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  • 101.
    Nilsson, Siv
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Drecoll, E
    Lütjen-Drecoll, E
    Toris, C
    Krauss, A
    Kharlamb, A
    Nieves, A
    Guerra, T
    Woodward, D
    The prostanoid EP2 receptor agonist butaprost increases uveoscleral outflow in the cynomolgus monkey2006Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 47, nr 9, s. 4042-4049Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE. To investigate the ocular hypotensive effect of the prostanoid EP2 receptor agonist butaprost and to establish its mechanism of action. METHODS. All experiments were performed in cynomolgus monkeys after topical application of butaprost (0.1%). The effects of butaprost on aqueous humor flow were determined by fluorophotometry. Total outflow facility was measured by the two-level, constant-pressure perfusion method, and uveoscleral outflow was determined by perfusion of FITC-labeled dextran through the anterior chamber. Effects on ocular morphology were studied after tissue fixation with transcardial perfusion by paraformaldehyde and immersion fixation of the globe, in animals subjected to long-term treatment with butaprost. Conscious ocular normotensive monkeys and monkeys with unilateral ocular hypertension were used for intraocular pressure (IOP) studies. RESULTS. Butaprost had no significant effect on aqueous humor flow or total outflow facility in ocular normotensive monkeys. Uveoscleral outflow was significantly higher in the butaprost treated eyes than in vehicle treated eyes, 1.03 ± 0.20 vs. 0.53 ± 0.18 μL · min-1. After a 1-year treatment with butaprost, the morphology of the ciliary muscle was changed, showing increased spaces between ciliary muscle bundles and the apparent formation of new outflow channels. In many instances, changes were observed in the trabecular meshwork as well. Butaprost, in a single 0.1% dose, decreased IOP significantly in ocular normotensive monkeys and reduced IOP in laser-induced glaucomatous monkey eyes to the same level as that in the ocular normotensive contralateral eyes. CONCLUSIONS. The prostanoid EP2 receptor agonist butaprost appears to lower IOP by increasing uveoscleral outflow, according to both physiological and morphologic findings. Although the prostanoid EP2 receptor is structurally and functionally distinct from the FP receptor, the effects of EP2 and FP receptor stimulation on aqueous humor outflow are similar. Copyright © Association for Research in Vision and Ophthalmology.

  • 102.
    Nilsson, Siv
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Geng, Lijung
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Persson, Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Angiotensin (1-7) inhibits DNA synthesis in vascular smooth muscle cells (VSMC) from porcine ciliary arteries2005Ingår i: Invest Ophtalmology Vis Sci IOVS, ARVO Association for Resarch in Vision and Ophtalmology,2005, 2005Konferensbidrag (Övrigt vetenskapligt)
  • 103.
    Nyhlén, Kristina
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Leukocyte sequestration associated with inflammation: mechanisms and modulations2003Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [sv]

    Inflammationsreaktionen är kroppens första försvar mot främmande partiklar t ex bakterier. Det är en komplex reaktion som bl a karakteriseras av att vita blodkroppar dras till det inflammerade området och att vätskao i blodet lättare tar sig igenom kärlväggen till vävnaden dvs det svullnar. Neutrafiler är en vit blodkropp, som samlas vid inflammationer och oskadliggör fi·ämmaode partiklar genom att fagocytera ("äta upp") dem, släppa ut giftiga ämnen och bilda fria syreradikaler. För att komma från blodet till den inflaonnerade vävnaden fastnar neutrofilema på kapillärväggen och tar sig sen igenom väggen. Vid inflammatoriska sjukdomar t ex reumatism ansamlas också neutrofiler, men angriper då istället kroppens egen vävnad. Vissa kliniska behaodlingar orsakar också att neutrafiler ansamlas t ex i lungorna vid hemodialys, men det är oklart om de har någon skadaode effekt på lungvävnaden. Det är däremot känt att en del hemodialyspatienter efter flera års behaodliog har problem med lungorna. Att förstå och blockera mekanismerna för ansamling av neutrafiler har därför stor betydelse vid många sjukdomar.

    I delarbete l studerades vilken effekt ansamlade neutrafiler har på lungvävnaden och lungfunktionen och för detta ändarnål utvecklades en variant av en försöksuppställning med en marsvinslunga upphängd i ett glaskärl. Lungan "andades", cirkulerades med blod och flera parametrar registrerades hela tiden. Modellen visade sig vara stabil med lungor som bl a var mindre vätskefyllda än i tidigare studier och hade ett högt syreinnehåll trots "andning" med rumsluft. För att påvisa systemets känslighet, tillfördes två substanser med känd effekt på kärlväggarna, histamin och oljesyra. Lungorna som fick oljesyra eller histamin reagerade som väntat med ökat kärhnotstånd, ökad genomsläpplighet för vätska genom kärlväggen samt ökat neutroftlinnehåll i lungan, vilket bevisade att lungmodellen var en pålitlig och känslig metod.

    I delarbete 2 simulerades en dialysbehaodliog med dialysmembraoet Cuprophan i lungmodellen, för att studera vad som händer i lungan när neutrafiler ansamlas. Hos hemodlalys-patienter fastnar flertalet av alla cirkulerande neutrafiler ca 15 min efter dialysstart och lossnar sedan efterhand under behandlingen. I lungmodellen visade det sig dock att utao dialysmembran fastnade ca 70 % av det totala antalet cirkulerande neutrafiler i lungan och var kvar under de två timmar långa försöken. För att kunna studera om lungvävnaden och andningen förändrades när neutrafilerna fastnade i lungao, järnfördes därför lungor med cirkolation av blod utao vita blodkroppar med lungor med cirkulation av normalt blod. Resultaten tydde på att neutrafiler kao fastna vid kapillärväggama i lungao utan att påverka genomsläppligheten för vätska eller bildaodet av fiia syreradikaler. Neutrafilerna fastnade aotagligen inte via de molekyler som nmmalt langar upp cirkulerande neutrafiler vid inflammationer. Dialysmembranet lyckades inte heller mätbart aktivera neutrofilema, men trots det har en del hernodialyspatienter som fått dialys länge vätskeansamling i lungorna.

    Förflyttningen av neutrafiler mot en inflammation startar bl a av att ämnena TNF-α och IL-1ß utsöndrade från inflammationsområdet stimulerar kapillärväggens celler, endotelcellema. I endatelcellerna aktiveras då faktorn NF-κB och celleroa börjar producera olika änmen för att locka till sig cirkulerande neutrafiler bl a släpper de ut ämnet IL-8 och molekylerna selekliner bildas på deras yta. IL-8 är specialiserad på att dra till sig neutrofiler och t ex patienter med inflammatoriska sjukdomar och autoimmuna sjukdomar typ reumatism har forhöjda halter av IL-8. De cirkulerande neutroftlerna hromsas av molekylerna selekliner på endotelcellemas yta och binder löst till dem via kolhydratstrukturer på sin egen yta. Denna bindning leder i sin tur till att IL-8 kan binda till sin receptor på neutrofilerna. Nu ökar molekylerna ß2-integriner på neutrofilemas yta och dessa binder hårt till en annan molekyl på endotelcellema.

    I delarbete 3 undersöktes om ämnena interferoner och glukokortikosteroider kunde hämma IL-8 utsläppet från endotelceller. Glukokortikosteroider är mycket använda som läkemedel mot inflammationer och deras anti-inflammatoriska effekt fungerar antagligen via NF-κB. Interferon er är ett ämne i kroppen, som har en invecklad roll vid inflammationer men som också används vid behandling av flera sjukdomar. Humana endotelceller frän navelsträngsvener (HUVEC) stimulerades med IL-1ß eller TNF-α för att simulera en inflammationsreaktion. Både stimulering med IL-1ß och TNF-α resulterade i en enorm ökning av utsläppt IL-8. Vid stimuleringen tillsattes också tre olika interferoner och två glukokortikosteroider. Alla interferoner och steroider hännnade utsläppet av IL-8 i forhållande till dosen. Med immunoflourescence fotograferades också hur IL-8 molekylerna var placerade inuti cellen. Resultatet tydde på att det mesta av bildat IL-8 släpps ut direkt och ej lagras i cellen.

    I delarbete 4 undersöktes om interferoner och glukokortikosteroider också hännnade bildandet av IL-8 genom att mäta mängden IL-8 inuti HUVEC med teknikerna ELISA och flödescytometri. För att kunna mäta den totala bildningen av IL-8 blockerades utsläppet med ämnet monensin. Förutom mätning av färdiga IL-8 molekyler undersöktes också med metoden RT-PCR om genen för IL-8 aktiverats. Både interferoner och glukokortikosteroider visade sig vara effektiva hämmare av IL-8 produktionen som var igångsatt av TNF-α. Interferon hämmade dessutom den lilla mängd IL-8 som bildades i ostimulerade endotelceller, vilket antydde att det finns flera sätt att stimulera produktionen än via NF-κB.

    Sammanfattningsvis kan sägas att detta arbete visat att vita blodkroppar under vissa forhållande kan ansamlas vid kapillärväggen i lungan, utan att vara så mycket aktiverade att de påverkar kärlväggen. Om neutrafilerna däremot är aktiverade och fastnar via inblandning av IL-8 sknlle glukokortikosteroider och interferoner eventuellt kunna vara möjliga att använda som medicin för att motverka oönskade inflammationsreaktioner.

    Delarbeten
    1. An isolated blood-perfused guinea-pig lung model for simultaneous registration of haemodynamic, microvascular and respiratory variables
    Öppna denna publikation i ny flik eller fönster >>An isolated blood-perfused guinea-pig lung model for simultaneous registration of haemodynamic, microvascular and respiratory variables
    1997 (Engelska)Ingår i: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 159, nr 4, s. 293-302Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    We have developed an optimized isolated lung perfusion system, which possesses several advantages. Firstly, studies of microvascular, respiratory, haematological and biochemical variables are combined in one model. Secondly, blood perfusion resulted in less oedema formation than buffer-perfused lungs, and high Po2 through ventilation with room air. Finally, data for the variables can be displayed, controlled and recorded in real time using a computerized system permitting subsequent processing (e.g. filtering without destroying original data). In this paper we discuss the basic behaviour of the model in terms of vascular resistance, vascular permeability, respiration and neutrophil sequestration. In addition, the effects of oleic acid, histamine and histamine receptor blockers were tested, and two methods of calculating vascular permeability are discussed. The way in which different anaesthetics affect the neutrophil content of lung tissue and blood was also investigated. In the model, oleic acid increased pulmonary vascular resistance and permeability, whereas histamine did not affect either permeability or the pre/postcapillary vascular resistance ratio. However, histamine receptor blockers increased this ratio, indicating that there was endogenous histamine release. The neutrophil content of the isolated lungs was increased, but this did not affect the variables measured. There was also accumulation of neutrophils in the lungs of blood donor animals, due to CO2 sedation. However, CO2 sedation proved to be superior to pentobarbital or ketamine anaesthesia in maintaining the levels of neutrophils circulating in the blood. In conclusion, this model seems to be sensitive and to yield reproducible results regarding the physiology or pathophysiology of the lung.

