Regulatory Peptides[JOURNAL]
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200 papers
Prokineticin 2 is involved in the thermoregulation and energy expenditure.
Zhou W, Li JD, Hu WP … +2 more , Cheng MY, Zhou QY
Regul Pept · 2012 Nov · PMID 22960406 · Publisher ↗
Animals have developed adaptive strategies to survive tough situations such as food shortage. However, the underlying molecular mechanism is not fully understood. Here, we provided evidence that the regulatory peptide pr...
Animals have developed adaptive strategies to survive tough situations such as food shortage. However, the underlying molecular mechanism is not fully understood. Here, we provided evidence that the regulatory peptide prokineticin 2 (PK2) played an important role in such an adaptation. The PK2 expression was rapidly induced in the hypothalamic paraventricular nucleus (PVN) after fasting, which can be mimicked by 2-deoxy-D-glucose (2-DG) injection. The fasting-induced arousal was absent in the PK2-deficient (PK2(-/-)) mice. Furthermore, PK2(-/-) mice showed less energy expenditure and body weight loss than wild-type (WT) controls upon fasting. As a result, PK2(-/-) mice entered torpor after fasting. Supply of limited food (equal to 5% of body weight) daily during fasting rescued the body weight loss and hypothermal phenotype in WT mice, but not in PK2(-/-) mice. Our study thus demonstrated PK2 as a regulator in the thermoregulation and energy expenditure.
Receptor-mediated inhibition of small bowel migrating complex by GLP-1 analog ROSE-010 delivered via pulmonary and systemic routes in the conscious rat.
Hellström PM, Smithson A, Stowell G … +7 more , Greene S, Kenny E, Damico C, Leone-Bay A, Baughman R, Grant M, Richardson P
Regul Pept · 2012 Nov · PMID 22960405 · Publisher ↗
BACKGROUND: ROSE-010, a Glucagon-Like Peptide-1 (GLP-1) analog, reduces gastrointestinal motility and relieves acute pain in patients with irritable bowel syndrome (IBS). The rat small bowel migrating myoelectric complex...
BACKGROUND: ROSE-010, a Glucagon-Like Peptide-1 (GLP-1) analog, reduces gastrointestinal motility and relieves acute pain in patients with irritable bowel syndrome (IBS). The rat small bowel migrating myoelectric complex (MMC) is a reliable model of pharmacological effects on gastrointestinal motility. Accordingly, we investigated whether ROSE-010 works through GLP-1 receptors in gut musculature and its effectiveness when administered by pulmonary inhalation. MATERIALS AND METHODS: Rats were implanted with bipolar electrodes at 5, 15 and 25 cm distal to pylorus and myoelectric activity was recorded. First, intravenous or subcutaneous injections of ROSE-010 or GLP-1 (1, 10, 100 μg/kg) with or without the GLP-1 receptor blocker exendin(9-39)amide (300 μg/kg·h), were studied. Second, ROSE-010 (100, 200 μg/kg) Technosphere® powder was studied by inhalation. RESULTS: The baseline MMC cycle length was 17.5±0.8 min. GLP-1 and ROSE-010, administered intravenously or subcutaneously, significantly inhibited myoelectric activity and prolonged MMC cycling; 100 μg/kg completely inhibited spiking activity for 49.1±4.2 and 73.3±7.7 min, while the MMC cycle length increased to 131.1±11.4 and 149.3±15.5 min, respectively. Effects of both drugs were inhibited by exendin(9-39)amide. Insufflation of ROSE-010 (100, 200 μg/kg) powder formulation totally inhibited myoelectric spiking for 52.6±5.8 and 70.1±5.4 min, and increased MMC cycle length to 102.6±18.3 and 105.9±9.5 min, respectively. CONCLUSIONS: Pulmonary delivery of ROSE-010 inhibits gut motility through the GLP-1R similar to natural GLP-1. ROSE-010 causes receptor-mediated inhibition of MMC comparable to that of intravenous or subcutaneous administration. This suggests that ROSE-010 administered as a Technosphere® inhalation powder has potential in IBS pain management and treatment.
Acute response of hypophysiotropic thyrotropin releasing hormone neurons and thyrotropin release to behavioral paradigms producing varying intensities of stress and physical activity.
Gutiérrez-Mariscal M, Sánchez E, García-Vázquez A … +3 more , Rebolledo-Solleiro D, Charli JL, Joseph-Bravo P
Regul Pept · 2012 Nov · PMID 22960404 · Publisher ↗
The activity of the hypothalamus-pituitary-thyroid (HPT) axis is essential for energy homeostasis and is differentially modulated by physical and by psychological stress. Contradictory effects of stressful behavioral par...
