Regulatory Peptides[JOURNAL]
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200 papers
Neuromedin B stimulates the hypothalamic-pituitary-gonadal axis in male rats.
Boughton CK, Patel SA, Thompson EL … +7 more , Patterson M, Curtis AE, Amin A, Chen K, Ghatei MA, Bloom SR, Murphy KG
Regul Pept · 2013 Nov · PMID 24120470 · Publisher ↗
Neuromedin B (NMB) is a highly conserved bombesin-related peptide found in mammals. NMB mRNA is detected in the central nervous system (CNS) and is highly expressed in the rat hypothalamus, in particular the medial preop...
Neuromedin B (NMB) is a highly conserved bombesin-related peptide found in mammals. NMB mRNA is detected in the central nervous system (CNS) and is highly expressed in the rat hypothalamus, in particular the medial preoptic area and the arcuate nucleus. The mammalian bombesin family of receptors consists of three closely related G protein coupled receptors, BB1, BB2 and BB3. The BB1 receptor subtype has the highest affinity for NMB. NMB has well documented roles in the regulation of the thyroid axis and the stress axis in rats. However, there is little available data regarding the role of NMB in the regulation of the hypothalamic-pituitary-gonadal (HPG) axis. It is known that the NMB receptor is expressed in immortalised gonadotrophin releasing hormone (GnRH) releasing GT1-7 cells and murine forebrain GnRH neurons, and that anterior pituitary NMB-immunoreactivity is altered by changes in the sex steroid environment. The objective of these studies was thus to further investigate the effects of NMB on the HPG axis. Intracerebroventricular (ICV) administration of NMB (10 nmol) to adult male rats significantly increased plasma luteinising hormone (LH) levels 30 min after injection (plasma LH ng/ml; saline 0.69±0.07, 10 nmol NMB 1.33±0.17, P<0.01). In vitro, NMB stimulated GnRH release from hypothalamic explants from male rats and from hypothalamic GT1-7 cells. NMB had no significant effect on LH release from anterior pituitary explants from male rats, or from pituitary LβT2 cells in vitro. These results suggest a previously unreported role for NMB in the stimulation of the HPG axis via hypothalamic GnRH. Further work is now required to determine the receptor mediating the effects of NMB on the reproductive axis and the physiological role of NMB in reproduction.
Expression and distribution of GnRH, LH, and FSH and their receptors in gastrointestinal tract of man and rat.
Sand E, Bergvall M, Ekblad E … +2 more , D'Amato M, Ohlsson B
Regul Pept · 2013 Nov · PMID 24103690 · Publisher ↗
BACKGROUND: Gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) regulate the reproductive axis. Their analogs have been found to influence gastrointestinal activity and...
BACKGROUND: Gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) regulate the reproductive axis. Their analogs have been found to influence gastrointestinal activity and enteric neuronal survival. The aims of the study were to investigate expression and cellular distribution of GnRH, LH, and FSH and their receptors in human and rat gastrointestinal tract. METHODS: Bioinformatic analysis of publicly available microarray gene expression data and Real-Time PCR mRNA quantification were used to study mRNA expression levels of hormones and receptors in human intestinal tissue. Full-thickness sections of human ileum and colon, and rat stomach, ileum, and colon, were used for immunocytochemistry. Antibodies against human neuronal protein HuC/D (HuC/D) were used as general neuronal marker. LH and FSH, and GnRH-, LH-, and FSH receptor immunoreactive (IR) neurons were evaluated. RESULTS: GnRH1 mRNA was detected in both small and large intestine, whereas GnRH2 was mainly expressed in small intestine. Approximately 20% of both submucous and myenteric neurons displayed LH receptor immunoreactivity in human ileum and colon. In rat, 4%-9% of all enteric neurons in fundus and ileum, and 13% of submucous neurons and 21% of myenteric neurons in colon were LH receptor-IR. Neither mRNA (man) nor the fully expressed proteins (man and rat) of LH and FSH, or GnRH and FSH receptors, could be detected. CONCLUSIONS: GnRH1 and GnRH2 mRNA are expressed in human intestine. LH receptor-IR enteric neurons are found along the entire gastrointestinal tract in both man and rat.
Restoration of endogenous substance P is associated with inhibition of apoptosis of retinal cells in diabetic rats.
Yang JH, Guo Z, Zhang T … +2 more , Meng XX, Xie LS
Regul Pept · 2013 Nov · PMID 24045094 · Publisher ↗
This study was designed to investigate the alterations of substance P (SP) and its correlation with apoptosis of the retinal neurons in diabetic rats. The study was carried out with diabetic rats induced by streptozotoci...
