| 1. |
- Abdulla, Aree, et al.
(författare)
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CD40L is not involved in acute experimental pancreatitis
- 2011
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 659:1, s. 85-88
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Tidskriftsartikel (refereegranskat)abstract
- Recent data suggest that platelets not only control thrombosis and hemostasis but may also regulate inflammatory processes such as acute pancreatitis. However, the specific role of platelet-derived mediators in the pathophysiology of acute pancreatitis is not known. Herein, we examined the role of CD40 ligand (CD40L, CD154) in different models of acute pancreatitis. Acute pancreatitis was induced by repetitive caerulein administration (50 mu g/kg, i.p.) or infusion of sodium taurocholate (5%-10 mu l) into the pancreatic duct in wild-type C578L/6 and CD40L-deficient mice. Neutrophil infiltration, myeloperoxidase (MPO), macrophage inflammatory protein-2 (MIP-2) levels, acinar cell necrosis, edema and hemorrhage in the pancreas as well as serum amylase activity and lung levels of MPO were quantified 24 h after induction of acute pancreatitis. Caerulein and taurocholate challenge caused a clear-cut pancreatic damage characterized by increased acinar cell necrosis, neutrophil infiltration, focal hemorrhage, edema formation as well as increased levels of serum amylase and MIP-2 in the pancreas and lung MPO and histological damage. Notably, CD40L gene-deficient animals exhibited a similar phenotype as wild-type mice after challenge with caerulein and taurocholate. Similarly, administration of an antibody directed against CD40L had no effect against acute pancreatitis. Our data suggest that CD40L does not play a functional role in experimental acute pancreatitis. Thus, other candidates than CD40L needs to be explored in order to identify platelet-derived mediators in the pathophysiology of acute pancreatitis. (C) 2011 Elsevier B.V. All rights reserved.
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| 2. |
- Abdulla, Aree, et al.
(författare)
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Platelets regulate P-selectin expression and leukocyte rolling in inflamed venules of the pancreas
- 2012
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 682:1-3, s. 153-160
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Tidskriftsartikel (refereegranskat)abstract
- Recent data suggest that platelets regulate inflammatory changes and tissue damage in acute pancreatitis although the role of platelets in leukocyte-endothelium interactions in the pancreatic microcirculation is not known. The aim of this study was to define the impact of platelets on leukocyte rolling and adhesion in acute pancreatitis. Acute pancreatitis was induced in C57BL/6 mice by caerulein challenge. Mice were treated with an a anti-GP1b alpha (CD42b) antibody, which depletes platelets, or a control antibody before caerulein. Leukocyte rolling and adhesion were determined by the use of intravital fluorescence microscopy 18 h after the last dose of caerulein. In separate experiments, leukocyte-endothelium interactions were determined before and after administration of an anti-P-selectin, anti-PSGL-1 and a control antibody in mice with caerulein pancreatitis. Circulating platelet-neutrophil aggregates and pancreatic P-selectin mRNA were quantified 1 and 6 h respectively after caerulein challenge. Caerulein administration increased leukocyte and platelet interactions in the pancreatic microvasculature, increased tissue damage and expression of P-selectin mRNA in the pancreas as well as platelet-neutrophil complexes in the circulation. Notably, platelet depletion markedly reduced caerulein-provoked leukocyte rolling and adhesion in postcapillary venules. Interestingly, depletion of platelets significantly decreased caerulein-induced gene expression of P-selectin in the pancreas. Moreover, immunoneutralization of P-selectin and PSGL-1 abolished leukocyte rolling in the pancreatic venules triggered by caerulein. Our novel findings demonstrate that platelets regulate leukocyte rolling in acute pancreatitis via induction of P-selectin, which was critical in supporting leukocyte rolling in inflamed venules of the pancreas. (C) 2012 Elsevier B.V. All rights reserved.
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| 3. |
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| 4. |
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| 5. |
- Baun, Michael, et al.
(författare)
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Pharmacological characterization and expression of VIP and PACAP receptors in isolated cranial arteries of the rat
- 2011
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 670:1, s. 186-194
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Tidskriftsartikel (refereegranskat)abstract
- Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide (PACAP) are potent vasodilators in animals and humans. PACAP infusion but not VIP infusion precipitates migraine attacks in migraine patients. The vascular effects of VIP and the two varieties of PACAP (PACAP-27 and PACAP-38) were investigated versus selective antagonists in segments of rat middle cerebral arteries (MCA), basilar arteries (BA) and middle meningeal arteries (MMA) using myographs. The luminal and abluminal effects of VIP were studied using perfusion myograph. mRNA expression of the relevant receptors (VPAC(1), VPAC(2) and PAC(1)) was examined by in situ hybridization. There was no significant difference in relaxant potency of the peptides in the MCA. In BA the relaxant potency was VIP>PACAP-27 = PACAP-38. Relaxant responses were either absent or very weak in MMA. VIP was found to be somewhat more potent in BA than in the MCA. Maxadilan, a selective PAC(1)-receptor agonist, showed no relaxant effect in either vessel. The VPAC(2)-antagonist PG 99-465 alone proved ineffective in the MCA, while it had a weak effect on BA. The VPAC(1)-antagonist PG 97269 inhibited relaxation induced by both VIP and the PACAPs in cerebral vessels. In combination, the two antagonists demonstrated better effect than either alone. VIP applied luminally via perfusion myograph caused no dilatation, indicating lack of endothelial involvement. In situ hybridization demonstrated the presence of mRNA for all three receptors in the smooth muscle cells of the vessels. In conclusion, migraine-like headache induced by PACAP-38 infusion is unlikely to be caused by direct vasodilator action on intracranial vessels. (C) 2011 Elsevier B.V. All rights reserved.
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| 6. |
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| 7. |
- Buono, Roberta, et al.
(författare)
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Silodosin and tadalafil have synergistic inhibitory effects on nerve-mediated contractions of human and rat isolated prostates
- 2014
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Ingår i: European Journal of Pharmacology. - : Elsevier. - 0014-2999 .- 1879-0712. ; 744, s. 42-51
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Tidskriftsartikel (refereegranskat)abstract
- Lower urinary tract symptoms (CUTS) in men with benign prostatic hyperplasia (BPH) are associated with erectile dysfunction. Alpha-1-adrenoceptor antagonists are effective drugs for treating symptomatic BPH. Clinical data show improvements in LUIS by phosphodiesterase 5 inhibitors. This study aimed to evaluate effects of siloclosin, a highly selective alpha(1A)-adrenoceptor antagonist, alone or in combination with the phosphocliesterase 5 inhibitor tadalafil on contractions of isolated human and rat prostates. In organbath studies, effects of increasing concentrations of siloclosin (1 nM-1 mu M) and tadalafil (100 nM-100 mu M) on contractions by electrical field stimulation or phenylephrine of human and rat prostate strip preparations were investigated. The combination silodosin and tadalafil reduced electrically-induced contractions of human prostate preparations better than single drugs alone. At any frequencies (1-32 Hz), inhibitory effects of combined therapy (P-values vs single drug) in human tissue were 26-42% (1 nM silodosin+100 nM tadalafil; P less than 0.05), 40-58% (10 nM silodosin+1 mu M tadalafil; P less than 0.001-0.05), 56-67% (100 nM silodosin+10 mu M tadalafil; P less than 0.01-0.05), and 33-55% (1 mu M silodosin+100 mu M tadalafil P less than 0.01-0.05), Similar findings were obtained in rat prostate preparations. In human and rat prostate tissue, the drug combination exerted similar inhibitory effect on phenylephrine contractions as silodosin alone. Silodosin plus tadalafil had greater potency than each drug alone to inhibit prostate contractions to electrical field stimulation but not to phenylephrine. This study supports the clinical application of a combination of an (alpha(1A)-adrenoceptor antagonist and a phosphodiesterase 5 inhibitor for symptomatic BPH and suggests that the drug combination requires endogenous nerve-activity for optimal effect.