The activity of the hypothalamus-pituitary-thyroid (HPT) axis is essential for energy homeostasis and is differentially modulated by physical and by psychological stress. Contradictory effects of stressful behavioral paradigms on TSH or thyroid hormone release are due to type, length and controllability of the stressor. We hypothesized that an additional determinant of the activity of the HPT axis is the energy demand due to physical activity. We thus evaluated the response of thyrotropin releasing hormone (TRH) neurons of the hypothalamic paraventricular nucleus (PVN) in Wistar male rats submitted to the elevated plus maze (EPM), the open field test (OFT), or restraint, and sacrificed within 1h after test completion; the response to OFT was compared during light (L) or dark (D) phases. Locomotion and anxiety behaviors were similar if animals were tested in L or D phases but their relation to the biochemical parameters differed. All paradigms increased serum corticosterone concentration; the levels of corticotropin releasing hormone receptor 1 and of glucocorticoid receptor (GR) mRNAs in the PVN were enhanced after restraint or OFT-L. Levels of proTRH mRNA increased in the PVN after exposure to EPM-L or OFT-D; serum levels of thyrotropin (TSH) and T(4) only after OFT-D. In contrast, restraint decreased TRH mRNA and serum TSH levels, while it increased TRH content in the mediobasal hypothalamus, implying reduced release. Expression of proTRH in the PVN varied proportionally to the degree of locomotion in OFT-D, while inversely to anxiety in the EPM-L, and to corticosterone in EPM-L and OFT-D. TRH mRNA levels were analyzed by in situ hybridization in the rostral, middle and caudal zones of the PVN in response to OFT-D; they increased in the middle PVN, where most TRH hypophysiotropic neurons reside; levels correlated positively with the velocity attained in the periphery of the OF and negatively, with anxiety. Variations of serum TSH levels correlated positively with locomotor activity in EPM-L and OFT-L or -D, while negatively to serum corticosterone levels in all paradigms. These results support the proposal that the hypophysiotropic PVN TRH neurons are activated by short term physical activity but that this response may be blunted by the inhibitory effect of stress.
[D-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, augments the effects of orally delivered exenatide and pramlintide acetate on energy balance and glycemic control in insulin-resistant male C57BLK/6-m db/db mice.
Leinung MC, Grasso P
Regul Pept · 2012 Nov · PMID 22960403 · Publisher ↗
The escalation predicted for the incidence of both type 2 diabetes mellitus and obesity has prompted investigators to search for additional pharmacotherapeutic approaches to their treatment. Two of these approaches, comb...
The escalation predicted for the incidence of both type 2 diabetes mellitus and obesity has prompted investigators to search for additional pharmacotherapeutic approaches to their treatment. Two of these approaches, combination pharmacotherapy and utilization of leptin-related bioactive synthetic peptides as anti-diabetes/anti-obesity agents, were used in the present study. Exenatide or pramlintide acetate was reconstituted in dodecyl maltoside (DDM) in the absence or presence of [D-Leu-4]-OB3, and delivered orally by gavage to insulin-resistant male C57BLK/6-m db/db mice twice daily for 14 days. Body weight gain, food and water intake, blood glucose, and serum insulin levels were measured. Mice given DDM alone for 14 days were 19.7% heavier than they were at the beginning of the study, while oral delivery of exenatide or [D-Leu-4]-OB3 in DDM reduced body weight gain to only 13.9% and 11.5%, respectively, of initial body weight. Mice receiving exenatide and [D-Leu-4]-OB3 were 4.2% lighter than they were at the beginning of the study. In another study, Intravail® treated control mice gained 38.2% of their initial body weight, while mice receiving pramlintide acetate or [D-Leu-4]-OB3 were only 26.8% and 25.4% heavier, respectively, at the end of the study, Co-administration of pramlintide acetate and [D-Leu-4]-OB3 did not further enhance the effect of pramlintide acetate on body weight gain. Food intake was reduced by exenatide, pramlintide acetate, and [D-Leu-4]-OB3 alone, and co-delivery with [D-Leu-4]-OB3 did not induce a further decrease. Water intake was not affected by exenatide, pramlintide acetate, or [D-Leu-4]-OB3 alone, but co-delivery of exenatide or pramlintide acetate with [D-Leu-4]-OB3 resulted in a significant reduction in water intake. Oral delivery of exenatide or pramlintide acetate in DDM significantly lowered blood glucose levels by 20.4% and 30.2%, respectively. Co-delivery with [D-Leu-4]-OB3 further reduced blood glucose by 38.3% and 50.5%, respectively. A concentration-dependent increase in serum insulin was observed in response to increasing concentrations of exenatide, and [D-Leu-4]-OB3 slightly reduced the insulin response to exenatide at all concentrations tested. Increasing concentrations of pramlintide acetate alone did not elevate serum insulin, and when given in combination with [D-Leu-4]-OB3, serum insulin levels fell below those of DDM-treated control mice. Our data indicate that (1) exenatide and pramlintide acetate, currently administered by subcutaneous injection, can be given orally in DDM; (2) the bioactivity of exenatide and pramlintide acetate is retained following oral delivery in DDM; and (3) the effects of exenatide and pramlintide acetate on energy balance and glycemic control can be enhanced by co-administration with [D-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity.
Myocardial angiogenesis after chronic ghrelin treatment in a rat myocardial infarction model.
Yuan MJ, He-Huang, Hu HY … +3 more , Li-Quan, Hong-Jiang, Huang CX
Regul Pept · 2012 Nov · PMID 22960289 · Publisher ↗
Ghrelin has a protective role in a rat model of myocardial infarction (MI), but the underlying mechanism is not clear. Here, we investigated the effects of ghrelin treatment on angiogenesis in an experimental rat MI mode...