This study was designed to investigate the alterations of substance P (SP) and its correlation with apoptosis of the retinal neurons in diabetic rats. The study was carried out with diabetic rats induced by streptozotocin. Changes of SP and its mRNA were examined using enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction. The effect of restoration of SP level by capsaicin (20mg/kg, s.c.) on the apoptosis of the retinal cells was studied. The apoptosis was evaluated by change of ratio of the apoptotic cells and caspase-3 activity in the retina. It was found that increase in apoptosis of retinal cells, by 3.5 fold of control, was accompanied by reduction of SP, by 28% in protein and 32% in the mRNA in the retina at 10 weeks of induction of diabetes, compared to the controls. Capsaicin significantly elevated endogenous SP, by 29% in the mRNA and 17% in protein in the retina, with marked inhibition of the apoptosis and the activity of caspase-3 in the diabetic rats. Induction of diabetes leads to the increase of cell apoptosis and the decrease of SP in the retina. The reduction of the endogenous SP and the increase of the cell apoptosis in the retina of the diabetic rats were reversed by pretreatment with capsaicin. Restoration of SP in the retina may be a novel option for prevention of the retinal injury during development of diabetes.
Therapeutic concentrations of valproate but not amitriptyline increase neuropeptide Y (NPY) expression in the human SH-SY5Y neuroblastoma cell line.
Farrelly LA, Savage NT, O'Callaghan C … +2 more , Toulouse A, Yilmazer-Hanke DM
Regul Pept · 2013 Sep · PMID 23994577 · Publisher ↗
Neuropeptide Y (NPY) is a peptide found in the brain and autonomic nervous system, which is associated with anxiety, depression, epilepsy, learning and memory, sleep, obesity and circadian rhythms. NPY has recently gaine...
Neuropeptide Y (NPY) is a peptide found in the brain and autonomic nervous system, which is associated with anxiety, depression, epilepsy, learning and memory, sleep, obesity and circadian rhythms. NPY has recently gained much attention as an endogenous antiepileptic and antidepressant agent, as drugs with antiepileptic and/or mood-stabilizing properties may exert their action by increasing NPY concentrations, which in turn can reduce anxiety and depression levels, dampen seizures or increase seizure threshold. We have used human neuroblastoma SH-SY5Y cells to investigate the effect of valproate (VPA) and amitriptyline (AMI) on NPY expression at therapeutic plasma concentrations of 0.6mM and 630nM, respectively. In addition, 12-O-tetradecanoylphorbol-13-acetate (TPA) known to differentiate SH-SY5Y cells into a neuronal phenotype and to increase NPY expression through activation of protein kinase C (PKC) was applied as a positive control (16nM). Cell viability after drug treatment was tested with a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. NPY expression was measured using immunofluorescence and quantitative RT-PCR (qRT-PCR). Results from immunocytochemistry have shown NPY levels to be significantly increased following a 72h but not 24h VPA treatment. A further increase in expression was observed with simultaneous VPA and TPA treatment, suggesting that the two agents may increase NPY expression through different mechanisms. The increase in NPY mRNA by VPA and TPA was confirmed with qRT-PCR after 72h. In contrast, AMI had no effect on NPY expression in SH-SY5Y cells. Together, the data point to an elevation of human NPY mRNA and peptide levels by therapeutic concentrations of VPA following chronic treatment. Thus, upregulation of NPY may have an impact in anti-cancer treatment of neuroblastomas with VPA, and antagonizing hypothalamic NPY effects may help to ameliorate VPA-induced weight gain and obesity without interfering with the desired central effects of VPA.
Esmolol activates endogenous neurokinin activity inhibiting infarction-induced arrhythmias in rats: novel mechanisms of anti-arrhythmia.
Wang LL, Han Y, Guo Z … +2 more , Han SQ, Liu T
Regul Pept · 2013 Sep · PMID 23994276 · Publisher ↗
Endogenous neurokinin and adrenergic mechanisms might co-participate in the pathology of acute myocardial infarction (MI). This study sought to investigate the role of endogenous neurokinin and its relationship with β1-a...
Endogenous neurokinin and adrenergic mechanisms might co-participate in the pathology of acute myocardial infarction (MI). This study sought to investigate the role of endogenous neurokinin and its relationship with β1-adrenergic mechanism in the infarction induced arrhythmias. In 60min of MI in rats, the contents of substance P (SP), a native agonist of neurokinin 1 receptor (NK1-R), norepinephrine (NE), NK1-R and β1-adrenergic receptor in the myocardium at risk of ischemia were examined and the ventricular arrhythmias were analyzed. The effects of pretreatment with D-SP (152ng/kg), a specific antagonist of NK1-R, esmolol (10mg/kg), a specific blocker of β1-adrenergic receptor, and a combination of the two blockers were studied. The results showed that the overlaps of up-regulation of NE, SP and the increase of ventricular arrhythmias were observed. D-SP exacerbated the episodes and duration of VT & VF by 54% and 104%, respectively (all P<0.05). Esmolol inhibited the morbidity rate, the episodes and the duration of VT & VF by 66%, 92% and 95%, respectively. Surprisingly, esmolol significantly attenuated the arrhythmogenic effect of D-SP throughout the MI, beyond the time span of esmolol action, during which a significant up-regulation of the NK1-R (by 19%, P<0.05) was detected. In conclusion, the findings of this study may indicate an anti-arrhythmic effect of endogenous neurokinin mechanism, through the activation of which, via up-regulation of NK1 receptor, esmolol may exert its anti-arrhythmic action at the early time of acute myocardial infarction.
Characterization of pericardial and plasma ghrelin levels in patients with ischemic and non-ischemic heart disease.