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| 8. |
- Carlsson, Anna, et al.
(författare)
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Substance P1-7 induces antihyperalgesia in diabetic mice through a mechanism involving the naloxone-sensitive sigma receptors
- 2010
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 626:2-3, s. 250-255
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Tidskriftsartikel (refereegranskat)abstract
- We have recently explored the role of the tachykinin substance P neuroactive fragment substance P1-7 in the mediation of anti-inflammatory effects using a blister model in the rat paw (Wiktelius et al., 2006). We observed that this heptapeptide induced a dose-dependent inhibitory effect on the substance P-induced response, which was reversible by the non-selective opioid receptor antagonist naloxone. In the present study, we examined the ability of substance P1-7 to induce antihyperalgesic effects in streptozotocin-induced diabetic mice. We found that the substance P fragment strongly and dose-dependently produced antihyperalgesia in diabetic mice. This effect was reversed by naloxone but not by the selective opioid receptor antagonist beta-funaltrexamine, naltrindole or nor-binaltorphimine. selective for the mu-, delta- or kappa-Opioid receptor, respectively. In addition, the anti hyperalgesic effect induced by substance P1-7 was partly reversed by a sigma(1) receptor agonist (+)-pentazocine. but not a a, receptor antagonist BD1047 ([2-(3,4-dichlorophenyl) ethyl]-N-methyl-2-(diamino)ethylamine), suggesting that involvement of the naloxone-sensitive sigma-receptor for the action of the SP related heptapeptides. These results suggest that hyperalgesia in diabetic mice may be, in part, due to the enhanced endogenous sigma(1) receptor systems in the spinal cord.
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| 9. |
- Carlsson-Jonsson, Anna, et al.
(författare)
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N-terminal truncations of substance P1-7 amide affect its action on spinal cord injury-induced mechanical allodynia in rats
- 2014
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 738, s. 319-325
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Tidskriftsartikel (refereegranskat)abstract
- Central neuropathic pain can arise from injury of the spinal cord and can become chronic. Treatment is difficult and, because complete pain relief is currently very hard to achieve, there is a need for new, more effective treatment options. In this study we used an animal model of spinal cord injury to evaluate the potency of a bioactive fragment of substance P (SP), i.e. SP1-7, in alleviating signs of allodynia and acute pain. SP1-7 is known from earlier studies to possess antinociceptive properties. We also studied the effects of intraperitoneal injection of an amidated analog of this heptapeptide and of its truncated analogs, all of which had high affinity to the SP1-7 binding site, to evaluate the importance of the removed amino acids for the bioclistribution and stability of the peptides. Most of the examined compounds alleviated mechanical alloclynia without any signs of sedation or motor impairment in the rats. In contrast, the response threshold to acute nociceptive stimulation was not affected by arty of the compounds tested. Most of the amino acids in the heptapepticle structure were essential for retaining the biological effect after peripheral injection. These observations suggest that the heptapepticle and its N-Lerminal truncated hexa- and pentapeptide analogs could be of interest for further development of analgesics in the management of mechanical allodynia.
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| 10. |
- Changhui, Yu, et al.
(författare)
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Rac1 signaling regulates neutrophil-dependent tissue damage in experimental colitis.
- 2014
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 741:Jul 30, s. 90-96
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Tidskriftsartikel (refereegranskat)abstract
- Excessive neutrophil recruitment in the colon is a major feature in acute colitis although the signaling mechanisms behind colonic recruitment of neutrophils remain elusive. Herein, we hypothesized that Rac1 activity might play an important role in neutrophil infiltration in the inflamed colon. Female Balb/c mice were treated with the Rac1 inhibitor NSC23766 (0.5 and 5mg/kg) before and daily after administration of 5% dextran sodium sulfate (DSS). Colonic tissue was collected for quantification of neutrophil recruitment, interleukin-6 (IL-6) and CXC chemokine formation as well as histological damage score five days after challenge with DSS. Rac1 activity was determined by western blot and Mac-1 expression by flow cytometry in neutrophils. Administration of NSC23766 decreased DSS-induced neutrophil recruitment and tissue damage in the colon. Rac1 inhibition decreased colonic formation of IL-6 and CXC chemokines in experimental colitis. Chemokine challenge increased Rac1 activity in neutrophils and NSC23766 markedly reduced this neutrophil activity of Rac1. Inhibition of Rac1 abolished CXC chemokine-induced neutrophil chemotaxis and up-regulation of Mac-1 in vitro. Taken together, Rac1 signaling plays a significant role in controlling accumulation of neutrophils and tissue injury in experimental colitis. Thus, our novel results suggest that targeting Rac1 signaling might be a useful way to protect against neutrophil-mediated tissue injury in acute colitis.
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| 11. |
- Cipriano, Mariateresa, et al.
(författare)
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Inhibition of fatty acid amide hydrolase and cyclooxygenase by the N-(3-methylpyridin-2-yl)amide derivatives of flurbiprofen and naproxen
- 2013
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Ingår i: European Journal of Pharmacology. - : Elsevier. - 0014-2999 .- 1879-0712. ; 720:1-3, s. 383-390
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Tidskriftsartikel (refereegranskat)abstract
- Inhibitors of the metabolism of the endogenous cannabinoid ligand anandamide by fatty acid amide hydrolase (FAAH) reduce the gastric damage produced by non-steroidal anti-inflammatory agents and synergise with them in experimental pain models. This motivates the design of compounds with joint FAAH/cyclooxygenase (COX) inhibitory activity. Here we present data on the N-(3-methylpyridin-2-yl) amide derivatives of flurbiprofen and naproxen (Flu-AM1 and Nap-AM1, respectively) with respect to their properties towards these two enzymes. Flu-AM1 and Nap-AM1 inhibited FAAH-catalysed hydrolysis of [H-3]anandamide by rat brain homogenates with IC50 values of 044 and 0.74 mu M. The corresponding values for flurbiprofen and naproxen were 29 and > 100 mu M, respectively. The inhibition by Flu-AM1 was reversible, mixed-type, with K-slope(i) and K-intercept(i) values of 0.21 and 1.4 mu M, respectively. Flurbiprofen and Flu-AM1 both inhibited COX in the same manner with the order of potencies COX-2 vs. 2-arachidonoylglycerol > COX-1 vs. arachidonic acid > COX-2 vs. arachidonic acid with flurbiprofen being approximately 2-3 fold more potent than Flu-AM 1 in the assays. Nap-AM1 was a less potent inhibitor of COX. Flu-AM1 at low micromolar concentrations inhibited the FAAH-driven uptake of [H-3]anandamide into RBL2H3 basophilic leukaemia cells in vitro, but did not penetrate the brain in vivo sufficiently to block the binding of [F-18]DOPP to brain FAAH. It is concluded that Flu-AM 1 is a dual-action inhibitor of FAAH and COX that may be useful in exploring the optimal balance of effects on these two enzyme systems in producing peripheral alleviation of pain and inflammation in experimental models.
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Ekman, Mari, et al.
(författare)
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Association of muscarinic M(3) receptors and Kir6.1 with caveolae in human detrusor muscle.
- 2012
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 683:1-3, s. 238-245
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Tidskriftsartikel (refereegranskat)abstract
- Caveolae are 50-100nm large membrane invaginations that play a role in cellular signaling. The aim of the present study was to assess whether muscarinic M(3) receptors and the K(ATP) channel subunit Kir6.1 are associated with human detrusor caveolae, and to pharmacologically assess the relevance of this organization for contractility. Detrusor strips were dissected and used in ultrastructural, biochemical and mechanical studies. Caveolae were manipulated by cholesterol desorption using mβcd (methyl-β-cyclodextrin). Mβcd disrupted caveolae and caused a cholesterol-dependent ~3-fold rightward shift of the concentration-response curve for the muscarinic receptor agonist carbachol. The effect of mβcd was inhibited by the K(ATP) blockers glibenclamide, repaglinide and PNU-37883, and it was mimicked by the K(ATP) activator levcromakalim. Immunoelectron microscopy showed muscarinic M(3) receptors and Kir6.1 to be enriched in caveolae. In conclusion, pharmacological K(ATP) channel inhibition antagonizes the effect of caveolae disruption on muscarinic contractility in the human detrusor, and the K(ATP) channel subunit Kir6.1 co-localizes with M(3) receptors in caveolae.