    Nyckelord
    anaesthesia; capillary permeability; histamine; histamine receptor blockers; MPO; oleic acid; pulmonary resistance
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-81852 (URN)10.1046/j.1365-201X.1997.00103.x (DOI)
    Tillgänglig från: 2012-09-24 Skapad: 2012-09-24 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
    2. Leukocyte sequestration in isolated guinea pig lungs during extracorporeal circulation: effects on microvascular function
    Öppna denna publikation i ny flik eller fönster >>Leukocyte sequestration in isolated guinea pig lungs during extracorporeal circulation: effects on microvascular function
    2000 (Engelska)Ingår i: Blood Purification, ISSN 0253-5068, E-ISSN 1421-9735, Vol. 18, nr 2, s. 121-127Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Neutrophils accumulate in patient lungs during clinical hemodialysis and in isolated blood-perfused guinea pig lungs due to the contact between blood and extracorporeal system. However, it is unclear how these sequestered and partly activated neutrophils affect the lung microvasculature. We, therefore, studied pulmonary vascular resistance, vascular permeability, gas exchange, and oxygen free radical production in isolated guinea pig lungs during perfusion with whole blood containing partly ‘activated’ neutrophils in comparison with perfusions using leukopenic blood. We also connected a Cuprophan hemodialysis membrane to the whole-blood perfusion system in order to investigate whether a dialyzer, which may further activate leukocytes, affects lung microvascular permeability, vascular resistances, and reactive oxygen species production. The sequestered neutrophils did not seem to markedly affect the lung microvascular function, since neither the leukocyte-free perfusion nor the hemodialysis membrane altered any of the measured variables as compared with whole-blood perfusion in a system without a dialyzer. We conclude that neutrophils, whether activated by a perfusion system or by a dialysis membrane, can accumulate in isolated lungs without adversely affecting the microvascular function.

    Nyckelord
    oxygen free radicals, isolated lung, capillary permeability, hemodialysis
    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-49687 (URN)10.1159/000014435 (DOI)10838471 (PubMedID)
    Tillgänglig från: 2009-10-11 Skapad: 2009-10-11 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
    3. Corticosteroids and interferons inhibit cytokine-induced production of IL-8 by human endothelial cells
    Öppna denna publikation i ny flik eller fönster >>Corticosteroids and interferons inhibit cytokine-induced production of IL-8 by human endothelial cells
    2000 (Engelska)Ingår i: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 12, nr 4, s. 355-360Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    IL-8, secreted by endothelial cells at the site of inflammation, participates in recruitment and transmigration of leukocytes. IL-8 may also have pathophysiological consequences in inflammatory and immunological disorders. We have investigated the effect of interferons (IFNs) and glucocorticosteroids (GCs) on cytokine induced secretion and production of IL-8 by human umbilical endothelial cells (HUVEC). There was a low spontaneous secretion of IL-8 by unstimulated HUVEC which increased after 6 or 24 h of stimulation with the pro-inflammatory cytokines TNF-α or IL-1β. IFN-γ as well as the GCs, Dexamethasone and Budesonide, inhibited TNF-α induced IL-8 secretion in a dose-dependent manner. IFNs may have a general modulating effect, since IFN-α also inhibited the TNF-α-induced IL-8 secretion. There was a slight, but significant, increase in the content of intracellular IL-8 in stimulated HUVEC. However, there was no difference between stimulation with IL-1β or TNF-α alone or in combination with IFNs or GCs, whereas inhibition of IL-8 secretion with monensin increased IL-8 content suggesting that IFNs and GCs inhibit synthesis rather than secretion of IL-8. In conclusion, IFNs or GCs may be useful for inhibiting IL-8 production by endothelial cells and could thus be used for therapeutic modulation of the inflammatory response.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-47672 (URN)10.1006/cyto.1999.0557 (DOI)
    Tillgänglig från: 2009-10-11 Skapad: 2009-10-11 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    4. Modulation of Cytokine-Induced Production of IL-8 in Vitro by Interferons and Glucocorticosteroids
    Öppna denna publikation i ny flik eller fönster >>Modulation of Cytokine-Induced Production of IL-8 in Vitro by Interferons and Glucocorticosteroids
    2004 (Engelska)Ingår i: Inflammation, ISSN 0360-3997, E-ISSN 1573-2576, Vol. 28, nr 2, s. 77-88Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Interleukin-8 (IL-8) has been implicated in the pathogenesis of inflammation and cancer. Intracellular levels of cytokine-induced IL-8 in human umbilical vein endothelial cells (HUVEC) were modulated using interferons and steroids to further elucidate their mechanism. Basal and cytokine-induced production of IL-8 was studied using a novel ELISA application, flow cytometry, and RT-PCR. The intracellular amount of IL-8 increased after 6-h stimulation with TNF- (30%) or IL-1ß (55%) which was doubled when Golgi transport was disrupted using monensin. IFN-γ decreased the intracellular amount of IL-8 by 60% in both unstimulated and TNF--stimulated cells, but only when secretion was blocked using monensin. Dexamethasone inhibited the TNF--induced production by 33%, but had no effect in unstimulated cells. Our study indicated that both, dexamethasone and IFN inhibit TNF--induced upregulation of IL-8 at the mRNA level. It could be speculated that they inhibit IL-8 production by affecting different gene regulatory mechanisms.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-24058 (URN)10.1023/B:IFLA.0000033023.76110.51 (DOI)3617 (Lokalt ID)3617 (Arkivnummer)3617 (OAI)
    Tillgänglig från: 2009-10-07 Skapad: 2009-10-07 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
  • 104.
    Nyhlén, Kristina
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Gautam, Chamilly
    Hospital Pharmacy, University Hospital, Linköping, Sweden.
    Andersson, Rolf
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Uppugunduri, Srinivas
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Modulation of Cytokine-Induced Production of IL-8 in Vitro by Interferons and Glucocorticosteroids2004Ingår i: Inflammation, ISSN 0360-3997, E-ISSN 1573-2576, Vol. 28, nr 2, s. 77-88Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Interleukin-8 (IL-8) has been implicated in the pathogenesis of inflammation and cancer. Intracellular levels of cytokine-induced IL-8 in human umbilical vein endothelial cells (HUVEC) were modulated using interferons and steroids to further elucidate their mechanism. Basal and cytokine-induced production of IL-8 was studied using a novel ELISA application, flow cytometry, and RT-PCR. The intracellular amount of IL-8 increased after 6-h stimulation with TNF- (30%) or IL-1ß (55%) which was doubled when Golgi transport was disrupted using monensin. IFN-γ decreased the intracellular amount of IL-8 by 60% in both unstimulated and TNF--stimulated cells, but only when secretion was blocked using monensin. Dexamethasone inhibited the TNF--induced production by 33%, but had no effect in unstimulated cells. Our study indicated that both, dexamethasone and IFN inhibit TNF--induced upregulation of IL-8 at the mRNA level. It could be speculated that they inhibit IL-8 production by affecting different gene regulatory mechanisms.

  • 105.
    Nyhlén, Kristina
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Linden, Margareta
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Rolf
    Department of Cell & Molecular Biology, Astra Draco AB, Lund, Sweden.
    Uppugunduri, Srinivas
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Corticosteroids and interferons inhibit cytokine-induced production of IL-8 by human endothelial cells2000Ingår i: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 12, nr 4, s. 355-360Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    IL-8, secreted by endothelial cells at the site of inflammation, participates in recruitment and transmigration of leukocytes. IL-8 may also have pathophysiological consequences in inflammatory and immunological disorders. We have investigated the effect of interferons (IFNs) and glucocorticosteroids (GCs) on cytokine induced secretion and production of IL-8 by human umbilical endothelial cells (HUVEC). There was a low spontaneous secretion of IL-8 by unstimulated HUVEC which increased after 6 or 24 h of stimulation with the pro-inflammatory cytokines TNF-α or IL-1β. IFN-γ as well as the GCs, Dexamethasone and Budesonide, inhibited TNF-α induced IL-8 secretion in a dose-dependent manner. IFNs may have a general modulating effect, since IFN-α also inhibited the TNF-α-induced IL-8 secretion. There was a slight, but significant, increase in the content of intracellular IL-8 in stimulated HUVEC. However, there was no difference between stimulation with IL-1β or TNF-α alone or in combination with IFNs or GCs, whereas inhibition of IL-8 secretion with monensin increased IL-8 content suggesting that IFNs and GCs inhibit synthesis rather than secretion of IL-8. In conclusion, IFNs or GCs may be useful for inhibiting IL-8 production by endothelial cells and could thus be used for therapeutic modulation of the inflammatory response.

  • 106.
    Persson, Ingrid
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Dong, Linda
    Persson, Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Effect of Panax ginseng extract (G115) on angiotensin-converting enzyme (ACE) activity and nitric oxide (NO) production2006Ingår i: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 105, nr 3, s. 321-325Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study investigates the effects of the Panax ginseng (Araliaceae) extract G115 on angiotensin-converting enzyme (ACE) activity and nitric oxide (NO) in cultured human endothelial cells from umbilical veins (HUVEC) and bovine mesenteric arteries (BMA). In HUVEC, ACE activity was significantly reduced after 10 min incubation with aqueous extract of ginseng 5.0 and 10 mg/ml. This effect was additative with the inhibition of the traditional ACE inhibitor enalaprilat. No effect was seen on NO production from the cells. Angiotensin I-induced contraction of BMA was significantly attenuated by 0.1 and 0.5 mg/ml ginseng, while no endothelium-dependent or -independent relaxation was seen. In conclusion, extract of Panax ginseng (G115) inhibits ACE activity, but does not affect NO production in HUVEC and BMA. © 2005 Elsevier Ireland Ltd. All rights reserved.

  • 107.
    Persson, Ingrid
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Josefsson, Martin
    Linköpings universitet, Institutionen för medicin och vård. Linköpings universitet, Hälsouniversitetet.
    Persson, Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Andersson, Rolf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Tea flavanols inhibit angiotensin-converting enzyme activity and increase nitric oxide production in human endothelial cells2006Ingår i: Journal of Pharmacy and Pharmacology (JPP), ISSN 0022-3573, E-ISSN 2042-7158, Vol. 58, nr 8, s. 1139-1144Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A diversity of pharmacological effects on the cardiovascular system have been reported for Camellia sinensis: antioxidative, antiproliferative and anti-angiogenic activity, and nitric oxide synthase activation. The purpose of this study was to investigate if the connection between tea and angiotensin-converting enzyme (ACE) and nitric oxide (NO) might be an explanation of the pharmacological effects of tea on the cardiovascular system. Cultured endothelial cells from human umbilical veins (HUVEC) were incubated with extracts of Japanese Sencha (green tea), Indian Assam Broken Orange Pekoe (black tea) and Rooibos tea, respectively. The main flavanols and purine alkaloids in green and black tea were examined for their effects on ACE and NO. After incubation with green tea, black tea and Rooibos tea for 10 min, a significant and dose-dependent inhibition of ACE activity in HUVEC was seen with the green tea and the black tea. No significant effect on ACE was seen with the Rooibos tea. After 10-min incubation with (-)-epicatechin, (-)- epigallocatechin, (-)-epicatechingallate and (-)-epigallocatechingallate, a dose-dependent inhibition of ACE activity in HUVEC was seen for all four tea catechins. After 24-h incubation, a significantly increased dose-dependent effect on NO production in HUVEC was seen for the green tea, the black tea and the Rooibos tea. After 24-h incubation with (-)-epicatechin, (-)-epigallocatechin, (-)-epicatechingallate and (-)-epigallocatechingallate, a dose-dependent increased NO production in HUVEC was seen. In conclusion, tea extracts from C. sinensis may have the potential to prevent and protect against cardiovascular disease. © 2006 The Authors.

