| 1. |
- Ahlkvist, Linda, et al.
(författare)
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Synergism by individual macronutrients explains the marked early GLP-1 and islet hormone responses to mixed meal challenge in mice
- 2012
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Ingår i: Regulatory Peptides. - : Elsevier. - 0167-0115 .- 1873-1686. ; 178:1-3, s. 29-35
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Tidskriftsartikel (refereegranskat)abstract
- Apart from glucose, proteins and lipids also stimulate incretin and islet hormone secretion. However, the glucoregulatory effect of macronutrients in combination is poorly understood. We therefore developed an oral mixed meal model in mice to 1) explore the glucagon-like peptide-1 (GLP-1) and islet hormone responses to mixed meal versus isocaloric glucose, and 2) characterize the relative contribution of individual macronutrients to these responses. Anesthetized C57BL/6J female mice were orally gavaged with 1) a mixed meal (0.285 kcal; glucose, whey protein and peanut oil; 60/20/20% kcal) versus an isocaloric glucose load (0.285 kcal), and 2) a mixed meal (0.285 kcal) versus glucose, whey protein or peanut oil administered individually in their mixed meal caloric quantity, i.e., 0.171, 0.055 and 0.055 kcal, respectively. Plasma was analyzed for glucose, insulin and intact GLP-1 before and during oral challenges. Plasma glucose was lower after mixed meal versus after isocaloric glucose ingestion. In spite of this, the peak insulin response (P=0.02), the peak intact GLP-1 levels (P=0.006) and the estimated β-cell function (P=0.005) were higher. Furthermore, the peak insulin (P=0.004) and intact GLP-1 (P=0.006) levels were higher after mixed meal ingestion than the sum of responses to individual macronutrients. Compared to glucose alone, we conclude that there is a marked early insulin response to mixed meal ingestion, which emanates from a synergistic, rather than an additive, effect of the individual macronutrients in the mixed meal and is in part likely caused by increased levels of GLP-1.
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| 2. |
- Ahrén, Bo, et al.
(författare)
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DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with beta-cell-specific overexpression of human islet amyloid polypeptide.
- 2007
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 143:1-3, s. 97-103
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently explored as a novel therapy of type 2 diabetes. The strategy has been shown to improve glycemia in most, but not all, rodent forms of glucose intolerance. In this study, we explored the effects of DPP-4 inhibition in mice with [beta-cell overexpression of human islet amyloid polypeptide (IAPP). We therefore administered the orally active and highly selective DPP-4 inhibitor, vildagliptin (3 pmol/mouse daily) to female mice with [beta-cell overexpression of human IAPP. Controls were given plain water, and a series of untreated wildtype mice was also included. After five weeks, an intravenous glucose tolerance test showed improved glucose disposal and a markedly enhanced insulin response in mice treated with vildagliptin. After eight weeks, a gastric tolerance test showed that vildagliptin improved glucose tolerance and markedly (approximately ten-fold) augmented the insulin response in association with augmented (approximately five-fold) levels of intact glucagon-like peptide-1 (GLP-1). Furthermore, after nine weeks, islets were isolated. Islets from vildagliptin-treated mice showed augmented glucose-stimulated insulin response and a normalization of the islet insulin content, which was reduced by approximately 50% in transgenic controls versus wildtype animals. Double immunostaining of pancreatic islets for insulin and glucagon revealed that transgenic islets displayed severely disturbed intra-islet topography with frequently observed centrally located a-cells. Treatment with vildagliptin restored the islet topography. We therefore conclude that DPP-4 inhibition improves islet function and islet topography in mice with [beta-cell specific transgenic overexpression of human IAPP. (c) 2007 Elsevier B.V. All rights reserved.
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| 3. |
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| 4. |
- Ahrén, Bo
(författare)
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The neuro-incretin concept.
- 2014
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 194:Sep 16, s. 3-5
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Andersson, Gustav, 1983-, et al.
(författare)
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Presence of substance P and the neurokinin-1 receptor in tenocytes of the human Achilles tendon
- 2008
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 150:1-3, s. 81-87
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Tidskriftsartikel (refereegranskat)abstract
- Nerve signal substances, such as the tachykinin substance P (SP), may be involved in the changes that occur in response to tendinopathy (tendinosis). It is previously known that the level of SP innervation within tendon tissue is limited, but results of experimental studies have suggested that SP may have stimulatory, angiogenetic and healing effects in injured tendons. Therefore, it would be of interest to know if there is a local SP-supply in tendon tissue. In the present study, the patterns of expression of SP and its preferred receptor, the neurokinin-1 receptor (NK-1 R), in normal and tendinosis human Achilles tendons were analyzed by use of both immunohistochemistry and in situ hybridization. We found that there was expression of SP mRNA in tenocytes, and that tenocytes showed expression of NK-1 R at protein as well as mRNA levels. The observations concerning both SP and NK-1 R were most evident for tenocytes in tendinosis tendons. Our findings suggest that SP is produced in tendinosis tendons, and furthermore that SP has marked effects on the tenocytes via the NK-1 R. It cannot be excluded that the SP effects are of importance concerning the processes of reorganization and healing that occur for tendon tissue in tendinosis. In conclusion, it appears as if SPergic autocrine/paracrine effects occur in tendon tissue during the processes of tendinosis, hitherto unknown effects for human tendons.
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| 6. |
- Andersson, Sven, et al.
(författare)
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CGRP(8-37) and CGRP(32-37) contract the iris sphincter in the rabbit eye: antagonism by spantide and GR82334
- 1993
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Ingår i: Regulatory Peptides. - 1873-1686. ; 49:1, s. 73-80
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Tidskriftsartikel (refereegranskat)abstract
- The effects of intracameral injections of CGRP(8-37) and CGRP(32-37) on pupil diameter and blood-aqueous barrier have been investigated in rabbits. The rabbits, which were pretreated with indomethacin and a muscarinic antagonist (biperiden), responded with miosis to both CGRP fragments. CGRP(8-37) was much more potent than CGRP(32-37) but one order of magnitude less potent than substance P. Nerve blockade with tetrodotoxin did not affect the response, indicating a direct effect on the iris sphincter muscle. Pre-treatment with the unselective tachykinin receptor antagonist spantide or the NK1 receptor selective antagonist GR82334 caused a rightward shift of the dose-response curves for both fragments, while the CCK receptor antagonist loxiglumide had no inhibitory effect. Neither of the fragments induced any marked leakage of Evans blue into the aqueous humor indicating that there was no agonistic interaction with CGRP receptors in the eye. We conclude that CGRP(8-37) and CGRP(32-37) are miotic agents in the rabbit eye, possibly by acting as neurokinin receptor agonists.
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| 7. |
- Arciszewski, M B, et al.
(författare)
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Effects of vasoactive intestinal peptide and galanin on survival of cultured porcine myenteric neurons
- 2005
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 125:1-3, s. 185-192
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Tidskriftsartikel (refereegranskat)abstract
- Enteric neuronal plasticity is probably fundamental in order to withstand injury or changes in intestinal activity. The role of the neuropeptides in neuroprotection is still enigmatic. The expression of galanin and vasoactive intestinal peptide (VIP) and the effects of the two peptides on survival of small intestinal porcine myenteric neurons cultured for 6 days were studied. Immunocytochemistry and cell counting were used to evaluate the numbers of surviving neurons and their expression of galanin and VIP. To reflect the in vivo situation, cryostat sections of porcine mid-jejunum were used. A concentration-dependent and marked increase in neuronal survival was noted when neurons were grown in the presence of VIP (10(-8) - 10(-6) M), whereas addition of galanin (10(-8) - 10(-6) M) slightly decreased neuronal survival. A dramatic increase in the proportions of myenteric neurons containing VIP or galanin immunoreactivity occurred during culturing. The presence of VIP further increased the number of galanin-expressing neurons. A majority of the galanin-immunoreactive neurons lacked VIP, while all VIP-immunoreactive neurons contained galanin. In conclusion, culturing porcine myenteric neurons in the presence of VIP increases, while the presence of galanin reduces, survival. Culturing significantly increased the proportion of neurons expressing VIP and/or galanin; the presence of VIP further increased the number of galanin-expressing neurons.
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| 8. |
- Arciszewski, MB, et al.