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| 16. |
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| 17. |
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| 18. |
- Hedegaard, Elise R., et al.
(författare)
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Mechanisms involved in increased sensitivity to adenosine A(2A) receptor activation and hypoxia-induced vasodilatation in porcine coronary arteries
- 2014
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Ingår i: European Journal of Pharmacology. - : Elsevier. - 0014-2999 .- 1879-0712. ; 723, s. 216-226
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxia-induced coronary vasorelaxation is a compensatory mechanism increasing blood flow. We hypothesized that hypoxia shares pathways with adenosine and causes vasorelaxation through the adenosine A(2A) receptor and force suppression by increasing cAMP and phosphorylated heat shock protein (HSP)20. Adenosine receptors in porcine left anterior descending coronary arteries (LAD) were examined by RT-PCR and isometric tension recording in myographs. Vasorelaxation was induced by adenosine, 1% oxygen, or both in the absence or presence of ZM241385, an adenosine A(2A) receptor antagonist, cAMP was determined by ELISA and p-HSP20/1-ISP20 and p-MLC/MLC were determined by immunoblotting and densitometric analyses. In coronary arteries exposed to 1% oxygen, there was increased sensitivity to adenosine, the adenosine 112 selective agonist NECA, and the adenosine A(2A) selective receptor agonist CGS21680. ZM241385 shifted concentration-response curves for CGS21680 to the right, whereas the adenosine A(1) antagonist DPCPX, the adenosine A(2B) receptor antagonist MRS1754 and the adenosine A(3) receptor antagonist MRS1523 failed to reduce vasodilatation induced by CGS21680. 1% oxygen or adenosine increased cAMP accumulation and HSP20 phosphorylation without changing T850-MYPT1 and MLC phosphorylation. ZM241385 failed to change 1% oxygen-induced vasodilation, cAMP accumulation, HSP20 phosphorylation and MLC phosphorylation. The PKA inhibitor Rp-8-CPT-cAMPS significantly reduced vasorelaxation induced by 1% oxygen or CGS21680. Our findings suggest that the increased sensitivity to adenosine, NECA, and CGS21680 at 1% oxygen involves adenosine A(2A) receptors. Adenosine and 1% oxygen induce vasorelaxation in PGF(2 alpha)-contracted porcine coronary arteries partly by force suppression caused by increased cAMP and phosphorylation of HSP20.
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| 19. |
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| 20. |
- Karbalaei, Mardjaneh, et al.
(författare)
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Impaired contractility and detrusor hypertrophy in cavin-1-deficient mice.
- 2012
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 689:1-3, s. 179-185
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Tidskriftsartikel (refereegranskat)abstract
- Caveolae are membrane invaginations present in a variety of cell types. Formation of caveolae depends on caveolins and on the more recently discovered family of proteins known as the cavins. Genetic ablation of caveolin-1 was previously shown to give rise to a number of urogenital alterations, but the effects of cavin-1 deletion on urogenital function remain unknown. Here we characterized detrusor contractility and structure in cavin-1-deficient mice. Electron microscopy demonstrated essentially complete lack of caveolae in the knock-out detrusor, and immunoblotting disclosed reduced levels of cavin-3 and of all caveolin proteins. Bladder weight was increased in male knock-out mice, and length-tension relationships demonstrated a reduction in depolarisation-induced contraction. Contractility in response to muscarinic receptor activation was similarly reduced. Despite these functional changes, micturition patterns were similar in conscious and freely moving animals and diuresis was unchanged. Our breeding additionally disclosed that the number of knock-out mice generated in heterozygous crosses was lower than expected, suggesting embryonic/perinatal lethality. In conclusion, this is the first study to show that cavin-1 is critical for detrusor caveolae and for the overall contractility and structure of the urinary bladder.
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| 21. |
- Karlsson, Lars O, 1975, et al.
(författare)
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Dose-dependent cardioprotection of enkephalin analogue Eribis peptide 94 and cardiac expression of opioid receptors in a porcine model of ischaemia and reperfusion
- 2012
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Ingår i: European journal of pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 674:2-3, s. 378-383
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Tidskriftsartikel (refereegranskat)abstract
- Opioids confer cardioprotection after myocardial ischaemia and reperfusion. The primary aim of the present study was to evaluate the cardioprotective effect of different doses of enkephalin analogue Eribis peptide 94 (EP 94) in a porcine model of ischaemia and reperfusion. A secondary aim was to analyse the impact of ischaemia and reperfusion on the expression of opioid receptor subtypes in the porcine heart. Thirty-four anesthetised pigs underwent 40 min of balloon occlusion of the left anterior descending coronary artery followed by four hours of reperfusion. Pigs were given either vehicle (0.9% NaCl) or one of four doses of EP 94 (0.2, 1, 5 or 25 ug/kg at each administration, respectively), intravenously after 26, 33 and 40 min of ischaemia. Hearts were stained to quantify area at risk and infarct size. mRNA and protein expressions of the opioid receptor subtypes were detected with RT-PCR, immunoblotting and immunohistochemistry in the control and ischaemic/reperfused areas. There was a significant dose-response relationship between higher doses of EP 94 and reduced infarct size. Expression of kappa- and delta-opioid receptors was detected at both mRNA and protein levels. In ischaemic/reperfused areas, an increased expression of mRNA for both receptors was observed, whereas only protein expression for the delta subtype was up-regulated. The mu-opioid receptor was not detected.
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| 22. |
- Karlsson, Lars O, 1975, et al.
(författare)
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Opioid receptor agonist Eribis peptide 94 reduces infarct size in different porcine models for myocardial ischaemia and reperfusion
- 2011
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 651:1-3, s. 146-151
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Tidskriftsartikel (refereegranskat)abstract
- Eribis peptide 94 (EP 94) is a novel enkephalin analog, thought to interact with the and delta-opioid receptors. The purpose of the present study was to examine the cardioprotective potential of EP 94 in two clinically relevant porcine models of myocardial ischaemia and reperfusion, and to investigate if such an effect is associated with an increased expression of endothelial nitric oxide synthase (eNOS). Forty-one anesthetized pigs underwent 40 min of coronary occlusion followed by 4 h of reperfusion. In Protocol I, balloon occlusion of the left anterior descending artery was performed with concurrent intravenous administration of (A) vehicle (n = 7), (B) EP 94 (1 ug/kg) after 5, 12, 19 and 26 min of ischaemia (n = 4) or (C) EP 94 (1 ug/kg) after 26, 33, 40 min of ischaemia (n = 6). In Protocol II, open-chest pigs were administered (D) vehicle (n = 6) or (E) 0.2 ug/kg/min of EP 94 (n = 6) through an intracoronary infusion into the jeopardized myocardium, started after 30 min of ischaemia and maintained for 15 min. The hearts were stained and the protein content of eNOS measured. EP 94 reduces infarct size when administered both early and late during ischaemia compared with vehicle (infarct size group A 61.6 +/- 2%, group B 50.2 +/- 3% and group C 49.2 +/- 2%, respectively, P < 0.05), as well as when infused intracoronary (infarct size group D 82.2 +/- 3.9% and group E 61.2 +/- 2.5% respectively, P < 0.01). Phosphorylated eNOS Ser(I177) in relation to total eNOS was significantly increased in the group administered EP 94. indicating activation of nitric oxide production.
