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| 2. |
- Jacobsson, Leif S., et al.
(författare)
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Antiatherosclerotic Effects of the Angiotensin-Converting Enzyme Inhibitors Captopril and Fosinopril in Hypercholesterolemic Minipigs
- 1994
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Ingår i: Journal of Cardiovascular Pharmacology. - 0160-2446 .- 1533-4023. ; 24:4, s. 670-677
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the two angiotensin-converting enzyme (ACE) inhibitors captopril and fosinopril with regard to possible antiatherosclerotic effects in minipigs. Experimental hypercholesterolemia and atherosclerosis was produced in 33 minipigs of the Gottingen strain by an egg yolk/cholesterol-enriched diet for 1 year. One group (n = 11) was fed the atherogenic diet alone and served as a control. A second group (n = 11) received captopril (80 mg/kg/day) added to the atherogenic diet, and a third group (n = 11) was treated in the same manner but with fosinopril (8 mg/kglday). The drug treatments produced significant reduction in serum ACE activity associated with a reactive increase in plasma renin activity (PRA), but had only minor effects on plasma lipids and lipoproteins. At the end of the treatment period, all animals were killed and examined for degree of atherosclerosis. The percentage of atherosclerotic area in the abdominal aorta was significantly lower in both drug-treated groups as compared with controls. Furthermore, accumulation of cholesterol in the thoracic and abdominal aorta was inhibited by drug treatment. Finally, the percentage of intimal thickening in abdominal aorta was significantly reduced in the drug-treated groups. In conclusion, the ACE inhibitors captopril and fosinopril inhibited development of atherosclerosis in hypercholesterolemic minipigs.
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| 4. |
- Brouns, Stan J. J., et al.
(författare)
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Identification of the missing links in prokaryotic pentose oxidation pathways : evidence for enzyme recruitment
- 2006
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 281:37, s. 27378-27388
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Tidskriftsartikel (refereegranskat)abstract
- The pentose metabolism of Archaea is largely unknown. Here, we have employed an integrated genomics approach including DNA microarray and proteomics analyses to elucidate the catabolic pathway for D-arabinose in Sulfolobus solfataricus. During growth on this sugar, a small set of genes appeared to be differentially expressed compared with growth on D-glucose. These genes were heterologously overexpressed in Escherichia coli, and the recombinant proteins were purified and biochemically studied. This showed that D-arabinose is oxidized to 2-oxoglutarate by the consecutive action of a number of previously uncharacterized enzymes, including a D-arabinose dehydrogenase, a D-arabinonate dehydratase, a novel 2-keto-3-deoxy-D-arabinonate dehydratase, and a 2,5-dioxopentanoate dehydrogenase. Promoter analysis of these genes revealed a palindromic sequence upstream of the TATA box, which is likely to be involved in their concerted transcriptional control. Integration of the obtained biochemical data with genomic context analysis strongly suggests the occurrence of pentose oxidation pathways in both Archaea and Bacteria, and predicts the involvement of additional enzyme components. Moreover, it revealed striking genetic similarities between the catabolic pathways for pentoses, hexaric acids, and hydroxyproline degradation, which support the theory of metabolic pathway genesis by enzyme recruitment.
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| 5. |
- Johansson, Fredrik, et al.