  • 108.
    Persson, Karin
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Pharmacological interactions between angiotensin-converting enzyme (ACE) inhibitors, bradykinin and nitric oxide2000Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Cardiovascular diseases are a major cause of death in Western countries. Angiotensin-converting enzyme (ACE) is as a key enzyme in the renin-angiotensin system involved in the regulation of blood pressure, and water and electrolyte balance in the body. ACE not ouly increases the conversion of angiotensin I to the active angiotensin II, but also degrades bradykinin. ACE inhibitors, like captopril, are today first-line treatment in hypertension and heart failure.

    We have shown that two structurally different ACE inhibitors, captopril and fosinopril, exhibit anti-atherosclerotic effects in hypercholesterolemic mini pigs. Captopril, but not fosinopril, improved endothelial function in the iliac arteries from the mini pigs.

    Bradykinin-induced relaxation of porcine iliac arteries was mediated by bradykinin B2 receptors and the subsequent release of nitric oxide (NO). ACE inhibitors did not affect the bradykinin-induced relaxation, implying that other enzymes than ACE (e. g. carboxypeptidase M; CPM) are involved in bradykinin degradation in these vessels. Bradykinin B, and B2 receptors on the vascular media elicited a contraction mediated by cyclooxygenase metabolite(s). Treatment with captopril potentiated bradykinin B, receptor-mediated contraction, due to CPM becoming responsible for bradykinin degradation.

    Captopril potentiated bradykinin- and inhibited angiotensin I-induced contractions only in arteries with intact NO synthesis. This implied that NO synthesis is necessary for an effective ACE inhibition. ACE activity analyses did reveal that both exogenous and endogenous NO are able to inhibit porcine and human ACE activity. It was also shown that this inhibition is additative with captopril and enalaprilat. This additative effect of NO and ACE inhibitors on ACE activity affected not only angiotensin I- and bradykinin- mediated contractions of porcine iliac arteries, but also reduced human platelet aggregation.

    In summary, ACE inhibitors show anti-atherosclerotic properties in hypercholesterolemic mini pigs. ACE inhibitor treatment of porcine iliac arteries did not affect bradykinin-induced relaxation, but instead shunted over bradykinin to other enzymes generating the bradykinin B 1 receptor agonist desArg9 -bradykinin. NO was found to be an endogenous inhibitor of ACE, acting in concert with therapeutically used ACE inhibitors to decrease vascular tone and human platelet aggregation.

    Delarbeten
    1. Antiatherosclerotic Effects of the Angiotensin-Converting Enzyme Inhibitors Captopril and Fosinopril in Hypercholesterolemic Minipigs
    Öppna denna publikation i ny flik eller fönster >>Antiatherosclerotic Effects of the Angiotensin-Converting Enzyme Inhibitors Captopril and Fosinopril in Hypercholesterolemic Minipigs
    Visa övriga...
    1994 (Engelska)Ingår i: Journal of Cardiovascular Pharmacology, ISSN 0160-2446, E-ISSN 1533-4023, Vol. 24, nr 4, s. 670-677Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    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.

    Nyckelord
    Angiotensin, converting enzyme inhibitors, Atherosclerosis, Captopril, Cholesterol, Fosinopril, lntimal thickening, Minipigs
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-79490 (URN)
    Tillgänglig från: 2012-08-06 Skapad: 2012-08-06 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
    2. Biphasic Response to Bradykinin in Isolated Porcine Iliac Arteries is Mediated by Bradykinin B1 and B2 Receptors
    Öppna denna publikation i ny flik eller fönster >>Biphasic Response to Bradykinin in Isolated Porcine Iliac Arteries is Mediated by Bradykinin B1 and B2 Receptors
    1998 (Engelska)Ingår i: Journal of Cardiovascular Pharmacology, ISSN 0160-2446, E-ISSN 1533-4023, Vol. 32, nr 2, s. 306-313Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Bradykinin-induced responses were studied in isolated porcine iliac arteries. Relaxation was endothelium dependent and seen at low concentrations (10-10-10-8 M) of bradykinin. It was inhibited by the bradykinin B2-receptor antagonist icatibant (HOE-140) and by the nitric oxide synthase inhibitor Nω-nitro-L-arginine. Bradykinin-induced relaxation was significantly potentiated by the kininase I carboxypeptidase inhibitor mergepta (10-6 M). Bradykinin (>10-7M) elicited contraction of preparations with or without endothelium. The contraction was abolished by indomethacin but was not affected by the thromboxane A2/prostaglandin H2-receptor antagonist SQ 29,548. Icatibant and the bradykinin B1-receptor antagonist desArg9[Leu8]bradykinin significantly decreased bradykinin-induced contraction regardless of endothelial function. The contraction also was decreased by treatment with mergepta. The bradykinin B1-receptor agonist desArg9-bradykinin contracted endothelium-denuded arterial strips. This contraction was significantly decreased by desArg9 [Leu8] bradykinin but not by icatibant. The desArg9-bradykinin-induced contraction also was inhibited by the protein-synthesis inhibitor cycloheximide. Neither bradykinin-induced relaxation nor contraction was affected by the ACE inhibitors enalaprilat or cilazaprilat. In conclusion, bradykinin-induced relaxation of isolated porcine iliac arteries was mediated by endothelial bradykinin B2 receptors and mainly nitric oxide. Bradykinin-induced contraction was endothelium independent, indomethacin sensitive, and probably mediated by bradykinin B1 (inducible) and B2 receptors located in the vascular smooth-muscle layer. Kininase I carboxypeptidase, and not ACE, is the main enzyme responsible for bradykinin degradation in these vessels.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-79491 (URN)
    Tillgänglig från: 2012-08-06 Skapad: 2012-08-06 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
    3. Nitric oxide modulates captopril-mediated angiotensin-converting enzyme inhibition in porcine iliac arteries
    Öppna denna publikation i ny flik eller fönster >>Nitric oxide modulates captopril-mediated angiotensin-converting enzyme inhibition in porcine iliac arteries
    1999 (Engelska)Ingår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 385, nr 1, s. 21-27Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The influence of the angiotensin-converting enzyme inhibitor captopril on bradykinin-and angiotensin I-induced responses with special regard to nitric oxide (NO) was studied. Auxometric tension and angiotensin-converting enzyme activity was studied in isolated porcine iliac arteries. Captopril potentiated bradykinin-induced contraction of preparations with intact endothelium; this potentiation was not seen with the kininase I inhibitor mergepta or a bradykinin B1-receptor antagonist. Captopril did not affect bradykinin-induced relaxation. The captopril-mediated increase of bradykinin-induced contraction was only seen in preparations with intact endothelium, while captopril did not affect arterial strips treated with Nω-nitro-L-arginine. Angiotensin I-induced contractions was less reduced by captopril when the strips were pretreated with Nω-nitro-L-arginine. Both captopril and the NO donor S-nitroso-N-acetyl-penicillamine inhibited angiotensin-converting enzyme activity. An additional reduction in angiotensin-converting enzyme activity was seen when S-nitroso-N-acetyl-penicillamine was added to captopril-treated preparations. In conclusion, captopril increased bradykinin-induced contraction in a NO-dependent manner. This potentiation is probably mediated by the increased metabolism of bradykinin by kininase I, and the additive angiotensin-converting enzyme inhibitory effect of captopril and NO.

    Ort, förlag, år, upplaga, sidor
    Elsevier, 1999
    Nyckelord
    Angiotensin-converting enzyme activity, Bradykinin, Captopril, Contraction, Nitric oxide (NO), Relaxation
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-79492 (URN)10.1016/S0014-2999(99)00689-5 (DOI)
    Tillgänglig från: 2012-08-06 Skapad: 2012-08-06 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
    4. NO donors and ACE inhibitors act in concert to inhibit human ACE activity and platelet aggregation in vitro
    Öppna denna publikation i ny flik eller fönster >>NO donors and ACE inhibitors act in concert to inhibit human ACE activity and platelet aggregation in vitro
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    This study investigates the effects of exogenous and endogenous nitric oxide (NO) on human circulating and endothelial angiotensin-converting enzyme (ACE) activity, and platelet aggregation. The NO donor S-nitroso N-acetylpenicillamine SNAP (10-8-10-6 M) significantly and dose-dependently inhibited serum ACE activity. The concomitant addition of SNAP to ACE inhibitor-treated (captopril or enalaprilat) serum, further reduced ACE activity. In cultured endothelial cells from human umbilical veins (HUVEC), both SNAP and 3-morpholinosydnonimine (SIN-1) significantly reduced ACE activity. An additative effect was seen with a combined treatment of captopril and SNAP. Treatment with the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) did not affect ACE activity. Thrombin inhibited endothelial ACE activity, an effect that was abolished when cells were pretreated with L-NMMA. ADP-induced platelet aggregation was inhibited with SNAP, SIN-1 and nitroglycerine (GTN). Captopril did not affect aggregation, while a high concentration of enalaprilat (10-4 M) reduced it. The concomitant addition of 10-5 M ACE inhibitor to NO donor-treated platelets resulted in a further reduction of platelet aggregation. This effect was most evident with SIN-I and enalaprilat. In conclusion, both exogenous and endogenous NO inhibit human ACE activity. NO donors and ACE inhibitors act in concert to inhibit ACE and platelet aggregation. 

    Nyckelord
    angiotensin-converting enzyme, ACE inhibitors, HUVEC, nitric oxide, platelet aggregation
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-79493 (URN)
    Tillgänglig från: 2012-08-06 Skapad: 2012-08-06 Senast uppdaterad: 2013-09-03Bibliografiskt granskad
  • 109.
    Persson, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Rolf G. G.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Biphasic Response to Bradykinin in Isolated Porcine Iliac Arteries is Mediated by Bradykinin B1 and B2 Receptors1998Ingår i: Journal of Cardiovascular Pharmacology, ISSN 0160-2446, E-ISSN 1533-4023, Vol. 32, nr 2, s. 306-313Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Bradykinin-induced responses were studied in isolated porcine iliac arteries. Relaxation was endothelium dependent and seen at low concentrations (10-10-10-8 M) of bradykinin. It was inhibited by the bradykinin B2-receptor antagonist icatibant (HOE-140) and by the nitric oxide synthase inhibitor Nω-nitro-L-arginine. Bradykinin-induced relaxation was significantly potentiated by the kininase I carboxypeptidase inhibitor mergepta (10-6 M). Bradykinin (>10-7M) elicited contraction of preparations with or without endothelium. The contraction was abolished by indomethacin but was not affected by the thromboxane A2/prostaglandin H2-receptor antagonist SQ 29,548. Icatibant and the bradykinin B1-receptor antagonist desArg9[Leu8]bradykinin significantly decreased bradykinin-induced contraction regardless of endothelial function. The contraction also was decreased by treatment with mergepta. The bradykinin B1-receptor agonist desArg9-bradykinin contracted endothelium-denuded arterial strips. This contraction was significantly decreased by desArg9 [Leu8] bradykinin but not by icatibant. The desArg9-bradykinin-induced contraction also was inhibited by the protein-synthesis inhibitor cycloheximide. Neither bradykinin-induced relaxation nor contraction was affected by the ACE inhibitors enalaprilat or cilazaprilat. In conclusion, bradykinin-induced relaxation of isolated porcine iliac arteries was mediated by endothelial bradykinin B2 receptors and mainly nitric oxide. Bradykinin-induced contraction was endothelium independent, indomethacin sensitive, and probably mediated by bradykinin B1 (inducible) and B2 receptors located in the vascular smooth-muscle layer. Kininase I carboxypeptidase, and not ACE, is the main enzyme responsible for bradykinin degradation in these vessels.