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| 23. |
- Kruuse, Christina, et al.
(författare)
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Differential vasoactive effects of sildenafil and tadalafil on cerebral arteries
- 2012
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 674:2-3, s. 345-351
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Tidskriftsartikel (refereegranskat)abstract
- Phosphodiesterase 5 (PDE5) is associated with migraine pathophysiology, stroke recovery and vasospasm treatment The potential vascular interplay of PDE5 inhibitors sildenafil, tadalafil and UK-114,542 was studied by intra- versus extra-luminal administration in rat middle cerebral arteries in vitro and on middle meningeal arteries in vivo. By Western blot PDE5 was detected in both cerebral and meningeal arteries, though with minor variations in band intensity between vascular beds. Rat middle cerebral artery diameter was investigated using pressurised arteriography, applying UK-114,542, sildenafil, and tadalafil intra- or extraluminally. Effects on the dural middle meningeal artery were studied in the in vivo closed cranial window model. At high concentrations, abluminal sildenafil and UK-114,542, but not tadalafil, induced dilatation of the middle cerebral artery. Luminal application elicited a contraction of 4% (sildenafil, P = 0.03) and 10% (tadalafil, P = 0.02). In vivo, sildenafil, but not tadalafil, dose-dependently dilated middle meningeal artery concomitant to blood pressure reduction (1-3 mg/kg);1 mg/kg sildenafil inducing 60 +/- 14% (P = 0.04) and vehicle (DMSO) 13 +/- 6% dilatation. In conclusion, PDE5 inhibitors applied luminally had minor contractile effect, whereas abluminal sildenafil induced middle cerebral artery dilatation above therapeutic levels. In vivo, sildenafil dilated middle meningeal artery concomitant with a reduction in blood pressure. Tadalafil had no dilatory effects. PDE5 inhibitors show differential vascular activity in cerebral arteries from healthy animals; arterial dilatation is seen primarily above therapeutic levels. Such findings support clinical studies showing no vasodilator effects of sildenafil on cerebral arteries in healthy subjects. (C) 2011 Elsevier B.V. All rights reserved.
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| 24. |
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| 25. |
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| 26. |
- Larsson Callerfelt, Anna-Karin, et al.
(författare)
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Modulation of antigen-induced responses by serotonin and prostaglandin E(2) via EP(1) and EP(4) receptors in the peripheral rat lung.
- 2013
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 699:1-3, s. 141-149
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Tidskriftsartikel (refereegranskat)abstract
- The cyclooxygenase (COX) pathway and prostanoids may critically contribute to the early allergic airway response. In the rat lung, serotonin (5-HT) is a major mediator of antigen-induced contractions. The aim of this study was therefore to examine the relative role of the COX pathway and serotonin for antigen-induced contractions in the rat lung. Airway responses were studied in rat precision-cut lung slices (PCLS). Lung slices were stimulated with ovalbumin or serotonin after pretreatment with COX inhibitors or specific TP or EP receptor antagonists. Changes in airway size (contractions/relaxations) were measured by a digital video camera. The supernatants were analysed for changes in prostaglandin and serotonin release. Airway contractions to ovalbumin were attenuated by the unselective COX inhibitor indomethacin, the selective COX-1 inhibitor FR-122047 and COX-2 inhibitor celecoxib. The EP(1) receptor antagonist ONO-8713 reduced the contractions, whereas the EP(4) receptor antagonist L-161,982 significantly increased the contractile response to ovalbumin. The 5-HT(2A) receptor antagonist ketanserin completely inhibited the ovalbumin-induced contractions. The different COX inhibitors decreased the production of prostaglandins but did not affect the synthesis of serotonin. The serotonin-induced bronchoconstriction was attenuated by celecoxib and ONO-8713, but not by methacholine. Taken together, our data indicate that PGE(2) is the main prostanoid involved in the early allergic airway response in the rat lung. PGE(2) appears to act both as a primary mediator of antigen-induced airway contraction via the EP(4) receptor and as a downstream modulator of serotonin-induced bronchoconstriction via the EP(1) receptor.
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| 27. |
- Larsson Callerfelt, Anna-Karin, et al.
(författare)
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Prostaglandin D(2) induces contractions through activation of TP receptors in peripheral lung tissue from the guinea pig.
- 2011
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 669:1-3, s. 136-142
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Tidskriftsartikel (refereegranskat)abstract
- Prostaglandin D(2) (PGD(2)), released through mast cell activation, is used as a non-invasive biomarker in patients with asthma. Since PGD(2) can elicit opposing effects on airway tone via activation of the PGD(2) receptors DP(1) and DP(2) as well as the thromboxane receptor TP, the aim of this study was to characterize the receptors that are activated by PGD(2) in the guinea pig lung parenchyma. PGD(2) and the thromboxane analog U46619 induced concentration-dependent contractions. U46619 was more potent and caused stronger effect than PGD(2). The specific TP receptor antagonist SQ-29548 and the combined TP and DP(2) receptor antagonist BAYu3405 concentration-dependently shifted the curves for both agonists to the right. The DP(1) receptor agonist BW245 induced a weak relaxation at high concentrations, whereas the DP(1) receptor antagonist BWA868C did not affect the PGD(2) induced contractions. The specific DP(2) receptor agonist 13,14-dihydro-15-keto-PGD(2) showed neither contractile nor relaxant effect in the parenchyma. Furthermore, studies in precision-cut lung slices specified that airways as well as pulmonary arteries and veins contracted to both PGD(2) and U46619. When the lung parenchyma from ovalbumin sensitized guinea pigs were exposed to ovalbumin, both thromboxane B(2) and PGD(2) were released. Ovalbumin also induced maximal contractions at similar level as PGD(2) in the parenchyma, which was partly reduced by SQ-29548. These data show that PGD(2) should be recognized as a TP receptor agonist in the peripheral lung inducing contraction on airways, arteries and veins. Therefore, a TP receptor antagonist can be useful in combination treatment of allergic responses in asthma.
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| 28. |
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| 29. |
- Laskar, Amit, et al.
(författare)
-
Prevention of 7beta-hydroxycholesterol-induced cell death by mangafodipir is mediated through lysosomal and mitochondrial pathways
- 2010
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; :640, s. 124-128
-
Tidskriftsartikel (refereegranskat)abstract
- Mangafodipir, a MRI contrast agent, has been used as a viability marker in patients with myocardial infarction and showed vascular relaxation effect. It confers myocardial protection against oxidative stress. However mechanisms underlying such protection have not yet been investigated. In this investigation we first studied whether mangafodipir inhibits apoptosis induced by 7beta-hydroxycholesterol (7betaOH), a cytotoxic cholesterol oxidation product found in atherosclerotic lesions in humans and in heart of ethanol-fed rats. We then focused on whether mangafodipir influences the production of reactive oxygen species, lysosomal and mitochondrial membrane permeabilities in the cell model. Our results revealed that pre-treatment with mangafodipir (400microM) protected against cellular reactive oxygen species production, apoptosis, and permeabilization of lysosomal and mitochondrial membranes induced by 7betaOH. In conclusion, a novel effect of mangafodipir on 7betaOH-induced apoptosis is via reduction of cellular reactive oxygen species and stabilization of lysosomal and mitochondrial membranes. This is the first report to show the additional cytoprotective effect of mangafodipir, which may suggest possible use of the drug.
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| 30. |
- Lei, Ying, et al.
(författare)
-
Enhanced airway smooth muscle cell thromboxane receptor signaling via activation of JNK MAPK and extracellular calcium influx.