Sax B, Merkely B, Túri K … +7 more , Nagy A, Ahres A, Hartyánszky I, Hüttl T, Szabolcs Z, Cseh K, Kékesi V
Regul Pept · 2013 Sep · PMID 23994275 · Publisher ↗
Ghrelin is an endocrine regulatory peptide with multiple functions including cardioprotective effects. It is produced in various tissues among others in the myocardium. Pericardial fluid has been proven to be a biologica...
Ghrelin is an endocrine regulatory peptide with multiple functions including cardioprotective effects. It is produced in various tissues among others in the myocardium. Pericardial fluid has been proven to be a biologically active compartment of the heart that communicates with the myocardial interstitium. Thus, pericardial level of certain agents may reflect their concentration in the myocardium well. In our study we measured acylated (active) and total (acylated and non-acylated) pericardial and plasma ghrelin levels of patients with ischemic and non-ischemic heart disease. Pericardial fluid and plasma samples were obtained from patients with coronary artery disease (ISCH, n=54) or valvular heart disease (VHD, n=41) undergoing cardiac surgery. Acylated pericardial ghrelin concentrations were found to be significantly higher in patients with ischemic heart disease (ISCH vs. VHD, 32±3 vs. 16±2pg/ml, p<0.01), whereas plasma levels of the peptide showed no difference between patient groups. Pericardial-to-plasma ratio, an index abolishing systemic effects on local ghrelin level was also significantly higher in ISCH group for both acylated and total ghrelin. Plasma total ghrelin showed negative correlation to BMI, plasma insulin and insulin resistance index HOMA-A. Pericardial acylated and total ghrelin concentrations were negatively correlated with posterior wall thickness (R=-0.31, p<0.05 and R=-0.35, p<0.01, respectively). Plasma insulin concentration and HOMA-A showed significant negative correlation with pericardial ghrelin levels. In conclusion, increased pericardial active ghrelin content and higher pericardial-to-plasma ghrelin ratio were found in ischemic heart disease as compared to non-ischemic patients suggesting an increased ghrelin production of the chronically ischemic myocardium. According to our results, pericardial ghrelin content is negatively influenced by left ventricular hypertrophy and insulin resistance.
Gestational hypertension in atrial natriuretic peptide knockout mice and the developmental origins of salt-sensitivity and cardiac hypertrophy.
Armstrong DW, Tse MY, O'Tierney-Ginn PF … +8 more , Wong PG, Ventura NM, Janzen-Pang JJ, Matangi MF, Johri AM, Croy BA, Adams MA, Pang SC
Regul Pept · 2013 Sep · PMID 23981445 · Publisher ↗
OBJECTIVE: To determine the effect of gestational hypertension on the developmental origins of blood pressure (BP), altered kidney gene expression, salt-sensitivity and cardiac hypertrophy (CH) in adult offspring. METHOD...
OBJECTIVE: To determine the effect of gestational hypertension on the developmental origins of blood pressure (BP), altered kidney gene expression, salt-sensitivity and cardiac hypertrophy (CH) in adult offspring. METHODS: Female mice lacking atrial natriuretic peptide (ANP-/-) were used as a model of gestational hypertension. Heterozygous ANP+/- offspring was bred from crossing either ANP+/+ females with ANP-/- males yielding ANP+/-(WT) offspring, or from ANP-/- females with ANP+/+ males yielding ANP+/-(KO) offspring. Maternal BP during pregnancy was measured using radiotelemetry. At 14weeks of age, offspring BP, gene and protein expression were measured in the kidney with real-time quantitative PCR, receptor binding assay and ELISA. RESULTS: ANP+/-(KO) offspring exhibited normal BP at 14weeks of age, but displayed significant CH (P<0.001) as compared to ANP+/-(WT) offspring. ANP+/-(KO) offspring exhibited significantly increased gene expression of natriuretic peptide receptor A (NPR-A) (P<0.001) and radioligand binding studies demonstrated significantly reduced NPR-C binding (P=0.01) in the kidney. Treatment with high salt diet increased BP (P<0.01) and caused LV hypertrophy (P<0.001) and interstitial myocardial fibrosis only in ANP+/-(WT) and not ANP+/-(KO) offspring, suggesting gestational hypertension programs the offspring to show resistance to salt-induced hypertension and LV remodeling. Our data demonstrate that altered maternal environments can determine the salt-sensitive phenotype of offspring.
Postpartum reversibility of impaired incretin effect in gestational diabetes mellitus.
Kosinski M, Knop FK, Vedtofte L … +4 more , Grycewiczv J, Swierzewska P, Cypryk K, Vilsbøll T
Regul Pept · 2013 Sep · PMID 23958841 · Publisher ↗
The potential reversibility of a reduced incretin effect is unclear. We investigated the incretin effect during third trimester and 3 to 4months postpartum in women with and without gestational diabetes mellitus (GDM). T...