(författare)
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Vasoactive intestinal peptide rescues cultured rat myenteric neurons from lipopolysaccharide induced cell death
- 2008
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 146:1-3, s. 218-223
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Tidskriftsartikel (refereegranskat)abstract
- The role of the enteric nervous system in intestinal inflammation is not fully understood and the plethora of cellular activities concurrently ongoing in vivo renders intelligible studies difficult. In order to explore possible effects of bacterial lipopolysaccharide (LPS) on enteric neurons we utilised cultured myenteric neurons from rat small intestine. Exposure to LPS caused markedly reduced neuronal survival and increased neuronal expression of vasoactive intestinal peptide (VIP), while the expression of Toll-like receptor 4 (TLR4) was unchanged. TLR4 was expressed in approximately 35% of all myenteric neurons irrespective of if they were cultured in the presence or absence of LPS. In neurons cultured in medium, without LPS, 50% of all TLR4-immunoreactive neurons contained also VIP. Addition of LPS to the neuronal cultures markedly increased the proportion of TLR4-immunoreactive neurons also expressing VIP, while the proportion of TLR4 neurons devoid of VIP decreased. Simultaneous addition of LPS and VIP to the neuronal cultures resulted in a neuronal survival comparable to controls. CONCLUSIONS: LPS recognition by myenteric neurons is mediated via TLR4 and causes neuronal cell death. Presence of VIP rescues the neurons from LPS-induced neurodegeneration.
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| 9. |
- Bakos, J., et al.
(författare)
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Oxytocin levels in the posterior pituitary and in the heart are modified by voluntary wheel running
- 2007
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 139:1-3, s. 96-101
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Tidskriftsartikel (refereegranskat)abstract
- We hypothesized that voluntary wheel running results in increased secretion of oxytocin, a peptide involved in the stress response. An additional hypothesis was that prolonged exercise affects oxytocin levels in the heart, which is in line with the potential role of oxytocin in cardiovascular functions. Voluntary wheel running lasted 3 weeks and daily running distances increased progressively reaching maximum levels about 8 km (Sprague-Dawley rats) and 4 km (Lewis strain). The exercise resulted in significant reduction of epididymal fat, slight increase in glucose transporter GLUT4 mRNA levels and significant enhancement of plasma density. Voluntary exercise failed to influence plasma oxytocin levels either in Lewis or Sprague-Dawley rats, but it resulted in a significant decrease of oxytocin concentrations in the posterior pituitary. Plasma oxytocin concentrations were not modified even if the measurements were made in the dark phase of the day. In voluntary wheel running Sprague-Dawley rats, the content of oxytocin in the right heart atrium was lower than in controls. Thus, the present findings demonstrate that prolonged voluntary wheel running results in a decrease in pituitary oxytocin content without evident changes in hormone concentrations in peripheral blood. However, prolonged exercise used has a significant impact on oxytocin levels in the heart. (c) 2006 Elsevier B.V. All rights reserved.
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| 10. |
- Banke, Elin, et al.
(författare)
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Cocaine- and amphetamine-regulated transcript is expressed in adipocytes and regulate lipid- and glucose homeostasis.
- 2013
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 182:Jan.,11, s. 35-40
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Tidskriftsartikel (refereegranskat)abstract
- Cocaine- and amphetamine-regulated transcript (CART) is a regulatory peptide expressed in the nervous system and in endocrine cells, e.g. in pancreatic islets. CART deficient mice exhibit islet dysfunction, impaired insulin secretion and increased body weight. A mutation in the CART gene in humans is associated with reduced metabolic rate, obesity and diabetes. Furthermore, CART is upregulated in islets of type-2 diabetic rats and regulates islet hormone secretion in vitro. While the function of CART in the nervous system has been extensively studied, there is no information on its expression or function in white adipose tissue. CART mRNA and protein were found to be expressed in both subcutaneous and visceral white adipose tissues from rat and man. Stimulating rat primary adipocytes with CART significantly potentiated isoprenaline-induced lipolysis, and hormone sensitive lipase activation (phosphorylation of Ser 563). On the other hand, CART significantly potentiated the inhibitory effect of insulin on isoprenaline-induced lipolysis. CART inhibited insulin-induced glucose uptake, which was associated with inhibition of PKB phosphorylation. In conclusion, CART is a novel constituent of human and rat adipocytes and affects several biological processes central in both lipid- and glucose homeostasis. Depending on the surrounding conditions, the effects of CART are insulin-like or insulin-antagonistic.
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| 11. |
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| 12. |
- Björkqvist, Maria, et al.
(författare)
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Role of gastrin in the development of gastric mucosa, ECL cells and A-like cells in newborn and young rats
- 2002
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Ingår i: Regulatory Peptides. - 1873-1686. ; 108:2-3, s. 73-82
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Tidskriftsartikel (refereegranskat)abstract
- Histamine-producing ECL cells and ghrelin-producing A-like cells are endocrine/paracrine cell populations in the acid-producing part of the rat stomach. While the A-like cells operate independently of gastrin, the ECL cells respond to gastrin with mobilization of histamine and chromogranin A (CGA)-derived peptides, such as pancreastatin. Gastrin is often assumed to be the driving force behind the postnatal development of the gastric mucosa in general and the ECL cells in particular. We tested this assumption by examining the oxyntic mucosa (with ECL cells and A-like cells) in developing rats under the influence of YF476, a cholecystokinin-2 (CCK2) receptor antagonist. The drug was administered by weekly subcutaneous injections starting at birth. The body weight gain was not affected. Weaning occurred at days 1522 in both YF476-treated and age-matched control rats. Circulating gastrin was low at birth and reached adult levels 2 weeks after birth. During and after weaning (but riot before), YF476 greatly raised the serum gastrin concentration (because of abolished acid feedback inhibition of gastrin release). The weight of the stomach was unaffected by YF476 during the first 2-3 weeks after birth. From 4 to 5 weeks of age, the weight and thickness of the gastric mucosa were lower in YF476-treated rats than in controls. Pancreastatin-immunoreactive cells (i.e. all endocrine cells in the stomach) and ghrelin-immunoreactive cells (A-like cells) were few at birth and increased gradually in number until 6-8 weeks of age (control rats). At first, YF476 did not affect the development of the pancreastatin-immunoreactive cells, but a few weeks after weaning, the cells were fewer in the YF476 rats. The ECL-cell parameters (oxyntic mucosal histamine and pancreastatin concentrations, the histidine decarboxylase (HDC) activity, the HDC mRNA levels and serum pancreastatin concentration) increased slowly until weaning in both YF476-treated and control rats. From then on, there was a further increase in the ECL-cell parameters in control rats but not in YF476 rats. The postnatal development of the ghrelin cells (i.e. the A-like cells) and of the A-like cell parameters (the oxyntic mucosal ghrelin concentration and the serum ghrelin concentrations) was not affected by YF476 at any point. We conclude that gastrin affects neither the oxyntic mucosa nor the endocrine cells before weaning. After weaning, CCK2 receptor blockade is associated with a somewhat impaired development of tire oxyntic mucosa and the ECL cells. While gastrin stimulation is of crucial importance for the onset of acid secretion during weaning and for the activation of ECL-cell histamine formation and secretion, the mucosal and ECL-cell growth at this stage is only partly gastrin-dependent. In contrast, the development of the A-like cells is independent of gastrin at all stages. (C) 2002 Elsevier Science B.V. All rights reserved.
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| 13. |
- Björkqvist, Maria, et al.
(författare)
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Somatostatin, misoprostol and galanin inhibit gastrin- and PACAP-stimulated secretion of histamine and pancreastatin from ECL cells by blocking specific Ca(2+) channels.
