| 1. |
- Ahlkvist, Linda, et al.
(författare)
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Evidence for neural contribution to islet effects of DPP-4 inhibition in mice
- 2016
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 780, s. 46-52
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Tidskriftsartikel (refereegranskat)abstract
- It has been suggested that neural mechanisms may contribute to effects of the incretin hormones, and, therefore, also to the effects of dipeptidyl peptidase (DPP-4) inhibition. We therefore examined whether muscarinic mechanisms are involved in the stimulation of insulin secretion by DPP-4 inhibition. Fasted, anesthetized mice were given intraperitoneal saline or the muscarinic antagonist atropine (5mg/kg) before duodenal glucose (75mg/mouse), with or without the DPP-4 inhibitor NVPDPP728 (0.095mg/mouse), or before intravenous glucose (0.35g/kg) with or without co-administration with GLP-1 or glucose-dependent insulinotropic polypeptide (GIP) (both 3nmol/kg). Furthermore, isolated islets were incubated (1h) in 2.8 and 11.1mM glucose, with or without GIP or GLP-1 (both 100nM), in the presence or absence of atropine (100µM). Duodenal glucose increased circulating insulin and this effect was potentiated by DPP-4 inhibition. The increase in insulin achieved by DPP-4 inhibition was reduced by atropine by approximately 35%. Duodenal glucose also elicited an increase in circulating intact GLP-1 and GIP and this was augmented by DPP-4 inhibition, but these effects were not affected by atropine. Atropine did also not affect the augmentation by GLP-1 and GIP on glucose-stimulated insulin secretion from isolated islets. Based on these findings, we suggest that muscarinic mechanisms contribute to the stimulation of insulin secretion by DPP-4 inhibition through neural effects induced by GLP-1 and GIP whereas neural effects do not affect the levels of GLP-1 or GIP or the islet effects of the two incretin hormones.
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| 2. |
- Andersen, Birgitte, et al.
(författare)
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Fibroblast growth factor 21 prevents glycemic deterioration in insulin deficient mouse models of diabetes.
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 764, s. 189-194
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Tidskriftsartikel (refereegranskat)abstract
- In type 1 diabetes, there is a rapid loss of glycemic control immediately after onset of the disease. We aimed to determine if the deterioration of glycemic control that occurs early after the onset of insulin-deficient diabetes could be blunted by treatment with recombinant fibroblast growth factor 21 (FGF21). Normal C57BL/6J mice made diabetic by a single high dose injection of streptozotocin (STZ) were randomized to receive twice daily subcutaneous injection of vehicle or recombinant human FGF21 at doses of 0.3 and 1.0mg/kg for 10 days. Body weight was recorded daily and 5h fasted glucose, insulin, glucagon, free fatty acids and ketones were determined at 6 and 10 days post-randomization. The increase in fasting plasma glucose induced by STZ in untreated mice was prevented with FGF21 at 0.3mg/kg BID. In contrast, at 1.0mg/kg BID, FGF21 did not prevent the rise in plasma glucose after STZ. At the end of the study, plasma glucagon was significantly higher in the diabetic group treated with FGF21 1.0mg/kg BID than in the untreated group. This was not seen for the group treated with FGF21 0.3mg/kg BID. There were significant dose dependent reductions in plasma free fatty acids with FGF21 treatment but no significant change in plasma ketones (β-hydroxybutyrate). FGF21 treatment did not have significant effects on body weight in lean insulin deficient mice. In conclusion, FGF21 prevents increases in glycaemia and has lipid lowering properties in mouse models of insulin deficient diabetes, although by increasing the dose increased glucagon levels are seen and hyperglycemia persists.
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| 3. |
- Babateen, Omar, et al.
(författare)
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Etomidate, propofol and diazepam potentiate GABA-evoked GABAA currents in a cell line derived from Human glioblastoma
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 748, s. 101-107
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Tidskriftsartikel (refereegranskat)abstract
- GABAA receptors are pentameric chloride ion channels that are opened by GABA. We have screened a cell line derived from human glioblastoma, U3047MG, for expression of GABAA receptor subunit isoforms and formation of functional ion channels. We identified GABAA receptors subunit α2, α3, α5, β1, β2, β3, δ, γ3, π, and θ mRNAs in the U3047MG cell line. Whole-cell GABA-activated currents were recorded and the half-maximal concentration (EC50) for the GABA-activated current was 36μM. The currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and enhanced by the benzodiazepine diazepam (1μM) and the general anesthetics etomidate and propofol (50μM). In line with the expressed GABAA receptors containing at least the α3β3θ subunits, the receptors were highly sensitive to etomidate (EC50=55nM). Immunocytochemistry identified expression of the α3 and β3 subunit proteins. Our results show that the GABAA receptors in the glial cell line are functional and are modulated by classical GABAA receptor drugs. We propose that the U3047MG cell line may be used as a model system to study GABAA receptors function and pharmacology in glial cells.
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| 4. |
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| 5. |
- Cardilin, Tim, 1989, et al.