Ghrelin has a protective role in a rat model of myocardial infarction (MI), but the underlying mechanism is not clear. Here, we investigated the effects of ghrelin treatment on angiogenesis in an experimental rat MI model. Adult male Sprague-Dawley rats were subjected to MI by ligating the anterior descending coronary artery. The rats were then treated with a subcutaneous injection of ghrelin (100 μg/kg) or saline (control group) for 4 weeks. Sham animals underwent thoracotomy and pericardiotomy, but not LAD ligation. At 28 days after ligation, the ghrelin treatment group showed a higher density of α-SMA positive vessels than the saline treatment MI group in myocardial infarct (6±2.1/mm(2) vs 4±1.8/mm(2), P<0.05) and peri-infarct zones (25±9.5/mm(2) vs 15±5.7/mm(2), P<0.05). RT-PCR and western-blot analyses showed that ghrelin significantly increased vascular endothelial growth factor (VEGF) expression in the peri-infarct zone compared with the control group. Moreover, there was a two-fold increase of Bcl-2 and a 3.5-fold reduction of the Bax protein in the ghrelin-treated MI group compared to the saline treatment MI group. Taken together, ghrelin could induce angiogenesis in rats after MI, the process that may be associated with the enhancement of VEGF and an anti-apoptosis effect.
Effect of exenatide on cholecystokinin-induced gallbladder emptying in fasting healthy subjects.
Keller J, Trautmann ME, Haber H … +4 more , Tham LS, Hunt T, Mace K, Linnebjerg H
Regul Pept · 2012 Nov · PMID 22960288 · Publisher ↗
Exenatide is a glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes and has been shown to lower blood glucose through multiple mechanisms, including glucose-dependent insulin secretion, suppressi...
Exenatide is a glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes and has been shown to lower blood glucose through multiple mechanisms, including glucose-dependent insulin secretion, suppression of postprandial glucagon release and slowing of gastric emptying. The effects of exenatide on biliary motility are unknown. This study evaluated the effect of a single dose of exenatide on cholecystokinin (CCK)-induced gallbladder emptying. Healthy subjects participated in this randomized, 2-period, double-blind crossover study. Fasting subjects received a single subcutaneous injection of exenatide (10 μg) or placebo 60 min before CCK infusion. Gallbladder volume and ejection fraction (EF) were assessed by ultrasonography before, during, and after CCK infusion (0.003 μg/kg infused over 50 min at 2 mL/min). The diameters of the main pancreatic duct and common bile duct were measured sonographically at the same time points before, during, and following CCK infusion. Administration of exenatide did not affect pre-CCK infusion gallbladder volume or EF compared to placebo. During the CCK-infusion, the mean minimum gallbladder volume was similar for exenatide (13.68 mL) and placebo (11.05 mL) (least squares mean [LSM] difference of 2.62 mL; 95% confidence interval [CI], -0.53, 5.78), but the mean maximum EF was lower for exenatide (28.79%) versus placebo (46.13%) (LSM difference of -17.34%; 95% CI, -30.54, -4.13). Exenatide had no clinically significant effects on pancreatic or bile duct diameters. In conclusion, exenatide reduced CCK-induced gallbladder emptying compared with placebo in fasting healthy subjects.
In vivo effect of glucose-dependent insulinotropic peptide (GIP) on the gene expression of calcitonin peptides in human subcutaneous adipose tissue.
Pivovarova O, Gögebakan O, Osterhoff MA … +3 more , Nauck M, Pfeiffer AF, Rudovich N
Regul Pept · 2012 Nov · PMID 22960196 · Publisher ↗
BACKGROUND: Increased plasma levels of calcitonin gene-related peptide-I (CGRP-I) and procalcitonin (Pro-CT) (both also named calcitonin peptides (CT peptides)) are associated with obesity and systemic inflammation. Gluc...
BACKGROUND: Increased plasma levels of calcitonin gene-related peptide-I (CGRP-I) and procalcitonin (Pro-CT) (both also named calcitonin peptides (CT peptides)) are associated with obesity and systemic inflammation. Glucose-dependent insulinotropic polypeptide (GIP), a nutrient-dependent incretin hormone, was recently found to induce CGRP-I and CT expression in human adipocytes in vitro. However, a physiological relevance of a possible interaction between GIP and CT peptides has not yet been studied. METHODS: In this study, we analyzed the effect of GIP on the expression of CGRP-I and CT mRNA in human subcutaneous adipose tissue within a randomized, controlled trial. Seventeen male obese subjects were infused with GIP [2.0 pmol kg(-1) min(-1) for 240 min] or placebo, either in the fasting state, during euglycemic-hyperinsulinemic (EC) or hyperglycemic-hyperinsulinemic clamps (HC). RESULTS: The CGRP-I gene expression was detected in all investigated adipose tissue samples, whereas very low CT expression was found in only 8 out of 116 analyzed samples. No significant influence of either GIP or glucose and insulin infusions on the CGRP-I and CT expression was observed in any of the individual experiments (GIP infusion, EC and HC) or in the combined analysis of all experiments with and without GIP. Furthermore, CGRP-I expression was not correlated with plasma GIP level before or after 240 min of infusions or clamps. CONCLUSION: In contrast to in vitro data, an acute application of GIP has no effect on mRNA expression of CT peptides in subcutaneous adipose tissue of obese humans.
Contribution of caveolin-1 to ventricular nitric oxide in age-related adaptation to hypovolemic state.