(författare)
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Direct and amplifying effects of the ß-adrenoceptor antagonist propranolol on guinea pig airway contractility in vitro
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In the present study we establish that the ß-AA antagonist propranolol can, besides its ß-AR blocking effect, either amplify or direct induce a contraction in guinea pig airway preparations, in vitro.Propranolol significantly enhanced the contractile response to ovalbumin (OA). The enhancement was reduced by capsaicin but insensitive to indomethacin pretreatment. These results suggest that propranolol produce airway hyperreactivity to OA by activating a pathway involving tachykinins and that COX-products are of minor significance.We also confirm that propranolol can induce a tracheal smooth muscle contraction directly, although pre-treatment with carbachol/formoterol is a prerequisite. Direct contractile responses were completely diminished by indomethacin and reduced by capsaicin and L-659,877 (a NK2-receptor antagonist) pre-treatment. The present study shows that propranolol also enhances NANC (excitatory non-adrenergic noncholinergic) contractions but this enhancement requires pre-treatment with a 13-agonist. When the pre-treatment was excluded propranolol failed to exert either a direct or an amplifying effect on EFS (electrical field stimulation). These results contrast to the recorded enhancement of the OA-induced response, which did not request any pre-treatment.In addition, propranolol induced an elevation of [Ca2+], in ASMC (airway smooth muscle cells), this effect was not dependent on any pre-treatment and inhibited by indomethacin treatment.The mechanism behind these adverse effects of propranolol is not known, but our results demonstrate that contractile mediators do not originate from the airway epithelium. Since, epithelium removal did not reduce the contractile response. Furthermore, pertussis toxin (PTX) treatment did not effect the propranolol-induced contraction, indicating that a PTX sensitive G-protein coupling pathway not is involved.In conclusion our results show that both indomethacin and capsaicin sensitive pathways are involved in the contractile response to propranolol. The relative significance of these systems differs; the direct contractile effect is strongly dependent on an indomethacin sensitive pathway, while the amplifying effect is sensitive to capsaicin and insensitive to indomethacin pre-treatment.Further studies are required to elucidate the clinical relevance of these results.
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| 7. |
- Laskar, Amit, et al.
(författare)
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Fodipir (Dp-dp) and its dephosphorylated derivative PLED are involved in mangafodipir mediated cyto-protection against 7β-hydroxycholesterol induced cell death
- 2013
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Mangafodipir exerts pharmacological effects, including vascular relaxation and protection against oxidative stress and cell death induced by oxysterols. Additionally, mangafodipir has been proposed for cardiovascular imaging. The primary metabolite of mangafodipir, manganese dipyridoxyl ethyldiamine (MnPLED) and its constituent, dipyridoxyl diphosphate (Dp-dp) also known as fodipir, are pharmacologically active. However, whether they affect oxysterol induced cytotoxicity is currently unknown. In this study, we examine whether the mangafodipir metabolite affects 7β-hydroxycholesterol (7βOH) induced cell death and identify the underlying mechanisms. U937 cells were pre-treated or not with mangafodipir substrate (Ms) (200 μm), MnPLED (100 μM) or Dp-dp (100 μM) for 8 hours and then exposed to 7βOH (28 μM) for 18 hours. Our results revealed that pre-treatment with MnPLED or Dp-dp protected against 7βOH induced cellular reactive oxygen species (ROS) production, apoptosis, and lysosomal membrane permeabilization (LMP). MnPLED and Dpdp in par with Ms, confer protection against 7βOH induced cytotoxicity by reducing cellular ROS and stabilization of lysosomal membrane. These results suggest that, fodipir is the active part in mangafodipir, which shows the noted effects and its activity is conserved in MnPLED. These results further confirm the cyto-protective effect of mangafodipir and justify its potential use as a cyto-protective adjuvant.
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| 8. |
- Laskar, Amit, et al.
(författare)
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Prevention of 7beta-hydroxycholesterol-induced cell death by mangafodipir is mediated through lysosomal and mitochondrial pathways
- 2010
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; :640, s. 124-128
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Tidskriftsartikel (refereegranskat)abstract
- Mangafodipir, a MRI contrast agent, has been used as a viability marker in patients with myocardial infarction and showed vascular relaxation effect. It confers myocardial protection against oxidative stress. However mechanisms underlying such protection have not yet been investigated. In this investigation we first studied whether mangafodipir inhibits apoptosis induced by 7beta-hydroxycholesterol (7betaOH), a cytotoxic cholesterol oxidation product found in atherosclerotic lesions in humans and in heart of ethanol-fed rats. We then focused on whether mangafodipir influences the production of reactive oxygen species, lysosomal and mitochondrial membrane permeabilities in the cell model. Our results revealed that pre-treatment with mangafodipir (400microM) protected against cellular reactive oxygen species production, apoptosis, and permeabilization of lysosomal and mitochondrial membranes induced by 7betaOH. In conclusion, a novel effect of mangafodipir on 7betaOH-induced apoptosis is via reduction of cellular reactive oxygen species and stabilization of lysosomal and mitochondrial membranes. This is the first report to show the additional cytoprotective effect of mangafodipir, which may suggest possible use of the drug.