(författare)
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Evaluation and translation of combination therapies in oncology – A quantitative approach
- 2018
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 834, s. 327-336
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Tidskriftsartikel (refereegranskat)abstract
- Quantitative techniques improve our understanding of tumor volume data for combination treatments and its translation across in vivo models and species. The focus of this paper is therefore on understanding in vivo data, highlighting key structural elements of pharmacodynamic tumor models, and challenging these methods from a translational point of view. We introduce the concept of Tumor Static Exposure (TSE) both for single and multiple combined anticancer agents. The TSE curve separates all possible exposure combinations into regions of tumor growth and tumor shrinkage. Moreover, the degree of curvature of the TSE curve indicates the degree of synergy or antagonism. We demonstrate the TSE approach by two case studies. The first examines a combination of the drugs cetuximab and cisplatin. The TSE curve associated with this combination reveals a weak synergistic effect, suggesting only modest gains from combination therapy. The second case study examines combinations of ionizing radiation and a radiosensitizing agent. In this case, the TSE curve exhibits a pronounced curvature, indicating a strong synergistic effect; tumor regression can be achieved at significantly lower exposure levels and/or radiation doses. Finally, an allometric approach to human dose prediction demonstrates the translational power of the model and the TSE concept. We conclude that the TSE approach, which embodies model-based measures of both drug (potency) and target properties (tumor growth rate), has a strong potential for ranking of compounds, supporting compound selection, and translating preclinical findings to humans.
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| 6. |
- Changhui, Yu, et al.
(författare)
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Inhibition of Ras signalling reduces neutrophil infiltration and tissue damage in severe acute pancreatitis.
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 746, s. 245-251
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil recruitment is known to be a rate-limiting step in mediating tissue injury in severe acute pancreatitis (AP). However, the signalling mechanisms controlling inflammation and organ damage in AP remain elusive. Herein, we examined the role of Ras signalling in AP. Male C57BL/6 mice were treated with a Ras inhibitor (farnesylthiosalicylic acid, FTS) before infusion of taurocholate into the pancreatic duct. Pancreatic and lung tissues as well as blood were collected 24h after pancreatitis induction. Pretreatment with FTS decreased serum amylase levels by 82% and significantly attenuated acinar cell necrosis, tissue haemorrhage and oedema formation in taurocholate-induced pancreatitis. Inhibition of Ras signalling reduced myeloperoxidase (MPO) levels in the inflamed pancreas by 42%. In addition, administration of FTS decreased pancreatic levels of CXC chemokines as well as circulating levels of interleukin-6 and high-mobility group box 1 in animals exposed to taurocholate. Moreover, treatment with FTS reduced taurocholate-induced MPO levels in the lung. Inhibition of Ras signalling had no effect on neutrophil expression of Mac-1 in mice with pancreatitis. Moreover, FTS had no direct impact on trypsin activation in isolated pancreatic acinar cells. These results indicate that Ras signalling controls CXC chemokine formation, neutrophil recruitment and tissue injury in severe AP. Thus, our findings highlight a new signalling mechanism regulating neutrophil recruitment in the pancreas and suggest that inhibition of Ras signalling might be a useful strategy to attenuate local and systemic inflammation in severe AP.
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| 7. |
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| 8. |
- da Silva, Luiz A, et al.
(författare)
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Unravelling the intravenous and in situ vasopressin effects on the urinary bladder in anesthetized female rats: More than one vasopressin receptor subtype involved?
- 2018
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Ingår i: European journal of pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 834, s. 109-117
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Tidskriftsartikel (refereegranskat)abstract
- Urinary bladder dysfunctions show high prevalence in women. We focused to investigate the intravenous and in situ (topic) vasopressin effects on the bladder and also to characterize the vasopressin receptor subtypes in the bladder. Adult female Wistar rats anesthetized with isoflurane underwent to the cannulation of the femoral artery and vein, and also urinary bladder for mean arterial pressure, heart rate and intravesical pressure (IP) recordings, respectively. Doppler flow probe was placed around the renal artery for blood flow measurement. After baseline recordings, intravenous injection of saline or vasopressin at different doses (0.25, 0.5, 1.0ng/ml/kg of b.w.); or 0.1ml of saline or 0.1ml of vasopressin at different doses (0.25, 0.5, 1.0ng/ml) was randomly dropped on the bladder. In another group of rats, the UB was harvest for gene expression by qPCR and also for protein expression by Western blotting of the vasopressin receptor subtypes. We observed that either intravenous or in situ vasopressin evoked a huge increase in the IP in a dose-dependent manner compared to saline, whilst no differences were observed in the cardiovascular parameters. The genes and the protein expression of V1a, V1b and V2 vasopressin receptors subtypes were found in the bladder. Intravenous injection of V1a or V2 receptor antagonist evoked a huge fall in IP and 30min later, i.v or in situ vasopressin evoked responses on IP were significantly attenuated. Therefore, intravenous or in situ vasopressin increases the IP due to binding in V1a or V2 receptors localized in the bladder.
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| 9. |
- Gabrielsson, Johan, et al.
(författare)
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Lost in translation: What's in an EC50? Innovative PK/PD reasoning in the drug development context
- 2018
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 835, s. 154-161
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Tidskriftsartikel (refereegranskat)abstract
- Translation across species and from in vitro to in vivo is a central tenet in drug discovery pharmacology. Successful implementation requires proper assessment of both in vivo potency and efficacy. This notwithstanding, in vivo data is typically defined mostly in terms of ligand-to-target binding affinity, similar to in vitro studies. As in vivo potency and efficacy involve a combination not only of drug, but also partitioning, target, and drug-target-complex events and processes, ignoring some of the central differences between in vivo and in vitro may result in serious miscalculations of in vivo efficacious exposure for translational predictions. We compare potency measures derived from two basic pharmacodynamic model situations: A 'closed' in vitro system defining target binding of a ligand when both concentrations remain essentially static, and an 'open' in vivo system where target turnover dynamics and elimination of the drug-target complex are also included. Corresponding equilibrium (steady-state) expressions in the central pharmacokinetic compartment are derived and presented. Three representative variants of 'open' in vivo systems are discussed, showing relationships for ligand-target complex and ligand for each of the systems and graphically illustrating corresponding shapes. The examples include i) two ligands competing for one target, ii) two targets competing for one ligand (/drug), and iii) target-ligand (/drug) interactions in a peripheral PK compartment. The expanded in vivo potency EC50 expression emphasises the contribution from target-related biology parameters that need accounting for, and particularly that 'closed' system (in vitro) properties should not be first choice when ranking compounds in vivo ('open' system).
