| 1. |
- Bengtsson, Torbjörn, 1955-, et al.
(författare)
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Leucocyte activation by collagen-stimulated platelets in whole blood
- 2002
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Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 0036-5513 .- 1502-7686. ; 62:6, s. 451-462
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Tidskriftsartikel (refereegranskat)abstract
- Interaction between vascular cells plays an important role in the initial phases of the inflammatory process, but the mechanisms responsible for cell-cell communication are not fully understood. In this study, activation of leucocytes and platelets in heparinized whole blood was assessed using lumi-aggregometry. This technique enables simultaneous measurement of aggregation and oxygen radical production by monitoring impedance and luminol-amplified chemiluminescence (CL), respectively. Collagen induced aggregation and CL, depending on dose, and markedly enhanced subsequent aggregation and CL-response triggered by the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (fMet-Leu-Phe). Collagen stimulation of whole blood down- and upregulated the expression of L-selectin and CD11b, respectively. Monoclonal antibodies against sialyl LewisX and P-selectin caused a pronounced inhibition of the oxidative burst, triggered by collagen itself or by a combination of collagen and fMet-Leu-Phe. Furthermore, the Arg-Gly-Asp-Ser(RGDS)-peptide effectively inhibited collagentriggered aggregation and CL, and the subsequent enhancement of the fMet-Leu-Phe-induced responses. This suggests that fibrinogen plays a part in linking platelet GpIIb/IIIa with CD11b on the leucocyte surface. However, neither anti-CD11b nor the PI-peptide (containing the ?-chain motif in fibrinogen that interacts with CD11b) counteracted the stimulatory effects of activated platelets on leucocyte functions. The selectin- and integrin-antagonizing substances were ineffective on the CL-responses induced by fMet-Leu-Phe itself. This study suggests that, through selectin- and integrin-dependent interaction, activated platelets potentiate leucocyte aggregation and oxygen radical production, which might be important for the outcome of inflammatory reactions.
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| 2. |
- Asplund Persson, Anna, 1966-, et al.
(författare)
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Cross-talk between adenosine and the oxatriazole derivative GEA 3175 in platelets
- 2005
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 517:3, s. 149-157
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Tidskriftsartikel (refereegranskat)abstract
- We examined the interplay between adenosine and the nitric oxide (NO)-containing oxatriazole derivative GEA 3175 in human platelets. The importance of cyclic guanosine 3′5′-monophosphate (cGMP)-inhibited phosphodiesterases (PDEs) was elucidated by treating the platelets with adenosine combined with either GEA 3175 or the PDE3-inhibitor milrinone. The drug combinations provoked similar cyclic adenosine 3′5′-monophosphate (cAMP) responses. On the contrary, cGMP levels were increased only in GEA 3175-treated platelets. Both drug combinations reduced P-selectin exposure, platelet adhesion and fibrinogen-binding. However, adenosine together with GEA 3175 was more effective in inhibiting platelet aggregation and ATP release. Thrombin-induced rises in cytosolic Ca2+ were suppressed by the two drug combinations. Adenosine administered with GEA 3175 was, however, more effective in reducing Ca2+ influx.In conclusion, the interaction between adenosine and GEA 3175 involves cGMP-mediated inhibition of PDE3. The results also imply that inhibition of Ca2+ influx represent another cGMP-specific mechanism that enhances the effect of adenosine.
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| 3. |
- Asplund Persson, Anna, 1966-, et al.
(författare)
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Dual actions of dephostatin on the nitric oxide/cGMP-signalling pathway in porcine iliac arteries
- 2005
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 521:1-3, s. 124-132
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Tidskriftsartikel (refereegranskat)abstract
- We examined the effects of the nitrosoamine dephostatin on the nitric oxide (NO)/cyclic guanosine 3′,5′-monophosphate (cGMP)-signalling in porcine iliac arteries. Dephostatin has been characterised as a tyrosine phosphatase inhibitor, but Western blot analyses showed that dephostatin did not augment tyrosine phosphorylation of arterial proteins. However, dephostatin relaxed pre-contracted arteries, and this effect was antagonised by the soluble guanylyl cyclase inhibitor 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Furthermore, dephostatin increased the cGMP content and the serine phosphorylation of vasodilator-stimulated phosphoprotein. Dephostatin also inhibited the relaxation induced by acetylcholine and the NO-donor S-nitroso-N-acetyl-penicillamine (SNAP). In contrast, dephostatin did not affect the NO-dependent actions of 1,2,3,4-Oxatriazolium, 3-(3-chloro-2-metylphenyl)-5-[[(4methylphenyl)sulfonyl]amino]-hydroxide inner salt (GEA 3175). Measurement of NO revealed that dephostatin accelerated the consumption of NO. In conclusion, dephostatin exerts dual effects on the NO/cGMP-signalling pathway in iliac arteries. The drug actions included scavenging of NO, but also stimulation of cGMP production. These effects were not related to inhibition of tyrosine phosphatases.
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| 4. |
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| 5. |
- Befekadu, Rahel, 1968-, et al.