  • 110.
    Persson, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Rolf G. G.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Nitric oxide modulates captopril-mediated angiotensin-converting enzyme inhibition in porcine iliac arteries1999Ingår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 385, nr 1, s. 21-27Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The influence of the angiotensin-converting enzyme inhibitor captopril on bradykinin-and angiotensin I-induced responses with special regard to nitric oxide (NO) was studied. Auxometric tension and angiotensin-converting enzyme activity was studied in isolated porcine iliac arteries. Captopril potentiated bradykinin-induced contraction of preparations with intact endothelium; this potentiation was not seen with the kininase I inhibitor mergepta or a bradykinin B1-receptor antagonist. Captopril did not affect bradykinin-induced relaxation. The captopril-mediated increase of bradykinin-induced contraction was only seen in preparations with intact endothelium, while captopril did not affect arterial strips treated with Nω-nitro-L-arginine. Angiotensin I-induced contractions was less reduced by captopril when the strips were pretreated with Nω-nitro-L-arginine. Both captopril and the NO donor S-nitroso-N-acetyl-penicillamine inhibited angiotensin-converting enzyme activity. An additional reduction in angiotensin-converting enzyme activity was seen when S-nitroso-N-acetyl-penicillamine was added to captopril-treated preparations. In conclusion, captopril increased bradykinin-induced contraction in a NO-dependent manner. This potentiation is probably mediated by the increased metabolism of bradykinin by kininase I, and the additive angiotensin-converting enzyme inhibitory effect of captopril and NO.

  • 111.
    Persson, Karin
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Säfholm, A C E
    Andersson, Rolf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Ahlner, Johan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Glyceryl trinitrate-induced angiotensin-converting enzyme (ACE) inhibition in healthy volunteers is dependent on ACE genotype2005Ingår i: Canadian Journal of Physiology and Pharmacology, ISSN 0008-4212, E-ISSN 1205-7541, Vol. 83, nr 12, s. 1117-1122Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Evidence concerning the importance of angiotensin-converting enzyme (ACE) genotype in cardiovascular diseases is accumulating. The aim of this study was to investigate if nitric oxide (NO), generated from glyceryl trinitrate (GTN), affects human serum ACE activity in vivo, and if so, whether this effect was dependent on ACE genotype and (or) reflected in blood pressure reduction. A tablet containing 5 mg GTN was bucally administered for 5 minutes to 17 healthy volunteers. Blood pressure (BP) was recorded, and serum ACE activity, ACE genotype, and plasma cGMP was analyzed. GTN administration significantly reduced BP only in individuals with the deletion/deletion (DD) genotype. Sixty minutes after GTN administration, serum ACE activity was reduced in individuals with the insertion/insertion (II) and insertion/deletion (ID) genotypes, but not the DD genotype. Comparing the change in ACE activity over time between the genotypes resulted in the following: II vs. DD, p < 0.01, II vs. ID, p < 0.05, and ID vs. DD, p < 0.05. There was no significant difference in plasma cGMp content neither between the ACE genotypes nor before and after GTN administration. In conclusion, GTN inhibits serum ACE in vivo in individuals with the II and ID, but not the DD genotype. © 2005 NRC Canada.

  • 112.
    Persson, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Whiss, Per A.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Nyhlén, Kristina
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jacobsson-Strier, Monica
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Glindell, Maria
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Rolf G. G.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    NO donors and ACE inhibitors act in concert to inhibit human ACE activity and platelet aggregation in vitroManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    This study investigates the effects of exogenous and endogenous nitric oxide (NO) on human circulating and endothelial angiotensin-converting enzyme (ACE) activity, and platelet aggregation. The NO donor S-nitroso N-acetylpenicillamine SNAP (10-8-10-6 M) significantly and dose-dependently inhibited serum ACE activity. The concomitant addition of SNAP to ACE inhibitor-treated (captopril or enalaprilat) serum, further reduced ACE activity. In cultured endothelial cells from human umbilical veins (HUVEC), both SNAP and 3-morpholinosydnonimine (SIN-1) significantly reduced ACE activity. An additative effect was seen with a combined treatment of captopril and SNAP. Treatment with the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) did not affect ACE activity. Thrombin inhibited endothelial ACE activity, an effect that was abolished when cells were pretreated with L-NMMA. ADP-induced platelet aggregation was inhibited with SNAP, SIN-1 and nitroglycerine (GTN). Captopril did not affect aggregation, while a high concentration of enalaprilat (10-4 M) reduced it. The concomitant addition of 10-5 M ACE inhibitor to NO donor-treated platelets resulted in a further reduction of platelet aggregation. This effect was most evident with SIN-I and enalaprilat. In conclusion, both exogenous and endogenous NO inhibit human ACE activity. NO donors and ACE inhibitors act in concert to inhibit ACE and platelet aggregation. 

  • 113. Porter, AC
    et al.
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Stamer, WD
    Bahl, JJ
    Richman, JG
    Reagan, J
    Alpha-2adrenergic receptors stimulate actin organization in developing fetal rat cardiac myocytes2003Ingår i: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 72, s. 1455-1466Artikel i tidskrift (Refereegranskat)
  • 114.
    Powell, Wendy
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Green, Henrik
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    A new method for screening the melanin binding ability of different antineoplastic agents.2001Ingår i: Pigment cell research,2001, 2001, s. 397-397Konferensbidrag (Refereegranskat)
  • 115.
    Raak, Ragnhild
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Identification of subgroups in experimental and chronic pain: Sensory, emotional and evaluative aspects2002Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    One hundred and two healthy subjects, 32 fibromyalgia patients and 12 chronic low back pain patients were included in the study. Quantitative sensory tests were performed to identify thermal hyperalgesia in the fibromyalgia group and to compare the results with those in healthy pain-free subjects. Different questionnaires were used to map pain and stress-coping strategies /styles. (Coping Strategy Questionnaire, Jalowiec Coping Scale) and quality of life (Life Satisfaction Questionnaire and the SF-36).

    Both healthy subjects and fibromyalgia patients suffering from chronic pain could be subgrouped according to experimental pain perception. On comparing the fibromyalgia subgroups, differences in both stress and pain-coping strategies were found. Thus, the confrontative stress-coping style was used more in the thermal painsensitive group than the others. Furthermore, attention-diverting and catastrophising pain-coping strategies were more frequent.

    The chronic back-pain patients who had decreased their catastrophising pain-coping strategy at the 3-year follow-up also perceived an improved quality of life at the 6-year follow-up.

    When. self-scoring life satisfaction, thermal pain-sensitive fibromyalgia patients experienced significantly more physical symptoms than slightly cold pain-sensitive patients and healthy subjects. They also had sleep disturbances, more tender points, more affective hand pain and increased hand pain intensity.

    The relation between sensation and emotion must be regarded as a product of a conscious mind while the emotional part of the pain sensation is not just a passive response to an external stimulus.

    Delarbeten
    1. Stress coping strategies in thermal pain sensitive and insensitive healthy subjects
    Öppna denna publikation i ny flik eller fönster >>Stress coping strategies in thermal pain sensitive and insensitive healthy subjects
    2001 (Engelska)Ingår i: International Journal of Nursing Practice, ISSN 1322-7114, E-ISSN 1440-172X, Vol. 7, nr 3, s. 162-168Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The aim of this study was to investigate stress coping strategies used in relation to heat and cold pain thresholds in healthy subjects. After using the Jalowiec Coping Scale, cold and heat pain thresholds were examined using the Quantitative Somatosensory Test in 47 healthy subjects. The participants were separated into thermal pain sensitive and insensitive groups, based on thermal pain perception. The results showed that subjects sensitive to thermal pain tended to adopt an emotive stress coping style significantly more commonly than the insensitive subjects. Furthermore, women displayed a marked preference for this style compared to men. The conclusion is that emotional stress coping did play a role in the perception of thermal pain in this group of healthy subjects and that clinical nursing interventions need to focus on the relationship between emotion and coping.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-27120 (URN)10.1046/j.1440-172X.2001.00258.x (DOI)11767 (Lokalt ID)11767 (Arkivnummer)11767 (OAI)
    Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    2. Background pain in fibromyalgia patients affecting clinical examination of the skin
    Öppna denna publikation i ny flik eller fönster >>Background pain in fibromyalgia patients affecting clinical examination of the skin
    2002 (Engelska)Ingår i: Journal of Clinical Nursing, ISSN 0962-1067, E-ISSN 1365-2702, Vol. 11, nr 1, s. 58-64Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    • The purpose of this study was to investigate the relationship between on-going pain and acute thermal pain in patients suffering from chronic pain.

    •  This experimental study in cold and heat sensitivity was performed in order to test the following hypothesis: that fibromyalgia patients scoring high in current background pain tolerate less experimental thermal pain in the skin than patients with low scores.

    • Ethical aspects of the study are discussed.

    •  The level of tolerable experimental thermal stimuli was tested and compared between the `low-score' and the `high-score' patients.

    • Background pain seemed to affect the intensity of experimental cold pain.

    •  Clinical routine examinations and bodily care of the skin that might interfere with background pain in the fibromyalgia patients are discussed.