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| 10. |
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| 11. |
- Ghofrani, Saeed, et al.
(författare)
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Naringenin improves learning and memory in an Alzheimer's disease rat model : Insights into the underlying mechanisms
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 764, s. 195-201
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is one of the prevalent neurological disorders of the central nervous system hallmarked by increased beta-amyloid (Aβ) deposition and ensuing learning and memory deficit. In the present study, the beneficial effect of naringenin on improvement of learning and memory was evaluated in an Alzheimer's disease rat model. The Aβ-injected rats showed a lower alternation score in Y-maze task, impairment of retention and recall capability in passive avoidance test, and lower correct choices and higher errors in radial arm maze (RAM) task as compared to sham group in addition to enhanced oxidative stress and apoptosis. Naringenin, but not a combination of naringenin and fulvestrant (an estrogenic receptor antagonist) significantly improved the performance of Aβ-injected rats in passive avoidance and RAM tasks. Naringenin pretreatment of Aβ-injected rats also lowered hippocampal malondialdehyde (MDA) with no significant effect on nitrite and superoxide dismutase (SOD) activity in addition to lowering apoptosis. These results suggest naringenin pretreatment attenuates Aβ-induced impairment of learning and memory through mitigation of lipid peroxidation and apoptosis and its beneficial effect is somewhat mediated via estrogenic pathway.
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| 12. |
- Hagsäter, S Melker, et al.
(författare)
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5-HT6 receptor antagonism reduces defecation in rat: A potential treatment strategy for irritable bowel syndrome with diarrhea
- 2019
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 864
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Tidskriftsartikel (refereegranskat)abstract
- © 2019 Elsevier B.V. Whereas the potential role of serotonin for the pathophysiology of irritable bowel syndrome (IBS) has since long been discussed, the possibility that 5-hydroxytryptamine 6 (5-HT6) receptors may serve as targets for the treatment of this condition has as yet not been explored. The aim of the current study was to assess to what extent defecation in rats is influenced by manipulation of 5-HT6 receptors. Reduced defecation following SB-399885 was observed in non-stressed animals assessed for 7 h after drug administration. While not impacting context-conditioned freezing, three 5-HT6 receptor antagonists (SB-399885, SB-271046 and SB-258585) also markedly reduced the number of faecal boli produced by rats exposed to context-conditioned fear. In contrast, a 5-HT6 receptor agonist, WAY-208466, influenced defecation neither in unstressed animals nor in rats experiencing conditioned fear stress. A clinical study on the possible effect of a 5-HT6 receptor antagonist in IBS with diarrhea appears warranted.
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| 13. |
- Hansson, Magnus, et al.
(författare)
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Differences in the profile of protection afforded by TRO40303 and mild hypothermia in models of cardiac ischemia/reperfusion injury.
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 760:Apr 17, s. 7-19
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Tidskriftsartikel (refereegranskat)abstract
- The mode of protection against cardiac reperfusion injury by mild hypothermia and TRO40303 was investigated in various experimental models and compared to MitoQ in vitro. In isolated cardiomyocytes subjected to hypoxia/reoxygenation, TRO40303, MitoQ and mild hypothermia delayed mPTP opening, inhibited generation of mitochondrial superoxide anions at reoxygenation and improved cell survival. Mild hypothermia, but not MitoQ and TRO40303, provided protection in a metabolic starvation model in H9c2 cells and preserved respiratory function in isolated rat heart mitochondria submitted to anoxia/reoxygenation. In the Langendorff-perfused rat heart, only mild hypothermia provided protection of hemodynamic function and reduced infarct size following ischemia/reperfusion. In biopsies from the left ventricle of pigs subjected to in vivo occlusion/reperfusion, TRO40303 specifically preserved respiratory functions in the peri-infarct zone whereas mild hypothermia preserved both the ischemic core area and the peri-infarct zones. Additionally in this pig model, only hypothermia reduced infarct size. We conclude that mild hypothermia provided protection in all models by reducing the detrimental effects of ischemia, and when initiated before occlusion, reduced subsequent reperfusion damage leading to a smaller infarct. By contrast, although TRO40303 provided similar protection to MitoQ in vitro and offered specific protection against some aspects of reperfusion injury in vivo, this was insufficient to reduce infarct size.
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| 14. |
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| 15. |
- Kardeby, Caroline, 1989-, et al.
