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| 3. |
- Lutgens, E., et al.
(författare)
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Genetic loss of Gas6 induces plaque stability in experimental atherosclerosis
- 2008
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 216:1, s. 55-63
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Tidskriftsartikel (refereegranskat)abstract
- The growth arrest-specific gene 6 (Gas6) plays a role in pro-atherogenic processes such as endothelial and leukocyte activation, smooth muscle cell migration and thrombosis, but its role in atherosclerosis remains uninvestigated. Here, we report that Gas6 is expressed in all stages of human and mouse atherosclerosis, in plaque endothelial cells, smooth muscle cells and macrophages. Gas6 expression is most abundant in lesions containing high amounts of macrophages, ie thin fibrous cap atheroma and ruptured plaque. Genetic loss of Gas6 does not affect the number and size of initial and advanced plaques in ApoE(-/-) mice, but alters its plaque composition. Compared to Gas6(+/+): ApoE(-/-) mice, initial and advanced plaques of Gas6(-/-): ApoE(-/-) mice contained more smooth muscle cells and more collagen and developed smaller lipid cores, while the expression of TGFbeta was increased. In addition, fewer macrophages were found in advanced plaques of Gas6(-/-): ApoE(-/-) mice. Hence, loss of Gas6 promotes the formation of more stable atherosclerotic lesions by increasing plaque fibrosis and by attenuating plaque inflammation. These findings identify a role for Gas6 in plaque composition and stability.
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| 5. |
- Briant, L. J. B., et al.
(författare)
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CPT1a-Dependent Long-Chain Fatty Acid Oxidation Contributes to Maintaining Glucagon Secretion from Pancreatic Islets
- 2018
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 23:11, s. 3300-3311
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon, the principal hyperglycemic hormone, is secreted from pancreatic islet a cells as part of the counter-regulatory response to hypoglycemia. Hence, secretory output from a cells is under high demand in conditions of low glucose supply. Many tissues oxidize fat as an alternate energy substrate. Here, we show that glucagon secretion in low glucose conditions is maintained by fatty acid metabolism in both mouse and human islets, and that inhibiting this metabolic pathway profoundly decreases glucagon output by depolarizing alpha cell membrane potential and decreasing action potential amplitude. We demonstrate, by using experimental and computational approaches, that this is not mediated by the K-ATP channel, but instead due to reduced operation of the Na+-K+ pump. These data suggest that counter-regulatory secretion of glucagon is driven by fatty acid metabolism, and that the Na+-K+ pump is an important ATP-dependent regulator of alpha cell function.
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| 11. |
- Nowak-Sliwinska, Patrycja, et al.
(författare)
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Consensus guidelines for the use and interpretation of angiogenesis assays
- 2018
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Ingår i: Angiogenesis. - : Springer. - 0969-6970 .- 1573-7209. ; 21:3, s. 425-532
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Forskningsöversikt (refereegranskat)abstract
- The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.
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| 12. |
- Ny, A, et al.
(författare)
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Ovulation in plasminogen-deficient mice.
- 1999
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Ingår i: Endocrinology. - 0013-7227 .- 1945-7170. ; 140:11, s. 5030-5
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Tidskriftsartikel (refereegranskat)abstract
- Many different studies suggest that plasmin generated from plasminogen plays a crucial role in the degradation of the follicular wall at the time of ovulation. We have assessed the physiological relevance of plasmin on ovulation by studying plasminogen-deficient mice. Ovulation efficiency (mean number of ova released per mouse) was determined both in a standardized ovulation model in which 25-day-old immature mice were injected with finite amounts of gonadotropins to induce ovulation and during physiological ovulation using adult normally cycling mice. Our results revealed that the temporal onset of follicular wall rupture (first ova observed in bursa or oviduct) was not delayed in plasminogen-deficient mice during gonadotropin-induced ovulation. However, there was a trend toward slightly reduced ovulation efficiency in the plasminogen-deficient mice. This reduction was only 13% and not statistically significant (P = 0.084) and may be connected to a delayed maturation of these mice manifested in reduced body and ovary weights. During physiological ovulation adult plasminogen-deficient mice had normal ovulation efficiency compared with plasminogen wild-type mice. Taken together our results indicate that under the conditions used in this study plasmin is not required for efficient follicular rupture or for activation of other proteases involved in this process. Alternatively, the role of plasmin may be effectively compensated for by other mechanisms in the absence of plasmin.
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| 18. |
- Leonardsson, G, et al.
(författare)
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Ovulation efficiency is reduced in mice that lack plasminogen activator gene function : functional redundancy among physiological plasminogen activators.
