| 1. |
- Çevik Aras, Hülya, 1975, et al.
(författare)
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A non-peptide receptor inhibitor with selectivity for one of the neutrophil formyl peptide receptors, FPR 1.
- 2012
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Ingår i: Biochemical pharmacology. - : Elsevier BV. - 1873-2968 .- 0006-2952. ; 83:12, s. 1655-1662
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Tidskriftsartikel (refereegranskat)abstract
- The neutrophil formyl peptide receptors (FPR1 and FPR2) are members of the G-protein coupled receptor family. The signals generated by occupied FPRs are both pro-inflammatory and anti-inflammatory. Accordingly, these receptors have become a therapeutic target for the development of novel drugs that may be used to reduce injuries in inflammatory diseases including asthma, rheumatoid arthritis, Alzheimer's disease and cardiovascular diseases. To support the basis for a future pharmacological characterization, we have identified a small molecular non-peptide inhibitor with selectivity for FPR1. We used the FPR1 and FPR2 specific ligands fMLF and WKYMVM, respectively, and an earlier described ratio technique, to determine inhibitory activity combined with selectivity. We show that the compound 3,5-dichloro-N-(2-chloro-5-methyl-phenyl)-2-hydroxy-benzamide (BVT173187) fulfills the criteria for an FPR1 inhibitor selective for FPR1 over FPR2, and it inhibits the same functional repertoire in neutrophils as earlier described peptide antagonists. Accordingly, the new inhibitor reduced neutrophil activation with FPR1 agonists, leading to mobilization of adhesion molecules (CR3) and the generation of superoxide anion from the neutrophil NADPH-oxidase. The effects of a number of structural analogs were determined but these were either without activity or less active/specific than BVT173187. The potency of the new inhibitor for reduction of FPR1 activity was the same as that of the earlier described FPR1 antagonist cyclosporine H, but signaling through the C5aR and CXCR (recognizing IL8) was also affected by BVT173187.
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| 2. |
- Çevik Aras, Hülya, 1975, et al.
(författare)
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Anti-inflammatory action of cholecystokinin and melatonin in the rat parotid gland
- 2010
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Ingår i: ORAL DISEASES. - 1354-523X. ; 16:7, s. 661-667
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:To define the influence of cholecystokinin and melatonin on the inflammatory response of the lipopolysaccharide-exposed rat parotid gland. MATERIALS AND METHODS: Bacterial lipopolysaccharide was infused retrogradely into the parotid duct. The degree of inflammation three hours postadministration was estimated from the activity of myeloperoxidase, reflecting glandular neutrophil infiltration. RESULTS: The myeloperoxidase activity of the lipopolysaccharide-exposed gland was 10-fold greater than that of the contralateral gland. Combined with sulphated cholecystokinin-8 (10 or 25 μg kg(-1) , given twice intraperitoneally) or melatonin (10 or 25 mg kg(-1) x 2) the lipopolysaccharide-induced response was elevated 4.6- and 3.5-folds at the most. The cholecystokinin-A receptor antagonist lorglumide reduced the inhibitory effect of cholecystokinin-8, while the melatonin 2-preferring receptor antagonist luzindole had no effect on the melatonin-induced inhibition. Unselective nitric oxide-synthase inhibition abolished the increase in myeloperoxidase activity, whereas inhibition of inducible or neuronal nitric oxide-synthase (of non-nervous origin) halved the inflammatory response. CONCLUSION: Some hormones may contribute to anti-inflammatory action in salivary glands in physiological conditions. They are potential pharmacological tools for treating gland inflammation. The inflammation, as judged from the myeloperoxidase activity, was entirely dependent on nitric oxide-synthase activity, indicating that the hormones directly or indirectly reduced the generation of nitric oxide.
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| 3. |
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| 4. |
- Çevik Aras, Hülya, 1975, et al.
(författare)
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Cholecystokinin- and gastrin-induced protein and amylase secretion from the parotid gland of the anaesthetized rat.
- 2006
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Ingår i: Regul Pept.. ; 134:2-3, s. 89-96
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Tidskriftsartikel (refereegranskat)abstract
- I.V. infusion of pentagastrin (20 microg/kg/h) or cholecystokinin (CCK)-8 (1 microg/kg/h) for 10 min caused secretion of salivary proteins from the parotid gland in the anaesthetized rat without any accompanying overt fluid secretion. This "occult" response was revealed by a subsequent wash-out injection of methacholine (5 microg/kg, I.V.) 10 min after the end of the infusion period (aiming at avoiding synergistic interactions). While the fluid response to methacholine was unaffected by the preceding infusion of pentagastrin and CCK-8, the output of protein increased by 147% (pentagastrin) and 74% (CCK-8) and that of amylase by 45% (CCK-8) compared to the responses to methacholine upon saline infusion. Those increases were abolished by the CCK-A receptor blocker (lorglumide), but not by the CCK-B receptor blocker (itriglumide). Evisceration, combined sympathetic and parasympathetic denervation of the glands and assay under adrenoceptor blockade excluded contribution from the gastro-intestinal tract, central or ganglionic mechanisms and circulating catecholamines to the increase in protein/amylase. Furthermore, Western blot demonstrated CCK receptors for both A and B subtypes in normal and chronically denervated glands. In the submandibular gland, both pentagastrin and CCK-8 evoked a trace secretion of saliva but, under the present experimental set-up, no statistically significant increase in protein output. Thus, in addition to the autonomic nervous system, gastrointestinal hormones may, in some types of glands, be involved in the secretion of salivary gland proteins.