The potential reversibility of a reduced incretin effect is unclear. We investigated the incretin effect during third trimester and 3 to 4months postpartum in women with and without gestational diabetes mellitus (GDM). Ten women with GDM (plasma glucose (PG) concentration at 120min after 75g-oral glucose tolerance test (OGTT) (PG120min): 10.1±0.6mmol/l (mean±SEM)) and eight women with normal glucose tolerance (NGT; PG120min: 7.0±0.1mmol/l) were investigated on four occasions: 4h 50g-OGTT and isoglycaemic intravenous glucose infusion during third trimester and 3 to 4months postpartum. In women with GDM, the incretin effect increased significantly postpartum (31±6 vs. 56±6%, p=0.02), whereas the increment in women with NGT was insignificant (35±12 vs. 56±9%, p=0.08). Similarly, the gastrointestinal-mediated glucose disposal (GIGD=100%×(glucoseOGTT-glucoseIIGI)/glucoseOGTT) was reduced to diabetic levels in women with GDM (37±3%), but increased (p=0.030) to normal levels post partum (58±6%). GIGD did not change significantly in NGT women (48±3 vs. 57±6%, p=0.94). Women with GDM exhibit a reduced incretin effect which is fully reversible alongside the restoration of normal glucose homeostasis, whereas the reduction in incretin effect during pregnancy in women with NGT was insignificant. Our results suggest that decreased incretin effect in women with GDM is a fully reversible phenomenon.
Keratinocytes express cytokines and nerve growth factor in response to neuropeptide activation of the ERK1/2 and JNK MAPK transcription pathways.
Shi X, Wang L, Clark JD … +1 more , Kingery WS
Regul Pept · 2013 Sep · PMID 23958840 · Full text
Sensory neurons innervating the skin can release neuropeptides that are believed to modulate cellular proliferation, wound healing, pigmentation, and keratinocyte innate immune responses. While the ability of neuropeptid...
Sensory neurons innervating the skin can release neuropeptides that are believed to modulate cellular proliferation, wound healing, pigmentation, and keratinocyte innate immune responses. While the ability of neuropeptides to stimulate keratinocyte production of inflammatory mediators has been demonstrated, there is no information concerning the mechanisms by which neuropeptide activation of keratinocyte cell surface receptors ultimately leads to the up-regulation of mediator production. In this study we used a keratinocyte cell line to identify the presence of substance P (SP) and calcitonin gene-related peptide (CGRP) receptors on keratinocytes and examined the effects of SP and CGRP stimulation on keratinocyte neuropeptide signaling, cell proliferation, and interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and nerve growth factor (NGF) expression. Neuropeptide stimulation caused an up-regulation of neuropeptide receptor expression in keratinocytes and a dramatic increase in keratinocyte secretion of SP and CGRP, suggesting possible autocrine or paracrine stimulatory effects and amplification of neuropeptide signaling. Both SP and CGRP concentration-dependently stimulated cellular proliferation and the expression and secretion of inflammatory cytokines and NGF in keratinocytes. SP also activated all 3 families of mitogen activated protein kinase (MAPK) and nuclear factor κB (NFκB) in keratinocytes, while CGRP only activated p38 and extracellular signal related kinase1/2 (ERK1/2) MAPKs. Neuropeptide stimulated inflammatory mediatory production in keratinocytes was reversed by ERK1/2 and JNK inhibitors. The current study is the first to observe; 1) that CGRP stimulates keratinocyte expression of CGRP and its receptor complex, 2) that SP and CGRP stimulate IL-6 and TNF-α secretion in keratinocytes, 3) that SP activated all three MAPK families and the NFκB transcriptional signaling pathway in keratinocytes, and 4) that SP and CGRP stimulated inflammatory mediator production in keratinocytes is dependent on ERK1/2 and JNK activation. These studies provide evidence suggesting that disruption of ERK1/2 and JNK signaling may potentially be an effective therapy for inflammatory skin diseases and pain syndromes mediated by exaggerated sensory neuron-keratinocyte signaling.
Parp1 deficient mice are protected from streptozotocin-induced diabetes but not caerulein-induced pancreatitis, independent of the induction of Reg family genes.
Li B, Luo C, Chowdhury S … +2 more , Gao ZH, Liu JL
Regul Pept · 2013 Sep · PMID 23954400 · Publisher ↗
Poly(ADP-ribose) polymerase (Parp) 1 is a key regulator of cell death, its inhibition prevented streptozotocin-induced diabetes and attenuated caerulein-induced acute pancreatitis. Reg family proteins are significantly i...
Poly(ADP-ribose) polymerase (Parp) 1 is a key regulator of cell death, its inhibition prevented streptozotocin-induced diabetes and attenuated caerulein-induced acute pancreatitis. Reg family proteins are significantly induced by Parp1 inhibitor, experimental diabetes and/or acute pancreatitis. We propose that Reg proteins are involved in the protection of pancreatic cells by Parp1 inhibition. To test this possibility, Parp1-/- and wild-type mice were injected with streptozotocin to induce diabetes. Separately, acute pancreatitis was induced with repeated injections of caerulein. Upon streptozotocin administration, Parp1-/- mice displayed much decreased hyperglycemia and preserved serum insulin level. The treatment induced similar levels of Reg1, -2, -3α and -3β genes in the pancreas of both wild-type and Parp1-/- mice, suggesting that the upregulation of Reg family genes during streptozotocin-induced diabetes was independent of Parp1 ablation. In caerulein-induced pancreatitis, unlike being reported, Parp1 knockout caused no relief on the severity of pancreatitis; the upregulation of pancreatic Reg1, -2, -3α and -3β genes upon caerulein was unaffected by Parp1 deletion. Our results reconfirmed the protective effect of Parp1 gene deletion on islet β-cells but questioned its effect on the acinar cells. In either case, the significant induction of Reg family genes seemed independent of Parp1-mediated cell death.
