distinguished pharmacologically and become separate drug targets.
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Distribution of vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, nitric oxide synthase, and their receptors in human and rat sphenopalatine ganglion.
Source
Department of Neurology, University of Szeged, Szeged, Hungary; Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden.
Abstract
Cranial parasympathetic outflow is mediated through the sphenopalatine ganglion (SPG). The present study was performed to examine the expression of the parasympathetic signaling transmitters and their receptors in human and rat SPG. Indirect immunofluorescence technique was used for the demonstration of vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating peptide (PACAP), nitric oxide synthase (NOS), glutamine synthetase (GS), glial fibrillary acidic protein (GFAP), VIP and PACAP common receptors (VPAC1, VPAC2), and PACAP receptor (PAC1). In addition, double labeling was carried out to reveal the co-localization of neurotransmitters. VIP-immunoreactive (-ir) neurons as well as fibers were frequently found in human SPG. Many, homogenously stained NOS-ir cells were found, but no positive fibers. In addition, PACAP-ir was observed in some of the neurons and in fibers. Co-localization was found between VIP and NOS. In rat VIP-, NOS-, and PACAP-ir were found in many neurons and fibers. Co-localization of PACAP and NOS was observed in neurons. PACAP and GS double staining revealed that the PACAP-ir was localized in/close to the cell membrane, but not in the satellite glial cells. PAC1 and VPAC1 immunoreactivity was found in the satellite glial cells of both human and rat. Western blot revealed protein expression of PAC1, VPAC1, and VPAC2 in rat SPG. The trigeminal-autonomic reflex may be active in migraine attacks. We hypothesized that VIP, PACAP, NOS, PAC1, VPAC1, and VPAC2 play a role in the activation of parasympathetic cranial outflow during migraine attacks.
Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.
Vasoactive Intestinal Peptide Knockout (VIP KO) Mouse Model of Sulfite-Sensitive Asthma: Up-regulation of Novel Lung Carbonyl Reductase.
Abstract
ABSTRACT:
BACKGROUND:
We earlier reported spontaneous features of asthma in Vasoactive Intestinal Peptide knockout mice (VIP KO): 1) peribronchiolar airway inflammation, with accumulation of lymphocytes and eosinophils, 2) pro-inflammatory cytokine production of IL-5, IL-6, with IFN-g, and 3) airway hyper-responsiveness to inhaled methacholine. In human asthma, a phenotype with sulfite sensitivity leads to airway inflammation and hyper-responsiveness to inhaled sulfites, and is associated with upregulation of anti-oxidant protein lung carbonyl reductase. For the present experiments, we examined the role of VIP in modulating anti-oxidant genes and their proteins, including lung carbonyl reductase.
RESULTS:
Four male VIP KO mice and four wild-type age- and gender matched mice had lungs examined for whole genome microarray and a proteomics approach using mass spectrometry. The proteomics analysis revealed that a novel variant of anti-oxidant protein lung carbonyl reductase (car3) was uniquely and markedly elevated in the VIP KO mice. RT-PCR indicated that carbonic anhydrase 3, which is an anti-oxidant protein, was elevated in the VIP KO mice.
CONCLUSIONS:
These data support the concept that VIP influences the endogenous oxidant/antioxidant balance. One potential implication is that VIP and its analogues may be used to treat inflammatory diseases, including asthma.
Reconsideration of the autonomic cranial Ganglia: an immunohistochemical study of mid-term human fetuses.
Source
Department of Otorhinolaryngology, Tohoku University School of Medicine, Sendai, Japan.
Abstract
The cranial parasympathetic ganglia have been reported to paradoxically contain the sympathetic nerve marker, tyrosine hydroxylase (TH), in addition to neurons expressing parasympathetic markers such as vasoactive intestinal peptide(VIP) and neuronal nitric oxide synthase (nNOS). However, the distribution of these molecules in the cranial ganglia of human fetuses has not yet been examined. Using paraffin sections from 10 mid-term human fetuses (12-15 weeks), we performed immunohistochemistry for TH, VIP, and nNOS in the parasympathetic ciliary, pterygopalatine, otic, and submandibular ganglia, and for comparison, the sensory inferior vagal ganglion. The ciliary and submandibular ganglia contained abundant TH-positive neurons. In the former, TH-positive neurons were much more numerous than nNOS-positive neurons, whereas in the latter, nNOS immunoreactivity was extremely strong. No or a few cells in the pterygopalatine, otic, and inferior vagal ganglia expressed TH. Ciliary TH neurons appeared to compensate for classically described sympathetic fibers arising from the superior cervical ganglion, whereas in the submandibular ganglion, nNOS-positive neurons as well as TH neurons might innervate the lingual artery in addition to the salivary glands. Significant individual variations in the density of all these markers suggested differences in sensitivity to medicine affecting autonomic nerve function. Consequently, in the human cranial autonomic ganglia, it appears that there is no simple dichotomy between sympathetic and parasympathetic function. Anat Rec, 2012. © 2011 Wiley Periodicals, Inc.
Copyright © 2011 Wiley Periodicals, Inc.
- PMID:
- 22095632
- [PubMed - in process]
Peptide polarity and the position of arginine as sources of selectivity during positive electrospray ionisation mass spectrometry.
Source
School of Science, University of Greenwich, Chatham Maritime, Kent, ME4 4TB, UK.
Abstract
Electrospray ionisation (ESI) is a selective process and, for similar sized analytes, the intrinsic properties of the molecules affect the ionisation process and their response. This research sets out to determine the effect of some of these properties in peptides: peptide polarity and the presence of arginine at positions 1 and 4 in the amino acid sequence on the ESI response. Six peptides; molecular mass ranges 1.3-1.6 kDa; substance P (SP) and glutamate fibrinopeptide (GFP) and 3.2-3.7 kDa; calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), glucagon-like peptide 1 (GLP1) and defensin human neutropeptide 2 (DHNP2), were investigated. We have demonstrated that in positive ESI, for similar sized peptides and the same charge state, the responsiveness is in the order: Peptides with N or C terminal arginine > most non-polar peptides > least non-polar peptides. Therefore, arginine at the terminal position is a source of selectivity. Data from matrix-assisted laser desorption ionisation (MALDI) analysis supports that of the ESI experiments: Peptides with a terminal arginine residue generated higher signal intensities. Our observations extend our understanding of the ESI process and provide a rational approach to optimising sensitivity of electrospray conditions where a narrow mass range of peptides are poorly chromatographically resolved. This information will provide for a more effective method development process, especially during label-free quantitative determination of peptides extracted in solution.
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