Arreche ND, Sarati LI, Martinez CR … +2 more , Fellet AL, Balaszczuk AM
Regul Pept · 2012 Nov · PMID 22954805 · Publisher ↗
Our previous results have shown that hypovolemic state induced by acute hemorrhage in young anesthetized rats triggers heterogeneous and dynamic nitric oxide synthase (NOS) activation, modulating the cardiovascular respo...
Our previous results have shown that hypovolemic state induced by acute hemorrhage in young anesthetized rats triggers heterogeneous and dynamic nitric oxide synthase (NOS) activation, modulating the cardiovascular response. Involvement of the nitric oxide pathway is both isoform-specific and time-dependent. The aim of the present study was to investigate changes in activity and protein levels of the different NOS forms, changes in the abundance of caveolin-1 during hypovolemic state and caveolin-1/eNOS association using young and middle-aged rats. Therefore, we studied (i) changes in NOS activity and protein levels and (ii) caveolin-1 abundance, as well as its association with endothelial NOS (eNOS) in ventricles from young and middle-aged rats during hypovolemic state. We used 2-month (young) and 12-month (middle-aged) old male Sprague-Dawley rats. Animals were divided into two groups (n=14/group): (a) sham; (b) hemorrhaged animals (20% blood loss). With advancing age, we observed an increase in ventricle NOS activity accompanied by a decrease in eNOS and caveolin-1 protein levels, but increased inducible NOS (iNOS). We also observed that aging is associated with caveolin-1 dissociation from eNOS. Myocardia from young and middle-aged rats subjected to hemorrhage-induced hypovolemia exhibited an increase in NOS activity and protein levels with a reduction in caveolin-1 abundance, accompanied by a greater dissociation between eNOS and its regulatory protein. Further, an increase in iNOS protein levels after blood loss was observed only in middle-aged rats. Our evidence suggests that aging and acute hemorrhage contribute to the development of upregulation in NOS activity. Our findings demonstrate that specific expression patterns of ventricular NOS isoforms, alterations in the amount of caveolin-1 and caveolin-1/eNOS interaction are involved in aged-related adjustment to hypovolemic state.
Involvement of brain ANG II in acute sodium depletion induced salty taste changes.
Lu B, Yan J, Yang X … +2 more , Li J, Chen K
Regul Pept · 2012 Nov · PMID 22846885 · Publisher ↗
Many investigations have been devoted to determining the role of angiotensin II (ANG II) and aldosterone (ALD) in sodium-depletion-induced sodium appetite, but few were focused on the mechanisms mediating the salty taste...
Many investigations have been devoted to determining the role of angiotensin II (ANG II) and aldosterone (ALD) in sodium-depletion-induced sodium appetite, but few were focused on the mechanisms mediating the salty taste changes accompanied with sodium depletion. To further elucidate the mechanism of renin-angiotensin-aldosterone system (RAAS) action in mediating sodium intake behavior and accompanied salty taste changes, the present study examined the salty taste function changes accompanied with sodium depletion induced by furosemide (Furo) combined with different doses of angiotensin converting enzyme (ACE) inhibitor, captopril (Cap). Both the peripheral and central RAAS activity and the nuclei Fos immunoreactivity (Fos-ir) expression in the forebrain area were investigated. Results showed that sodium depletion induced by Furo+low-Cap increased taste preference for hypertonic NaCl solution with amplified brain action of ANG II but without peripheral action, while Furosemide combined with a high dose of captopril can partially inhibit the formation of brain ANG II, with parallel decreased effects on salty taste changes. And the resulting elevating forebrain ANG II may activate a variety of brain areas including SFO, PVN, SON and OVLT in sodium depleted rats injected with Furo+low-Cap, which underlines salty taste function and sodium intake behavioral changes. Neurons in SFO and OVLT may be activated mainly by brain ANG II, while PVN and SON activation may not be completely ANG II dependent. These findings suggested that forebrain derived ANG II may play a critical role in the salty taste function changes accompanied with acute sodium depletion.
GLP-2 enhances barrier formation and attenuates TNFα-induced changes in a Caco-2 cell model of the intestinal barrier.
Moran GW, O'Neill C, McLaughlin JT
Regul Pept · 2012 Oct · PMID 22809889 · Publisher ↗
INTRODUCTION: Tight junctions are intercellular permeability seals that regulate paracellular transport across epithelia. Tight junction function, expression and localisation of constituent proteins are significantly alt...
INTRODUCTION: Tight junctions are intercellular permeability seals that regulate paracellular transport across epithelia. Tight junction function, expression and localisation of constituent proteins are significantly altered by cytokines such as TNFα. Glucagon-like peptide-2 (GLP-2) is an intestinotrophic enteroendocrine peptide. It is not known whether GLP-2 regulates the barrier or tight junctions. The aim of this study was to investigate whether GLP-2 has an effect on tight junction function or protein expression, alone or in response to TNFα exposure. METHODS: Caco-2 cells were grown to confluence on filters in the presence or absence of GLP-2. The time course of transepithelial electrical resistance developing across the monolayer was measured; tight junction protein expression was quantified by immunoblotting. At day 20, TNFα in the presence or absence of GLP-2 was added. Changes in TEER and tight junction proteins expression were quantified. Both TNFα and GLP-2 were added on the basolateral side. RESULTS: GLP-2 exposed Caco-2 cell monolayers showed a significant increase in transepithelial electrical resistance compared to that in untreated control cells. At the same time, expression of the tight junction proteins occludin and zona occludens-1 (ZO-1) was increased at day 17 post-seeding (1.6-fold; p=0.037 and 4.7 fold; p=0.039 respectively). Subsequent TNFα exposure induced a significant 9.3-fold (p<0.001) decrease in transepithelial electrical resistance and a corresponding reduction in the expression of ZO-1 (5.3 fold; p<0.01). However, the TNFα-induced reduction in transepithelial electrical resistance in GLP-2-exposed cells was highly attenuated to 1.8-fold (p<0.01). No change in tight junction protein expression was noted in GLP-2 exposed cells after cytokine exposure. CONCLUSION: GLP-2 enhances formation of the epithelial barrier and its constituent proteins in Caco-2 cells, and diminishes the effects of TNFα. If these effects are replicated in vivo the GLP-2 receptor may present a therapeutic target in intestinal inflammation.