    • Clinical practice should be carefully planned in order to assist fibromyalgia patients in understanding and coping with thermal conditions that might influence background pain.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-27119 (URN)10.1046/j.1365-2702.2002.00542.x (DOI)11766 (Lokalt ID)11766 (Arkivnummer)11766 (OAI)
    Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    3. Quantitative sensory testing in fibromyalgia patients and in healthy subjects: identification of subgroups
    Öppna denna publikation i ny flik eller fönster >>Quantitative sensory testing in fibromyalgia patients and in healthy subjects: identification of subgroups
    Visa övriga...
    2001 (Engelska)Ingår i: The Clinical Journal of Pain, ISSN 0749-8047, E-ISSN 1536-5409, Vol. 17, nr 4, s. 316-322Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Objective: To determine perception and pain thresholds in patients with fibromyalgia syndrome and in healthy controls, and to investigate whether patients with fibromyalgia syndrome can be grouped with respect to thermal hyperalgesia and whether these subgroups differ from healthy controls and in clinical appearance. Design: The authors conducted a quasi-experimental clinical study. Subjects: Twenty-nine women patients with fibromyalgia syndrome and 21 healthy pain-free age-matched women participated in the study. Methods: Quantitative sensory testing using a Thermotest instrument was performed on the dorsum of the left hand. Sleep and pain intensity were rated using visual analog scales. Results: Cold and heat pain but not perception thresholds differed significantly between patients with fibromyalgia syndrome and healthy subjects. Based on thermal pain thresholds, two subgroups could be identified in fibromyalgia syndrome using cluster analysis. Conclusion: Patients with fibromyalgia syndrome were subgrouped by quantitative sensory testing (i.e., thermal pain thresholds). Subgroups show clinical differences in pain intensities, number of tender points, and sleep quality. Cold pain threshold was especially linked to these clinical aspects.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-26941 (URN)10.1097/00002508-200112000-00005 (DOI)11569 (Lokalt ID)11569 (Arkivnummer)11569 (OAI)
    Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    4. Coping strategies and life satisfaction in subgrouped fibromyalgia patients
    Öppna denna publikation i ny flik eller fönster >>Coping strategies and life satisfaction in subgrouped fibromyalgia patients
    2003 (Engelska)Ingår i: Biological Research for Nursing, ISSN 1099-8004, E-ISSN 1552-4175, Vol. 4, nr 3, s. 193-202Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The present study describes pain- and stress-coping strategies and life satisfaction in subgroups of fibromyalgia patients. Thirty-two females with fibromyalgia syndrome (FMS) and 21 healthy pain-free women were studied. Those with FMS were classified as thermal (both heat and cold) pain sensitive or slightly cold pain sensitive based on pain thresholds determined using a Thermotest device. Global stress-coping styles, life satisfaction, and specific pain-coping strategies were measured. Patients classified as thermal pain sensitive were affected by physical symptoms to a greater extent than were those classified as slightly cold pain sensitive. The thermal pain sensitive group used more diverting attention coping strategies than the slightly cold pain sensitive group did. Separating fibromyalgia patients into subgroups might increase the potential for improving nursing care of these patients. Through the use of effective coping strategies in dealing with stress and pain, life satisfaction may also be enhanced.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-26942 (URN)10.1177/1099800402239622 (DOI)11570 (Lokalt ID)11570 (Arkivnummer)11570 (OAI)
    Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    5. Catastrophizing and health related quality of life: A 6-year follow-up of patients with chronic low back pain
    Öppna denna publikation i ny flik eller fönster >>Catastrophizing and health related quality of life: A 6-year follow-up of patients with chronic low back pain
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    2002 (Engelska)Ingår i: Rehabilitation Nursing, ISSN 0278-4807, Vol. 27, nr 3, s. 110-117Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A pain rehabilitation model that focused on emotions was implemented to influence catastrophizing by, and health-related quality of life (HRQL) for, persons with chronic low back pain. Twelve individuals, 7 men and 5 women (aged 33 to 57 years), all with long-term pain despite treatment, were included in the study and a single case research experimental design (SCRED) was used to follow the patterns of coping with pain for 6 years. The HRQL was measured before and 6 years after the intervention. Coping strategies and HRQL were evaluated with the Coping Strategy Questionnaire (CSQ) and the SF-36, respectively. The evaluation of pain coping strategies after 3 years found decreased catastrophizing, a decrease that had continued 3 years later. HRQL showed significantly improved mental health and impaired physical capacity at the 6-year follow-up. Changes in catastrophizing or in HRQL did not appear to influence self-scored bodily pain. Altered catastrophizing appeared to be a long-term process. This research indicates the need for rehabilitation programs to assess and evaluate patients' pain and their need for improved quality of life, rather than focusing only on the elimination of pain.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-28114 (URN)10.1002/j.2048-7940.2002.tb01999.x (DOI)12923 (Lokalt ID)12923 (Arkivnummer)12923 (OAI)
    Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2012-09-18Bibliografiskt granskad
  • 116.
    Raak, Ragnhild
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Hurtig, Ingrid
    Linköpings universitet, Institutionen för medicin och vård, Omvårdnad. Linköpings universitet, Hälsouniversitetet.
    Wahren, Lis Karin
    Linköpings universitet, Institutionen för vård och välfärd. Linköpings universitet, Hälsouniversitetet.
    Coping strategies and life satisfaction in subgrouped fibromyalgia patients2003Ingår i: Biological Research for Nursing, ISSN 1099-8004, E-ISSN 1552-4175, Vol. 4, nr 3, s. 193-202Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The present study describes pain- and stress-coping strategies and life satisfaction in subgroups of fibromyalgia patients. Thirty-two females with fibromyalgia syndrome (FMS) and 21 healthy pain-free women were studied. Those with FMS were classified as thermal (both heat and cold) pain sensitive or slightly cold pain sensitive based on pain thresholds determined using a Thermotest device. Global stress-coping styles, life satisfaction, and specific pain-coping strategies were measured. Patients classified as thermal pain sensitive were affected by physical symptoms to a greater extent than were those classified as slightly cold pain sensitive. The thermal pain sensitive group used more diverting attention coping strategies than the slightly cold pain sensitive group did. Separating fibromyalgia patients into subgroups might increase the potential for improving nursing care of these patients. Through the use of effective coping strategies in dealing with stress and pain, life satisfaction may also be enhanced.

  • 117.
    Raak, Ragnhild
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Wahren, Lis Karin
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Background pain in fibromyalgia patients affecting clinical examination of the skin2002Ingår i: Journal of Clinical Nursing, ISSN 0962-1067, E-ISSN 1365-2702, Vol. 11, nr 1, s. 58-64Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    • The purpose of this study was to investigate the relationship between on-going pain and acute thermal pain in patients suffering from chronic pain.

    •  This experimental study in cold and heat sensitivity was performed in order to test the following hypothesis: that fibromyalgia patients scoring high in current background pain tolerate less experimental thermal pain in the skin than patients with low scores.

    • Ethical aspects of the study are discussed.

    •  The level of tolerable experimental thermal stimuli was tested and compared between the `low-score' and the `high-score' patients.

    • Background pain seemed to affect the intensity of experimental cold pain.

    •  Clinical routine examinations and bodily care of the skin that might interfere with background pain in the fibromyalgia patients are discussed.

    • Clinical practice should be carefully planned in order to assist fibromyalgia patients in understanding and coping with thermal conditions that might influence background pain.

  • 118.
    Raak, Ragnhild
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Wahren, Lis Karin
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Stress coping strategies in thermal pain sensitive and insensitive healthy subjects2001Ingår i: International Journal of Nursing Practice, ISSN 1322-7114, E-ISSN 1440-172X, Vol. 7, nr 3, s. 162-168Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this study was to investigate stress coping strategies used in relation to heat and cold pain thresholds in healthy subjects. After using the Jalowiec Coping Scale, cold and heat pain thresholds were examined using the Quantitative Somatosensory Test in 47 healthy subjects. The participants were separated into thermal pain sensitive and insensitive groups, based on thermal pain perception. The results showed that subjects sensitive to thermal pain tended to adopt an emotive stress coping style significantly more commonly than the insensitive subjects. Furthermore, women displayed a marked preference for this style compared to men. The conclusion is that emotional stress coping did play a role in the perception of thermal pain in this group of healthy subjects and that clinical nursing interventions need to focus on the relationship between emotion and coping.

  • 119.
    Rydell, Ewa
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Magnusson, Karl-Eric
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Sjö, Anita
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Axelsson, Krister
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Protein kinase C and casein kinase II activities in two human colon carcinoma cell lines, HT-29 and CaCo-2: Possible correlation with differentiation1990Ingår i: Bioscience Reports, ISSN 0144-8463, E-ISSN 1573-4935, Vol. 10, s. 293-299Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Protein kinase C (PK-C) and casein kinase II (CK-II) activities were studied in two human colon carcinoma cell lines (HT-29 and CaCO-2) undergoing differentiationin vitro resulting, in small-intestine-like cells. CaCo-2 cells, when grown under standard conditions, appear to undergo spontaneous differentiation. In these cells PK-C and CK-II activities were determined on day 5, 10 and 15. No significant differences in activities were seen either in PK-C or CK-II activity. HT-29 cells, when grown in glucose-free medium can be stimulated to undergo differentiation which is completed within 20 days. PK-C and CK-II activities were determined after 5, 10, 15, 20 and 25 days, respectively. PK-C activity rose from 7.9±3.5 pmole32P/mg protein/min at day 5 to 37.5±14.8 pmole32P/mg protein/min at day 20. After 25 days the activity was reduced to 20.0±7.8 pmole32P/mg protein/min. CK-II activity did not change significantly during day 5 to 20, but on day 25 there was a significant decrease in CK-II activity from 94.9±6.4 pmole32P/mg protein/min (day 20) to 62.6±3.9 pmole32P/mg protein/min (day 25) p=0.003. The results in this study indicate a role for PK-C and CK-II in cell growth and differentiation.

  • 120.
    Saldeen, Katarina
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Studies on vasoactivity of fibrin(ogen) derived peptides1992Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Fibrin accumulation is a common fmding in many pathological conditions, such as in inflammatory processes, e.g. in the lungs in pneumonia or pulmonary insufficiency after sepsis. During lysis of the fibrin by plasmin or leukocyte elastase, peptides are released that may contribute to the pathophysiological changes. Peptide 6A, Ala-Arg-Pro-Aia-Lys, released duting plasmin degradation of fibrin( ogen) induced dilation of bovine mesenteric arteries in vitro, increased cAMP in the vessels and released prostacyclin. It also increased coronary and femoral artery blood flow in the dog, probably due to release of prostacyclin and nitric oxide. L-arginine increased femoral blood flow in the dog, but was less potent than peptide 6A, indicating that properties beside the arginine content are important for the vasoactive effect of the peptide. D-arginine had much less effect than Laiginine, indicating that the effect of lrarginine is related to its utilization for synthesis of nitric oxide. Peptide 6A was an effective inhibitor of pulmonary angiotensin converting enzyme (ACE) in vivo in rabbits. It also potentiated the hemodynamic responses to bradykinin, an ACE substrate, and elicited bradykinin responses from normally subeffective circulating bradykinin levels. Peptide 6A showed an endothelium-dependent relaxant effect on rat aorta. Two different ACE inhibitors, one with and one without sulfhydryl groups, both enhanced this effect, indicating that the mechanism underlying the potentiation effect is inhibition of ACE and not related to sulhydryl supplementation.Peptide Bp 30-43, Arg-Pro-Ala-Pro-Pro-Pro-lle-Ser-Gly-Gly-Gly-Tyr-Arg-Ala, caused vasodilation of bovine mesenteric arteries, an increase m both cAMP and cGMP in the vessels and an increased release of prostacyclin. It also induced polymorphonuclear leukocyte emigration in rabbit skin in vivo. A contributory cause of this effect may be release of the vasodilator prostacyctin.

    In summary, these investigations showed that certain peptides released during degradation of human fibrin(ogen) have vasoactive properties and that the effects are mediated by prostacyclin, nitric oxide and inhibition of ACE. Endogenously released such peptides might contribute to the pathophysiology in inflammation or thrombolysis via the mechanisms described. In addition analogues to these peptides might be of therapeutic interest in the future, e.g. in thrombolysis or critical limb ischemia.