- 2011
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 650:2-3, s. 629-638
-
Tidskriftsartikel (refereegranskat)abstract
- Thromboxane is a key inflammatory mediator and potent airway constrictor. It acts on thromboxane A(2) (TP) receptors and contributes to airway inflammation and airway hyperresponsiveness that is the characteristic feature of asthma. The present study was designed to study TP receptor signaling in airway smooth muscle cells by using an organ culture model and a set of selective pharmacological inhibitors for mitogen-activated protein kinase (MAPK) and calcium signal pathways. Western-blot, immunohistochemistry, myograph and a selective TP receptor agonist U46619 were used for examining TP receptor signal proteins and function. Organ culture of rat bronchial segments for up to 48h induces a time-dependently increased airway contractile response to U46619. This indicates that organ culture increases TP receptor signaling in the airway smooth muscle cells. The enhanced bronchial contraction was attenuated by the inhibition of c-Jun N-terminal kinase (JNK) MAPK activity, chelation of extracellular calcium and calcium channel blocker nifedipine, suggesting that JNK MAPK activity and elevated intracellular calcium level are required for the TP receptor signaling. In conclusion, airway smooth muscle cell TP receptor signaling occurs via JNK MAPK activity and the elevation of extracellular calcium influx, which may provide knowledge for understanding the signaling pathway responsible for the modulation of TP receptor mediated airway hyperresponsiveness to thromboxane.
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| 31. |
- Lei, Ying, et al.
(författare)
-
Up-regulation of bradykinin receptors in rat bronchia via IkappaB kinase-mediated inflammatory signaling pathway.
- 2010
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 634:1-3, s. 149-161
-
Tidskriftsartikel (refereegranskat)abstract
- IkappaB kinase (IKK)-mediated intracellular signaling mechanisms may be involved in airway hyperresponsiveness through up-regulation of bradykinin receptors. This study was designed to examine if organ culture of rat bronchial segments induces airway hyperresponsiveness to bradykinin and if inhibition of IKK can abrogate the airway hyperresponsiveness to bradykinin via suppressing the expression of bradykinin B(1) and B(2) receptors. Rat bronchi were isolated and cut into ring segments. The segments were then organ cultured in the presence or absence of IKK inhibitors, BMS-345541 or TPCA-1. des-Arg(9)-bradykinin (B(1) receptor agonist) - and bradykinin (B(2) receptor agonist) - induced contractions of the segments were monitored by a sensitive organ bath system. The expression of bradykinin B(1) and B(2) receptors, inflammatory mediators and phosphorylated IKK were studied by a real-time PCR and/or by immunohistochemistry using confocal microscopy. Organ culture of the bronchial segments induced a time-dependent up-regulation of bradykinin B(1) and B(2) receptors. The IKK inhibitors abolished the organ culture-induced up-regulation of bradykinin B(1) and B(2) receptor-mediated contractions in a concentration-dependent manner. This was paralleled with inhibition of IKK activity (phosphorylation), reduced mRNA and protein expressions of bradykinin B(1) and B(2) receptors and decreased mRNA expression of inflammatory mediators (interleukin-6, inducible nitric oxide synthase, cyclooxygenase 2 and matrix metalloproteinase 9). Our results show that organ culture induces IKK-mediated inflammatory changes in airways which subsequently results in airway hyperresponsiveness to bradykinin via the up-regulated bradykinin receptors. Thus, IKK inhibition might be a promising approach for treatment of airway inflammation and airway hyperresponsiveness that are often seen in asthmatic patients.
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| 32. |
- Lundberg, Kristina, et al.
(författare)
-
Histamine H(4) receptor antagonism inhibits allergen-specific T-cell responses mediated by human dendritic cells.
- 2011
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 651:1-3, s. 197-204
-
Tidskriftsartikel (refereegranskat)abstract
- Dendritic cells are potential targets in allergy therapy as they, under the influence of their microenvironment, regulate T-cell responses. Histamine has been shown to promote Th2 polarization by dendritic cells. However, neither the mechanism nor the functionality of the different histamine receptors in this process has been fully elucidated. The aim of the present study was to identify factors involved in histamine-mediated dendritic cell activation as well as to study dendritic cell expression of histamine H(1) and H(4) receptors and their influence on allergen-specific T-cell responses in grass pollen allergy. Assessment of dendritic cell gene regulation by histamine using mRNA microarrays demonstrated that histamine alters many immunoregulatory genes of which the majority are novel in this context. Additionally, immunocytochemical stainings showed protein expression of histamine H(1) and H(4) receptors on dendritic cells from healthy and allergic donors. Furthermore, histamine H(1) and H(4) receptor antagonists (pyrilamine/N-(4-methoxybenzyl)-N',N'-dimethyl-N-pyridin-2-ylethane-1,2-diamine and JNJ7777120/1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine, respectively) were shown to influence histamine-induced dendritic cell maturation. Interestingly, JNJ7777120 inhibited dendritic cells' capacity to induce allergen-specific T-cell proliferation. In conclusion, H(4) receptor antagonism suppressed DC-induced, allergen-specific T-cell responses in humans and might thus inhibit allergic responses. This finding indicates that the H(4) receptor is a potential treatment target in human allergic conditions.
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| 33. |
- Malmlöf, Kjell
(författare)
-
Effect of the cannabinoid receptor-1 antagonist rimonabant on lipolysis in rats
- 2010
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 646, s. 38-45
-
Tidskriftsartikel (refereegranskat)abstract
- The cannabinoid receptor 1 antagonist, rimonabant, reduces food intake and body weight, but contradictory findings have been reported as to whether the weight-reducing effect is fully accounted for by the reduced food intake or if rimonabant also mediates a lipolytic effect. In the present study, the effect on weight loss was studied in diet-induced obese rats after 3 days and 3 weeks of exposure to rimonabant, respectively. Induction of lipolysis was examined following acute administration and following 3 weeks of repeated dosing. Rimonabant-treated rats lost significantly more weight than their food-restricted controls. This effect was most pronounced in the beginning of the treatment period. No increase in lipolytic activity was found after 3 weeks of repeated dosing as measured by microdialysis in adipose tissue whereas acute administration of 10 mg/kg produced a significant increase in microdialysate levels of glycerol illustrating an acute stimulation of lipolysis. No equivalent increase in glycerol was, however, observed in vitro following incubation of isolated rat adipocytes with rimonabant. This finding excludes a direct lipolytic action of rimonabant on tissue level. Instead, administration of 10 mg/kg produced a significant increase in noradrenaline excretion in diet-induced obese rats, suggesting an increase in sympathoadrenal activity. In conclusion, the present study suggests an acute lipolytic effect of rimonabant mediated through activation of the sympathoadrenal system. (C) 2010 Elsevier B.V. All rights reserved.
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| 34. |
- Manson, Martijn L, et al.
(författare)
-
Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle.
- 2014
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 740:Jul 15, s. 302-311
-
Tidskriftsartikel (refereegranskat)abstract
- Taste-sensing type 2 receptors (TAS2Rs) have been implicated in extraoral functions. Airway smooth muscle expresses TAS2Rs and is strongly relaxed by TAS2R agonists. We hypothesised that TAS2R agonists might affect vascular smooth muscle as well. Moreover, the general pharmacological profile of TAS2R agonists, which are used to investigate the functions of TAS2R׳s, are undefined. The aim of this study was to pharmacologically characterise the effects of five prototype TAS2R agonists in vascular smooth muscle. Responses to the TAS2R agonists were investigated in guinea-pig aorta and taenia coli, mouse aorta (wild-type and caveolin-1(-/-) mice) and human pulmonary arteries. Chloroquine, denatonium, dextromethorphan, noscapine and quinine, agonists for TAS2R3, TAS2R4, TAS2R10 and TAS2R14, induced strong endothelium-independent relaxations (responses between 82-96% of maximal relaxations) in phenylephrine pre-contracted guinea-pig aorta that persisted in the presence of L-type Ca(2+) and KCa1.1-channel blockers. Experiments in guinea-pig taenia coli revealed that denatonium and quinine also inhibited relaxations to phenylephrine, indicating antagonism of α-adrenoceptors. Only chloroquine and noscapine mediated relaxations when the guinea pig aorta was pre-contracted by U-46619 or PGF2α. Relaxations to chloroquine and noscapine after U-46619 pre-contractions were however markedly impaired in aortae from caveolin-1(-/-) mice. Chloroquine and noscapine mediated relaxations of human pulmonary arteries that expressed also mRNA for TAS2R3, TAS2R4, TAS2R10 and TAS2R14, at levels similar to that of the α1A adrenoceptor. Notwithstanding whether TAS2Rs are involved or not, TAS2R agonists have profound effects on vascular smooth muscle. Chloroquine and noscapine are of special interest as their effects cannot be accounted for by conventional pathways.