Insulin-like peptide 3 stimulates testosterone secretion in mouse Leydig cells via cAMP pathway.
Pathirana IN, Kawate N, Büllesbach EE … +4 more , Takahashi M, Hatoya S, Inaba T, Tamada H
Regul Pept · 2012 Oct · PMID 22800961 · Publisher ↗
Testicular Leydig cells secrete insulin-like peptide 3 (INSL3) and express its receptor, RXFP2. However, the effects of INSL3 on endocrine function of Leydig cells are unknown. The present study examines the effects of I...
Testicular Leydig cells secrete insulin-like peptide 3 (INSL3) and express its receptor, RXFP2. However, the effects of INSL3 on endocrine function of Leydig cells are unknown. The present study examines the effects of INSL3 on mouse Leydig cells taking testosterone and cAMP secretions as endpoints. Leydig cells were isolated from testicular interstitial cells obtained from 8-week-old male mice. Cells were then plated in the presence or absence of mouse, human, canine or bovine INSL3 (0-100 ng/ml) for 18 h in multiwell-plates (96 wells) in different cell densities (2500, 5000, 10,000 or 20,000 cells per well). The effects of bovine INSL3 (100 ng/ml) on testosterone secretion by Leydig cells were examined in the presence or absence of, an adenylate cyclase inhibitor, SQ 22536 (1μM) or INSL3 antagonist (bovine and human; 100 ng/ml). Testosterone and cAMP in spent medium were measured by enzyme immunoassay. All INSL3 species tested significantly stimulated the testosterone secretion in Leydig cells, and the maximum stimulation was observed with 100 ng/ml bovine INSL3 at the lowest Leydig cell density (2500 cells per well). Moreover, bovine INSL3 (100 ng/ml) significantly stimulated the cAMP production from Leydig cells maximally at 1h, and remained significantly elevated even at 18 h. SQ 22536 and INSL3 antagonists (bovine and human) significantly reduced INSL3-stimulated testosterone secretion from Leydig cells. Taken together, stimulatory effects of INSL3 on testosterone secretion in Leydig cells are exerted via the activation of cAMP, suggesting a new autocrine function of INSL3 in males.
Brain-derived neurotrophic factor enhances the contraction of intestinal muscle strips induced by SP and CGRP in mice.
Chen FX, Yu YB, Yuan XM … +2 more , Zuo XL, Li YQ
Regul Pept · 2012 Oct · PMID 22800960 · Publisher ↗
BACKGROUND AND AIMS: Brain-derived neurotrophic factor (BDNF) has been found in the intestinal tract of a variety of species. Its effects on visceral hyperalgesia have been examined to some degree, but limited studies ha...
BACKGROUND AND AIMS: Brain-derived neurotrophic factor (BDNF) has been found in the intestinal tract of a variety of species. Its effects on visceral hyperalgesia have been examined to some degree, but limited studies have focused on gut motility. The aim of the present study was to investigate the effects of BDNF on gut motility of mice. METHODS: Longitudinal muscle (LM) strips were prepared from mice ileum and distal colon. The motility of gut was evaluated by the contraction of LM strips, which was recorded by a polyphisograph in vitro. Firstly, the roles of substance P (SP), calcitonin gene-related peptide (CGRP), and acetylcholine (ACh) on the contraction of LM strips were clarified. Then the exogenous BDNF was administered, and the alterations of SP/CGRP/ACh-induced contractions of the muscle strips were explored. Finally, heterozygous BDNF(+/-) mice and antibody of TrkB were introduced to investigate the role of endogenous BDNF on the SP/CGRP/ACh-induced gut motility. KEY RESULTS: SP (10(-8)-10(-6) mol L(-1)), CGRP (10(-8)-10(-7) mol L(-1)) and ACh (10(-8)-10(-6) mol L(-1)) dose-dependently caused the contraction of LM strips from ileum and distal colon, while the excitatory effect of CGRP was preceded by a transient inhibition. But 10(-6) mol L(-1) CGRP inhibited the contraction of LM strips. Pretreatment with exogenous BDNF (10(-8) mol L(-1)) remarkably enhanced the contraction of LM strips induced by SP (10(-9)-10(-7) mol L(-1)) and CGRP (10(-8)-10(-9) mol L(-1)). However, exogenous BDNF couldn't affect the contraction induced by ACh (10(-9)-10(-7) mol L(-1)). The excitatory effects of SP (10(-8)-10(-6) mol L(-1)) and CGRP (10(-8)-10(-7) mol L(-1)) on the contractions of LM strips from ileum and distal colon were significantly attenuated in BDNF(+/-) mice compared with those in BDNF(+/+) mice, while no difference of the effects of ACh (10(-8)-10(-6) mol L(-1)) on LM strips was observed between BDNF(+/-) mice and BDNF(+/+) mice. The monoclonal antibody of TrkB (TrkB-Ab) dramatically attenuated the excitatory effects of SP and CGRP on the contractions of LM strips, without affecting the excitatory effects of ACh. CONCLUSIONS AND INFERENCES: These data clarified the excitatory effects of SP, ACh and bilateral effects of CGRP on gut motility of mice and confirmed an essential role of BDNF on accelerating gut motility by enhancing the excitatory effects of SP/CGRP.