  • 121. Samuelsson Almen, M
    et al.
    Nilsson, S F
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Pituitary adenylate cyclase-activating polypeptide and VIP-induced activation of adnylate cyclase in the porcine non-pigmented ciliary epithelium: effects of antagonists.1999Ingår i: Journal of Ocular Pharmacology and Therapeutics, ISSN 1080-7683, E-ISSN 1557-7732, Vol. 15, s. 389-400Artikel i tidskrift (Refereegranskat)
  • 122. Samuelsson, U
    et al.
    Hanås, Ragnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Pediatrik.
    Whiss, Per A
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Ludvigsson, J
    Blood glucose peaks give high HbA1c2004Ingår i: International Society for Pediatric and Adolescent Diabetes ISPAD,2004, 2004Konferensbidrag (Övrigt vetenskapligt)
  • 123.
    Schmekel, Birgitta
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Klinisk fysiologi. Linköpings universitet, Hälsouniversitetet.
    Rydberg, Irene
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Norlander, Björn
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Naidu Sjöswärd, Kerstin
    Linköpings universitet, Institutionen för medicin och vård, Anestesiologi. Linköpings universitet, Hälsouniversitetet.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Rolf
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Stereoselective pharmacokinetics of S-salbutamol after administration of the racemate in healthy volunteers1999Ingår i: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 13, nr 6, s. 1230-1235Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Racemic R,S-salbutamol is taken to relieve bronchial constriction. Only the R-enantiomer has bronchodilating properties. The S-enantiomer has been proposed to cause in vitro bronchial hyperreactivity in guinea-pigs. Stereoselective elimination of salbutamol has been shown, with S-salbutamol being eliminated at a slower rate than R-salbutamol. This study questioned whether rates of stereoselective elimination were similar after oral or lung delivery, and whether the S:R ratio would increase after repeated inhalations in a situation resembling a common clinical use. Eighteen healthy volunteers received single-dose racemic salbutamol as a solution instilled in the trachea during anaesthesia, as inhaled micronized powder and/or as ingested tablets. Five volunteers inhaled repeated doses of racemic salbutamol. Concentrations in plasma and urine were measured using a technique which allowed chiral separation of samples with concentrations as low as 0.1 ng·mL -1. The bioavailability of S-salbutamol was significantly higher than that of R-salbutamol after the different modes of administration. Stereoselective elimination was more pronounced after oral administration than after inhalation. Repeated inhalations resulted in successive increases in the S:R ratio as steady state was approached. In conclusion, the clinical consequences of increasing plasma concentrations of S-salbutamol need to be further assessed.

  • 124.
    Skoglund, Caroline
    et al.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Sjöwall, Christoffer
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Skogh, Thomas
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Tengvall, Pentti
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    Bengtsson, Torbjörn
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    C-reactive protein inhibit complement-mediated platelet activation suggesting a protective role in atherogenesis2006Ingår i: Atherosclerosis Supplements, ISSN 1567-5688, E-ISSN 1878-5050, Vol. 7, nr 3, s. 284-284Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

      Objective: C-reactive protein (CRP) represents a powerful predictor of coro- nary artery disease. However, its physiological role is not fully understood. The binding of CRP to its ligand phosphorylcholine (PC) activates the com- plement system via the classical pathway, although limited to the initial stages, i.e. no membrane attack complex is formed. The aim of this study was to chaxacterize CRP-induced complement activation on PC-coated surfaces, and to investigate the regulatory effects of PC-bound crp on complement induced platelet activation.

    Methods: PC conjugated to keyhole limpet hemocyanin was immobilized to cross-linked fibrinogen on silica particles. Ellipsometry and polyclonal anti- bodies were used to quantify deposition of serum proteins, complement factors and CRP on the surfaces. Washed platelets as well as serum were prepared according to standard protocols. CRP concentrations were measured with a high sensitivity assay. Lumi-aggregometry was used to evaluate the effects of PC-coated particles and CRP on complement-induced platelet aggregation and secretion.

    Results: Serum (5%) induced platelet aggregation and secretion through complement-dependent mechanisms. PC-coated particles antagonized the complement-mediated platelet activation but only if CRP was present. Inter- estingly, we found that a minor elevation of CRR below 5 rag/1 was sufficient to inhibit platelet activation.

    Conclusions: We suggest that CRP bound to PC-expressing ligands, e.g. bacteria or modified low-density lipoproteins in an atherosclerotic lesion, modulate complement activation and thereby prevent a harmful platelet activation.

  • 125.
    Stoen, R
    et al.
    Trondheim, Norge.
    Lossius, K
    Trondheim, Norge.
    Karlsson, JO
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Acetylcholine-induced vasodilation may depend entirely upon NO in the femoral artery of young piglets2003Ingår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 138, nr 1, s. 39-46Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    1. To characterize agonist-induced relaxation in femoral artery rings from young piglets, we compared the effect of a NOS-inhibitor N?-nitro-L-arginine (L-NOARG), an NO-inactivator oxyhaemoglobin (HbO) and a soluble guanyl cyclase(sGC)-inhibitor 1H-[1,2,4]Oxadiazolo-[4,3,-a]quinoxalin-1-one (ODQ) on acetylcholine(ACh)-induced relaxation. The involvement of K+ channel activation was studied on relaxations induced by ACh, the two NO donors sodium nitroprusside (SNP) and diethylamine (DEA) NONOate, and the cell membrane permeable guanosine 3'5' cyclic monophosphate (cGMP) analogue 8-Br-cGMP. 2. Full reversal of phenylephrine-mediated precontraction was induced by ACh (1 nM-1 ╡M) (pD2 8.2▒0.01 and Rmax 98.7▒0.3%). L-NOARG (100 ╡M) partly inhibited relaxation (pD2 7.4▒0.02 and Rmax 49.6▒0.8%). The L-NOARG/indomethacin(IM)-resistant response displayed characteristics typical for endothelium-derived hyperpolarizing factor (EDHF), being sensitive to a combination of the K+ channel blockers charybdotoxin (CTX) (0.1 ╡M) and apamin (0.3 ╡M). 3. ODQ (10 ╡M) abolished relaxations induced by ACh and SNP. L-NOARG/IM-resistant relaxations to ACh were abolished by HbO (20 ╡M). 4. Ouabain (1 ╡M) significantly inhibited ACh-induced L-NOARG/IM-resistant relaxations and relaxations induced by SNP (10 ╡M) and 8-Br-cGMP (0.1 mM). A combination of ouabain and Ba2+ (30 ╡M) almost abolished L-NOARG/IM-resistant ACh-induced relaxation (Rmax 7.7▒2.5% vs 23.4▒6.4%, with and without Ba2+, respectively, P<0.05). 5. The present study demonstrates that in femoral artery rings from young piglets, despite an L-NOARG/IM-resistant component sensitive to K+ channel blockade with CTX and apamin, ACh-induced relaxation is abolished by sGC-inhibition or a combination of L-NOARG and HbO. These findings suggest that relaxation can be fully explained by the NO/cGMP pathway.

  • 126.
    Strömberg, H
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi.
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Hermansson, O
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi.
    Distribution of CREB-binding protein immunreactivity in the adult rat brain1999Ingår i: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 818, s. 510-514Artikel i tidskrift (Refereegranskat)
  • 127.
    Strömberg, H
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi.
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Hermansson, O
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi.
    Distribution of the transcription factor Signal Transducer and Activator of Transcription 3 in the rat central nervous system and dorsal root ganglia2000Ingår i: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 853, nr 1, s. 105-114Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor that acts as an intracellular signalling molecule after receptor activation by several cytokines, e.g., interleukin-6, leptin and ciliary neurotrophic factor. We have investigated the localization of STAT3 in the rat central nervous system and dorsal root ganglia. Light microscopic immunohistochemistry showed that STAT3-like immunoreactivity (STAT3-LI) was present in the nucleus and cytoplasm of neurons. STAT3-LI was seen both in cell bodies and in proximal and distal dendrites. Many structures involved in motor functions, such as the ventral horn of the spinal cord, the motor cranial nerve nuclei, the red nucleus and the Purkinje cells of the cerebellum showed STAT3-LI. STAT3-LI was also present in many regions involved in autonomic regulation, such as the intermediolateral cell column of the spinal cord, the nucleus of the solitary tract, the dorsal motor nucleus of the vagus nerve, the area postrema, the locus coeruleus, the Barrington's nucleus and the arcuate, the lateral, the dorsomedial, the ventromedial, and the paraventricular hypothalamic nuclei. Other structures showing STAT3-LI were the dorsal root ganglia, the thalamus (the anterodorsal and paraventricular nucleus), the cerebral neocortex (layer 5) and the olfactory bulb. The wide distribution of STAT3-LI in the nervous system is consistent with reports of cytokine actions in the brain, but the present findings further suggest novel roles for STAT3 in mediating influences of cytokines on specific neuronal circuits regulating motor, sensory and autonomic functions.

  • 128.
    Støen, R.
    et al.
    Department of Pediatrics, University Hospital, Trondheim, Norway and Department of Physiology and Biomechanical Engineering, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
    Lossius, K.
    Department of Pediatrics, University Hospital, Trondheim, Norway and Department of Physiology and Biomechanical Engineering, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
    Asplund-Persson, Anna
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Karlsson, J.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Relative significance of the nitric oxide (NO)/cGMP pathway and K+ channel activation in endothelium-dependent vasodilation in the femoral artery of developing piglets2001Ingår i: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 171, nr 1, s. 29-35Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mechanisms mediating endothelium-dependent vasodilation were investigated in femoral artery rings from <2-day-old (newborn) and 2-week-old piglets. Based on previous results we hypothesized an age difference in the relative contribution of nitric oxide(NO)-cyclic 3′,5′-guanosine monophosphate (cGMP) and K+ channel-activation to acetylcholine (ACh)-induced vasodilation. Changes in vascular tone were studied in organ baths in the absence or presence of NO synthase(NOS) inhibition or K+ channel blockade and the intra-arterial accumulation of cGMP in response to ACh was measured with radioimmunoassay (RIA). In control experiments, relaxant responses to ACh were equal in the two age groups. In the presence of the NOS-inhibitors N G-monomethyl-L-arginine acetate (L-NMMA; 100 μM) or NG-nitro-L-arginine (L-NOARG; 1–100 μM), however, relaxation was significantly more reduced in femoral artery rings from 2-week-old than from newborn, with lower pD2 values in the older age group. Inhibition of large (BKCa) conductance calcium-sensitive K+ channels with tetraethylammonium chloride (TEA; 1 mM), gave a significant rightward shift in the concentration-response curves to ACh which was of the same magnitude in both age groups. The ACh-induced vasodilation was abolished in both age groups by high K+ (20 mM) in combination with L-NOARG (100 μM). The relative increase in cGMP levels after addition of ACh (10 nM) was significantly larger in rings from newborn compared with 2-week-old piglets (12- vs. four-fold). In summary, sensitivity to NOS inhibition increased with age while the effect of K+ channel blockade with TEA was the same in femoral artery rings from newborn to 2-week-old piglets. Lower sensitivity to NOS inhibition and a larger increase in cGMP in response to ACh could indicate a higher efficacy of the NO/cGMP pathway in this vessel in the newborn piglet.