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| 5. |
- Çevik Aras, Hülya, 1975, et al.
(författare)
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Melatonin-evoked in vivo secretion of protein and amylase from the parotid gland of the anaesthetised rat.
- 2008
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Ingår i: Journal of pineal research. - 1600-079X. ; 45:4, s. 413-21
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Tidskriftsartikel (refereegranskat)abstract
- The intravenous infusion of melatonin (5 and 25 mg/kg over 10 min) evoked a dose-dependent output of protein and amylase but no overt fluid secretion from the parotid gland of the pentobarbitone-anaesthetised rat, as revealed by increased concentrations of protein and amylase activity in a subsequent wash-out flow of saliva in response to an intravenous bolus injection of methacholine (5 microg/kg) 10 min later. The secretory responses to melatonin occurred in the presence of alpha- and beta-adrenoceptor antagonists. They were not affected by the cholecystokinin A-receptor antagonist, lorglumide, and they were reproduced in eviscerated animals acutely subjected to postganglionic sympathetic and parasympathetic denervation of the gland. The responses to melatonin were partially dependent on nitric oxide generation, through the activity of nitric oxide synthase of the neuronal type. Immunoblotting showed both melatonin receptors of type 1 and type 2 to be expressed in parotid gland tissue. The relative specific melatonin 2-receptor antagonist luzindole prevented the expected secretory effects of melatonin. The results favour a direct action by melatonin on melatonin receptors of parotid secretory cells and suggest a potential physiological role for melatonin in the regulation of salivary glandular activities.
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| 6. |
- Çevik Aras, Hülya, 1975, et al.
(författare)
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Melatonin-evoked protein secretion from the rat parotid gland.
- 2006
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Ingår i: 3rd International Symposium on salivary glands in honor of Niels Stensen, eds Murakami M, Suigya A, Riva A, Okazaki Conference Center, NINS, Japan, October 20-24.
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Konferensbidrag (refereegranskat)
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| 7. |
- Çevik Aras, Hülya, 1975, et al.
(författare)
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Melatonin-induced protein synthesis in the rat parotid gland
- 2011
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Ingår i: Journal of physiology and pharmacology. - 0867-5910. ; 62:1, s. 95-99
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Tidskriftsartikel (refereegranskat)abstract
- Melatonin occurs in large amounts in the intestinal mucosa and is released during a meal. Recent studies of ours reveal that exogenous melatonin evokes the in vivo secretion of protein and amylase from the rat parotid gland. The aim of the present study was to investigate the effect of melatonin on the protein synthesis of the parotid gland of pentobarbitone-anaesthetized rats as estimated by the rate of incorporation of [3H]leucine into trichloroacetic acid-insoluble material of the gland. Compared with the parotid protein synthesis (set at 100 %) of those rats exposed to an intravenous infusion of melatonin (25 mg/kg during 1 hour), under muscarinic and α- and β-adrenoceptor blockade, the synthesis in the corresponding glands of saline-treated control rats was less (by 25%). The synthesis was also less when the melatonin administration was combined with the melatonin 2-preffering receptor antagonist luzindole (24%), the non-selective nitric oxide synthase inhibitor L-NAME (18%) and the neuronal nitric oxide synthase inhibitor N-PLA (21%). Almost all the melatonin receptor-mediated effect was due to nitric oxide generation via the activity of neuronal type nitric oxide synthase. The present findings lend further weight to the idea that salivary glandular activity associated with food intake is hormonally influenced and they also suggest clinical implications for melatonin in the treatment of xerostomia. Since melatonin is known to exert anti-inflammatory actions in the oral cavity, the stimulatory effect of melatonin may include the synthesis of proteins of importance for the oral defence.
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| 8. |
- Çevik Aras, Hülya, 1975, et al.