- 2005
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 130:1-2, s. 81-90
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Tidskriftsartikel (refereegranskat)abstract
- The oxyntic mucosa is rich in ECL cells. They secrete histamine and chromogranin A-derived peptides, such as pancreastatin, in response to gastrin and pituitary adenylate cyclase-activating peptide (PACAP). Secretion is initiated by Ca2+ entry. While gastrin stimulates secretion by opening L-type and N-type Ca2+ channels, PACAP stimulates secretion by activating L-type and receptor-operated Ca2+ channels. Somatostatin, galanin and prostaglandin E2 (PGE2) inhibit gastrin- and PACAP-stimulated secretion from the ECL cells. In the present study, somatostatin and the PGE2 congener misoprostol inhibited gastrin- and PACAP-stimulated secretion 100%, while galanin inhibited at most 60–65%. Bay K 8644, a specific activator of L-type Ca2+ channels, stimulated ECL-cell secretion, an effect that was inhibited equally effectively by somatostatin, misoprostol and galanin (75–80% inhibition). Pretreatment with pertussis toxin, that inactivates inhibitory G-proteins, prevented all three agents from inhibiting stimulated secretion (regardless of the stimulus). Pretreatment with nifedipine (10 μM), an L-type Ca2+ channel blocker, reduced PACAP-evoked pancreastatin secretion by 50–60%, gastrin-evoked secretion by not, vert, similar 80% and abolished the response to Bay K 8644. The nifedipine-resistant response to PACAP was abolished by somatostatin and misoprostol but not by galanin. Gastrin and PACAP raised the intracellular Ca2+ concentration in a biphasic manner, believed to reflect mobilization of internal Ca2+ followed by Ca2+ entry. Somatostatin and misoprostol blocked Ca2+ entry (and histamine and pancreastatin secretion) but not mobilization of internal Ca2+. The present observations on isolated ECL cells suggest that Ca2+ entry rather than mobilization of internal Ca2+ triggers exocytosis, that gastrin and PACAP activate different (but over-lapping) Ca2+ channels, that somatostatin, misoprostol and galanin interact with inhibitory G-proteins to block Ca2+ entry via L-type Ca2+ channels, and that somatostatin and misoprostol (but not galanin) in addition block N-type and/or receptor-operated Ca2+ channels.
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| 14. |
- Carlini, Valeria P., et al.
(författare)
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Selective serotonin reuptake inhibitor (fluoxetine) decreases the effects of ghrelin on memory retention and food intake
- 2007
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 140:1-2, s. 65-73
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Tidskriftsartikel (refereegranskat)abstract
- Ghrelin (Ghr) is an appetite stimulating hormone that is produced peripherally, by the stomach, and centrally as well. Previous investigations show that Ghr increases food intake and memory retention in rats, and that extra-hypothalamic structures, such as the hippocampus, participate in these effects. In the present work we analyzed the effect on food intake and memory retention induced by Ghr after serotonin (5-HT) availability modification at the serotoninergic synapses. Animals only treated with a selective serotonin reuptake inhibitor (SSRI), fluoxetine (FLU) 5 mg/kg or clomipramine (CLO) 2.5 and 5 mg/kg, showed a significant reduction in both food intake and memory retention. On the contrary, Ghr administration induces a significant increase in food intake and a dose-dependent increase in short and long term memory retention. When the animals were treated with FLU prior to Ghr injection, the food intake induced, as well as the expression of short and long term memory retention, was decreased. In conclusion, evidence presented in this paper suggests that the effects of Ghr on both feeding and memory retention in extra-hypothalamic structures such as the hippocampus, could depend on the availability of 5-HT.
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| 15. |
- Cervin, Anders
(författare)
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Neuropeptide Y 16-36 inhibits mucociliary activity but does not affect blood flow in the rabbit maxillary sinus in vivo
- 1992
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 39:2-3, s. 237-246
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Tidskriftsartikel (refereegranskat)abstract
- Recent investigations have shown neuropeptide Y (NPY) to be present in the rabbit maxillary sinus, and NPY is known to be released upon sympathetic nerve stimulation. To study, in vivo, the effect on mucociliary activity and blood flow, NPY 1-36 and some of its analogues were injected intra-arterially. The effects of the Y1/Y2 agonist NPY 1-36 was compared with the ones of the Y2 agonist NPY 16-36, the Y1-agonist [Leu31,Pro34]NPY and the Y1/Y2 agonist peptide YY. Mucociliary response was recorded photoelectrically and expressed as a percentage of the basal mucociliary activity immediately prior to challenge. The effect on blood flow was measured with laser Doppler flowmetry and expressed as a percentage of the mean blood flow during the 60 s preceding challenge. NPY 1-36 and NPY 16-36 both reduced mucociliary activity dose-dependently at equimolar dosages (0.024-1.2 nmol/kg). The greatest effect was seen after the highest dosage tested. NPY 1-36 reduced mucociliary activity by 14.6 +/- 1.8%, and NPY 16-36 by 13.2 +/- 1.4%. At the highest dosage tested the Y1 receptor agonist [Leu31,Pro34]NPY did not significantly reduce mucociliary activity, whereas PYY reduced mucociliary activity by 15.0 +/- 1.8%. Injections of NPY 16-36 had no effect on blood flow whereas NPY 1-36, [Leu31,Pro34]NPY and PYY all reduced blood flow dose-dependently. Maximal decrease was seen at the highest dosage tested and was 47.1 +/- 5.4%, 70.4 +/- 7.4% and 58.2 +/- 8.4%, respectively. These findings suggest the mucociliary effects to be mediated via Y2 receptors whereas blood flow is regulated via Y1 receptors.
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| 16. |
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| 17. |
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| 18. |
- de la Cour, Charlotta, et al.
(författare)
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A-like cells in the rat stomach contain ghrelin and do not operate under gastrin control
- 2001
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Ingår i: Regulatory Peptides. - 1873-1686. ; 99:2-3, s. 141-150
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Tidskriftsartikel (refereegranskat)abstract
- Ghrelin is a 28 a.a. gastric peptide, recently identified as a natural ligand of the growth hormone secretagogue receptor (orphan receptor distinct from the receptor fur growth hormone releasing hormone). In the present study. radioimmunoassay demonstrated ghrelin-like material in the rat oxyntic mucosa with moderate amounts also in antrum and duodenum. Small amounts: were found in the distal intestines and pancreas. Northern blot analysis revealed abundant ghrelin mRNA in thr oxyntic mucosa. Immunocytochemistry demonstrated ghrelin-immunoreactivity in endocrine-like cells in the oxyntic mucosa. Such cells occurred in low numbers also in the antrum and duodenum. The mt oxyntic mucosa is rich in endocrine (chromogranin A/pancreastatin-immunoreactive) cells. such as the histamine-rich ECL cells (65-75% of the endocrine cells). the A-like cells (20-25%) and the D cells (somatostatin cells) (10%). The ghrelin-immunoreactive (IR) cells contained pancreastatin but differed from ECL cells and D cells by being devoid of histamine-forming enzyme (ECL cell constituent) and somatostatin (D cell constituent). Hence. ghrelin seems to occur in the A-like cells. The ghrelin-IR cells in the antrum were distinct from the gastrin cells, the serotonin-containing enterochromaffin cells and the D cells. Conceivably, ghrelin cells in the antrum and distally in the intestines also belong to the A-like cell population. The concentration of ghrelin in the circulation was: lowered by about 80% following the surgical removal of the acid-producing part of the stomach in line with the view that the oxyntic mucosa is the major sourer of ghrelin. The serum ghrelin concentration was higher in fasted rats than in fed rats; it was reduced upon re-feeding and seemed unaffected by 1-week treatment with the proton pump inhibitor omeprazole, resulting in elevated serum gastrin concentration. Infusion of gastrin-17 for 2 days failed to raise the serum ghrelin concentration. Omeprazole treatment for 10 weeks raised the level of HDC mRNA but not that of ghrelin mRNA or somatostatin mRNA in the oxyntic mucosa. Hence, unlike the ECL cells, ghrelin-containing A-like cells do not seem to operate under gastrin control.
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| 19. |
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| 20. |
- de la Cour, Charlotta, et al.
(författare)
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Secretion of ghrelin from rat stomach ghrelin cells in response to local microinfusion of candidate messenger compounds: A microdialysis study
- 2007
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 143:1-3, s. 118-126
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Tidskriftsartikel (refereegranskat)abstract
- Ghrelin is produced by A-like cells (ghrelin cells) in the mucosa of the acid-producing part of the stomach. The mobilization of ghrelin is stimulated by nutritional deficiency and suppressed by nutritional abundance. In an attempt to identify neurotransmitters and regulatory peptides that may contribute to the physiological, nutrient-related regulation of ghrelin secretion, we challenged the ghrelin cells in situ with a wide variety of candidate messengers, including known neurotransmitters (e.g. acetylcholine, catecholamines), candidate neurotransmitters (e.g. neuropeptides), local tissue hormones (e.g. serotonin, histamine, bradykinin, endothelin), circulating gut hormones (e.g. gastrin, CCK, GIP, neurotensin, PYY, secretin) and other circulating hormones/regulatory peptides (e.g. calcitonin, glucagon, insulin, PTH). Microdialysis probes were placed in the submucosa of the acid-producing part of the rat stomach. Three days later, the putative messenger compounds were administered via the microdialysis probe (reverse microdialysis) at a screening dose of 0.1 mmol 1(-1) for regulatory peptides and 0.1 and 1 mmol 1(-1) for amines and amino acids. The rats were awake during the experiments. The resulting microdialysate ghrelin concentration was monitored continuously for 3 h (radioimmunoassay), thereby revealing stimulators or inhibitors of ghrelin secretion. Dose-response curves were constructed for each candidate messenger that significantly (p < 0.05) affected ghrelin mobilization at the screening dose. Peptides that showed a (non-significant) tendency to affect ghrelin release at the screening dose were also given at a dose of 0.3 or 1 mmol 1(-1). Adrenaline, noradrenaline, endothelin and secretin stimulated ghrelin release, while somatostatin and GRP inhibited. Whether these agents act directly or indirectly on the ghrelin cells remains to be investigated. All other candidate messengers were without measurable effects, including acetylcholine, serotonin, histamine, GABA, aspartic acid, glutamic acid, glycine, VIP, PACAP, CGRP, substance P, NPY, PYY, PP, gastrin, CCK, GIP, insulin, glucagon, GLP and glucose. (c) 2007 Elsevier B.V. All rights reserved.