Ghrelin stimulates synaptic formation in cultured cortical networks in a dose-dependent manner.
Stoyanova II, le Feber J, Rutten WL
Regul Pept · 2013 Sep · PMID 23892033 · Publisher ↗
Ghrelin was initially related to appetite stimulation and growth hormone secretion. However, it also has a neuroprotective effect in neurodegenerative diseases and regulates cognitive function. The cellular basis of thes...
Ghrelin was initially related to appetite stimulation and growth hormone secretion. However, it also has a neuroprotective effect in neurodegenerative diseases and regulates cognitive function. The cellular basis of these processes is related to synaptic efficacy and plasticity. Previous studies indicated that ghrelin has an excitatory effect on neuronal activity, and stimulates synaptic plasticity in vivo. Plasticity in the adult brain occurs in many different ways, including changes in synapse morphology and number. Therefore, we used in vitro neuronal cultures to investigate how ghrelin affects synaptogenesis. We used dissociated cortical cultures of newborn rats, chronically treated with different doses of ghrelin (0.5, 1, 1.5 and 2μM). After one-, two-, three- or four weeks cultures were immunostained for the presynaptic marker synaptophysin. In parallel, additional groups of non-treated cultures were immunostained for detection of ghrelin receptor (GHSR1). During development, GHSR1was increasingly expressed in all type of neurons, as well as the synaptophysin. Synaptic density depended on ghrelin concentration, and was much higher than in controls in all age groups. In conclusion, ghrelin leads to earlier network formation in dissociated cortical networks and an increase in number of synapses. The effect is probably mediated by GHSR1. These findings suggest that ghrelin may provide a novel therapeutic strategy for the treatment of disorders related to synaptic impairment.
Comparison of immunomodulatory functions of three peptides from the chicken bursa of Fabricius.
Liu XD, Zhou B, Cao RB … +3 more , Feng XL, Li XF, Chen PY
Regul Pept · 2013 Sep · PMID 23892032 · Publisher ↗
The bursa of Fabricius (BF) is the acknowledged central humoral immune organ unique to birds which plays important roles in B cell development and antibody production. Little information on immunomodulatory functions of...
The bursa of Fabricius (BF) is the acknowledged central humoral immune organ unique to birds which plays important roles in B cell development and antibody production. Little information on immunomodulatory functions of BF is reported, except for several reported active bursal-derived peptides. Three peptides were identified and characterized from BF through RP-HPLC and MADIL-TOF methods. They are named as bursal peptide (BP)-I, BP-II, BP-III. These peptides promoted CFU pre-B formation and decreased PU.1 expression. The different immunomodulatory activities of these three bursal peptides on antibody and cytokine productions were verified by the immunization comparative experiment. The results showed the three bursal peptides enhanced AIV-specific antibody and cytokine production, T-cell immunophenotyping at reachable concentrations. These results indicate the important orientations for the comprehensive understanding of the humoral central immune system, and provide a novel insight on new experimental reagents for immuno-adjuvant or immunopharmacological.
Anxiolytic action of neuromedin-U and neurotransmitters involved in mice.
Telegdy G, Adamik A
Regul Pept · 2013 Sep · PMID 23892031 · Publisher ↗
Peptide Neuromedin-U (NmU) is widely distributed in the central nervous system and the peripheral tissues. Its physiological effects include the regulation of blood pressure, heart rate, and body temperature, and the inh...
Peptide Neuromedin-U (NmU) is widely distributed in the central nervous system and the peripheral tissues. Its physiological effects include the regulation of blood pressure, heart rate, and body temperature, and the inhibition of gastric acid secretion. The action of NmU in rats is mediated by two G-protein-coupled receptors, NmU-1R and NmU-2R. NmU-2R is present mainly in the brain, and NmU-1R mainly in the periphery. Despite the great variety of the physiological action of NmU, little is known about its possible effects in different forms of behavior, such as anxiety. In the present work, NmU-23 (the rodent form of the peptide) was tested for its effect on anxiety in elevated plus maze test in mice. For detection of the possible involvement of neurotransmitters, the mice were pretreated with receptor blockers: haloperidol (a D2, dopamine receptor antagonist), propranolol (a β-adrenergic receptor antagonist), atropine (a nonselective muscarinic acetylcholine receptor antagonist), phenoxybenzamine (a nonselective α-adrenergic receptor antagonist) or nitro-l-arginine (a nitric oxide synthase inhibitor). The peptide and nitro-l-arginine were administered into the lateral brain ventricle, while the receptor blockers were applied intraperitoneally. An NmU-23 dose 0.5μg elicited anxiolytic action, whereas this action is faded away when the dose was increased. For further testing therefore 0.5μg i.c.v. was used. Propranolol and atropine fully blocked the NmU-induced anxiolytic action, while haloperidol, phenoxybenzamine and nitro-l-arginine were ineffective. The results suggest that β-adrenergic and cholinergic mechanisms are involved in the anxiolytic action of NmU.