(författare)
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A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
- 2019
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Ingår i: European Journal of Pharmacology. - : Elsevier. - 0014-2999 .- 1879-0712. ; 857
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Tidskriftsartikel (refereegranskat)abstract
- Natural purines like ATP, ADP and adenosine have crucial roles in platelet physiology. This knowledge has been significant in drug development and today ADP receptor antagonists are widely used for prevention of thrombotic events following myocardial infarction and ischaemic stroke.Recent studies have shown that a purine analogue bearing nitrate ester group (denoted MK128) has anti-inflammatory effects probably due to its ability to donate nitric oxide (NO). However, other pharmacological mechanisms may contribute to the observed effect. The aim of the present study was to establish the anti-platelet activity and elucidate the underlying molecular mechanism(s) of the purine analogue MK128.We found that MK128 reduced aggregation and secretion induced by the thrombin receptor agonist SFLLRN and nearly abolished aggregation and secretion induced by thromboxane A2 (TxA2) and collagen receptor agonists. The inhibition took place despite blockage of the NO/cGMP signalling system. Furthermore, interaction between MK128 and platelet purinergic receptors did not explain the observed inhibition. Instead, we found that MK128 concentration-dependently inhibited Rho-associated kinase (ROCK), which led to decreased ROCK-dependent myosin phosphatase target subunit (MYPT)-1 phosphorylation and suppression of platelet functional responses.
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| 16. |
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| 17. |
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| 18. |
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| 19. |
- Mizoguchi, Hirokazu, et al.
(författare)
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The involvement of spinal release of histamine on nociceptive behaviors induced by intrathecally administered spermine
- 2017
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 800, s. 9-15
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Tidskriftsartikel (refereegranskat)abstract
- The involvement of spinal release of histamine on nociceptive behaviors induced by spermine was examined in mice. Intrathecal spermine produced dose-dependent nociceptive behaviors, consisting of scratching, biting and licking. The nociceptive behaviors induced by spermine at 0.02 amol and 10 pmol were markedly suppressed by i.t. pretreatment with antiserum against histamine and were abolished in histidine decarboxylase-deficient mice. In histamine H-1 receptor-deficient mice, the nociceptive behaviors induced by spermine were completely abolished after treatment with 0.02 amol of spermine and significantly suppressed after treatment with 10 pmol of spermine. The i.t. pretreatment with takykinin NK1 receptor antagonists eliminated the nociceptive behaviors induced by 0.02 amol of spermine, but did not affect the nociceptive behaviors induced by 10 pmol of spermine. On the other hand, the nociceptive behaviors induced by spermine at both 0.02 amol and 10 pmol were suppressed by i.t. pretreatment with antagonists for the NMDA receptor polyamine-binding site. The present results suggest that the nociceptive behaviors induced by i.t. administration of spermine are mediated through the spinal release of histamine and are elicited via activation of NMDA receptors.
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| 20. |
- Moller, Kristina Angeby, et al.
(författare)
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Using gait analysis to assess weight bearing in rats with Freund's complete adjuvant-induced monoarthritis to improve predictivity : Interfering with the cyclooxygenase and nerve growth factor pathways
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 756, s. 75-84
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Tidskriftsartikel (refereegranskat)abstract
- Lack of predictive power for drug effects has been a major criticism against animal pain models. It is therefore important to define the utility and limitations of different models. The aim of this study was to extend previous work on gait analysis as a tool to investigate pharmacological effects in monoarthritic rats, specifically to test the hypothesis that monoarthritis induced by Freund's complete adjuvant (FCA) provides a better estimate of overall analgesic efficacy of established, and novel, clinically effective and ineffective therapeutic approaches. Male rats injected intra-articularly into one ankle joint with FCA (1.0mg/ml) were treated with the monoclonal antibody to nerve growth factor (NGF), MEDI-578, the inhibitors of tropomyosin receptor kinases A, B and C (pan-Trk) AZ6623 or AZ7092, the transient receptor potential vanilloid 1 (TRPV1) inhibitor AZD1386, or the cyclooxygenase (COX) inhibitors naproxen, ibuprofen, valdecoxib or rofecoxib. Effects on weight bearing during locomotion were tested using video capture of print images. The apparent efficacy in this model was Trk inhibitors >= anti-NGF antibody > COX inhibitors. The TRPV1 inhibitor was ineffective. Together with previous data, the results support using gait-related parameters in the monoarthritis model. FCA as induction agent seems to provide a good overall prediction of analgesic efficacy in disorders with inflammatory joint pain. (C) 2015 Elsevier B.V. All rights reserved.
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| 21. |
- Olivier, Jocelien D A, 1978-, et al.
(författare)
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Antenatal depression and antidepressants during pregnancy : Unraveling the complex interactions for the offspring
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 753, s. 257-262
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Tidskriftsartikel (refereegranskat)abstract
- During pregnancy the risk for a woman to develop a depressive episode is as high as 20%. Antenatal depression is not harmless for the developing child as several changes, including neurodevelopmental alterations, have been reported. Sometimes it is unavoidable to treat a pregnant mother with antidepressants, especially when she is suicidal. Currently, selective serotonin reuptake inhibitors (SSRIs) are the pharmacological choice of antidepressant treatment. SSRIs do not cause gross teratogenic alterations and are generally considered safe for use in pregnancy. However, although SSRIs may relieve the maternal symptoms, they definitively cross the placenta partially influencing the neurodevelopment of the fetus. In this review an overview is given of the effects on the offspring of maternal antenatal depression and the putative neurodevelopmental effects of SSRI treatment during pregnancy. Although we primarily focus on human data, some animal data are discussed to describe possible mechanisms on how SSRIs are affecting underlying biological mechanisms associated with depression. In summary, maternal depression may have long-lasting effects on the offspring, whereas prenatal SSRI exposure also increases the risk for long-lasting effects. It remains to be determined whether the effects found after SSRI treatment in pregnant women are only due to the SSRI exposure or if the underlying depression is also contributing to these effects. The possibility of epigenetic alterations as one of the underlying mechanisms that is altered by SSRI exposure is discussed. However much more research in this area is needed to explain the exact role of epigenetic mechanisms in SSRI exposure during pregnancy.