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| 21. |
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| 22. |
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| 23. |
- Egecioglu, Emil, 1977, et al.
(författare)
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Hypothalamic gene expression following ghrelin therapy to gastrectomized rodents.
- 2008
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Ingår i: Regulatory peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 146:1-3, s. 176-82
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Tidskriftsartikel (refereegranskat)abstract
- We investigated whether ghrelin depletion (by gastrectomy surgery) and/or treatment/replacement with the gastric hormone ghrelin alters the expression of key hypothalamic genes involved in energy balance, in a manner consistent with ghrelin's pro-obesity effects. At 2 weeks after surgery mice were treated with ghrelin (12 nmol/mouse/day, sc) or vehicle for 8 weeks. Gastrectomy had little effect on the expression of these genes, with the exception of NPY mRNA in the arcuate nucleus that was increased. Ghrelin treatment (to gastrectomized and sham mice) increased the mRNA expression of orexigenic peptides NPY and AgRP while decreasing mRNA expression of the anorexigenic peptide POMC. Two weeks gavage treatment with the ghrelin mimetic, MK-0677, to rats increased NPY and POMC mRNA in the arcuate nucleus and MCH mRNA in the lateral hypothalamus. Thus, while predicted pro-obesity ghrelin signalling pathways were activated by ghrelin and ghrelin mimetics, these were largely unaffected by gastrectomy.
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| 24. |
- Ehrström, M, et al.
(författare)
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Pharmacokinetic profile of orexin A and effects on plasma insulin and glucagon in the rat
- 2004
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 119:3, s. 209-212
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Tidskriftsartikel (refereegranskat)abstract
- Orexin A (OXA) is found in the central nervous system (CNS) and in the gut. Peripheral administration of OXA to rats results in an inhibition of fasting motility. Plasma OXA increases during fasting and central administration of OXA increases food intake. The aim of the present study was to assess the pharmacokinetic profile of OXA and the effect of intravenously (IV) administered OXA on plasma concentrations of insulin and glucagon concentrations. Rats were given OXA IV (100 pmol kg-1 min-1) for time periods of 0, 10, 20, 30 min and for 10, 20, 30 min after ceasing a 30-min infusion. After each time period, rats were then sacrificed and blood obtained. OXA was also administered at increasing doses (0, 100, 300 and 500 pmol kg-1 min-1) for 30 min and blood was obtained. Plasma OXA, insulin and glucagon levels were measured using commercially available radioimmunoassay (RIA) kits. The plasma half-life of OXA was 27.1±9.5 min. Stepwise increasing infusion rates of OXA confirmed a linear concentration-time curve and thus first-order kinetics. Its volume of distribution indicated no binding to peripheral tissues. Plasma glucagon decreased during infusion of OXA, while insulin was unaffected. Plasma OXA was raised fourfold after food intake. Thus, OXA has a longer plasma half-life than many other peptides found in the gut. This needs to be taken into account when assessing effects of OXA on biological parameters after peripheral administration.reserved.
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| 25. |
- El-Salhy, M, et al.
(författare)
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Neuroendocrine peptide levels in the gastrointestinal tract of mice after unilateral cervical vagotomy
- 2000
-
Ingår i: Regulatory Peptides. - 0167-0115 .- 1873-1686. ; 88:1-3, s. 15-20
-
Tidskriftsartikel (refereegranskat)abstract
- The effects of left and right unilateral cervical vagotomy on the content of several neuroendocrine peptides were studied in different parts of the murine gastrointestinal tract, known to receive vagal innervation. The neuroendocrine peptides investigated were secretin, gastric inhibitory peptide (GIP), gastrin, motilin, peptide YY (PYY), somatostatin, substance P, VIP, neurotensin, neuropeptide Y (NPY), and galanin. The neuroendocrine peptide concentration was affected after both left and right vagotomy, and that the changes in the concentrations of the neuroendocrine peptide levels occurred in all the gastrointestinal segments investigated, namely antrum, small and large intestine. However, these changes varied, depending on which side was vagotomized and the interval after vagotomy. It is concluded that the vagus nerve had an important impact on the neuroendocrine system in the murine gut. It is suggested, furthermore that the contradictory results obtained earlier on the effect of vagotomy on the gastrointestinal peptides may depend on differences in the vagotomy methods used and on differences in observation time after vagotomy.
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| 26. |
- El-Salhy, Magdy, et al.
(författare)
-
Triple therapy with octreotide, galanin and serotonin induces necrosis and increases apoptosis of a rat colon carcinoma
- 2002
-
Ingår i: Regulatory Peptides. - : Elsevier. - 0167-0115 .- 1873-1686. ; 108:2-3, s. 55-62
-
Tidskriftsartikel (refereegranskat)abstract
- A rat colonic adenocarcinoma was implanted subcutaneously (s.c.) in nude mice. After 7 days, the animals were divided into different groups. Two groups received subcutaneous injections twice daily with 3 or 6 μg/kg body weight octreotide, galanin and serotonin. Three groups were respectively treated with 20, 30, and 40 μg/kg body weight of the previously mentioned bioactive substances. Control group received only saline solution in the same fashion as treated animals. The treatment lasted for 5 days. The tumour volume and weight, the relative density of blood vessels, of tumour necrotic tissue, of apoptotic nuclei and of proliferating nuclei were measured. Apoptosis was detected by in situ labelling of nuclear DNA fragmentation according to TUNEL method, and proliferation by immunocytochemistry. Morphometry was done with the classical stereological point-counting method. Food consumption, animal weight, faeces weight and its water content were measured for 3 days before and after treatment. Triple therapy with 3 and 6 μg/kg body weight had no effect on any of the parameters measured, except in reducing the relative volume density of tumour blood vessels. Treatment with 20, 30 and 40 μg/kg body weight of the previously mentioned bioactive substances reduced the tumour volume, the relative volume density of blood vessels and increased the relative volume density of necrotic tissue and of apoptotic nuclei (in the 20 μg group). However, there was no difference between treated mice and controls regarding the relative volume density of proliferating nuclei. There was no statistical difference between treated animals regarding food consumption, body weight, faeces weight and its water content before and during treatment. The present study confirms that triple therapy with octreotide, galanin and serotonin causes regression of a rat colon carcinoma. It further showed that optimum treatment dose is 20 μg/kg body weight of each bioactive substance. Moreover, this therapy regime does not show apparent side effects in the experiments carried out on mice.
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| 27. |
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| 28. |
- El-Salhy, Magdy, et al.
(författare)
-
Triple therapy with octreotide, galanin, and serotonin reduces the size and blood vessel density and increases apoptosis of a rat colon carcinoma
- 2003
-
Ingår i: Regulatory Peptides. - : Elsevier. - 0167-0115 .- 1873-1686. ; 111:1-3, s. 145-152
-
Tidskriftsartikel (refereegranskat)abstract
- A rat colonic adenocarcinoma was implanted subcutaneously in female nude (C57BL/6JBom-nu) mice. After 7 days, the animals were divided into different groups. One group received triple therapy with octreotide, galanin, and serotonin, 10 μg/kg body weight of each, twice daily. The second group served as controls and received only saline solution. Three groups received 10 μg/kg body weight twice daily of octreotide, galanin, or serotonin. The last group consisted of controls that received only saline solution. The treatment lasted for 5 days. The tumour volume, wet weight, and relative volume density of blood vessels were significantly decreased after the triple treatment, as compared to controls. Apoptotic index was significantly increased, but the proliferation index was not affected in the group of mice that received triple therapy. There was no significant difference between controls and mice treated with octreotide, galanin, or serotonin regarding tumour volume or weight. The relative volume density of blood vessels was decreased in tumours treated with galanin, but not with octreotide or serotonin. There was no statistical difference in the proliferation index between controls and animals treated with octreotide, galanin, or serotonin, as compared with controls. Tumour necrosis and increased apoptosis may be responsible for the reduction in the volume and weight of the tumour after triple therapy. Tumour necrosis may be caused by the induction of tumour ischemia due to a reduction in tumour blood flow, which is caused by decreased incidence of tumour-feeding blood vessels, and by constriction of tumour-feeding arterioles. These results are promising and may offer treatment for colon cancer.