Obestatin prevents analgesic tolerance to morphine and reverses the effects of mild morphine withdrawal in mice.
Lipták N, Dochnal R, Csabafi K … +2 more , Szakács J, Szabó G
Regul Pept · 2013 Sep · PMID 23891980 · Publisher ↗
Obestatin is a 23-amino acid gut-derived neuropeptide, encoded by the same gene with ghrelin. The goal of this study was to examine the effects of obestatin on the acute and chronic analgesic actions of morphine and on m...
Obestatin is a 23-amino acid gut-derived neuropeptide, encoded by the same gene with ghrelin. The goal of this study was to examine the effects of obestatin on the acute and chronic analgesic actions of morphine and on mild morphine withdrawal. Open-field (OF) and elevated plus maze (EPM) tests were used to assess mild morphine withdrawal-induced behavior changes and the heat-radiant tail-flick assay was used to investigate analgesic actions of morphine. CFLP male mice were treated twice a day with graded doses of morphine in EPM and OF experiments and once a day in tail-flick studies. Obestatin (1.5μg/2μl) was administrated once a day in all experiments. Furthermore, 0.2mg/kg naloxone or saline was administered after the final injection of morphine at a dose of 20mg/kg in EPM and OF. These behavioral parameters were monitored in the OF: the percentage of center ambulation time and distance; whereas in the EPM: the time spent in open arms and the entries into open arms compared to the total time (%OAT) and entries (%OAE). In the OF, obestatin significantly decreased the percentage of time spent in the center in mice undergoing naloxone-precipitated mild morphine withdrawal. EPM results were similar to open field, but obestatin had no significant effect on parameters mentioned above. Besides, obestatin maintained the analgesic effect of morphine 90 and 120min after morphine injection in mice treated with morphine receiving obestatin compared to mice treated with morphine. In tolerance studies, obestatin diminished the analgesic tolerance to morphine on the 5th day. In this study we confirmed that obestatin reversed the effect of mild morphine withdrawal and enhances the analgesic effect of morphine. These data suggest that obestatin may have a role in opioid-induced analgesia and in behavioral responses induced by opioid withdrawal.
Effects of exogenous vasoactive intestinal peptide on mesenteric lymph pathway during early intestinal ischemia-reperfusion injury in rats.
Yang H, Jin Y, Wang CH … +1 more , Tang CW
Regul Pept · 2013 Sep · PMID 23872373 · Publisher ↗
Mesenteric lymph pathway serves as the primary route by which gut injury leads to systemic inflammation and distant organ injury. The inflammation of the intestinal tract is partially mediated by vasoactive intestinal pe...
Mesenteric lymph pathway serves as the primary route by which gut injury leads to systemic inflammation and distant organ injury. The inflammation of the intestinal tract is partially mediated by vasoactive intestinal peptide (VIP). Therefore, the aim of this study was to test whether exogenous VIP affects mesenteric lymph pathway during early intestinal ischemia-reperfusion (IIR) injury. Rats were randomized into control, control+VIP, IIR and IIR+VIP groups. The observation of mesenteric lymph flow was carried out by cannulation of mesenteric lymphatics. The distribution of in vivo lymphocyte trafficking was performed by (51)Cr labeled lymphocytes and was measured by γ-counter. Endotoxin concentration was assayed using the limulus test kit and TNF-α level was detected by ELISA. When IIR injury treated with VIP, the volumes of lymph flow increased by 80%, which caused the number of lymphocytes exiting in mesenteric lymphatic increased by 50% while the proportion of (51)Cr-lymphocytes in Peyer's patches, intestinal effector tissues, mesenteric nodes, large intestine, stomach decreased by 58%, 51%, 58%, 63%, 64% respectively at the 6th h after reperfusion following intestinal ischemia. Meanwhile, endotoxin and TNF-α levels in intestinal lymph decreased by 51% and 83%. These results suggest that exogenous VIP ameliorates IIR induced splanchnic organ damage via inhibition of toxic mediators reaching systemic circulation and reinforcement of the effective immune responses in gut-associated lymphoid tissues (GALT).
Intracerebroventricular injection of stresscopin-related peptide enhances cardiovascular function in conscious rats.
Jin R, Li MZ, Bing YH … +6 more , Piao RL, Li YJ, Jin QH, Qiu DL, Kannan H, Chu CP
Regul Pept · 2013 Sep · PMID 23850799 · Publisher ↗
Stresscopin-related peptide (SRP), which is a member of the corticotropin-releasing factor (CRF) family, is a high-affinity ligand for the type 2 corticotropin-releasing factor receptor (CRF-R2) and is involved in stress...