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| 22. |
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| 23. |
- Sagar, Seil, et al.
(författare)
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Translational value of animal models of asthma: Challenges and promises.
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 759:Mar 28, s. 272-277
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Forskningsöversikt (refereegranskat)abstract
- Asthma is a heterogeneous disease in which various environmental stimuli as well as different genes, cell types, cytokines and mediators are implicated. This chronic inflammatory disorder of the airways is estimated to affect as many as 300 million people worldwide. Animal models of asthma, despite their limitations, have contributed greatly to our understanding of disease pathology and the identification of key processes, cells and mediators in asthma. However, it is less likely to develop an animal model of asthma that takes into account all aspects of human disease. The focus in current asthma research is increasingly on severe asthma because this group of patients is not well treated today. Recent advances in studies of asthma exacerbation are thus considered. We therefore need to develop translational model systems for pharmacological evaluation and molecular target discovery of severe asthma and asthma exacerbations. In this review we attempted to discuss the different animal models of asthma, with special emphasis on ovalbumin and house dust mite models, their merits and their limitations.
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| 24. |
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| 25. |
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| 26. |
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| 27. |
- Turpaev, Kyril, et al.
(författare)
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Aromatic malononitriles stimulate the resistance of insulin-producing beta-cells to oxidants and inflammatory cytokines
- 2016
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 784, s. 69-80
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Tidskriftsartikel (refereegranskat)abstract
- We presently report that treatment with tyrphostin AG-126 (2-(3-hydroxy-4-nitrobenzylidene)malononitrile) and ten other aromatic malononitrile compounds (AMN) improves the resistance of insulin producing beta TC6, RIN-5AH, and MIN6 cells to oxidative stress and pro-inflammatory cytokines. On the molecular level AMN compounds promote nuclear accumulation of the Nrf2 transcription factor and expression of the cytoprotective genes heme ogygenase 1 (HO-1) and NAD(P)H/quinone oxidoreductase 1 (NQO1), inhibit cytokine-dependent inducible nitric oxide synthase (iNOS) induction, suppress intracellular production of reactive oxygen species in beta TC6 and counteract to impairments of glucose stimulated insulin secretion induced by pro-inflammatory cytokines in MIN6 cells. Nrf2 up-regulation and HO-1 induction by AG-126 are attenuated at the presence of siRNA against Nrf2 and brusatol, an inhibitor of the Nrf2 signaling pathway. Our present results indicate that in respect of inhibition of IL-1 beta-dependent iNOS induction, beta TC6 cells are more sensitive to EMK 1071 (2-((5-methylthiophen-2-yl) methylene)malononitrile) and EMK 31 (2-(4-hydroxy-3-methoxybenzylidene)malononitrile) as compared to other analyzed AMN compounds. We suggest that the ability of AMN compounds to inhibit iNOS induction and other cytokine-induced transcriptional events might be a tool to achieve improved beta-cell survival and functionality.
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| 28. |
- Uhlén, Staffan, et al.
(författare)
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A new, simple and robust radioligand binding method used to determine kinetic off-rate constants for unlabeled ligands. Application at alpha(2A)- and alpha(2C)-adrenoceptors
- 2016
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 788, s. 113-121
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Tidskriftsartikel (refereegranskat)abstract
- Kinetic on and off rate constants for many receptor ligands are difficult to determine with regular radioligand binding technique since only few of the ligands are available in labeled form. Here we developed a new and simple radioligand binding method for determining the kinetic off-rate constant for unlabeled ligands, using whole cells expressing alpha(2A)- and alpha(2C)-adrenoceptors. The new method involves pre-incubation with unlabeled ligand, centrifugation of microtiter plates in order to adhere the cells to the bottom surface, and then upside-down centrifugation of the plates for few seconds to wash away the non-bound fraction of the pre-incubated ligand. The final on-reaction assay for the radioligand is then started by quick addition of a relatively fast-associating radioligand to the cells. The curve obtained is defined by a fairly simple mathematical formula that reflects the simultaneous dissociation of pre-incubated ligand and association of the radioligand. The method proved to produce highly reproducible results in determining the k(off) constants for various unlabeled ligands. The results show that the alpha(2C)-selectivity of MK912 depends mainly on a very slow off-rate at the alpha(2C)-adrenoceptor subtype. Regarding the markedly alpha(2C)- over alpha(2A)-selective compound spiroxatrine, its much faster on-rate at alpha(2C)- than alpha(2A)-adrenoceptors explains much of its exceptional alpha(2C)-selectivity. Several new techniques for determining the kinetic component of ligand-receptor interactions at molecular level are currently developing. As a reference, based on standard radioligand binding techniques, the present study describes a simple and robust experimental and mathematical procedure for determining k(off) constants of unlabeled drugs.
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| 29. |
- Yao, Xingang, et al.