  • 129.
    Sund Levander, Märtha
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk fysiologi.
    Wahren, Lis Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Assessment and prevention of shivering in patients with severe cerebral injury. A pilot study.2000Ingår i: Journal of Clinical Nursing, ISSN 0962-1067, E-ISSN 1365-2702, Vol. 9, s. 55-61Artikel i tidskrift (Refereegranskat)
  • 130.
    Svensson, Ann-Charlotte
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Bengtsson, Torbjörn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Grenegård, Magnus
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Lindström, Eva
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Platelets induce airway smooth muscle cell proliferation2005Ingår i: Young Investigators Symposium,2005, 2005Konferensbidrag (Övrigt vetenskapligt)
  • 131.
    Svensson, Ann-Charlotte
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Bengtsson, Torbjörn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Grenegård, Magnus
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Lindström, Eva
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Platelets induce proliferation of airway smooth muscle cells through mechanisms dependent on ROS and 5-LOX metabolites2005Ingår i: European respiratory Society Annual Congress,2005, 2005Konferensbidrag (Övrigt vetenskapligt)
  • 132.
    Svensson, Samuel
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Lysophophatidic Acid Stimulates Proliferation of Cultured Smooth Muscle Cells From Human BPH.Tissue: Sildenafil and Papaverin Generate InhibitionThe Prostate2002Ingår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 50, s. 50-58Artikel i tidskrift (Övrig (populärvetenskap, debatt, mm))
  • 133.
    Svensson, Samuel
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Lindgren, Sofi
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Powell, Wendy
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Green, Henrik
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Melanin inhibits cytotoxic effects of doxorubicin and daunorubicin in MOLT 4 cells2003Ingår i: Pigment Cell Research, ISSN 1755-1471, E-ISSN 1755-148X, Vol. 16, nr 4, s. 351-354Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In the present study we have developed a simple method to elucidate the melanin binding ability of different chemotherapeutic agents. The anthracyclines, doxorubicin and daunorubicin, or the alkylating agent cisplatin were preincubated with melanin (Sepia). Melanin and free drug was then separated through centrifugation and the cytotoxic effects of corresponding drug were evaluated in a MTT (3-(4,5-dimetyltiazol-2-yl)-2,5-difenyl-tetrazoliumbromide) assay using MOLT-4 cells. Our results show that melanin pretreatment shifted the IC50 value for doxorubicin from 0.06 to 0.97 ╡M and for daunorubicin from 0.04 to 0.80 pM. In contrast, the IC50 values of cisplatin was not influenced by melanin pretreatment indicating that cisplatin does not bind to melanin. By comparing equi-active concentrations from concentration-response curves with or without melanin pretreatment an approximate binding capacity of melanin could be estimated. Our results show that melanin binds about 900 nmol/mg doxorubicin and 760 nmol/mg daunorubicin. Chloroquine, which is known to bind to melanin with high affinity, was found to inhibit melanin binding of both daunorubicin and doxorubicin, thereby leading to an increased sensitivity of the anthracyclines. The clinical implications of melanin binding regarding unwanted accumulation of anthracyclines in the skin as well as chemoprotective effects against chemotherapy are discussed.

  • 134.
    Szabó, Zoltán
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Thoraxkirurgi. Östergötlands Läns Landsting, Hjärtcentrum, Thorax-kärlkliniken.
    Andersson, Rolf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Arnqvist, Hans
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Insulin resistance during coronary surgery in diabetic and non-diabetic patients-parallel microdialysis and organ balance technique studying skeletal muscle (preliminary results)2007Ingår i: Diabetologia(ISSN 0012-186X), vol 50, 2007, Vol. 50, s. 275-276Konferensbidrag (Refereegranskat)
  • 135.
    Szabó, Zoltán
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Thoraxkirurgi. Östergötlands Läns Landsting, Hjärtcentrum, Thorax-kärlkliniken.
    Andersson, Rolf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Arnqvist, Hans
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Insulin resistance during coronary surgery in diabetic and non-diabetic patients-parallel microdialysis and organ balance technique studying skeletal muscle (preliminary results)2007Ingår i: European Association for the Study of Diabetes EASD,2007, 2007Konferensbidrag (Refereegranskat)
    Abstract [en]

        

  • 136. Tedla, N
    et al.
    Glaros, EN
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Jessup, W
    Garner, B
    Heterogeneous expression of apolipoprotein-E by human macrophages2004Ingår i: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 113, nr 3, s. 338-347Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Apolipoprotein-E (apoE) is expressed at high levels by macrophages. In addition to its role in lipid transport, macrophage-derived apoE plays an important role in immunoregulation. Previous studies have identified macrophage subpopulations that differ substantially in their ability to synthesize specific cytokines and enzymes, however, potential heterogeneous macrophage apoE expression has not been studied. Here we examined apoE expression in human THP-1 macrophages and monocyte-derived macrophages (MDM). Using immunocytochemistry and flow cytometry methods we reveal a striking heterogeneity in macrophage apoE expression in both cell types. In phorbol-ester-differentiated THP-1 macrophages, 5% of the cells over-expressed apoE at levels more than 50-fold higher than the rest of the population. ApoE over-expressing THP-1 macrophages contained condensed/fragmented nuclei and increased levels of activated caspase-3 indicating induction of apoptosis. In MDM, 3-5% of the cells also highly over-expressed apoE, up to 50-fold higher than the rest of the population, however, this was not associated with obvious nuclear alterations. The apoE over-expressing MDM were larger, more granular, and more autofluorescent than the majority of cells and they contained numerous vesicle-like structures that appeared to be coated by apoE. Flow cytometry experiments indicated that the apoE over-expressing subpopulation of MDM were positive for CD14, CD11b/Mac-1 and CD68. These observations suggest that specific macrophage subpopulations may be important for apoE-mediated immunoregulation and clearly indicate that subpopulation heterogeneity should be taken into account when investigating macrophage apoE expression.

  • 137. Tenopoulou, M
    et al.
    Doulias, PT
    Barbouti, A
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Galaris, D
    Role of compartmentalized redox-active iron in hydrogen peroxide-induced DNA damage and apoptosis2005Ingår i: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 387, nr 3, s. 703-710Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Jurkat cells in culture were exposed to oxidative stress in the form of continuously generated hydrogen peroxide, obtained by the addition of glucose oxidase to the medium. This treatment induced a rapid, dose-dependent increase in the ICIP (intracellular calcein-chelatable iron pool). Early destabilization of lysosomal membranes and subsequent nuclear DNA strand breaks were also observed, as evaluated by the Acridine Orange relocation test and the comet assay respectively. Somewhat later, these effects were followed by a lowered mitochondrial membrane potential, with release of cytochrome c and apoptosis-inducing factor. These events were all prevented if cells were pretreated with the potent iron chelator DFO (desferrioxamine) for a period of time (2-3 h) long enough to allow the drug to reach the lysosomal compartment following fluid-phase endocytosis. The hydrophilic calcein, a cleavage product of calcein acetoxymethyl ester following the action of cytosolic esterases, obviously does not penetrate intact lysosomal membranes, thus explaining why ICIP increased dramatically following lysosomal rupture. The rapid decrease in ICIP after addition of DFO to the medium suggests draining of cytosolic iron to the medium, rather than penetration of DFO through the plasma membrane. Most importantly, these observations directly connect oxidative stress and resultant DNA damage with lysosomal rupture and the release of redox-active iron into the cytosol and, apparently, the nucleus. © 2005 Biochemical Society.

  • 138.
    Tenopoulou, Margarita
    et al.
    Ioannina, Greece.
    Kurz, Tino
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Doulias, Paschalis-Thomas
    Ioannina, Greece.
    Galaris, Dimitrios
    Ioannina, Greece.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Does the calcein-AM method assay the total cellular 'labile iron pool' or only a fraction of it?2007Ingår i: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 403, nr 2, s. 261-266Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The calcein-AM (calcein-acetoxymethyl ester) method is a widely used technique that is supposed to assay the intracellular 'labile iron pool' (LIP). When cells in culture are exposed to this ester, it passes the plasma membrane and reacts with cytosolic unspecific esterases. One of the reaction products, calcein, is a fluorochrome and a hydrophilic alcohol to which membranes are non-permeable and which, consequently, is retained within the cytosol of cells. Calcein fluorescence is quenched following chelation of low-mass labile iron, and the degree of quenching gives an estimate of the amounts of chelatable iron. However, a requirement for the assay to be able to demonstrate cellular LIP in total is that such iron be localized in the cytosol and not in a membrane-limited compartment. For some time it has been known that a major part of cellular, redox-active, labile, low-mass iron is temporarily localized in the lysosomal compartment as a result of the autophagic degradation of ferruginous materials, such as mitochondrial complexes and ferritin. Even if some calcein-AM may escape cytosolic esterases and enter lysosomes to be cleaved by lysosomal acidic esterases, the resulting calcein does not significantly chelate iron at < pH 5. In the present study we show that the calcein-AM method does not capture lysosomal low-mass iron and, therefore, that the method seriously underestimates total cellular labile iron. © 2007 Biochemical Society.

  • 139.
    Terman, Alexei
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Autophagy in cardiac myocyte homeostasis, aging, and pathology2005Ingår i: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 68, nr 3, s. 355-365Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Autophagy, an intralysosomal degradation of cells' own constituents that includes macro-, micro-, and chaperone-mediated autophagy, plays an important role in the renewal of cardiac myocytes. This cell type is represented by long-lived postmitotic cells with very poor (if any) replacement through differentiation of stem cells. Macroautophagy, the most universal form of autophagy, is responsible for the degradation of various macromolecules and organelles including mitochondria and is activated in response to stress, promoting cell survival. This process is also involved in programmed cell death when injury is irreversible. Even under normal conditions, autophagy is somewhat imperfect, underlying gradual accumulation of defective mitochondria and lipofuscin granules within aging cardiac myocytes. Autophagy is involved in the most important cardiac pathologies including myocardial hypertrophy, cardiomyopathies, and ischemic heart disease, a fact that has led to increasing attention to this process. © 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

  • 140.
    Terman, Alexei
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Is aging the price for memory?2005Ingår i: Biogerontology (Dordrecht), ISSN 1389-5729, E-ISSN 1573-6768, Vol. 6, nr 3, s. 205-210Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Aging (senescence) is apparent in animals that possess long-lived postmitotic cells but is negligible in primitive species, such as hydras and other Cnidarians, all of whose cells are constantly renewed by cell division. This repetitive mitotic activity precludes the progressive intracellular accumulation of damaged biomolecules and organelles, which are obvious concomitants of aging in neurons and other long-lived cells of higher animals. We assume that the development of long-lived postmitotic cells, now found in the overwhelming majority of species, represented a useful evolutionary change. Probably, of particular importance was the evolution of long-lived neurons, which are required for long-term memory. However, the appearance of long-lived postmitotic cells not only increased fitness, but also gave rise to the aging process.