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| 29. |
- Ericson, Ann-Charlott, 1965-, et al.
(författare)
-
Morphological examination of the termination pattern of substance P-immunoreactive nerve fibers in human antral mucosa
- 2002
-
Ingår i: Regulatory Peptides. - 0167-0115 .- 1873-1686. ; 107:1-3, s. 79-86
-
Tidskriftsartikel (refereegranskat)abstract
- The termination pattern of substance P (SP)-containing axons in human antral mucosa was examined using immunohistochemical techniques at the light and electron microscopic level. SP-immunoreactive (IR) axons were found to extend towards the pit region of the glands, where intraepithelial axons were observed. Electron microscopy showed immunostained axon profiles in close contact with the basement membrane of surface mucous cells. Membrane-to-membrane contacts between labeled axons and myofibroblast-like cells were identified, and SP-IR axons that were apposed to the epithelium were also in contact with subjacent myofibroblast-like cells. The anatomical relationship between SP-IR axons and the cells of the muscularis mucosae was investigated by light microscopy. Immunoreactivity for a-smooth muscle actin (a-sma) was used to visualize the smooth muscle cells, and the a-sma-IR cells were found to create a network that surrounded the gastric glands. Immunostained varicose axons ran alongside and in close apposition to the labeled muscle strands. Ultrastructural examination showed close contacts between SP-IR axon profiles and smooth muscle-like cells. In conclusion, SP-containing neurons may be important for sensory and secretomotor functions in the human antral mucosa.
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| 30. |
- Ericsson, Peter, et al.
(författare)
-
Gastrin release: Antrum microdialysis reveals a complex neural control.
- 2010
-
Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 161, s. 22-32
-
Tidskriftsartikel (refereegranskat)abstract
- We used microdialysis to monitor local gastrin release in response to food, acid blockade and acute vagal excitation. For the first time, gastrin release has been monitored continuously in intact conscious rats in a physiologically relevant experimental setting in a fashion that minimizes confounding systemic effects. Microdialysis probes were placed in the submucosa on either side of the antrum, 3days before the experiments. The concentration of gastrin in the antral submucosal compartment was 5-10 times higher than in serum regardless of the prandial state. The rats were conscious during microdialysis except when subjected to electrical vagal stimulation. Acid blockade (omeprazole treatment of freely fed rats for 4days), or bilateral sectioning of the abdominal vagal trunks (fasted rats), raised the gastrin concentration in blood as well as microdialysate. The high gastrin concentration following omeprazole treatment was not affected by vagotomy. Vagal excitation stimulated the G cells: electrical vagal stimulation and pylorus ligation (fasted rats) raised the gastrin concentration transiently in both serum and microdialysate. Food intake induced a 2- to 3-fold increase in serum gastrin, while gastrin in antral microdialysate increased 10- to 15-fold. In unilaterally vagotomized rats, food evoked a prompt peak gastrin release followed by a gradual decline on the intact side. On the vagotomized side of the antrum, the peak response seemed to be reduced while the microdialysate gastrin concentration remained elevated. Thus, unilateral vagotomy surprisingly raised the integrated gastrin response to food on the denervated side compared to the intact side, indicating that vagotomy suppresses an inhibitory as well as a stimulating effect on the G cells. While local infusion of atropine was without effect, infusion of the neuronal blocker tetrodotoxin (TTX) (which had no effect on basal gastrin) virtually abolished the food-evoked gastrin response and lowered the high microdialysate gastrin concentration in omeprazole-treated rats by 65%. We conclude that activated gastrin release, unlike basal gastrin release, is highly dependent on a neural input: 1) Vagal excitation has a transient stimulating effect on the G cells. The transient nature of the response suggests that the vagus has not only a prompt stimulatory but also a slow inhibitory effect on gastrin release. 2) Although vagal denervation did not affect the gastrin response to anacidity, the TTX experiments revealed that both food-evoked and anacidity-evoked gastrin release depends on neural input.
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| 31. |
- Ericsson, Peter, et al.
(författare)
-
Gastrin response to candidate messengers in intact conscious rats monitored by antrum microdialysis.
- 2010
-
Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 163, s. 24-30
-
Tidskriftsartikel (refereegranskat)abstract
- We monitored gastrin release in response to locally applied candidate messengers in intact conscious rats. Earlier studies have been performed on anaesthetized animals, isolated pieces of antrum, or purified preparations of gastrin cells. In this study we created an experimental situation to resemble physiological conditions, using reverse microdialysis to administer regulatory peptides and amines that might affect gastrin secretion. Microdialysis probes were implanted in the submucosa of the antrum of the rat stomach. Three days later, putative messenger compounds were administered via the probe. Their effects on basal (24h fast) and omeprazole-stimulated (400mumol/kg/day, 4days peroral administration) gastrin release were monitored by continuous measurement (3h) of gastrin in the perfusate (radioimmunoassay). Fasted rats (low microdialysate gastrin, 2.1+/-0.1pmoll(-1)) were used to study stimulation of gastrin release. Omeprazole-treated rats (high microdialysate gastrin, 95.8+/-6.7pmoll(-1)) were used to study suppression of gastrin release. The following agents raised the concentration of microdialysate gastrin (peak response): gastrin-releasing peptide (GRP) (11-fold increase at a near-maximal dose), carbachol (5-fold increase), serotonin (2-fold increase) and isoprenaline (20-fold increase). Adrenaline and noradrenaline induced transient but powerful elevation (40- and 20-fold increase). Somatostatin, galanin and bradykinin (at near-maximal doses) suppressed omeprazole-stimulated gastrin release (50% decrease). Calcitonin gene-related peptide, ghrelin, gastric inhibitory peptide, motilin, neurotensin, neuromedin U-25, peptide YY and vasoactive intestinal peptide were without effect on gastrin release, as were aspartate, gamma-aminobutyric acid, glutamate, glycine, dopamine and histamine. The results support the view that G cells operate under neurocrine/paracrine control. They were stimulated by agents present in enteric neurons (GRP, galanin, choline ester and catechol amines) and in gastric endocrine cells (serotonin). They were inhibited by somatostatin (D cell peptide), galanin (neuropeptide) and by the inflammatory agent bradykinin.
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| 32. |
- Erlanson-Albertsson, Charlotte, et al.
(författare)
-
Fructose affects enzymes involved in the synthesis and degradation of hypothalamic endocannabinoids.
- 2010
-
Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 161, s. 87-91
-
Tidskriftsartikel (refereegranskat)abstract
- Endocannabinoids have been implicated in the regulation of consumption of palatable food, sugar in particular. In this study, we investigated how palatable solutions would affect the hypothalamic mRNA expression of enzymes involved in the synthesis and degradation of the two main endocannabinoids, anandamide and 2-arachidonoyl-glycerol. Rats were offered sugar solutions to drink for one week, during which daily food and drink intake, and body weight gain was monitored. Rats offered sugar solutions to drink consumed less solid food but drank more of their respective sugar solution than did water-drinking control rats, resulting in increased total calorie intake. However, this increase in caloric intake did not result in increased body weight or adiposity in the rats. The mRNA expression of fatty acid amid hydrolase was up-regulated by sucrose and fructose. N-acyl phospatidyl ethanolamine phospholipase D mRNA was up-regulated by sucrose, whereas phospholipase C was down-regulated by all forms of sugar tested. The mRNA expression of monoglyceride lipase was down-regulated by all three forms of sugar. Also, the mRNA expression of diacylglycerol lipase 1alpha was down-regulated by sucrose and fructose, whereas the mRNA expression of diacylglycerol lipase 1beta was up-regulated by fructose. In this study, we show that sugars in liquid form affect enzymes involved in the degradation and synthesis of endocannabinoids in the hypothalamus and that this effect predates obesity.
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| 33. |
- Erlanson-Albertsson, Charlotte, et al.