(författare)
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Inhibition of dengue viral infection by diasarone-I is associated with 2'O methyltransferase of NS5
- 2018
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Ingår i: European Journal of Pharmacology. - Amsterdam : Elsevier. - 0014-2999 .- 1879-0712. ; 821, s. 11-20
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Tidskriftsartikel (refereegranskat)abstract
- Dengue virus (DENV) is the most prevalent mosquito borne viral pathogen worldwide. However, antiviral drugs against this infection are not available. To identify novel anti-DENV compound from traditional Chinese medicine, we discovered the ethanol extract of Acorus tatarinowii Schott containing potent anti-DENV activity and diasarone-I was isolated from this extract. Diasarone-I has antiviral effect with half maximal effective concentration (EC50) of 4.5μM and half maximal cytotoxicity concentration (CC50) of >80μM. Time of drug addition assay suggested that this compound inhibited at RNA replication step in the DENV life cycle. Further, in silico analysis indicated that diasarone-I might act as an inhibitor of 2'O Methyltransferase of NS5. Diasarone-I has also decreased the DENV2-induced STAT1 phosphorylation and ISGs. In summary, we suggest that diasarone-I may be a 2'O Methyltransferase inhibitor and might serve as a potential candidate for the treatment of DENV2 infections. © 2017 Elsevier B.V.
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| 30. |
- Yu, Qi, et al.
(författare)
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Apolipoprotein B, the villain in the drama?
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 748:Sep 16, s. 166-169
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Tidskriftsartikel (refereegranskat)abstract
- Low-density lipoprotein (LDL) is the major atherogenic lipoprotein and the primary target of lipid-lowering therapy for treating ischemic cardiovascular disease. Apolipoprotein B (apoB), an important structural component of LDL, plays a key role in cholesterol transport and removal in vascular wall. On the other hand, under pathological process, apoB interacts with the arterial wall to initiate the cascade of events that leads to atherosclerosis. However, interactions between apoB and vascular wall remain to be determined. Here, we address a pathological role of apoB per se and whole LDL particle in dysfunction of vascular endothelium and smooth muscle cells i.e. decreased endothelium-dependent vasodilation and increased receptor-mediated vasoconstriction. We intend to discuss: i) how apoB is responsible for the deleterious effects of LDL in the development of ischemic cardiovascular disease; ii) why vaccine based on peptides derived from apoB-100 is a promising therapy for treating ischemic cardiovascular disease, and iii) direct inhibition of apoB production should be a better therapeutic option than simple LDL-cholesterol lowering therapy in the patients with severe hypercholesterolemia at high cardiovascular risk with statin intolerance. In conclusion, apoB, but not cholesterol, plays a major role in LDL-induced dysfunction of endothelium, suggesting that direct apoB-targeting agents might be a promising therapy for the treatment of ischemic cardiovascular disease.
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| 31. |
- Zeng, Jianwen, et al.
(författare)
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Non-uniform changes in membrane receptors in the rat urinary bladder following outlet obstruction.
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 762, s. 82-88
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to investigate the expression and distribution of membrane receptors after bladder outlet obstruction (BOO). Partial bladder outlet obstruction (BOO) was induced in female rats and bladders were harvested after either 10 days or 6 weeks of BOO. The expression of different receptors was surveyed by microarrays and corroborated by immunohistochemistry and western blotting. A microarray experiment identified 10 membrane receptors that were differentially expressed compared to sham-operated rats including both upregulated and downregulated receptors. Four of these were selected for functional experiments on the basis of magnitude of change and relevance to bladder physiology. At 6 weeks of BOO, maximal contraction was reduced for neuromedin B and vasopressin (AVP), consistent with reductions of receptor mRNA levels. Glycine receptor-induced contraction on the other hand was increased and receptor mRNA expression was accordingly upregulated. Maximal relaxation by the β3-adrenergic receptor agonist CL316243 was reduced as was the receptor mRNA level. Immunohistochemistry supported reduced expression of neuromedin B receptors, V1a receptors and β3-adrenergic receptors, but glycine receptor expression appeared unchanged. Western blotting confirmed repression of V1a receptors and induction of glycine receptors in BOO. mRNA for vasopressin was detectable in the bladder, suggesting local AVP production. We conclude that changes in receptor expression following bladder outlet obstruction are non-uniform. Some receptors are upregulated, conferring increased responsiveness to agonist, whereas others are downregulated, leading to decreased agonist-induced responses. This study might help to select pharmacological agents that are effective in modulating lower urinary tract symptoms in BOO.
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| 32. |
- Zeng, Jianwen, et al.
(författare)
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Vasopressin-induced mouse urethral contraction is modulated by caveolin-1.
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 750, s. 59-65
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Tidskriftsartikel (refereegranskat)abstract
- Caveolae are 50-100nm large invaginations in the cell membrane that are considered to play roles in receptor signaling. Here we aimed to investigate the expression and distribution of the arginine-vasopressin (AVP) V1a receptor and its functional dependence on caveolin-1 (Cav1) in the mouse urethra. Female Cav1 knockout (KO) and wild type (WT) mice were used, and urethral preparations were micro-dissected for mechanical experiments. Methyl-β-cyclodextrin (mβcd) was used to deplete cholesterol and to disrupt caveolae. Protein expression and localization was determined using immunofluorescence and western blotting and transcript expression was determined by qRT-PCR. We found that Cav1 and AVP V1a receptors were expressed in urethral smooth muscle cells with apparent co-localization at the cell membrane. AVP caused urethral contraction that was inhibited by the V1a receptor antagonist SR49059. Concentration-response curves for AVP were right-shifted and maximal contraction was reduced in Cav1 KO mice and after mβcd treatment. In addition to caveolin-1 we also detected caveolin-2, cavin-1 and cavin-3 in the mouse urethra by western blotting. Caveolin-2, cavin-1 and cavin-3 as well as V1a receptor expression was reduced in KO urethra. We conclude that AVP regulates urethral contractility via the V1a receptor through a Cav1-dependent mechanism involving, in part, altered V1a receptor expression.