Stresscopin-related peptide (SRP), which is a member of the corticotropin-releasing factor (CRF) family, is a high-affinity ligand for the type 2 corticotropin-releasing factor receptor (CRF-R2) and is involved in stress-coping responses. Central treatment with SRP suppresses food intake, delays gastric emptying and decreases heat-induced edema, but the effects of central administration of SRP on the cardiovascular system are unclear. Here we examined the effects of intracerebroventricular (i.c.v.) administration of SRP on cardiovascular function, and compared the cardiovascular effects of SRP and stresscopin (SCP). Our results showed that i.c.v. administration of SRP (0.5nmol) increased mean arterial blood pressure (MABP) and heart rate (HR), but failed to increase plasma norepinephrine and epinephrine levels. Compared with an equivalent dose of SCP, the area under the curve (AUC) values for the changes in MABP and HR were significantly smaller with SRP, indicating that the cardiovascular effects of SRP were weaker than those mediated by SCP. Pre-treatment with a selective CRF-R2 antagonist, antisauvagine-30 (4nmol, i.c.v.) abolished the SRP and SCP induced changes in MABP and HR. These results indicate that central administration of SRP induces a weaker enhancement of cardiovascular function through CRF-R2 than that induced by SCP and that these effects are mediated without increasing plasma norepinephrine and epinephrine levels.
Identification, tissue distribution and regulation of preproghrelin in the brain and gut of Schizothorax prenanti.
Wei R, Liu T, Zhou C … +7 more , Zhang X, Yuan D, Wang T, Lin F, Chen H, Wu H, Li Z
Regul Pept · 2013 Sep · PMID 23850798 · Publisher ↗
Ghrelin is an important gastrointestinal hormone involved in the regulation of feeding in both mammals and fish. In this study, the preproghrelin cDNA sequence was cloning in the gut of Schizothorax prenanti (S. prenanti...
Ghrelin is an important gastrointestinal hormone involved in the regulation of feeding in both mammals and fish. In this study, the preproghrelin cDNA sequence was cloning in the gut of Schizothorax prenanti (S. prenanti). The preproghrelin gene, encoding 103-amino acids, was strongly expressed in the gut and brain using real-time quantitative RT-PCR (qPCR). The S. prenanti preproghrelin was detected in embryonic developmental stages. Further, it was detectable in unfertilized eggs, suggesting that ghrelin could be classified as maternal mRNA. An experiment was conducted to determine the expression profile of ghrelin during post-feeding and fasting status of the brain and gut. The results revealed a significant postprandial decrease in ghrelin mRNA expression in the gut 6h post-feeding (hpf) and brain (1.5 and 9hpf) compared to an unfed control group, indicating that food intake and processing affect the regulation of expression of ghrelin in S. prenanti. The constructed recombinant plasmid pMD-19T-ghrelin was transformed to Escherichia coli BL21 and induced with IPTG, and the expressed product was identified by SDS-PAGE. The prokaryotic expression vector for ghrelin was constructed successfully, and fusion protein was expressed in E. coli BL21, which laid the foundation for the further study on the function of this protein and its mechanism. Overall, our results provide evidence for a highly conserved structure and biological actions of ghrelin in S. prenanti. Further studies are required to identify the tissue specific functions of ghrelin in S. prenanti.
Effect of angiotensin II on rhythmic per2 expression in the suprachiasmatic nucleus and heart and daily rhythm of activity in Wistar rats.
Herichová I, Šoltésová D, Szántóová K … +4 more , Mravec B, Neupauerová D, Veselá A, Zeman M
Regul Pept · 2013 Sep · PMID 23850797 · Publisher ↗
Endogenous daily rhythms are generated by the hierarchically organized circadian system predominantly synchronized by the external light (L): dark (D) cycle. During recent years several humoral signals have been found to...
Endogenous daily rhythms are generated by the hierarchically organized circadian system predominantly synchronized by the external light (L): dark (D) cycle. During recent years several humoral signals have been found to influence the generation and manifestation of daily rhythm. Since most studies have been performed under in vitro conditions, the mechanisms employed under in vivo conditions need to be investigated. Our study focused on angiotensin II (angII)-mediated regulation of Per2 expression in the suprachiasmatic nuclei (SCN) and heart and spontaneous locomotor activity in Wistar rats under synchronized conditions. Angiotensin II was infused (100ng/kg/min) via subcutaneously implanted osmotic minipumps for 7 or 28days. Samples were taken in 4-h intervals during a 24hcycle and after a light pulse applied in the first and second part of the dark phase. Gene expression was measured using real time PCR. Locomotor activity was monitored using an infrared camera with a remote control installed in the animal facility. Seven days of angII infusion caused an increase in blood pressure and heart/body weight index and 28days of angII infusion also increased water intake in comparison with controls. We observed a distinct daily rhythm in Per2 expression in the SCN and heart of control rats and infused rats. Seven days of angII infusion did not influence Per2 expression in the heart. 28days of angII treatment caused significant phase advance and a decrease in nighttime expression of Per2 and influenced expression of clock controlled genes Rev-erb alpha and Dbp in the heart compared to the control. Four weeks of angII infusion decreased the responsiveness of Per2 expression in the SCN to a light pulse at the end of the dark phase of the 24hcycle. Expression of mRNA coding angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) showed a daily rhythm in the heart of control rats. Four weeks of angII infusion caused a decrease in amplitude of rhythmic expression of Ace, the disappearance of rhythm and an increase in Ace2 expression. The Ace/Ace2 ratio showed a rhythmic pattern in the heart of control rats with peak levels during the dark phase. Angiotensin II infusion decreased the mean Ace/Ace2 mRNA ratio in the heart. We observed a significant daily rhythm in expression of brain natriuretic peptide (BNP) in the heart of control rats. In hypertensive rats mean value of Bnp expression increased. Locomotor activity showed a distinct daily rhythm in both groups. Angiotensin II time dependently decreased ratio of locomotor activity in active versus passive phase of 24hcycle. To conclude, 28days of subcutaneous infusion of angII modulates the functioning of the central and peripheral circadian system measured at the level of Per2 expression and locomotor activity.