Valsartan, a specific angiotensin II receptor blocker, inhibits pancreatic fluid secretion via vagal afferent pathway in conscious rats.
Yamamoto M, Wei L, Otani M … +2 more , Harada M, Otsuki M
Regul Pept · 2012 Oct · PMID 22796317 · Publisher ↗
BACKGROUND/AIM: The renin-angiotensin system (RAS) exists in the pancreas, but the role of RAS in the regulation of pancreatic exocrine secretion under physiological conditions has been little known. The present study ad...
BACKGROUND/AIM: The renin-angiotensin system (RAS) exists in the pancreas, but the role of RAS in the regulation of pancreatic exocrine secretion under physiological conditions has been little known. The present study addressed the RAS's effect on the pancreatic secretion by using valsartan, a specific angiotensin II receptor blocker, in conscious rats. METHOD: Male Wistar rats prepared with pancreatic, biliary, duodenal and jugular vein cannulas were used. To examine the role of RAS in the pancreatic secretion, valsartan at 1, 5, or 25 mg/kg was administered into the duodenum via cannula, and volume of pancreatic juice and protein concentration were determined. In addition, to examine the role of RAS in hormone-stimulated pancreatic hypersecretion, pancreatic secretion was examined in response to stimulation of secretin or cholecystokinin after intraduodenal infusion of valsartan at 25 mg/kg. Furthermore, to examine the mechanism of action of RAS on pancreatic secretion, intravenous infusion of atropine or perivagal application of capsaicin was conducted and then the pancreatic secretion was examined following intraduodenal infusion of valsartan at 25 mg/kg. RESULTS: Volume of pancreatic juice, but not protein output, significantly decreased after administration of valsartan. However, administration of valsartan did not exert significant effects on secretin- or cholesystokinin-stimulated pancreatic secretion. Treatment with atropine and perivagal application of capsaicin completely abolished the suppressive effect of valsartan on pancreatic juice secretion. CONCLUSION: Present results suggest that RAS plays a stimulatory role in pancreatic juice secretion via cholinergic afferent pathway without affecting protein secretion and hormonally stimulated pancreatic secretion under physiological conditions.
Apelin receptor expression in ischemic and non- ischemic kidneys and cardiovascular responses to apelin in chronic two-kidney-one-clip hypertension in rats.
Najafipour H, Soltani Hekmat A, Nekooian AA … +1 more , Esmaeili-Mahani S
Regul Pept · 2012 Oct · PMID 22796316 · Publisher ↗
BACKGROUND: Chronic kidney diseases lead to severe cardiovascular consequences such as hypertension and cardiac failure. Apelin, along with its receptor APJ have been shown to involve in cardiovascular functions includin...
BACKGROUND: Chronic kidney diseases lead to severe cardiovascular consequences such as hypertension and cardiac failure. Apelin, along with its receptor APJ have been shown to involve in cardiovascular functions including blood pressure (BP) lowering effect and also a positive inotropic effect on failing hearts. Therefore we investigated the effect of apelin on BP and cardiac contractility in chronic two-kidney-one-clip (2K1C) hypertension, a kidney disease hypertension model. The changes in the level of apelin and some other hemodynamically effective hormones in serum and apelin receptor gene expression in nonischemic and ischemic kidneys were also assessed. METHODS: 2K1C was produced by placing a Plexiglas clip around the left renal artery. 16 weeks later, BP and cardiac indices of contractility were measured by power lab system. The mRNA and protein level of APJ were determined by RT-PCR and Western blot methods respectively. RESULTS: 2K1C increased BP from 115/75 mmHg in sham to 180/120 mmHg in test group. Hypertensive rats had about ten times higher basal left ventricular end-diastolic pressure (LVEDP) (P<0.001) and higher basal LV systolic pressure (LVSP) (P<0.01). Apelin-13 (20 μg/kg, iv) significantly decreased LVEDP and LVSP (P<0.001). Furthermore, apelin in 20 μg/kg dose significantly decreased systolic (SBP) and diastolic (DBP) blood pressures in hypertensive rats. This reduction was persistent and prominent in 40 μg/kg dose. 20 μg/kg apelin increased +LVdp/dt max and -LV dp/dt max. However in the dose of 40 μg/kg SBP, DBP, +LVdp/dt max and -LV dp/dt max greatly decreased. All of these effects were completely blocked by apelin antagonist F13A. 2K1C decreased serum apelin (P<0.05), did not change ang II and arginine-vasopressin levels, and slightly increased serum aldosterone. Apelin receptor mRNA and protein expression significantly decreased in both ischemic and non-ischemic kidneys. CONCLUSION: Overall, chronic 2K1C rats showed hypertension and signs of cardiac failure. Apelin in medium doses induced antihypertensive and positive myocardial inotropic effects. Reduction of serum apelin and down regulation of apelin receptors in kidneys of hypertensive rats may play a role in pathophysiology of cardiovascular complications.