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| 33. |
- Ermund, Anna, et al.
(författare)
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Hyper-osmolarity and calcium chelation: Effects on cystic fibrosis mucus
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 764, s. 109-117
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Tidskriftsartikel (refereegranskat)abstract
- A non-functional Cystic Fibrosis Transmembrane conductance Regulator (CFTR) leads to the disease cystic fibrosis (CF). Although the CFTR is expressed in multiple organs, pulmonary disease is the major cause of illness and death in patients with CF. Stagnant mucus, causing airway obstruction, bacterial overgrowth, persistent inflammation and tissue destruction characterizes the disease, but how the defect in CFTR function is coupled to the mucus phenotype is still controversial. We have recently shown that bicarbonate ions passing through CFTR are necessary for proper unfolding of the MUC2 mucin, thus highlighting the importance of bicarbonate ion transport via the CFTR and the ability of these ions to raise the pH and chelate calcium bound to the mucin as the important steps in forming normal mucus. In order to find potential CF treatments and expand our knowledge about the usefulness of bicarbonate as an active ingredient in formulations to alleviate mucus plugging, we used an Ussing-type chamber and explants from the F508del-CFTR mutant mouse ileum to test the effect of calcium chelators on mucus attachment, either in isolation or in combination with osmolytes such as mannitol or hypertonic saline. We found that increasing the concentration of bicarbonate, both alone or in combination with increased osmolarity of the solution, detached the otherwise attached CF mucus. (C) 2015 Elsevier B.V. All rights reserved.
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| 34. |
- Grönberg, Caitríona, et al.
(författare)
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Recent advances on CD4+ T cells in atherosclerosis and its implications for therapy
- 2017
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 816, s. 58-66
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Tidskriftsartikel (refereegranskat)abstract
- Atherosclerosis is an arterial inflammatory disease and the primary cause of cardiovascular disease. T helper (Th) cells are an important part in atherosclerotic plaque as they can be either disease promoting or protective. A body of evidence points to a pro-atherosclerotic role of Th1 cells, whereas the role of Th2, Th17 and iNKT cells seems more complex and dependent on surrounding factors, including the developmental stage of the disease. Opposed to Th1 cells, there is convincing support for an anti-atherogenic role of Tregs. Recent data identify the plasticity of Th cells as an important challenge in understanding the functional role of different Th cell subsets in atherosclerosis. Much of the knowledge of Th cell function in atherosclerosis is based on findings from experimental models and translating this into human disease is challenging. Targeting Th cells and/or their specific cytokines represents an attractive option for future therapy against atherosclerosis, although the benefits and the risk of modulation of Th cells with these novel drug targets must first be carefully assessed.
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| 35. |
- Johansson, Sara Ellinor, et al.
(författare)
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Vascular pathology of large cerebral arteries in experimental subarachnoid hemorrhage : Vasoconstriction, functional CGRP depletion and maintained CGRP sensitivity
- 2019
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 846, s. 109-118
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Tidskriftsartikel (refereegranskat)abstract
- Subarachnoid hemorrhage (SAH) is associated with increased cerebral artery sensitivity to vasoconstrictors and release of the perivascular sensory vasodilator CGRP. In the current study the constrictive phenotype and the vasodilatory effects of exogenous and endogenous perivascular CGRP were characterized in detail applying myograph technology to cerebral artery segments isolated from experimental SAH and sham-operated rats. Following experimental SAH, cerebral arteries exhibited increased vasoconstriction to endothelin-1, 5-hydroxytryptamine and U46419. In addition, depolarization-induced vasoconstriction (60 mM potassium) was significantly increased, supporting a general SAH-associated vasoconstrictive phenotype. Using exogenous CGRP, we demonstrated that sensitivity of the arteries to CGRP-induced vasodilation was unchanged after SAH. However, vasodilation in response to capsaicin (100 nM), a sensory nerve activator used to release perivascular CGRP, was significantly reduced by SAH (P = 0.0079). Because CGRP-mediated dilation is an important counterbalance to increased arterial contractility, a reduction in CGRP release after SAH would exacerbate the vasospasms that occur after SAH. A similar finding was obtained with artery culture (24 h), an in vitro model of SAH-induced vascular dysfunction. The arterial segments maintained sensitivity to exogenous CGRP but showed reduced capsaicin-induced vasodilation. To test whether a metabolically stable CGRP analogue could be used to supplement the loss of perivascular CGRP release in SAH, SAX was systemically administered in our in vivo SAH model. SAX treatment, however, induced CGRP-desensitization and did not prevent the development of vasoconstriction in cerebral arteries after SAH.
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| 36. |
- Senek, Marina, et al.