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| 9. |
- Nilsson, Ulrika K., et al.
(författare)
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Lack of stereospecificity in lysophosphatidic acid enantiomerinduced calcium mobilization in human erythroleukemia cells
- 2003
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Ingår i: Lipids. - 0024-4201. ; 38:10, s. 1057-1064
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Tidskriftsartikel (refereegranskat)abstract
- Lysophosphatidic acid (LPA) is a lipid mediator that, among several other cellular responses, can stimulate cells to mobilize calcium (Ca2+). LPA is known to activate at least three different subtypes of G protein-coupled receptors. These receptors can then stimulate different kinds of G proteins. In the present study, LPA and LPA analogs were synthesized from (R)- and (S)-glycidol and used to characterize the ability to stimulate Ca2+ mobilization. The cytosolic Ca2+ concentration ([Ca2+]i) was measured in fura-2-acetoxymethylester-loaded human erythroleukemia (HEL) cells. Furthermore, a reverse transcriptase polymerase chain reaction was used to characterize LPA receptor subtypes expressed in HEL cells. The results show that HEL cells mainly express LPA1 and LPA2, although LPA3 might possibly be expressed as well. Moreover, LPA and its analogs concentration-dependently increased [Ca2+]i in HEL cells. The response involved both influx of extracellular Ca2+ and release of Ca2+ from intracellular stores. This is the first time the unnatural (S)-enantiomer of LPA, (S)-3-O-oleoyl-1-O-phosphoryl-glycerol, has been synthesized and studied according to its ability to activate cells. The results indicate that this group of receptors does not discriminate between (R)- and (S)-enantiomers of LPA and its analogs. When comparing ether analogs having different hydrocarbon chain lengths, the tetradecyl analog (14 carbons) was found to be the most effective in increasing [Ca2+]i. Pertussis toxin treatment of the HEL cells resulted in an even more efficient Ca2+ mobilization stimulated by LPA and its analogs. Furthermore, at repeated incubation with the same ligand no further increase in [Ca2+]i was obtained. When combining LPA with the ether analogs no suppression of the new Ca2+ signal occurred. All these findings may be of significance in the process of searching for specific agonists and antagonists of the LPA receptor subtypes.
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| 10. |
- Persson, Ingrid A L, et al.
(författare)
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Effects of cocoa extract and dark chocolate on angiotensin-converting enzyme and nitric oxide in human endothelial cells and healthy volunteers--a nutrigenomics perspective.
- 2011
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Ingår i: Journal of Cardiovascular Pharmacology. - 0160-2446 .- 1533-4023. ; 57:1, s. 44-50
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Tidskriftsartikel (refereegranskat)abstract
- Evidence suggests that cocoa from the bean of Theobroma cacao L. has beneficial effects on cardiovascular disease. The aim of this study was to investigate if cocoa extract and dark chocolate influence angiotensin-converting enzyme (ACE) and nitric oxide (NO) in human endothelial cells (in vitro) and in healthy volunteers (in vivo). ACE activity was analyzed with a commercial radioenzymatic assay and measured in human endothelial cells from umbilical veins (HUVEC) after 10 minutes of incubation with cocoa extract. NO was measured after 24 hours of incubation. ACE activity and NO were measured at baseline and after 30, 60, and 180 minutes in 16 healthy volunteers after a single intake of 75 g of dark chocolate containing 72% cocoa. Significant inhibition of ACE activity (P < 0.01) and significant increase of NO (P < 0.001) were seen in HUVEC. In the study subjects, a significant inhibition of ACE activity (mean 18%) 3 hours after intake of dark chocolate was seen, but no significant change in NO was seen. According to ACE genotype, significant inhibition of ACE activity was seen after 3 hours in individuals with genotype insertion/insertion and deletion/deletion (mean 21% and 28%, respectively). Data suggest that intake of dark chocolate containing high amount of cocoa inhibits ACE activity in vitro and in vivo.
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