DPP8 and DPP9 expression in cynomolgus monkey and Sprague Dawley rat tissues.
Harstad EB, Rosenblum JS, Gorrell MD … +10 more , Achanzar WE, Minimo L, Wu J, Rosini-Marthaler L, Gullo R, Ordway ND, Kirby MS, Chadwick KD, Cosma GN, Moyer CF
Regul Pept · 2013 Sep · PMID 23850796 · Publisher ↗
Dipeptidyl peptidases (DPPs) are proteolytic enzymes that regulate many physiological systems by degrading signaling peptides. DPP8 and DPP9 are distinct from DPP4 in sequence, cellular localization and expression levels...
Dipeptidyl peptidases (DPPs) are proteolytic enzymes that regulate many physiological systems by degrading signaling peptides. DPP8 and DPP9 are distinct from DPP4 in sequence, cellular localization and expression levels, thus implying distinct functions. However, DPP8 and DPP9 expression needs further delineation. We evaluated DPP4, DPP8 and DPP9 expression using three independent methods at the mRNA, protein, and functional levels to better understand the local physiological contribution of each enzyme. Sprague Dawley rats and cynomolgus monkeys were selected for DPP4, DPP8 and DPP9 expression profiling to represent animal species commonly utilized for drug preclinical safety evaluation. A novel Xhibit assay of DPP protease activity was applied in addition to newly available antibodies for immunohistochemical localization. This combined approach can facilitate a functional evaluation of protease expression, which is important for understanding physiological relevance. Few inter-species differences were observed. Tissue mRNA and protein levels generally correlated to functional DPP4 and DPP8/9 enzymatic activity. All three proteins were seen in epithelial cells, lymphoid cells and some endothelial and vascular smooth muscle cells. Combined DPP8/DPP9 enzymatic activity was uniformly intracellular across tissues at approximately 10-fold lower levels than non-renal DPP4. Consistent levels of each DPP were detected among most non-renal tissues in rats and monkeys. DPP4 was ubiquitous, principally detected on cell membranes of epithelial and endothelial cells and was greatest in the kidney. The expression patterns suggest that DPP8 and DPP9 may act similarly across tissues, and that their actions might in part overlap with DPP4.
Expressions of neuropeptide Y and Y1 receptor in subcutaneous and visceral fat tissues in normal weight and obese humans and their correlations with clinical parameters and peripheral metabolic factors.
Sitticharoon C, Chatree S, Churintaraphan M
Regul Pept · 2013 Aug · PMID 23838112 · Publisher ↗
Recently, neuropeptide Y (NPY) and Y1 receptor (Y1R) were found to be expressed and synthesized in adipose tissue. This study aimed to compare NPY and Y1R mRNA expressions in subcutaneous and visceral fat tissues as well...
Recently, neuropeptide Y (NPY) and Y1 receptor (Y1R) were found to be expressed and synthesized in adipose tissue. This study aimed to compare NPY and Y1R mRNA expressions in subcutaneous and visceral fat tissues as well as serum NPY in normal weight and obese humans and their correlations with clinical parameters and peripheral metabolic factors. We demonstrated that NPY mRNA expression was higher in obese than in normal weight humans (p<0.05) in both subcutaneous and visceral adipose tissues and was significantly greater in visceral when compared with subcutaneous fat in overall (p<0.01), obese (p<0.05) and normal weight humans (p<0.05). Y1R mRNA expression was higher in obese than normal weight subjects in visceral (p<0.01) but not in subcutaneous adipose tissue and was statistically greater in subcutaneous when compared to visceral adipose tissue in obese (p<0.05) and overall subjects (p<0.05). Serum NPY was higher in obese than normal weight groups (p<0.05). Obese subjects showed significantly greater levels of systolic blood pressure (SBP) (p<0.01), diastolic blood pressure (DBP) (p<0.05), plasma insulin (p<0.05), and HOMA-IR (p<0.05) when compared with normal weight subjects. Additionally, Y1R mRNA expression in visceral adipose tissue was positively correlated with body weight (R=0.586), BMI (R=0.611), waist (R=0.474) and hip (R=0.483) circumferences, insulin levels (R=0.539), and HOMA-IR (R=0.480). As the result, Y1R expression in visceral adipose tissue might be an indicator of increased risk of metabolic syndrome. Further studies about blocking specific Y1R may propose strategies for risk reduction in metabolic syndrome and prevention or treatment of obesity.
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