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| 35. |
- Novotny, Ann, 1982-, et al.
(författare)
-
A pharmacological analysis of the cholinergic regulation of urokinase-type plasminogen activator, and plasminogen activator inhibitor-1 secretion in the human colon cancer cell line, HT-29
- 2010
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 646:1-3, s. 22-30
-
Tidskriftsartikel (refereegranskat)abstract
- Urokinase-type plasminogen activator (uPA) is an important factor for tumour cell invasion and metastasis. We recently showed that acetylcholine is an autocrine/paracrine growth factor for the human colon cancer cell line, HT-29, in part via the α7 subtype of the nicotinic acetylcholine receptors. In the current study, we investigated whether acetylcholine participates in the regulation of the protein expressions of also uPA and its receptor (uPAR) in the HT-29 cell line. Such were investigated by immunocytochemistry and Western blotting, and quantitation of uPA secretion was undertaken by ELISA. Stimulation of the cells for 24 h with nicotine caused increased uPA secretion with peak effect (78% above the control) occurring at a nicotine concentration of 10 nM. This effect was markedly inhibited by α-Bungarotoxin, thus showing the involvement of α7 nicotinic acetylcholine receptors. Basal uPA secretion was found to be partly dependent on ongoing activation of nicotinic receptors, suggesting tonic production of acetylcholine. Conversely, there was no cholinergic influence on the expression of uPAR. The current findings demonstrate novel aspects of receptor-mediated regulation of tumour metastatic potential via uPA secretion. This may suggest future pharmaceutical strategies in treatment of colorectal cancer.
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| 36. |
- Novotny, Ann, 1982, et al.
(författare)
-
A pharmacological analysis of the cholinergic regulation of urokinase-type plasminogen activator secretion in the human colon cancer cell line, HT-29.
- 2010
-
Ingår i: European journal of pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 646:1-3, s. 22-30
-
Tidskriftsartikel (refereegranskat)abstract
- Urokinase-type plasminogen activator (uPA) is an important factor for tumour cell invasion and metastasis. We recently showed that acetylcholine is an autocrine/paracrine growth factor for the human colon cancer cell line, HT-29, in part via the alpha7 subtype of the nicotinic acetylcholine receptors. In the current study, we investigated whether acetylcholine participates in the regulation of the protein expressions of also uPA and its receptor (uPAR) in the HT-29 cell line. Such were investigated by immunocytochemistry and Western blotting, and quantitation of uPA secretion was undertaken by ELISA. Stimulation of the cells for 24h with nicotine caused increased uPA secretion with peak effect (78% above the control) occurring at a nicotine concentration of 10nM. This effect was markedly inhibited by alpha-Bungarotoxin, thus showing the involvement of alpha7 nicotinic acetylcholine receptors. Basal uPA secretion was found to be partly dependent on ongoing activation of nicotinic receptors, suggesting tonic production of acetylcholine. Conversely, there was no cholinergic influence on the expression of uPAR. The current findings demonstrate novel aspects of receptor-mediated regulation of tumour metastatic potential via uPA secretion. This may suggest future pharmaceutical strategies in treatment of colorectal cancer.
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| 37. |
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| 38. |
- Palani, Karzan, et al.
(författare)
-
Rho-kinase regulates adhesive and mechanical mechanisms of pulmonary recruitment of neutrophils in abdominal sepsis.
- 2012
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 682:1-3, s. 181-187
-
Tidskriftsartikel (refereegranskat)abstract
- We hypothesized that Rho-kinase signaling plays a role in mechanical and adhesive mechanisms of neutrophil accumulation in lung. Male C57BL/6 mice were treated with the Rho-kinase inhibitor Y-27632 prior to cecal ligation and puncture (CLP). Lung levels of myeloperoxidase (MPO) and histological tissue damage were determined 6h and 24h after CLP. Expression of Mac-1 and F-actin formation in neutrophils were quantified by using flow cytometry 6h after CLP. Mac-1 expression and F-actin formation were also determined in isolated neutrophils up to 3h after stimulation with CXCL2. Labeled and activated neutrophils co-incubated with Y-27632, an anti-Mac-1 antibody and cytochalasin B were adoptively transferred to CLP mice. Y-27632 reduced the CLP-induced pulmonary injury and MPO activity as well as Mac-1 on neutrophils. Neutrophil F-actin formation peaked at 6h and returned to baseline levels 24h after CLP induction. Rho-kinase inhibition decreased CLP-provoked F-actin formation in neutrophils. CXCL2 rapidly increased Mac-1 expression and F-actin formation in neutrophils. Co-incubation with Y-27632 abolished CXCL2-induced Mac-1 up-regulation and formation of F-actin in neutrophils. Notably, co-incubation with cytochalasin B inhibited formation of F-actin but did not reduce Mac-1 expression on activated neutrophils. Adoptive transfer experiments revealed that co-incubation of neutrophils with the anti-Mac-1 antibody or cytochalasin B significantly decreased pulmonary accumulation of neutrophils in septic mice. Our data show that targeting Rho-kinase effectively reduces neutrophil recruitment and tissue damage in abdominal sepsis. Moreover, these findings demonstrate that Rho-kinase-dependent neutrophil accumulation in septic lung injury is regulated by both adhesive and mechanical mechanisms.
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| 39. |
- Papathanou, Maria, et al.
(författare)
-
The H3 receptor agonist immepip does not affect l-dopa-induced abnormal involuntary movements in 6-OHDA-lesioned rats
- 2014
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 741, s. 304-310
-
Tidskriftsartikel (refereegranskat)abstract
- The treatment of dyskinesia in Parkinson׳s disease remains poor but H3 receptor agonists have been suggested as a novel pharmacological approach. We examined the effects of the H3 agonist, immepip, in 6-OHDA-lesioned rats exhibiting AIMs (abnormal involuntary movements), a rat analogue of dyskinesia, in response to l-dopa compared to the known anti-dyskinetic agents amantadine, MK-801 and 8-OHDPAT. We then attempted to extend these studies in to dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated common marmosets.Amantadine, MK-801 and 8-OHDPAT all dose-dependently reduced l-dopa-induced axial, lingual and oral (ALO) AIMs in 6-OHDA-lesioned animals accompanied by a reduction in contralateral rotation with higher doses of amantadine and MK-801. By contrast, immepip had no effect on AIMs expression or contralateral rotation. In the MPTP-treated common marmoset exhibiting dyskinesia to l-dopa, immepip alone induced retching and in combination with l-dopa administered subcutaneously or orally induced the rapid onset of retching and vomiting which was not controlled by pretreatment with domperidone. Administration of the unrelated H3 agonist, imetit had the same effect. Despite causing negative side-effects, it appears that both agonists reduced the antiparkinsonian response to l-dopa resulting in reduced dyskinesia.H3 agonists appear unlikely candidates for the treatment of dyskinesia in PD based on lack of evidence of efficacy and potential adverse effects.
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| 40. |
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| 41. |
- Rahman, Awahan, et al.
(författare)
-
Late onset vascular dysfunction in the R6/1 model of Huntington's disease.
- 2012
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999.