(författare)
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Vagotomy and accompanying pyloroplasty down-regulates ghrelin mRNA but does not affect ghrelin secretion.
- 2008
-
Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 151, s. 14-18
-
Tidskriftsartikel (refereegranskat)abstract
- In this study, we have examined how the lack of vagus activity affects the long-term secretion of total and active ghrelin. We subjected mice to sham-operation, pyloroplasty or vagotomy and pyloroplasty. The study lasted for 2 weeks, during which body weight development and daily food intake was monitored. At the end of the study, the mice were sacrificed, and serum and fundus were collected. Measurements of total and active serum ghrelin revealed no difference between the surgical groups and sham-operated mice, despite the fact that fundic ghrelin mRNA was down-regulated. The results presented here suggest that the vagus activity is not required for the long-term secretion of neither total nor active ghrelin in mice. They also suggest that fundic ghrelin mRNA expression is affected by pyloroplasty and vagotomy but that this effect does not translate into changes in ghrelin levels in the circulation.
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| 34. |
- Erlinge, David, et al.
(författare)
-
Neuropeptide Y stimulates proliferation of human vascular smooth muscle cells: cooperation with noradrenaline and ATP
- 1994
-
Ingår i: Regulatory Peptides. - 1873-1686. ; 50:3, s. 259-265
-
Tidskriftsartikel (refereegranskat)abstract
- Since the sympathetic nervous system has been shown to exert a trophic influence on vascular smooth muscle cells (SMC), we studied the growth regulating effects of neuropeptide Y (NPY) in cooperation with the sympathetic co-transmitters noradrenaline and adenosine triphosphate (ATP) in human vascular SMC. NPY stimulated DNA synthesis in human SMC grown from subcutaneous arteries and veins (diameter: 0.4 mm) measured by [3H]thymidine incorporation. Also cell number and protein synthesis were stimulated. The effect was mediated through the Y1-receptor and not Y2 or Y3 since the Y1-selective NPY analogue Pro34-NPY and peptide YY stimulated mitogenesis in the same magnitude as NPY while the NPY-fragment NPY13-36 only had minor effects. The effect was blocked by pretreating the cells with pertussis toxin indicating a Gi/o-coupled effect. The other sympathetic co-transmitters, noradrenaline and ATP, also stimulated mitogenesis in the human SMC in a similar magnitude as NPY. When added together NPY and noradrenaline potentiated each other in the mitogenic response. ATP had mainly additive effects. This is the first demonstration that NPY, noradrenaline and ATP stimulates growth in human vascular SMC. This suggests a role of the sympathetic cotransmitters in modulating vascular tone, but also by inducing hypertrophy/hyperplasia with possible clinical consequences.
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| 35. |
- Farkas, Orsolya, et al.
(författare)
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Effects of pituitary adenylate cyclase activating polypeptide in a rat model of traumatic brain injury
- 2004
-
Ingår i: Regulatory Peptides. - : Elsevier. - 0167-0115 .- 1873-1686. ; 123:1-3, s. 69-75
-
Tidskriftsartikel (refereegranskat)abstract
- Pituitary adenylate cyclase activating polypeptide (PACAP) is a widely distributed neuropeptide that has numerous different actions. Recent studies have shown that PACAP exerts neuroprotective effects not only in vitro but also in vivo, in animal models of global and focal cerebral ischemia, Parkinson's disease and axonal injuries. Traumatic brain injury has an increasing mortality and morbidity and it evokes diffuse axonal injury which further contributes to its damaging effects. The aim of the present study was to examine the possible neuroprotective effect of PACAP in a rat model of diffuse axonal injury induced by impact acceleration. Axonal damage was assessed by immunohistochemistry using an antiserum against beta-amyloid precursor protein, a marker of altered axoplasmic transport considered as key feature in axonal injury. In these experiments, we have established the dose response curves for PACAP administration in traumatic axonal injury, demonstrating that a single post-injury intracerebroventricular injection of 100 microg PACAP significantly reduced the density of damaged, beta-amyloid precursor protein-immunoreactive axons in the corticospinal tract.
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| 36. |
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| 37. |
- Forsgren, Sture, et al.
(författare)
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Vascular NK-1 receptor occurrence in normal and chronic painful Achilles and patellar tendons : studies on chemically unfixed as well as fixed specimens.
- 2005
-
Ingår i: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 126:3, s. 173-181
-
Tidskriftsartikel (refereegranskat)abstract
- It is not known as to whether the Achilles and patellar tendons contain neurokinin-1 (NK-1) receptors. This is a drawback when considering the fact that pain symptoms are frequent in these and as recent studies show that the pain symptoms might be cured via interference with blood vessel function. In the present study, the human Achilles and patellar tendons were examined concerning immunohistochemical expression of the NK-1 receptor. Chemically unfixed and fixed specimens, TRITC and PAP stainings and a battery of NK-1 receptor antibodies, including antibodies against the C-terminus and the N-terminal region, were utilized. NK-1 receptor immunoreaction could be detected in inner parts of the walls of large blood vessels and in the walls of small blood vessels. To some extent, NK-1 immunoreaction was also detectable in small nerve fascicles and in tenocytes. It was found to be of utmost importance to apply both chemically unfixed and fixed specimens. The use of chemically unfixed tissue was found advantageous in order to depict the immunoreactions in the blood vessel walls. The observations represent new findings and are of relevance as substance P (SP) is known to be of importance where neurogenic angiogenesis contributes to diseases and as SP on the whole has profound effects concerning blood vessel regulation.
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| 38. |
- Friis-Hansen, Lennart, et al.
(författare)
-
Characteristics of gastrin controlled ECL cell specific gene expression
- 2007
-
Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 140:3, s. 153-161
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The ECL cells are histamine-producing endocrine cells in the oxymic mucosa that synthesize and secrete proteins and peptides. They are the primary target for gastrin and mediate the control of gastrin on acid secretion and oxyntic mucosal growth. Knowledge of the molecular biology of the ECL cell is therefore important for understanding gastric physiology. Accordingly, we wanted to identify genes that are characteristically expressed in the ECL cells and controlled by gastrin. Methods: Using Affymetrix GeneChips((R)), RNA expression profiles were generated from ECL cells isolated by counterflow elutriation from hyper- or hypogastrinemic rats. Contamination from non-endocrine cells was eliminated by subtraction of the expression profiles of the fundic and antral mucosa. Results: The expression of 365 genes was ECL cell characteristic. Gastrin was found to control the expression of 120 which could be divided into two major groups depending on the known or anticipated biological function of the encoded protein: genes encoding proteins involved in the secretory process and genes encoding proteins needed to generate energy for secretion. Interestingly, gastrin stimulation also increased ECL cells expression of anti-apoptotic genes. Conclusion: The ECL cell specific expression profile is reminiscent of that of neurons and other endocrine cells exhibiting high expression of genes encoding proteins involved in the synthesis, storage and secretion of neuropeptides or peptide hormones. Gastrin regulated the expression of one third of these genes and is thus involved in the control of secretion from the ECL cells.
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| 39. |
- Gagnemo Persson, Rebecca, et al.
(författare)
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Rat stomach ECL-cell histidine decarboxylase activity is suppressed by ergocalciferol but unaffected by parathyroid hormone and calcitonin.
- 1999
-
Ingår i: Regulatory Peptides. - 1873-1686. ; 79:2-3, s. 131-139
-
Tidskriftsartikel (refereegranskat)abstract
- The ECL cells are peptide hormone-producing cells, rich in histamine and chromogranin A (CGA)-derived peptides, that operate under the control of gastrin. Gastrin and the ECL cells form a functional unit, the gastrin-ECL-cell axis. The aims of the present study were to examine (1) if calcitonin (CT), parathyroid hormone (PTH) and vitamin D affect the gastrin-ECL-cell axis (by measuring the activity of the histamine-forming enzyme, histidine decarboxylase (HDC), and the expression of HDC mRNA and CGA mRNA in the ECL cells), and (2) if activation of the gastrin-ECL-cell axis affects the parathyroid glands (by measuring plasma PTH and mRNA expression). We also examined the possibility that the oxyntic mucosa harbours vitamin D receptors. Fasted rats received intravenous infusion of PTH and CT with or without gastrin. PTH raised the blood Ca2+ concentration, whereas CT infusion lowered it. Plasma PTH rose in response to CT, while serum gastrin remained unaffected. ECL-cell HDC was activated by gastrin but not by CT and PTH. Five daily subcutaneous injections of large amounts of ergocalciferol raised the blood Ca2+ concentration, while reducing the oxyntic mucosal HDC activity and the expression of HDC and CGA mRNA. The serum gastrin concentration was not affected. The findings are in line with the idea that the gastrin-ECL-cell axis can be suppressed by vitamin D or by vitamin D-dependent mechanisms. Western blot analysis revealed the presence of vitamin D receptor immunoreactivity and reverse transcription PCR detected vitamin D receptor gene expression in the rat oxyntic mucosa. Hypergastrinemia was induced by daily peroral treatment with the H+/K+-ATPase inhibitor, omeprazole, for 2 weeks or by continuous subcutaneous infusion of gastrin for 7 days. Elevated serum gastrin concentration was associated with increased HDC activity and increased HDC and CGA mRNA expression in the oxyntic mucosa. There was no elevation of plasma PTH or PTH mRNA expression in the parathyroid gland.