(författare)
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Dynamic Changes in Pentraxin-3 and Neprilysin in ST Segment Elevation Myocardial Infarction
- 2022
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- Pentraxin-3 (PTX3) and neprilysin have been associated with increased morbidity and mortality in chronic inflammatory disease and heart failure, but these biomarkers have been studied less in patients with ST segment elevation myocardial infarction (STEMI). We investigated the dynamic changes in these biomarkers, as well as the well-known C-reactive protein (CRP), in STEMI patients. PTX3, neprilysin and CRP were measured in samples from 165 STEMI patients, collected at the acute stage, 1-3 days after and 3 months after percutaneous coronary intervention (PCI), and from 40 healthy donors. Patient survival was followed for approximately 8 years after the PCI. As compared with samples from healthy donors, plasma levels of CRP and PTX3 were significantly increased in the acute samples and 1-3 days after PCI, but not at 3 months. CRP levels peaked at 1-3 days, while PTX3 was similarly high in both acute and 1-3 days samples. For neprilysin, no significant differences were observed at the group level. We found no significant differences when comparing patients with patent versus occluded culprit vessels or between patients having a thrombus aspiration or not. However, we found a significant reduction in survival for individuals with PTX3 above the median, both for samples collected at the acute stage and 1-3 days after PCI (p = 0.0001 and p = 0.0008, respectively). For CRP, no significant differences were observed using this approach, but patients above the reference range for healthy donors in the acute samples showed significantly lower survival (p = 0.0476). Conclusions: Survival analysis suggests that PTX3 might be a promising marker to predict mortality in this patient population.
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| 6. |
- Befekadu, Rahel, 1968-, et al.
(författare)
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Increased plasma cathepsin S and trombospondin-1 in patients with acute ST-segment elevation myocardial infarction
- 2019
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Ingår i: Cardiology Journal. - : Via Medica. - 1897-5593 .- 1898-018X. ; 26:4, s. 385-393
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Tidskriftsartikel (refereegranskat)abstract
- Background: The role of cathepsins in the pathological progression of atherosclerotic lesions in ischemic heart disease have been defined in detail more than numerous times. This investigation examined the platelet-specific biomarker trombospondin-1 (TSP-1) and platelet function ex vivo, and compared this with cathepsin S (Cat-S; a biomarker unrelated to platelet activation but also associated this with increased mortality risk) in patients with ST-segment elevation myocardial infarction (STEMI).Methods: The STEMI patients were divided into two groups depending on the degree of coronary vessel occlusion: those with closed (n = 90) and open culprit vessel (n = 40). Cat-S and TSP-1 were analyzed before, 1-3 days after and 3 months after percutanous coronary intervention (PCI).Results: During acute STEMI, plasma TSP-1 was significantly elevated in patients with closed culprit lesions, but rapidly declined after PCI. In fact, TSP-1 after PCI was significantly lower inpatient samples compared to healthy individuals. In comparison, plasma Cat-S was significantly elevated both before and after PCI. In patients with closed culprit lesions, Cat-S was significantly higher compared to patients with open culprit lesions 3 months after PCI. Although troponin-I were higher (p < 0.01) in patients with closed culprit lesion, there was no correlation with Cat-S and TSP-1.Conclusions: Cat-S but not TSP-1 may be a useful risk biomarker in relation to the severity of STEMI. However, the causality of Cat-S as a predictor for long-term mortality in STEMI remains to be ascertained in future studies.
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| 7. |
- Befekadu, Rahel, 1968-, et al.
(författare)
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Levels of soluble tumor necrosis factor receptor 1 and 2 are associated with survival after ST segment elevation myocardial infarction
- 2022
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- The soluble tumor necrosis factor receptors (sTNFR1 and sTNFR2) are suggested to play dual roles on physiological and pathophysiological actions of TNF-α. The aim of this study was to investigate the dynamic changes of these biomarkers in patients with ST-segment elevation myocardial infarction (STEMI). Blood was collected from 165 STEMI patients at admission, 1-3 days and 3 months after percutaneous coronary intervention (PCI) and from 40 healthy blood donors. sTNFR1 and sTNFR2 were measured with ELISA. The plasma levels of both sTNFR1 and sTNFR2 were significantly higher than in healthy donors at all three time points. We found no significant differences in sTNFR1 or sTNFR2 when comparing patients with patent versus occluded culprit vessels, or between patients having a thrombus aspiration or not. Survival analysis was performed comparing patients with levels of biomarkers above and below the median values at that time point. We found significant differences in survival for sTNFR2 in acute samples (p = 0.0151) and for both sTNFR1 and sTNFR2 in samples 1-3 days after PCI (p = 0.0054 and p = 0.0003, respectively). Survival analyses suggest that sTNFR1 or sTNFR2 could be promising markers to predict mortality in STEMI patients after PCI.