- 1995
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424 .- 1091-6490. ; 92:26, s. 12446-50
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Tidskriftsartikel (refereegranskat)abstract
- Several lines of indirect evidence suggest that plasminogen activation plays a crucial role in degradation of the follicular wall during ovulation. However, single-deficient mice lacking tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), or PA inhibitor type 1(PAI-1) gene function were recently found to have normal reproduction, although mice with a combined deficiency of tPA and uPA were significantly less fertile. To investigate whether the reduced fertility of mice lacking PA gene function is due to a reduced ovulation mechanism, we have determined the ovulation efficiency in 25-day-old mice during gonadotropin-induced ovulation. Our results reveal that ovulation efficiency is normal in mice with a single deficiency of tPA or uPA but reduced by 26% in mice lacking both physiological PAs. This result suggests that plasminogen activation plays a role in ovulatory response, although neither tPA nor uPA individually or in combination is obligatory for ovulation. The loss of an individual PA seems to be functionally complemented by the remaining PA but this compensation does not appear to involve any compensatory up-regulation. Our data imply that a functionally redundant mechanism for plasmin formation operates during gonadotropin-induced ovulation and that PAs together with other proteases generate the proteolytic activity required for follicular wall degradation.
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| 19. |
- Li, Lizhen, 1977, et al.
(författare)
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Protective role of reactive astrocytes in brain ischemia.
- 2008
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Ingår i: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 28:3, s. 468-81
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Tidskriftsartikel (refereegranskat)abstract
- Reactive astrocytes are thought to protect the penumbra during brain ischemia, but direct evidence has been lacking due to the absence of suitable experimental models. Previously, we generated mice deficient in two intermediate filament (IF) proteins, glial fibrillary acidic protein (GFAP) and vimentin, whose upregulation is the hallmark of reactive astrocytes. GFAP(-/-)Vim(-/-) mice exhibit attenuated posttraumatic reactive gliosis, improved integration of neural grafts, and posttraumatic regeneration. Seven days after middle cerebral artery (MCA) transection, infarct volume was 210 to 350% higher in GFAP(-/-)Vim(-/-) than in wild-type (WT) mice; GFAP(-/-), Vim(-/-) and WT mice had the same infarct volume. Endothelin B receptor (ET(B)R) immunoreactivity was strong on cultured astrocytes and reactive astrocytes around infarct in WT mice but undetectable in GFAP(-/-)Vim(-/-) astrocytes. In WT astrocytes, ET(B)R colocalized extensively with bundles of IFs. GFAP(-/-)Vim(-/-) astrocytes showed attenuated endothelin-3-induced blockage of gap junctions. Total and glutamate transporter-1 (GLT-1)-mediated glutamate transport was lower in GFAP(-/-)Vim(-/-) than in WT mice. DNA array analysis and quantitative real-time PCR showed downregulation of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of tissue plasminogen activator. Thus, reactive astrocytes have a protective role in brain ischemia, and the absence of astrocyte IFs is linked to changes in glutamate transport, ET(B)R-mediated control of gap junctions, and PAI-1 expression.
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| 22. |
- Mogilenko, Denis A., et al.
(författare)
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Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR
- 2019
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Ingår i: Cell. - : CELL PRESS. - 0092-8674 .- 1097-4172. ; 177:5, s. 1201-
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Tidskriftsartikel (refereegranskat)abstract
- Innate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-like receptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatory signals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect the immune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DCs) are exacerbated by a high-fatty-acid (FA) metabolic environment. FAs suppress the TLR-induced hexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changes enhance mitochondria! reactive oxygen species (mtROS) production and, in turn, the unfolded protein response (UPR), leading to a distinct transcriptomic signature with IL-23 as hallmark. Interestingly, chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response. Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23 expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innate immunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR.
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| 23. |
- Ny, A, et al.
(författare)
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Studies of mice lacking plasminogen activator gene function suggest that plasmin production prior to ovulation exceeds the amount needed for optimal ovulation efficiency.
- 1997
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Ingår i: European Journal of Biochemistry. - 0014-2956 .- 1432-1033. ; 244:2, s. 487-93
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Tidskriftsartikel (refereegranskat)abstract
- Many studies suggest that the plasminogen activator (PA) system plays a role in the proteolytic degradation of the follicle wall at the time of ovulation. Consistently, the ovulation efficiency is reduced by 26% in mice where both physiological PA genes have been inactivated. To reveal the mechanism behind reduced ovulation efficiency in PA-deficient mice and its effect on ovarian proteolysis. we have studied the regulation of plasmin activity in the ovaries of 25-day-old wild-type mice and mice with deficient PA gene function during gonadotropin-induced ovulation. In wild-type mice the plasmin activity was low in ovarian extracts from mice treated with pregnant mare's serum gonadotropin. However, this activity was increased between 2-8 h after an ovulatory dose of human choriogonadotropins. In mice lacking either tissue-type PA (tPA) or PA inhibitor type 1 (PAI-1) the plasmin activity levels prior to ovulation were similar to wild-type mice, while extracts prepared from urokinase-type PA (uPA) deficient mice had 10% or less of the plasmin activity. This indicates that most of the plasmin activity in the mouse ovary is generated by uPA. In addition, as the ovulation efficiency is impaired in tPA/uPA-deficient mice but appears normal in uPA-deficient mice, our data indicates that the amount of plasmin generated by PAs prior to ovulation in wild-type mice greatly exceeds the amount required for efficient ovulation.
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