(författare)
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Monitoring Salivary Levels of Interleukin 1 Beta (IL-1 β) and Vascular Endothelial Growth Factor (VEGF) for Two Years of Orthodontic Treatment: A Prospective Pilot Study
- 2021
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Ingår i: Mediators of Inflammation. - : Hindawi Limited. - 0962-9351 .- 1466-1861. ; 2021
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objective. Vascular endothelial growth factor (VEGF) and interleukin 1 beta (IL-1β) perform functions in orthodontic tooth movement and can be measured in the saliva. This novel approach is aimed at monitoring continuous changes in IL-1β and VEGF levels in saliva during two years of orthodontic treatment. Material and Methods. Nine healthy females (15-20 years of age) with crowding requiring four premolar extractions and fixed appliances in both jaws were included in this prospective pilot study. A total of 134 stimulated and 134 unstimulated saliva samples were collected during two years of treatment: before tooth extractions (baseline) and then every 6-8 weeks at follow-up appointments. All saliva samples were analysed by the enzyme-linked immunosorbent assay. The mean levels of IL-1β and VEGF were calculated according to the different orthodontic treatment stages: alignment, space closure, and finishing. Repeated analysis of variance (ANOVA) measurements were used to compare the means between different treatment stages. The percentage difference in IL-1β and VEGF between the different treatment stages was analysed by Bland-Altman plots. Results. A gradual increase in IL-1β and VEGF was observed at alignment, reaching significance at space closure (p=0.002 and p=0.025, respectively). At finishing, both IL-1β and VEGF declined, however, without reverting to baseline values (p=0.172 and p=0.207, respectively). Bland-Altman analysis showed the agreement between IL-1β and VEGF in terms of a systematic increase, with a higher percentage difference for VEGF. Conclusions. The salivary levels of both IL-1β and VEGF increased following orthodontic treatment and reached their peaks during the treatment stage of space closure. This novel approach provides a hint on how and when to sample saliva during orthodontic treatment to analyse bone remodelling. © 2021 Hülya Çevik-Aras et al.
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| 9. |
- Çevik Aras, Hülya, 1975, et al.
(författare)
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Pentagastrin-induced nitric-oxide dependent protein secretion from the parotid gland of the anaesthetized rat.
- 2006
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Ingår i: Exp Physiol. ; 91:6, s. 977-82
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Tidskriftsartikel (refereegranskat)abstract
- Infusion of pentagastrin (20 microg kg(-1) h(-1), i.v.) for 10 min evokes protein output but no overt fluid secretion from the parotid gland of the rat, as revealed by increased protein concentration in a subsequent wash-out flow of saliva in response to a bolus injection of methacholine (5 microg kg(-1), i.v.) 10 min later. Using this experimental set-up, the contribution of nitric oxide (NO) generation to the protein and amylase response evoked by pentagastrin was investigated. Neither the neuronal type NO synthase inhibitor N(omega)-propyl-L-arginine (N-PLA; 30 mg kg(-1), i.v.) nor the non-selective NO synthase inhibitor L-NAME (30 mg kg(-1), i.v.) as such affected the methacholine-evoked volume response or the outputs of protein and amylase. However, when preceeded by the pentagastrin infusion, the expected increases in concentrations of protein (145%) and amylase activity (127%) of the methacholine-evoked response (compared to a pre-infusion methacholine response) were reduced to 68 and 74%, respectively, in the presence of N-PLA, and to 70 and 63%, respectively, in the presence of L-NAME. Thus, NO generation resulting from the activity of the neuronal type NO synthase, most probably of parenchymal origin, plays an important role in the pentagastrin-induced protein and amylase secretion of the rat parotid gland.
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| 10. |
- Çevik Aras, Hülya, 1975, et al.
(författare)
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Pentagastrin-induced protein synthesis in the parotid gland of the anaesthetized rat, and its dependence on CCK-A and -B receptors and nitric oxide generation.
- 2006
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Ingår i: Exp Physiol. ; 91:4, s. 673-79
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Tidskriftsartikel (refereegranskat)abstract
- In parotid glands of pentobarbitone-anaesthetized rats, the incorporation of [3H]leucine into trichloroacetic acid-insoluble materials, reflecting protein synthesis, increased by 17% (compared to saline-treated rats) in response to infusion of pentagastrin (20 microg kg(-1), i.v. for 1 h) under muscarinic and alpha- and beta-adrenoceptor blockade. Both the CCK-A receptor antagonist lorglumide (48 mg kg(-1), i.v.) and the CCK-B receptor antagonist itriglumide (5.5 mg kg(-1), i.v.), given separately, prevented the expected increase in pentagastrin and, in addition, reduced the glandular protein synthesis by 16 and 12%, respectively, below the level of saline-treated rats. In rats treated with saline only, the glandular protein synthesis was reduced by 22% by the CCK-A receptor antagonist and by 17% by the CCK-B receptor antagonist; combined, the two antagonists caused no further reduction (20%). There was no increase in the glandular protein synthesis of pentagastrin-treated rats compared to that of the saline-treated rats when both groups of rats were exposed to a combination of the two types of CCK receptor antagonists. In pentagastrin-treated rats, the protein synthesis in the parotid glands was 23% less in the presence of the non-selective nitric oxide (NO) synthase inhibitor L-NAME (30 mg kg(-1), i.v.) than in its absence; the result was the same (23%) when the neuronal NO synthase inhibitor Nomega-propyl-L-arginine (N-PLA; 30 mg kg(-1), i.v.) replaced L-NAME. The protein synthesis in rats treated with saline only was not reduced by L-NAME; nor was the protein synthesis of saline-treated rats different from that of pentagastrin- and L-NAME-treated rats. Thus, under 'basal' conditions, a portion of the glandular protein synthesis, as well as the whole increase in synthesis in response to administration of pentagastrin, engaged both types of CCK receptors. Furthermore, NO generation, owing to neuronal NO synthase activity, was required for the increase to occur in response to pentagastrin, whereas a non-NO-dependent pathway was responsible for the protein synthesis under 'basal' conditions.
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