Opiorphin highly improves the specific binding and affinity of MERF and MEGY to rat brain opioid receptors.
Tóth F, Tóth G, Benyhe S … +2 more , Rougeot C, Wollemann M
Regul Pept · 2012 Oct · PMID 22771829 · Publisher ↗
Endogenously occurring opioid peptides are rapidly metabolized by different ectopeptidases. Human opiorphin is a recently discovered natural inhibitor of the enkephalin-inactivating neutral endopeptidase (NEP) and aminop...
Endogenously occurring opioid peptides are rapidly metabolized by different ectopeptidases. Human opiorphin is a recently discovered natural inhibitor of the enkephalin-inactivating neutral endopeptidase (NEP) and aminopeptidase-N (AP-N) (Wisner et al., 2006). To date, in vitro receptor binding experiments must be performed either in the presence of a mixture of peptidase inhibitors and/or at low temperatures, to block peptidase activity. Here we demonstrate that, compared to classic inhibitor cocktails, opiorphin dramatically increases the binding of [(3)H]MERF and [(3)H]MEGY ligands to rat brain membrane preparations. We found that at 0 °C the increase in specific binding is as high as 40-60% and at 24 °C this rise was even higher. In contrast, the binding of the control [(3)H]endomorphin-1, which is relatively slowly degraded in rat brain membrane preparations, was not enhanced by opiorphin compared to other inhibitors. In addition, in homologous binding displacement experiments, the IC(50) affinity values measured at 24 °C were also significantly improved using opiorphin compared to the inhibitor cocktail. In heterologous binding experiments the differences were less obvious, but still pronounced using [(3)H]MERF and MEGY compared to dynorphin(1-11), or naloxone and DAGO competitor ligands.
Erythropoietin acutely decreases airway resistance in the rat.
Rubini A, del Monte D, Catena V
Regul Pept · 2012 Oct · PMID 22766248 · Publisher ↗
While some experimental data suggest that erythropoietin (EPO) influences respiratory mechanics, reports on scientific trials are lacking. In the present work, respiratory mechanics were measured using the end-inflation...
While some experimental data suggest that erythropoietin (EPO) influences respiratory mechanics, reports on scientific trials are lacking. In the present work, respiratory mechanics were measured using the end-inflation occlusion method in control and EPO treated anaesthetised and positive-pressure ventilated rats. Causing an abrupt inspiratory flow arrest, the end-inflation occlusion method makes it possible to measure the ohmic airway resistance and the respiratory system elastance. It was found that EPO induces a significant decrement in the ohmic airway resistance, not noted in control animals, 20 and 30 min after intraperitoneal EPO injection. The elastic characteristics of the respiratory system did not vary. Hypotheses about the mechanism (s) explaining these results were addressed. In particular, additional experiments have indicated that the decrement in airway resistance could be related to an increase in nitric oxide production induced by EPO. Spontaneous increments in plasmatic erythropoietin levels, such as those that take place in association with hypoxia and/or blood loss, appear to be related to the decrement in airway resistance, allowing pulmonary ventilation to increase without altering respiratory mechanics leading to deleterious increments in energy dissipation during breathing.
Mini-review: the evolution of neuropeptide signaling.
Grimmelikhuijzen CJ, Hauser F
Regul Pept · 2012 Aug · PMID 22726357 · Publisher ↗
Neuropeptides and their G protein-coupled receptors (GPCRs) have an early evolutionary origin and are already abundant in basal animals with primitive nervous systems such as cnidarians (Hydra, jellyfishes, corals, and s...
Neuropeptides and their G protein-coupled receptors (GPCRs) have an early evolutionary origin and are already abundant in basal animals with primitive nervous systems such as cnidarians (Hydra, jellyfishes, corals, and sea anemones). Most animals emerging after the Cnidaria belong to two evolutionary lineages, the Protostomia (to which the majority of invertebrates belong) and Deuterostomia (to which some minor groups of invertebrates, and all vertebrates belong). These two lineages split about 700 million years (Myr) ago. Many mammalian neuropeptide GPCRs have orthologues in the Protostomia and this is also true for some of the mammalian neuropeptides. Examples are oxytocin/vasopressin, GnRH, gastrin/CCK, and neuropeptide Y and their GPCRs. These results implicate that protostomes (for example insects and nematodes) can be used as models to study the biology of neuropeptide signaling.
Beginnings: a reflection on the history of gastrointestinal endocrinology.
Rehfeld JF
Regul Pept · 2012 Aug · PMID 22726356 · Publisher ↗
The gut is the largest endocrine organ in the body. Gut hormones share some characteristics: Their structure groups hormones into families, each of which originate from a single gene. A hormone gene is often expressed in...