-
Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease is a neurodegenerative disorder that also gives raise to widespread changes in peripheral organs and tissues. We tested the hypothesis that vascular dysfunction may occur in Huntington's disease by studying R6/1 mice which express exon 1 of the mutant huntingtin gene. We assessed arterial function in R6/1 and wild type (WT) mice using myography. Arterial contractility was largely unaltered in R6/1 arteries at 15 and 32 weeks of age. By 40 weeks, contractility was impaired irrespective of which vasoconstrictor we tested. Endothelium-dependent relaxation was not affected, and we observed no changes in arterial geometry or expression of contractile proteins, such as myosin regulatory light chains or smooth muscle α-actin. The frequency of calcium oscillations in R6/1 arterial smooth muscle cells was higher than in WT control tissue, whereas myosin phosphorylation was unaltered. Impairment of force by the mitochondrial inhibitors cyanide and rotenone was less pronounced in R6/1 than in WT arteries and mitochondria were enlarged, in keeping with an effect related to altered mitochondrial function. Our results reveal that arteries in the R6/1 model of Huntington's disease exhibit an age-dependent impairment of contractility and that they depend less on mitochondrial function when they contract.
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| 42. |
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| 43. |
- Sandhu, Hardip, et al.
(författare)
-
Comparison of MEK/ERK pathway inhibitors on the upregulation of vascular G-protein coupled receptors in rat cerebral arteries
- 2010
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 644:1-3, s. 128-137
-
Tidskriftsartikel (refereegranskat)abstract
- Organ culture is an in vitro method for investigating cellular mechanisms involved in upregulation of vasocontractile G-protein coupled receptors. We hypothesize that mitogen-activated-protein kinase (MEK) and/or extracellular-signal-regulated kinase (ERK) specific inhibitors will attenuate the G-protein coupled receptor expression following organ culture. Rat cerebral arteries were incubated 48 h in the presence of MEK/ERK specific inhibitors U0126, PD98059, SL327, or AG126 for different time periods. Contractile responses by activation of endothelin receptor type A and type B. serotonin receptor 5-FIT18, prostanoid TP receptor, and angiotensin II receptor type 1 and type 2 were investigated. Results were verified by measurement of mRNA with real time PCR and by protein immunohistochemistry. Organ culture induced transcriptional upregulation of endothelin ETB receptor and of serotonin 5-HTIB receptor on translational level and increased respective contractions. The prostanoid TP receptor mediated contraction curve was left-wards shifted by organ culture. Organ culture was associated with elevated pERK1/2 in the vascular smooth muscle cells: the MEK1/2 inhibitor U0126 attenuated the endothelin ETB receptor mediated contraction at post-translational level or by changing the receptor affinities. The serotonin 5-HT,B receptor and prostanoid TP receptor mediated contractions were abolished by U0126. Administration of U0126 6 h after start of incubation blocked the receptor upregulation. In conclusion, MEK specific inhibitor U0126 is a potent inhibitor of G-protein coupled receptor alteration seen during organ culture. Given the ability to inhibit G-protein coupled receptor alteration at the clinically relevant time-point 6 h post incubation makes it an attractive therapeutic agent for in vivo studies. (C) 2010 Elsevier By. All rights reserved.
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| 44. |
- Shakirova, Yulia, et al.
(författare)
-
Biochemical and functional correlates of an increased membrane density of caveolae in hypertrophic rat urinary bladder.
- 2010
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 649, s. 362-368
-
Tidskriftsartikel (refereegranskat)abstract
- Organ hypertrophy is often found to be associated with changes in the expression of caveolins and altered density of caveolae in the membrane. A plethora of signalling intermediaries are associated with caveolae and loss of caveolae has profound effects on contractility of the urinary bladder. We hypothesized that smooth muscle hypertrophy caused by bladder outflow obstruction (BOO) might lead to an altered caveola density with consequences for contractile regulation. Rat BOO for 6weeks caused a 2.56-fold increase in the number of smooth muscle caveolae per μm membrane. No changes in the expression of caveolin-1 or cavin-1, normalized to β-actin were seen, but membrane area per unit muscle volume dropped to 0.346. Hypertrophy was associated with altered contraction in response to carbachol. The effect on contraction of cholesterol desorption, which disrupts lipid rafts and caveolae, was however not changed. Contraction in response to bradykinin resisted mβcd in control destrusor, but was inhibited by it after 6weeks of obstruction. It is concluded that rat detrusor hypertrophy leads to an increased number of caveolae per unit membrane area. This change is due to a reduction of membrane area per volume muscle and it does not play a role for cholinergic activation, but promotes contraction in response to bradykinin after long-term obstruction.
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| 45. |
- Shakirova, Yulia, et al.
(författare)
-
Human urinary bladder smooth muscle is dependent on membrane cholesterol for cholinergic activation.
- 2010
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 634, s. 142-148
-
Tidskriftsartikel (refereegranskat)abstract
- Voiding is mediated by muscarinic receptors in urinary bladder smooth muscle cells. Lipid rafts and caveolae are cholesterol enriched membrane domains that modulate the activity of G protein-coupled receptors and second messenger systems. Conflicting findings regarding sensitivity of muscarinic signalling to cholesterol desorption, which perturbs lipid rafts and caveolae, have been reported, and no study has used human urinary bladder. Here, the dependence of human bladder muscarinic receptor signalling on plasma membrane cholesterol was examined. Nerve-mediated contraction, elicited by electrical field stimulation of human bladder strips, was impaired by desorption of cholesterol using methyl-beta-cyclodextrin, and the concentration-response curve for the muscarinic agonist carbachol was right-shifted. No effect of cholesterol desorption was observed in rat, and in mouse increased maximum contraction was seen. Expression of caveolin-1, PLC(beta1) and M(3) muscarinic receptors did not differ between species in a manner that would explain the differential sensitivity to cholesterol desorption. In human bladder, threshold depolarisation eliminated the difference between cyclodextrin-treated and control preparations. Contraction elicited by depolarisation per se was not affected. M(3) muscarinic receptors appeared clustered along plasma membrane profiles as shown by immunohistochemical staining of human bladder, but no redistribution in association with cholesterol reduction were seen. Thus, muscarinic receptor-induced contraction of the urinary bladder exhibits species-specific differences in its sensitivity to cholesterol desorption suggesting differential roles of lipid rafts/caveolae in muscarinic receptor signalling between species.
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| 46. |
- Shao, Yangzhen, 1981, et al.
(författare)
-
Adenosine prevents isoprenaline-induced cardiac contractile and electrophysiological dysfunction.
- 2013
-
Ingår i: European journal of pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 718:1-3, s. 475-483
-
Tidskriftsartikel (refereegranskat)abstract
- Excessive levels of catecholamines are believed to contribute to cardiac dysfunction in a variety of disease states, including myocardial infarction and heart failure, and are particularly implicated in stress-induced cardiomyopathy, an increasingly recognized cardiomyopathy associated with significant morbidity and mortality. We have previously shown that a high dose of isoprenaline induces reversible regional dysfunction of the left ventricle in mice. We now hypothesize that adenosine can prevent cardiac dysfunction in this mouse model of stress-induced cardiomyopathy. Hundred male C57BL/6 mice were injected with 400mg/kg isoprenaline and then randomized to either 400mg/kg adenosine or saline. Cardiac function was evaluated by echocardiography at baseline and 2, 24, 48, 72, 96 and 120min post isoprenaline. Myocardial fibrosis was quantified after 10 days. Intracellular lipid accumulation was quantified after 2 and 24h. Electrophysiological parameters and degree of lipid accumulation were evaluated in cultured HL1 cardiomyocytes. Two hours post isoprenaline treatment, echocardiographic parameters of global and posterior wall regional function were significantly better in adenosine-treated mice (P<0.05). This difference persisted at 24h, but saline-treated mice gradually recovered over the next 96h. Intracellular lipid accumulation was also significantly lower in adenosine mice. We found no sign of fibrosis in the adenosine mice, whereas the extent of fibrosis in isoprenaline mice was 1.3% (P<0.05). Furthermore, adenosine-treated HL1 cells showed preserved electrophysiological function and displayed less severe intracellular lipid accumulation in response to isoprenaline. In conclusion, adenosine attenuates isoprenaline-induced cardiac dysfunction in mice and cells.