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| 40. |
- Grönberg, Malin, 1980-, et al.
(författare)
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Neuroendocrine markers are expressed in human mammary glands
- 2010
-
Ingår i: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 160:1-3, s. 68-74
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundRegulatory peptides have previously been detected in epithelial cells of human mammary glands. As these peptides are produced by scattered neuroendocrine cells in the epithelium of other tissues the aim of this study was to investigate whether the mammary glands express molecular markers for neuroendocrine cells.Material and methodsSpecimens from 28 human mammary glands were retrieved. The distribution of immunoreactive cells was determined using immunohistochemistry with antibodies versus a set of endocrine markers including peptide hormones, chromogranins/secretogranins, vesicular monoamine transporters, synaptophysin, serotonin and synaptic vesicle protein 2.ResultsCells of the luminal epithelium of ducts and lobules of human mammary glands expressed vesicular monoamine transporter 2 and chromogranin B, as well as the previously reported regulatory peptides obestatin, ghrelin, adrenomedullin and apelin. Using consecutive sections, it was revealed that the immunoreactivity patterns of the regulatory peptides and vesicular monoamine transporter 2 were similar. Interestingly, immunoreactivity for secretogranin II, secretogranin III and chromogranin B was identified in myoepithelial cells. No immunoreactivity was detected for chromogranin A or synaptophysin.ConclusionSpecific cells in the epithelium and myoepithelium of mammary glands express neuroendocrine markers suggesting that mammary glands may have neuroendocrine functions.
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| 41. |
- Gunnarsson, Tove, et al.
(författare)
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Cholecystokinin peptides in cerebrospinal fluid : a study in healthy male subjects
- 1997
-
Ingår i: Regulatory Peptides. - 0167-0115 .- 1873-1686. ; 68:1, s. 57-61
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Tidskriftsartikel (refereegranskat)abstract
- The clinical reliability of measuring cholecystokinin (CCK) peptides in the cerebrospinal fluid (CSF) has not been fully elucidated. Therefore, we have assayed CCK-8S and CCK-4 in CSF obtained from 14 healthy male subjects, lumbar-punctured at the L4–5 level following a strictly standardised procedure. CSF concentrations of free CCK-8S and free CCK-4 were used as dependent variables while age, height, body weight, atmospheric pressure and some other factors served as independent variables. It was shown that the CCK-8S ratio between the second (7–12 ml) and first (0–6 ml) CSF fractions, correlated significantly with the atmospheric pressure at the time of puncture. Neither CCK-8S nor CCK-4 displayed concentration gradients in CSF. The CCK-4 levels, expressed as pmol l−1 in the total amount of CSF were found to be positively correlated with the neuraxis distance in the lying position and negatively with the neuraxis distance in the sitting position. Furthermore, CCK-4, expressed as pmol l−1 per min of tapping-time (pmol l−1 min−1), showed a negative correlation with storage time, presumably mirroring a proteolytic process. CCK-8S and CCK-4 intercorrelated positively independently of whether expressed as pmol l−1 or pmol l−1 min−1. In conclusion, the results of this exploratory study indicate that the neuraxis distance (in the sitting and lying positions) and storage-time have to be accounted for when interpreting data on CSF levels of CCK-4. Attention has to be paid to the potential influence of atmospheric pressure on the concentration ratio of CCK-8S.
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| 42. |
- Hellstrand, Per, et al.
(författare)
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Role of vasoactive intestinal polypeptide (VIP) in the neurogenic vasodilatation of the portal vein in the rabbit
- 1985
-
Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 12:4, s. 309-316
-
Tidskriftsartikel (refereegranskat)abstract
- A coarse network of nerve fibres displaying immunoreactivity for vasoactive intestinal polypeptide (VIP) was found in the wall of the hepatic portal vein of the rabbit. Electrical field stimulation of the rabbit portal vein in vitro, in the presence of adrenergic and cholinergic blockade, caused a marked relaxation of the vessel and a release of VIP into the perfusate. Addition of VIP to the tissue bath elicited a concentration-dependent inhibition of the mechanical activity of the portal vein. The results suggest that VIP containing neurones might participate in the non-cholinergic, non-adrenergic vasodilatation of the portal vein in the rabbit.
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| 43. |
- Hellström, Per M., 1954-
(författare)
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GLP-1 : broadening the incretin concept to involve gut motility
- 2009
-
Ingår i: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 156:1-3, s. 9-12
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Tidskriftsartikel (refereegranskat)abstract
- The incretin effect of the gut peptide hormone glucagon-like peptide-1 (GLP-1) is a combined result of inhibition of gastric emptying and stimulation of insulin secretion via an incretin mechanism. The temporal pattern of these events implicate that gastric emptying is primarily delayed, while later in the digestive process insulin is released for nutrient disposal. Since the inhibitory effect of GLP-1 on gastric motility is very outspoken, we considered it of value to study its effects on gut motility. Animal experimentation in the rat clearly showed that not only gastric emptying, but also small bowel motility with the migrating myoelectric complex was profoundly inhibited by GLP-1 at low doses. Similar effects were seen with analogues of the peptide. Extending the studies to man supported our earliest data indicating that the migrating motor complex of the small intestine was affected, and even more noticeable, the summarized motility index inhibited. Further extension of our studies to patients with irritable bowel syndrome (IBS) displayed similar results. This encouraged us to embark on a clinical pain-relief multi-centre study in IBS patients using a GLP-1 analogue, ROSE-010, with longer half-life than the native peptide. The outcome of the IBS study proved ROSE-010 to be superior to placebo with a pain-relief response rate of 24% for ROSE-010 compared to 12% for placebo. Taken together, the GLP-1 analogue ROSE-010 is believed to cause relaxation of the gut and can thereby relieve an acute pain attack of IBS, even though its precise mechanism is yet to be defined.
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| 44. |
- Hellström, Per M., et al.
(författare)
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Receptor-mediated inhibition of small bowel migrating complex by GLP-1 analog ROSE-010 delivered via pulmonary and systemic routes in the conscious rat
- 2012
-
Ingår i: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 179:1-3, s. 71-76
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Tidskriftsartikel (refereegranskat)abstract
- 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 mu g/kg) with or without the GLP-1 receptor blocker exendin(9-39)amide (300 mu g/kg.h), were studied. Second, ROSE-010 (100, 200 mu g/kg) Technosphere (R) 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 mu g/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 mu g/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 (R) inhalation powder has potential in IBS pain management and treatment.
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| 45. |
- Holmberg, Sara K S, et al.
(författare)
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Localization of neuropeptide Y receptor Y5 mRNA in the guinea pig brain
- 2004
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 117, s. 61-67
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Tidskriftsartikel (refereegranskat)abstract
- Neuropeptide Y (NPY) has prominent stimulatory effects on food intake in virtually all animals that have been studied. In mammals, the effect is primarily mediated by receptors Y1 and Y5, which seem to contribute to different aspects of feeding behavior in guinea pigs and rats/mice. Interestingly, differences in receptor distribution among mammalian species have been reported. To get a broader perspective on the role of Y5, we describe here studies of guinea pig (Cavia porcellus), a species which due to its phylogenetic position in the mammalian radiation is an interesting complement to previous studies in rat and mouse. Guinea pig brain sections were hybridized with two 35S-labeled oligonucleotides complementary to Y5 mRNA. The highest expression levels of Y5 mRNA were observed in the hippocampus and several hypothalamic and brain stem nuclei implicated in the regulation of feeding, such as the paraventricular, arcuate and ventromedial hypothalamic nuclei. This contrasts with autoradiography studies that detected low Y5-like binding in these areas, a discrepancy observed also in rat and human. Y5 mRNA expression was also seen in the striatum, in great contrast to mouse and rat. Taken together, these data show that Y5 mRNA distribution displays some interesting species differences, but that its expression in feeding centers seems to be essentially conserved among mammals, adding further support for an important role in food intake.