The gut is the largest endocrine organ in the body. Gut hormones share some characteristics: Their structure groups hormones into families, each of which originate from a single gene. A hormone gene is often expressed in multiple peptides due to tandem genes, alternative splicing or differentiated posttranslational processing. By these mechanisms, more than 100 different hormonally active peptides are produced in the gastrointestinal tract. In addition, gut hormones are widely expressed outside the gut. The different cell types often express different products of the same gene and release the peptides in different ways. Consequently, the same peptide may act as a hormone, a local growth factor, or a neurotransmitter. This new biology suggests that gastrointestinal hormones should be conceived as intercellular messengers of major general impact. The following short review is a vignette on steps in the history of gastrointestinal endocrinology from classic studies of digestive juice secretion over peptide chemistry, immunochemistry, and molecular genetics to modern receptor pharmacology and drug development. From shadowy beginnings, gastrointestinal endocrinology has emerged as a central discipline in the understanding of multicellular life and its diseases.
Association of expression of XIAP-associated factor 1 (XAF1) with clinicopathologic factors, overall survival, microvessel density and cisplatin-resistance in ovarian cancer.
Wang Y, Mao H, Hao Q … +5 more , Wang Y, Yang Y, Shen L, Huang S, Liu P
Regul Pept · 2012 Oct · PMID 22759793 · Publisher ↗
XIAP-associated factor 1 (XAF1) was identified as a novel X-linked inhibitor of apoptosis (XIAP) binding partner that can reverse the anti-apoptotic effect of XIAP. XAF1 levels are greatly decreased in many cancer tissue...
XIAP-associated factor 1 (XAF1) was identified as a novel X-linked inhibitor of apoptosis (XIAP) binding partner that can reverse the anti-apoptotic effect of XIAP. XAF1 levels are greatly decreased in many cancer tissues and cell lines. The aim of this study was to investigate the expression of XAF1 and XIAP in advanced epithelial ovarian cancer and role of XAF1 in cisplatin resistance of ovarian cancer cells. Tissues from 94 patients with advanced epithelial ovarian cancer (EOC) and 30 ovarian cystadenomas were obtained. We analyzed the association of the immunohistochemical-determined expression of these two factors and clinicopathologic variables, overall survival, and angiogenesis. We established SKOV3 cells stably overexpressing XAF1 and explored the possible functions of XAF1 in ovarian cancer cells in vitro and in vivo. The protein expression of XAF1 was significantly lower and that of XIAP higher in malignant than nonmalignant tissues. Low XAF1 expression was associated with high-grade tumors and poor overall survival for patients. XAF1 expression was associated with microvessel density. Overexpression of XAF1 suppressed cell proliferation and enhanced SKOV3 cells sensitivity to cisplatin, as well as inhibited tumor growth and decreased MVD in vivo. Overexpression of XAF1 induced XIAP inactivation, caspase-3 activation and cytosolic expression of cytochrome c. These results suggested that XAF1 may be involved in ovarian cancer development and up-regulation of XAF1 may confer sensitivity of ovarian cancer cells to cisplatin-mediated apoptosis.
Low pre-transplant adiponectin multimers are associated with adverse allograft outcomes in kidney transplant recipients a 3-year prospective study.
Roos M, Baumann M, Liu D … +8 more , Heinemann FM, Lindemann M, Horn PA, Türk T, Lutz J, Heemann U, Witzke O, von Eynatten M
Regul Pept · 2012 Oct · PMID 22750635 · Publisher ↗
BACKGROUND: In kidney transplant recipients endothelial dysfunction is almost a universal risk factor for allograft failure. Adiponectin, an adipocyte derived hormone, has endothelial-protective properties and the high-m...
BACKGROUND: In kidney transplant recipients endothelial dysfunction is almost a universal risk factor for allograft failure. Adiponectin, an adipocyte derived hormone, has endothelial-protective properties and the high-molecular weight (HMW) multimer is the major active form, exerting anti-inflammatory and anti-apoptotic effects on endothelial cells. This study evaluated, whether pre-transplant total and HMW multimer adiponectin levels are associated with markers of endothelial dysfunction and arteriosclerosis and predict long-term graft survival in patients after kidney transplantation. METHODS: In 206 renal transplant recipients pre-transplant total and HMW adiponectin levels were measured in serum by ELISA and Western blot, respectively. During the 36 months active follow up (median [interquartile range] 1249 [1020; 1445] days) 13 patients died (94% patient survival) and renal allograft failure was reported in 18 patients (91% graft survival). RESULTS: Pre-transplant total and HMW adiponectin levels were significantly associated with lipid and glucose parameters at baseline. After 3 years follow-up pre-transplant total and HMW adiponectin levels were significantly inversely associated with the incidence of allograft failure (adiponectin: r=-0.216; p=0.002: HMW: r=-0.218; p=0.002). In multivariable adjusted Cox proportional hazard regression models patients in the lowest total and HMW adiponectin quartile had a significantly increased risk for allograft failure within 3 years post-transplantation: odds ratio [95%CI]: total adiponectin: 4.25 [1.27-14.24; p=0.019], and HMW multimers: 3.35 [1.04-10.76; p=0.042], respectively. CONCLUSION: Low pre-transplant levels of total and HMW adiponectin reflect a pro-atherogenic endothelial milieu and independently predict an increased risk of allograft failure in kidney-transplant recipients. Measurement of adiponectin levels may identify patients at risk for adverse allograft outcomes after kidney transplantation.
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