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| 47. |
- Strittmatter, Frank, et al.
(författare)
-
Thromboxane A2 induces contraction of human prostate smooth muscle by Rho kinase- and calmodulin-dependent mechanisms
- 2011
-
Ingår i: European Journal of Pharmacology. - : Elsevier. - 0014-2999 .- 1879-0712. ; 650:2-3, s. 650-655
-
Tidskriftsartikel (refereegranskat)abstract
- Thromboxane A(2) (TXA(2)) induces contraction in different smooth muscle types via its receptor (TXA(2) receptor). However, any motoric role of TXA(2) in prostate smooth muscle tone has not been studied to date. Here, we investigated whether TXA(2) induces contraction of human prostate tissue. After ethical approval, prostate tissue was obtained from 47 patients undergoing radical prostatectomy. Effects of the TXA(2) analogue U46619 ((5Z)-7-[(1R,4S,5S,6R)-6-[(1E,3S)-3-hydroxy-1-octenyl]-2-oxabicyclo[2.2.1]hept-5-yl]-5-heptonic acid) in isolated human prostate strips were studied in organ bath experiments with or without the Rho kinase inhibitor, Y27632 (trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide dihydrochloride), or the calmodulin antagonist W7 (N-(6-aminohexyl)-5-chloro-1-naphtalenesulfonamide hydrochloride). Expression of TXA(2) synthase and TXA(2) receptors were examined by Western blot analysis and immunohistochemistry. Endogenous TXA(2) was quantified by enzyme immunoassay. U46619 induced concentration-dependent contractions of human prostate strips, with a maximum contraction at 3 μM. U46619-induced prostate contraction was significantly inhibited by Y27632 (30 μM) and by W7 (100 μM). TXA(2) synthase and TXA(2) receptors were detected by Western blot analysis. Immunohistochemical stainings showed that expression of TXA(2) synthase in prostate tissue was located to glandular cells, while prostate TXA(2) receptors were located to smooth muscle and glandular cells. The stable TXA(2) metabolite TXB(2) was detected by enzyme immunoassay in the prostate. TXA(2) induces contraction of isolated human prostate tissue by TXA(2) receptor activation. Prostate smooth muscle TXA(2) receptors are coupled to Rho kinase and Ca(2+)-dependent mechanisms. The distribution of TXA(2) synthase and TXA(2) receptors in the human prostate suggests TXA(2)-mediated paracrine epithelial-stromal interactions.
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| 48. |
- Sörhede Winzell, Maria, et al.
(författare)
-
Chronic glucokinase activation reduces glycaemia and improves glucose tolerance in high-fat diet fed mice.
- 2011
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 663, s. 80-86
-
Tidskriftsartikel (refereegranskat)abstract
- Glucokinase (GK) plays a key role in maintaining glucose homeostasis by promoting insulin secretion from pancreatic beta cells and increasing hepatic glucose uptake. Here we investigate the effects of acute and chronic GK activation on glucose tolerance and insulin secretion in mice with diet-induced insulin resistance. In the acute study, a small molecule GK activator (GKA71) was administered to mice fed a high-fat diet for 8weeks. In the long-term study, GKA71 was provided in the diet for 4weeks to high-fat diet-fed mice. Glucose tolerance was measured after intravenous glucose administration, and insulin secretion was measured both in vivo and in vitro. Acute GK activation efficiently improved glucose tolerance in association with increased insulin secretion after intravenous glucose both in control and high-fat fed mice. Chronic GK activation significantly reduced basal plasma glucose and insulin, and improved glucose tolerance despite reduced insulin secretion after intravenous glucose, suggesting improved insulin sensitivity. Isolated islets from chronically GKA71-treated mice displayed augmented insulin secretion at 8.3mmol/l glucose, without affecting glucose oxidation. High-fat diet fed mice had reduced glycogen and increased triglyceride in liver compared to control mice, and these parameters were not altered by long-term GK activation. We conclude that GK activation in high-fat diet-fed mice potently reduces glycaemia and improves glucose tolerance, with combined effect both to stimulate insulin secretion from islets and improve insulin sensitivity.
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| 49. |
- Sörhede Winzell, Maria, et al.
(författare)
-
Improved insulin sensitivity and islet function after PPARdelta activation in diabetic db/db mice.
- 2010
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 626:2-3, s. 297-305
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Tidskriftsartikel (refereegranskat)abstract
- The peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. Several reports have shown that PPARdelta is involved in lipid metabolism, increasing fat oxidation and depleting lipid accumulation. Whether PPARdelta is involved in the regulation of glucose metabolism is not completely understood. In this study, we examined effects of long-term PPARdelta activation on glycemic control, islet function and insulin sensitivity in diabetic db/db mice. Male db/db mice were administered orally once daily with a selective and partial PPARdelta agonist (NNC 61-5920, 30mg/kg) for eight weeks; control mice received vehicle. Fasting and non-fasting plasma glucose were reduced, reflected in reduced hemoglobinA(1c) (3.6+/-1.6% vs. 5.4+/-1.8 in db/db controls, P<0.05) and furthermore, the AUC(glucose) after oral glucose (3g/kg) was reduced by 67% (P<0.05) after long-term PPARdelta activation. Following intravenous glucose (1g/kg), glucose tolerance was improved after PPARdelta activation (K(G) 1.3+/-0.6 vs. -0.05+/-0.7 %/min, P=0.048). Insulin sensitivity, measured as the glucose clearance after intravenous injection of glucose (1g/kg) and insulin (0.75 or 1.0U/kg), during inhibition of endogenous insulin secretion by diazoxide (25mg/kg), was improved (K(G) 2.9+/-0.6 vs. 1.3+/-0.3 %/min in controls, P<0.05) despite lower insulin levels. Furthermore, islets isolated from PPARdelta agonist treated mice demonstrated improved glucose responsiveness as well as improved cellular topography. In conclusion, PPARdelta agonism alleviates insulin resistance and improves islet function and topography, resulting in improved glycemia in diabetic db/db mice. This suggests that activation of PPARdelta improves glucose metabolism and may therefore potentially be target for treatment of type 2 diabetes.
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- Ternouth, Andrew, et al.
(författare)
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Association study of POMC variants with body composition measures and nutrient choice.
- 2011
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Ingår i: European journal of pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 660:1, s. 220-225
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Tidskriftsartikel (refereegranskat)abstract
- Genome linkage scans and candidate gene studies have implicated the pro-opiomelanocortin (POMC) locus in traits related to food intake, metabolic function, and body mass index. Here we investigate single nucleotide polymorphisms at the POMC locus in order to evaluate the influence of its genetic variance on body fat distribution and diet in a sample of middle-aged men from The Netherlands. 366 Dutch males from the Hamlet cohort were asked detailed questions about food choice, nutrient intake and exercise. Furthermore, their weight and body fat composition were measured. Each cohort member was genotyped for a set of single nucleotide polymorphisms (SNPs) at the POMC locus. Regression analysis, adjusted for several covariates, was used to test for the association between genetic variants and the phenotypes measured. POMC variation was associated with waist:hip ratio, visceral fat and abdominal fat (rs6713532, P=0.020, 0.019, and 0.021, respectively), and nutrient choice (rs1042571, P=0.034), but in light of limited power and multiple testing these results should be taken with caution. POMC is a strong candidate for involvement in appetite regulation as supported by animal, physiological, and genetic studies and variation at the POMC locus may affect an individual's energy intake which in turn leads to variation in body composition and body fat.
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