  • 141.
    Terman, Alexei
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Oxidative stress, accumulation of biological 'garbage', and aging2006Ingår i: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 8, nr 1-2, s. 197-204Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Normal metabolism is associated with unavoidable mild oxidative stress resulting in biomolecular damage that cannot be totally repaired or removed by cellular degradative systems, including lysosomes, proteasomes, and cytosolic and mitochondrial proteases. Consequently, irreversibly damaged and functionally defective structures (biological 'garbage') accumulate within long-lived postmitotic cells, such as cardiac myocytes and neurons, leading to progressive loss of adaptability and increased probability of death and characterizing a process called aging, or senescence. Intralysosomal 'garbage' is represented by lipofuscin (age pigment), an undegradable autophagocytosed material, while extralysosomal 'garbage' involves oxidatively modified cytosolic proteins, altered biomembranes, defective mitochondria and other organelles. In aged postmitotic cells, heavily lipofuscin-loaded lysosomes perform poorly, resulting in the enhanced accumulation of defective mitochondria, which in turn produce more reactive oxygen species causing additional damage (the mitochondrial- lysosomal axis theory). Potential anti-aging strategies may involve not only overall reduction of oxidative stress, but also the use of intralysosomal iron chelators hampering Fenton-type chemistry as well as the stimulation of cellular degradative systems. © Mary Ann Liebert, Inc.

  • 142.
    Terman, Alexei
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    The aging myocardium: Roles of mitochondrial damage and lysosomal degradation2005Ingår i: Heart, Lung and Circulation, ISSN 1443-9506, E-ISSN 1444-2892, Vol. 14, nr 2, s. 107-114Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Myocardial aging, leading to circulatory dysfunction, complicates numerous pathologies and is an important contributor to overall mortality at old age. In cardiac myocytes, mitochondria and lysosomes suffer remarkable age-related alterations. Mitochondrial changes include structural disorganization and enlargement, while lysosomes, which are responsible for autophagic turnover of mitochondria, accumulate lipofuscin (age pigment), a polymeric, autofluorescent, undegradable material. These changes are caused by continuous physiological oxidative stress, and they advance with age because the cellular turnover machinery is inherently imperfect. Several mechanisms contribute to age-related accumulation of damaged mitochondria following initial oxidative injury. Such mechanisms may include clonal expansion of defective mitochondria, decreased propensity of altered mitochondria to become autophagocytosed (due to mitochondrial enlargement or decreased membrane damage associated with weakened respiration), suppressed autophagy because of heavy lipofuscin loading of lysosomes, and decreased efficiency of Lon and AAA proteases. Because lipofuscin-laden lysosomes still receive newly synthesized lysosomal enzymes, even though they fail to degrade the pigment, the cells become in short supply of lysosomal hydrolases for functional autophagy, further limiting mitochondrial turnover. This interrelated mitochondrial and lysosomal damage eventually results in functional failure and death of cardiac myocytes. © 2005 Published by Elsevier Inc on behalf of Australasian Society of Caridac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand.

  • 143.
    Terman, Alexei
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Geriatrik.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Mitochondrial damage and intralysosomal degradation in cellular aging2006Ingår i: Molecular Aspects of Medicine, ISSN 0098-2997, E-ISSN 1872-9452, Vol. 27, nr 5-6, s. 471-482Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Normal mitochondrial respiration is associated with a continuous production of superoxide and hydrogen peroxide, inevitably resulting in minor macromolecular damage. Damaged cellular components are not completely turned over by autophagy and other cellular repair systems, leading to a progressive age-related accumulation of biological "garbage" material, such as defective mitochondria, cytoplasmic protein aggregates and an intralysosomal undegradable material, lipofuscin. These changes primarily affect neurons, cardiac myocytes and other long-lived postmitotic cells that neither dilute this "garbage" by mitotic activity, nor are replaced by newly differentiated cells. Defective mitochondria are insufficient in ATP production and often generate increased amounts of reactive oxygen species, further enhancing oxidative stress. Lipofuscin-loaded lysosomes, in turn, poorly turn over mitochondria that gradually leads to the overload of long-lived postmitotic cells with "garbage" material, decreased adaptability and eventual cell death. © 2006 Elsevier Ltd. All rights reserved.

  • 144.
    Terman, Alexei
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Geriatrik.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    The lysosomal-mitochondrial axis theory of postmitotic aging and cell death2006Ingår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 163, nr 1-2, s. 29-37Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aging (senescence) is characterized by a progressive accumulation of macromolecular damage, supposedly due to a continuous minor oxidative stress associated with mitochondrial respiration. Aging mainly affects long-lived postmitotic cells, such as neurons and cardiac myocytes, which neither divide and dilute damaged structures, nor are replaced by newly differentiated cells. Because of inherent imperfect lysosomal degradation (autophagy) and other self-repair mechanisms, damaged structures (biological "garbage") progressively accumulate within such cells, both extra- and intralysosomally. Defective mitochondria and aggregated proteins are the most typical forms of extralysosomal "garbage", while lipofuscin that forms due to iron-catalyzed oxidation of autophagocytosed or heterophagocytosed material, represents intralysosomal "garbage". Based on findings that autophagy is diminished in lipofuscin-loaded cells and that cellular lipofuscin content positively correlates with oxidative stress and mitochondrial damage, we have proposed the mitochondrial-lysosomal axis theory of aging, according to which mitochondrial turnover progressively declines with age, resulting in decreased ATP production and increased oxidative damage. Due to autophagy of ferruginous material, lysosomes contain a pool of redox-active iron, which makes these organelles particularly susceptible to oxidative damage. Oxidant-mediated destabilization of lysosomal membranes releases hydrolytic enzymes to the cytosol, eventuating in cell death (either apoptotic or necrotic depending on the magnitude of the insult), while chelation of the intralysosomal pool of redox-active iron prevents these effects. In relation to the onset of oxidant-induced apoptosis, but after the initiating lysosomal rupture, cytochrome c is released from mitochondria and caspases are activated. Mitochondrial damage follows the release of lysosomal hydrolases, which may act either directly or indirectly, through activation of phospholipases or pro-apoptotic proteins such as Bid. Additional lysosomal rupture seems to be a consequence of a transient oxidative stress of mitochondrial origin that follows the attack by lysosomal hydrolases and/or phospholipases, creating an amplifying loop system. © 2006 Elsevier Ireland Ltd. All rights reserved.

  • 145.
    Testorf, Martin
    et al.
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Tekniska högskolan.
    Karlsson, Annika M.
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Öberg, Åke
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Tekniska högskolan.
    Lundström, Ingemar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    A model for switch-like phenomena in biological systems2001Ingår i: Biophysical Chemistry, ISSN 0301-4622, E-ISSN 1873-4200, Vol. 94, nr 1-2, s. 1-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We present a model for the activity of protein clusters based on a simultaneous desorption of an activator (agonist, substrate molecule, etc.) and an inactivator (antagonist, inhibitor, etc.) caused by the collision or interaction between two effector molecules (e.g. receptors, enzymes). This model gives rise to switch-like dose–response curves, which are difficult to explain by ordinary co-operativity. It fits with recent experimental results obtained on single cells. Some other interesting aspects of the model are also pointed out. The model is similar to the model used to explain steep ‘dose–response curves’ in heterogeneous catalysis, caused by the reaction between two different molecules or atoms on the surface of the catalyst.

  • 146.
    Testorf, Martin
    et al.
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Hälsouniversitetet.
    Roback, Kerstin
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Tekniska högskolan.
    Lundström, Ingemar
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    Svensson, Samuel
    Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Volume changes of individual melanosomes measured by scanning force microscopy2001Ingår i: Pigment Cell Research, ISSN 1755-1471, E-ISSN 1755-148X, Vol. 14, nr 6, s. 445-449Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Black pigment cells, melanophores, e.g. located in the epidermis and dermis of frogs, are large flat cells having intracellular black pigment granules, called melanosomes. Due to a large size, high optical contrast, and quick response to drugs, melanophores are attractive as biosensors as well as for model studies of intracellular processes; e.g. organelle transport and G-protein coupled receptors. The geometry of melanosomes from African clawed toad, Xenopus laevis, has been measured using scanning force microscopy (SFM). Three-dimensional images from SFM were used to measure height, width, and length of the melanosomes (100 from aggregated cells and 100 from dispersed cells). The volumes of melanosomes isolated from aggregated and dispersed melanophores were significantly different (P<0.05, n=200). The average ellipsoidal volume was 0.14±0.01 (aggregated) and 0.17±0.01 μm3 (dispersed), a difference of 18%. The average major diameter was 810±20 and 880±20 nm for aggregated and dispersed melanosomes, respectively. To our knowledge, this is the first time SFM has been used to study melanosomes. This may provide an alternative non-destructive technique that may be particularly suitable for studying morphological aspects of various melanin granules.

  • 147.
    Toll, Johan B
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Andersson, Rolf G
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Effects of enprofylline and theophylline on purified human basophils1984Ingår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 39, nr 7, s. 515-520Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Extracts from purified human basophils revealed activity of cAMP-phosphodiesterase with a km-value of 0.59 microM. The enzyme was not activated by Ca-ions. Enprofylline and theophylline inhibited the enzyme in a competitive manner. Enprofylline was more potent than theophylline. These drugs did also inhibit the anti-IgE-induced histamine release from the basophils. These results favour the hypothesis that inhibition of histamine release of enprofylline is caused by an inhibition of phosphodiesterase. Although accumulating data have indicated that theophylline, at therapeutic concentrations, is a weak inhibitor of cAMP-phosphodiesterase activity, there is reason to believe that enprofylline, at therapeutic concentrations, may act at least partly as a phosphodiesterase inhibitor.

  • 148.
    Toll, Johan B
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Andersson, Rolf G
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Effects of mepacrine and p-bromophenacyl bromide on anti-IgE and phospholipase A2-induced histamine release from human basophils1986Ingår i: Agents and actions, ISSN 0065-4299, Vol. 18, nr 5-6, s. 518-523Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Exposure of human basophils to purified phospholipase A2 caused a release of histamine, the process could be divided in one Ca2+-independent and one Ca2+-dependent stage. Low concentrations of mepacrine and p-bromophenacyl bromide (BPB) inhibited both phospholipase A2- and anti-IgE-induced histamine release. Mepacrine was more potent than BPB when the two-stage-method was used. The inhibition of mepacrine was most effective when the drug was added in the second Ca2+-dependent stage. The effect of mepacrine in the whole reaction of the anti-IgE-induced histamine release was biphasic and mepacrine was less effective than in the inhibition of the separated stages. The effect of BPB on the whole reaction was rather similar to mepacrine, although it was not biphasic. The results presented in this work confirm a previous hypothesis suggesting that activation of phospholipase A2 is an important step in the IgE-mediated histamine release process. The results also suggest that inhibition of histamine release due to inhibition of phospholipase A2 might be of therapeutical value as the system can be inhibited at very low drug concentrations.

  • 149.
    Toll, Johan B
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Wikberg, J E
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Andersson, Rolf G
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Purification of human basophils by affinity chromatography on anti-IgE-sepharose 6MB1981Ingår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 36, nr 6, s. 411-417Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This work describes a method for the purification of basophil leukocytes from human peripheral blood by the use of a three-step separation technique including affinity chromatography on anti-IgE-sepharose 6MB. The purity of the obtained basophils was 50--95% and the recovery was 30--40%. The basophils separated by this method appeared normal and were found to be reactive with anti-IgE in subsequent tests.

  • 150.
    Whiss, Per A
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Analyses of surface receptors on isolated platelets upon adhesion to protein surfaces: Platelet adhesion to collagen induces more P-selectin expression than adhesion to fibrinogen1999Ingår i: XVIIth Congress of the International Society of Thrombosis and Haemostasis,1999, 1999Konferensbidrag (Övrigt vetenskapligt)
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