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| 46. |
- Höckerfelt, U, et al.
(författare)
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Substance P (NK1) receptor in relation to substance P innervation in rat duodenum after irradiation.
- 2001
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Ingår i: Regulatory Peptides. - 0167-0115 .- 1873-1686. ; 98:3, s. 115-26
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Tidskriftsartikel (refereegranskat)abstract
- It has previously been shown that high dose of irradiation to the rat abdomen leads to an increased level of substance P (SP) in the duodenum. In the present study the pattern of distribution of NK1 receptors (NK1-R) in rat duodenum after irradiation (5-30 Gy), was examined at the same time-point (7 days) after irradiation, comparisons being made with the distribution of SP-innervation. Immunohistochemical methods were used. In controls, NK1-R-like immunoreactivity (-LI) was detected in epithelial cells, in cells in the region of the intestinal cells of Cajal within the deep muscular plexus (ICC-DMP), in neuronal cells in the myenteric plexus, and variably in granulocytes in the mucosa. Irradiation with 5-10 Gy did not lead to obvious changes in the pattern of NK1-R-LI. After irradiation with the highest doses (25-30 Gy), the mucosa was often gravely damaged, displaying granulation tissue. No epithelial NK1-R-LI was detected in this tissue, but was present in less affected mucosa after these doses. In the region of the ICC-DMP, in the myenteric plexus, and in granulocytes, NK1-R-LI was detected also after high dose irradiation. However, the degree of NK1-R-LI in the region of the ICC-DMP was somewhat lower than seen in controls and after low doses. SP-immunoreactive nerve fibers were present in the regions where NK1-R-LI was detected. These findings support a suggestion that an increased level of SP after irradiation may contribute to the dose-dependent gastrointestinal adverse effects that occur after radiotherapy.
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| 47. |
- Høyerup, P., et al.
(författare)
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Glucagon-like peptide-2 stimulates mucosal microcirculation measured by laser Doppler flowmetry in end-jejunostomy short bowel syndrome patients
- 2013
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 180:1, s. 12-16
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Tidskriftsartikel (refereegranskat)abstract
- Background: In animal and human studies glucagon-like peptide-2 (GLP-2) has been shown to increase blood flow in the superior mesenteric artery and the portal vein. This study describes the effect of GLP-2 measured directly on the intestinal mucosal blood flow by laser Doppler flowmetry (LDF) in end-jejunostomy short bowel syndrome (SBS) patients. Methods: In five SBS patients with end-jejunostomy a specially designed laser Doppler probe was inserted into the stoma nipple, and blood flow measured directly on the jejunal mucosa for 105. min in relation to no treatment, systemic saline infusion, topical adrenaline application and a subcutaneous injection of 800μg native GLP-2. Results: The GLP-2 injection increased jejunal mucosal blood flow by 79 ± 37% compared to conditions, where no treatment was given (p < 0.001). The significant effect was present at least 105. min. Systemic saline infusion and topical, mucosal adrenaline application did not affect mucosal microcirculation. Conclusions: GLP-2 raises jejunal microcirculation in SBS patients with end-jejunostomy. This may explain the redness and increase in the end-jejunostomy nipple size imminently after commencing GLP-2 injections. The potential beneficial effects of this GLP-2-mediated increase of blood flow in the mesenteric bed should be investigated in clinical conditions other than the short bowel syndrome.
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| 48. |
- Jimenez, Javier, et al.
(författare)
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Abnormally decreased NO and augmented CO production in islets of the leptin-deficient ob/ob mouse might contribute to explain hyperinsulinemia and islet survival in leptin-resistant type 2 obese diabetes.
- 2011
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 170, s. 43-51
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Tidskriftsartikel (refereegranskat)abstract
- The role of the gaseous messengers NO and CO for β-cell function and survival is controversial. We examined this issue in the hyperglycemic-hyperinsulinemic ob/ob mouse, an animal model of type 2 obese diabetes, by studying islets from obese vs lean mice regarding glucose-stimulated insulin release in relation to islet NO and CO production and the influence of modulating peptide hormones. Glucose-stimulated increase in ncNOS-activity in incubated lean islets was converted to a decrease in ob/ob islets associated with markedly increased insulin release. Both types of islet displayed iNOS activity appearing after ~60min in high-glucose. In ob/ob islets the insulinotropic peptides glucagon, GLP-1 and GIP suppressed NOS activities and amplified glucose-stimulated insulin release. The insulinostatic peptide leptin induced the opposite effects. Suppression of islet CO production inhibited, while stimulation amplified glucose-stimulated insulin release. Nonincubated isolated islets from young and adult obese mice displayed very low ncNOS and negligible iNOS activity. In contrast, production of CO, a NOS inhibitor, was impressively raised. Glucose injections induced strong activities of islet NOS isoforms in lean but not in obese mice and confocal microscopy revealed iNOS expression only in lean islets. Islets from ob/ob mice existing in a hyperglycemic in vivo milieu maintain elevated insulin secretion and protection from glucotoxicity through a general suppression of islet NOS activities achieved by leptin deficiency, high CO production and insulinotropic cyclic-AMP-generating hormones. Such a beneficial effect on islet function and survival might have its clinical counterpart in human leptin-resistant type 2 obese diabetes with hyperinsulinemia.
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| 49. |
- Jimenez, Javier, et al.
(författare)
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Insulin feedback actions: complex effects involving isoforms of islet nitric oxide synthase.
- 2004
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 122:2, s. 109-118
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Tidskriftsartikel (refereegranskat)abstract
- The present study examined the effects of exogenous insulin on C-peptide release in relation to islet activities of neural constitutive nitric oxide synthase (ncNOS) and inducible NOS (iNOS). The dose–response curves for glucose-stimulated insulin and C-peptide release from isolated islets were practically identical: 0.05–0.1 nmol/l insulin stimulated, 1–100 nmol/l had no effect, whereas concentrations ≥250 nmol/l (“high insulin”), inhibited C-peptide release. Both the stimulatory and inhibitory effects were abolished by the phosphatidylinositol 3′-kinase inhibitor wortmannin. Addition of a NOS inhibitor partially reversed the inhibitory action of high insulin, but had no effect on the stimulatory action of low insulin (0.1 nmol/l). Moreover, high insulin markedly increased islet ncNOS activity and induced a strong iNOS activity. As shown biochemically and with confocal microscopy, the stimulatory action of high insulin on NOS activities and the associated inhibition of C-peptide release were reversed by raising cyclic AMP through addition of either glucagon-like peptide 1 (GLP-1) or dibutyryl cyclic AMP (Bt2cAMP) to the incubated islets. We conclude that the positive feedback mechanisms of action of insulin are independent of islet NOS activities and remain unclear. The negative feedback action of insulin, however, can be explained by its ability to stimulate both islet ncNOS activity and the expression and activity of iNOS. The effects on iNOS are most likely transduced through phosphatidylinositol 3′-kinase and are counteracted by raising islet cyclic AMP levels.
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| 50. |
- Kristensson, E, et al.
(författare)
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Acute psychological stress raises plasma ghrelin in the rat.
- 2006
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 134:2-3, s. 114-117
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Tidskriftsartikel (refereegranskat)abstract
- Ghrelin is produced by the A-like cells of the stomach and mobilized by food deprivation. It was reported recently that acute psychological stress increases ghrelin gene expression in rat oxyntic mucosa. The aim of this study was to examine the effect of such stress on circulating ghrelin levels. To this end, we measured plasma ghrelin in Wistar Kyoto (WKY) rats (a high-anxiety strain) and Sprague–Dawley (SPD) rats (a low-anxiety strain), exposed to water avoidance stress for 60 min. Blood was collected before and after the stress. Acute stress increased the plasma ACTH concentration not, vert, similar5-fold (p < 0.01) in both strains of rats, while plasma ghrelin increased by 85% (p < 0.01) in the SPD rats and by 40% (p < 0.001) in the WKY rats. Ghrelin levels after acute stress were higher (p < 0.05) in the SPD rats than in the WKY rats. Sham stress did not affect plasma ghrelin. We conclude that acute psychological stress mobilizes ghrelin and that the SPD rats respond with a higher plasma ghrelin concentration than the WKY rats.
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