(författare)
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Levodopa/carbidopa microtablets in Parkinson's disease : a study of pharmacokinetics and blinded motor assessment
- 2017
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Ingår i: European Journal of Clinical Pharmacology. - Heidelberg, Germany : Springer. - 0031-6970 .- 1432-1041 .- 0014-2999. ; 73:5, s. 563-571
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Tidskriftsartikel (refereegranskat)abstract
- Background: Motor function assessments with rating scales in relation to the pharmacokinetics of levodopa may increase the understanding of how to individualize and fine-tune treatments.Objectives: This study aimed to investigate the pharmacokinetic profiles of levodopa-carbidopa and the motor function following a single-dose microtablet administration in Parkinson’s disease.Methods: This was a single-center, open-label, single-dose study in 19 patients experiencing motor fluctuations. Patients received 150% of their individual levodopa equivalent morning dose in levodopa-carbidopa microtablets. Blood samples were collected at pre-specified time points. Patients were video recorded and motor function was assessed with six UPDRS part III motor items, dyskinesia score, and the treatment response scale (TRS), rated by three blinded movement disorder specialists.Results: AUC0–4/dose and Cmax/dose for levodopa was found to be higher in Parkinson’s disease patients compared with healthy subjects from a previous study, (p = 0.0008 and p = 0.026, respectively). The mean time to maximum improvement in sum of six UPDRS items score was 78 min (±59) (n = 16), and the mean time to TRS score maximum effect was 54 min (±51) (n = 15). Mean time to onset of dyskinesia was 41 min (±38) (n = 13).Conclusions: In the PD population, following levodopa/carbidopa microtablet administration in fasting state, the Cmax and AUC0–4/dose were found to be higher compared with results from a previous study in young, healthy subjects. A large between subject variability in response and duration of effect was observed, highlighting the importance of a continuous and individual assessment of motor function in order to optimize treatment effect.
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| 37. |
- Spanos, Elias, et al.
(författare)
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Cardioprotection of the enkephalin analog Eribis peptide 94 in a rat model of ischemia and reperfusion is highly dependent on dosing regimen and timing of administration
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 747, s. 1-6
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Tidskriftsartikel (refereegranskat)abstract
- Eribis Peptide 94 (EP94) is an enkephalin analog with cardioprotective properties in ischemia and reperfusion. The aim of the present study was to define the optimal timing and dosing of the administration of EP94 during ischemia and reperfusion in a rat model. 172 anesthetized and mechanically ventilated male Sprague-Dawley rats were randomly assigned to different administration protocols of EP94 and subjected to 30 or 40min of coronary artery occlusion followed by 2h of reperfusion. EP94 was administered intravenously at different doses and time intervals. Area at risk (AAR) and infarct size (IS) were determined by staining with Evans Blue (EB) and Triphenyl tetrazolium chloride (TTC), respectively. EP94 reduced IS/AAR when administered as a double bolus (0.5µg/kg per dose), whereas single (1μg/kg) or triple boluses (0.5μg/kg per dose) did not confer any protection. Reduction of IS/AAR was of highest magnitude if EP94 was administered 5 and 0min before the 30min ischemic period (47% reduction, P<0.05), with declining cardioprotective effect with later administration during ischemia. When EP94 was administered after 15 and 20min of a 40-min ischemic period, reduction of IS/AAR was of the same magnitude as when given after 5 and 10min of a 30-min ischemic period. It is concluded that EP94 confers cardioprotection after double bolus administration. The effects are highly dependent on the timing of administration in relation to ischemia and reperfusion. Time of reperfusion from drug administration seems to be more critical than the total duration of ischemia.
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| 38. |
- Stenqvist, Johanna, et al.
(författare)
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Urothelial acetylcholine involvement in ATP-induced contractile responses of the rat urinary bladder
- 2017
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 809, s. 253-260
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Tidskriftsartikel (refereegranskat)abstract
- Both acetylcholine and adenosine 5'-triphosphate (ATP) are released from the urothelium. In in vivo experiments ATP has been shown to evoke contractile responses that are significantly reduced by atropine. Currently, we aimed to examine the cholinergic part of the ATP-evoked contractile response of normal and inflamed (cyclophosphamide-treated rats) bladders. A whole bladder preparation that enabled drug administration either outside or inside the urinary bladder was used. The responses were examined in bladders from control and cyclophosphamide-treated rats that were either intact or urothelium-denuded. The expression of choline acetyltransferase and carnitine acetyltransferase were examined by Western blotting of normal and inflamed bladders. Methacholine evoked larger contractions when administered to the outside of the bladder in comparison to instillation. For ATP, an opposite trend emerged. While atropine substantially reduced the ATP-induced responses at internal administration (7.4 +/- 1.1 and 3.7 +/- 0.9 mN at 10-3 M; n=13; P < 0.001), it had no effect when administered outside the bladder. The removal of the urothelium caused a similar reduction of the responses to internal administration of ATP as caused by atropine. In cyclophosphamide-treated rats, neither atropine nor urothelium-denudation had any effect on the ATP-evoked responses. No changes in the expressions of the acetylcholine synthesising enzymes were observed. The current study shows that ATP induces a release of urothelial acetylcholine that contributes to the purinergic contractile response in the rat urinary bladder. This atropine-sensitive part of the purinergic contractile response is absent in the inflamed bladder. This may be one pathological mechanism involved in bladder dysfunction.
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| 39. |
- Witjes, J. J., et al.
(författare)
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About the gut microbiome as a pharmacological target in atherosclerosis
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier. - 0014-2999. ; 763, s. 75-78
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Tidskriftsartikel (refereegranskat)abstract
- The contribution of intestinal bacterial strains (gut microbiota) in the development of cardiometabolic disease is increasingly recognized as potential diagnostic and pharmacological target. Changes in the intestinal bacterial composition and subsequent altered diversity has been associated with presence of chronic low-grade inflammation of mesenteric visceral adipose tissue, a known feature of malign obesity which can eventually lead to insulin resistance and type 2 diabetes mellitus. However, causality still needs to be proven. In this regard, both fecal transplantation studies as well as multiethnic prospective cohorts can help to identify the causally involved driving intestinal bacterial strains in human cardiometabolism. Ultimately, it is expected that novel diagnostic markers as well as therapeutics (pharmabiotics and vaccine strategies) can be developed. © 2015 Elsevier B.V. All rights reserved.
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