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| 8. |
- Befekadu Wodajo, Rahel, 1968-
(författare)
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Analysis of new biomarkers and their kinetics in connection with ST-elevation myocardial infarction and percutaneous coronary intervention
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis studies different biomarkers in a cohort of patients suffering from ST-elevation myocardial infarction (STEMI) who underwent Percutaneous coronary intervention (PCI) in Örebro in 2011-2012. Blood samples were collected at three time points, at the arrival at the hospital, 1-3 days after PCI and for a smaller group of patients also 3 months after PCI. The study is a sub-study of the TASTE study, so half of the patients were also randomized to thrombus aspiration in conjunction with their PCI. For all patients, it was also recorded whether the culprit coronary vessel was totally occluded or partially patent. In total, there are samples from 165 patients, but not all markers have been measured in all patients, and 3-month samples are only available from those who had their follow-up in Örebro. The plasma levels of the biomarkers have also been measured in plasma from blood donors for comparison. In March 2019, a follow-up was made of the patients' survival, and the time of death was noted in cases where this had occurred.The markers studied are the lysosome protein Cathepsin S (Cat-S), the platelet granule protein thrombospondin 1 (TSP-1), the pentraxins C-reactive protein (CRP) and pentraxin 3 (PTX3), the endopeptidase neprilysin, the soluble forms of TNF-receptor 1 and 2 (sTNFR1 and sTNFR2), markers showing activation of the lectin pathway for complement activation (MASP-1/AT, MASP-1/C1-INH, MASP-2/C1-INH, MASP-2/AT) and common activation markers for complement activation (C3a and sC5b-9).In summary, the thesis shows that the plasma levels of all markers, except neprilysin and sC5b-9, are elevated at the time of arrival compared to healthy blood donors. Neprilysin is at the same level, and sC5b-9 is lower compared to blood donors. 1-3 days after PCI, the levels for CRP, sTNFR1 and sC5b-9 have risen strongly (>50%) compared to the levels at arrival. MASP-1/AT and MASP-2/AT have fallen moderately (about 50%), Cat-S and TSP-1 have decreased strongly, while the remaining markers are relatively similar to the levels at arrival (± 25%). The levels for CRP, PTX3, sTNFR1, sTNFR2 and neprilysin decreased even further between 1-3 days and 3 months, sC5b-9 rises slightly while the other markers remain at roughly the same levels. At 3 months, most markers still show higher levels compared to corresponding levels in blood donors, only MASP-2/C1-INH has the same level, while neprilysin is slightly lower and TSP-1 much lower compared to blood donors (the latter presumably an effect of ongoing medication with platelet inhibitors in the patients). No relevant differences were observed between patients with and without thrombus aspiration, and few differences were seen between patients with occluded or partially patent vessels. This may indicate that these factors were of minor importance for the levels of the analyzed markers. In contrast, analysis of survival showed that individuals with plasma levels above the median value for PTX3, sTNFR1 and sTNFR2 at admission and/or at 1-3 days had a significantly increased mortality compared to those with levels below the median value, which indicates that these markers could be interesting for further studies in a material where also analysis of possible interfering factors can be implemented.
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| 9. |
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| 10. |
- Berg, Anna, 1975-, et al.
(författare)
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Nitric oxide inhibits gastric acid secretion by increasing intraparietal cell levels of cGMP in isolated human gastric glands
- 2005
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Ingår i: American Journal of Physiology - Gastrointestinal and Liver Physiology. - : American Physiological Society. - 0193-1857 .- 1522-1547. ; 289:6, s. G1061-G1066
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Tidskriftsartikel (refereegranskat)abstract
- We have previously identified cells containing the enzyme nitric oxide (NO) synthase (NOS) in the human gastric mucosa. Moreover, we have demonstrated that endogenous and exogenous NO has been shown to decrease histamine-stimulated acid secretion in isolated human gastric glands. The present investigation aimed to further determine whether this action of NO was mediated by the activation of guanylyl cyclase (GC) and subsequent production of cGMP. Isolated gastric glands were obtained after enzymatic digestion of biopsies taken from the oxyntic mucosa of healthy volunteers. Acid secretion was assessed by measuring [14C]aminopyrine accumulation, and the concentration of cGMP was determined by radioimmunoassay. In addition, immunohistochemistry was used to examine the localization of cGMP in mucosal preparations after stimulation with the NO donor S-nitroso-N-acetylpenicillamine (SNAP). SNAP (0.1 mM) was shown to decrease acid secretion stimulated by histamine (50 μM); this effect was accompanied by an increase in cGMP production, which was histologically localized to parietal cells. The membrane-permeable cGMP analog dibuturyl-cGMP (db-cGMP; 0.1–1 mM) dose dependently inhibited acid secretion. Additionally, the effect of SNAP was prevented by preincubating the glands with the GC inhibitor 4H-8-bromo-1,2,4-oxadiazolo[3,4-d]benz[b][1,4]oxazin-1-one (10 μM). We therefore suggest that NO in the human gastric mucosa is of physiological importance in regulating acid secretion. Furthermore, the results show that NO-induced inhibition of gastric acid secretion is a cGMP-dependent mechanism in the parietal cell involving the activation of GC.
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