| 1. |
- Brederlau, Anke, 1968, et al.
(författare)
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The bone morphogenetic protein type Ib receptor is a major mediator of glial differentiation and cell survival in adult hippocampal progenitor cell culture.
- 2004
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Ingår i: Molecular biology of the cell. - 1059-1524. ; 15:8, s. 3863-75
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Tidskriftsartikel (refereegranskat)abstract
- Bone morphogenetic proteins (BMPs) act as growth regulators and inducers of differentiation. They transduce their signal via three different type I receptors, termed activin receptor-like kinase 2 (Alk2), Alk3, or bone morphogenetic protein receptor Ia (BMPRIa) and Alk6 or BMPRIb. Little is known about functional differences between the three type I receptors. Here, we have investigated consequences of constitutively active (ca) and dominant negative (dn) type I receptor overexpression in adult-derived hippocampal progenitor cells (AHPs). The dn receptors have a nonfunctional intracellular but functional extracellular domain. They thus trap BMPs that are endogenously produced by AHPs. We found that effects obtained by overexpression of dnAlk2 and dnAlk6 were similar, suggesting similar ligand binding patterns for these receptors. Thus, cell survival was decreased, glial fibrillary acidic protein (GFAP) expression was reduced, whereas the number of oligodendrocytes increased. No effect on neuronal differentiation was seen. Whereas the expression of Alk2 and Alk3 mRNA remained unchanged, the Alk6 mRNA was induced after impaired BMP signaling. After dnAlk3 overexpression, cell survival and astroglial differentiation increased in parallel to augmented Alk6 receptor signaling. We conclude that endogenous BMPs mediate cell survival, astroglial differentiation and the suppression of oligodendrocytic cell fate mainly via the Alk6 receptor in AHP culture.
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| 2. |
- Ewert, Sara, 1974, et al.
(författare)
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Dynamic expression of the angiotensin II type 2 receptor and duodenal mucosal alkaline secretion in the Sprague-Dawley rat
- 2006
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Ingår i: Experimental Physiology. - : Wiley. - 0958-0670. ; 91:1, s. 191-199
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Tidskriftsartikel (refereegranskat)abstract
- Activation of angiotensin II type 2 receptors (AT2R) has been shown to stimulate duodenal mucosal alkaline secretion (DMAS) in Sprague-Dawley rats (S-D). This finding could not be confirmed in another line of S-D, and the present study investigates whether the level of AT2R expression determines the response to the AT2R agonist CGP42112A. DMAS was measured in anaesthetized rats using in situ pH-stat titration. Real-time PCR and Western blot were used to assess AT1R and AT2R RNA and protein expression, respectively. CGP42112A (0.1 microg kg(-1)min(-1) I.V.) elicited a 45% net increase in DMAS in the previous S-D line studied, whereas no change occurred in the new S-D line. Luminal administration of prostaglandin E2 (10(-5) M) increased DMAS similarly in both S-D lines. AT2R protein expression was significantly higher in tissue from the previous line compared to the new line. Individual AT1R to AT2R ratios (RNA and protein) were significantly higher in the new line compared to the previous S-D line. In the new S-D line intravenous infusion of angiotensin II (Ang II; 10 microg kg(-1) h(-1)) over 120 min significantly lowered the duodenal AT1aR to AT2R RNA ratio. Prolonged Ang II infusion over 240 min increased AT2R protein expression and evoked a 42% stimulatory response in DMAS to CGP42112A. The level of local AT2R expression determines the effect of the AT2R agonist CGP42112A on rat duodenal mucosal alkaline secretion. AT2R expression should be confirmed before interpreting the experimental effects of pharmacological interferences with this receptor.
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| 3. |
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| 4. |
- Fagman, Johan Bourghardt, 1980, et al.
(författare)
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The endogenous estradiol metabolite 2-methoxyestradiol reduces atherosclerotic lesion formation in female apolipoprotein E-deficient mice
- 2007
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Ingår i: Endocrinology. - : Endocrine Society. - 0013-7227 .- 1945-7170. ; 148:9, s. 4128-4132
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Tidskriftsartikel (refereegranskat)abstract
- Estradiol, the major endogenous estrogen, reduces experimental atherosclerosis and metabolizes to 2-methoxyestradiol in vascular cells. Currently undergoing evaluation in clinical cancer trials, 2-methoxyestradiol potently inhibits cell proliferation independently of the classical estrogen receptors. This study examined whether 2-methoxyestradiol affects atherosclerosis development in female mice. Apolipoprotein E-deficient mice, a well-established mouse model of atherosclerosis, were ovariectomized and treated through slow-release pellets with placebo, 17beta-estradiol (6 microg/d), or 2-methoxyestradiol [6.66 microg/d (low-dose) or 66.6 microg/d (high-dose)]. After 90 d, body weight gain decreased and uterine weight increased in the high-dose but not low-dose 2-methoxyestradiol group. En face analysis showed that the fractional area of the aorta covered by atherosclerotic lesions decreased in the high-dose 2-methoxyestradiol (52%) but not in the low-dose 2-methoxyestradiol group. Total serum cholesterol levels decreased in the high- and low-dose 2-methoxyestradiol groups (19%, P < 0.05 and 21%, P = 0.062, respectively). Estradiol treatment reduced the fractional atherosclerotic lesion area (85%) and decreased cholesterol levels (42%). In conclusion, our study shows for the first time that 2-methoxyestradiol reduces atherosclerotic lesion formation in vivo. The antiatherogenic activity of an estradiol metabolite lacking estrogen receptor activating capacity may argue that trials on cardiovascular effects of hormone replacement therapy should use estradiol rather than other estrogens. Future research should define the role of 2-methoxyestradiol as a mediator of the antiatherosclerotic actions of estradiol. Furthermore, evaluation of the effects of 2-methoxyestradiol on cardiovascular disease endpoints in ongoing clinical trials is of great interest.
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| 5. |
- Göthlin, Sara, 1979-
(författare)
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Prioritet och avtal : Intercreditoravtal i svensk rätt, särskilt vid insolvens
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- An intercreditor agreement is a contract between two or more creditors in relation to a common debtor. It regulates, among other things, the priority of payment and the distribution of proceeds from the enforcement of security. Intercreditor agreements are widely used in corporate finance transactions, in connection with private as well as public loan issuance. The main aim of the thesis is to clarify under which circumstances, if any, agreements whereby a creditor is subordinated towards one or more other creditors are effective in the bankruptcy of either the borrower or a junior creditor. It is suggested that the ranking of claims be analysed as falling into one of two main types of legal construction. First, it is possible to construe the transaction as a transfer or pledge of rights over a junior creditor’s claim, or its claim on future dividends in the debtor’s bankruptcy. Second, it is possible that an agreement to subordinate in favour of one or more other creditors should be understood as a condition for repayment, making the junior claim conditional on the discharge of the senior debt. The thesis concludes that a receiver in bankruptcy should, as a main rule, observe a waterfall that certain creditors and the debtor have agreed ex ante. The same principle should apply in formal company reorganization proceedings. The conclusions are supported by a legal analysis carried out in Part III of the thesis. Further, such interpretation is in line with the normative framework set out in Part II of the thesis, which emphasises the interest of legal certainty and the upholding of pre-bankruptcy entitlements. In addition, the ongoing harmonisation of financial markets and insolvency law that is taking place on the EU level indicates the need to find paths under Swedish law that are consistent with international developments. The final chapter of Part III includes an analysis of the function of an agent as representative of a group of creditors under Swedish law. It is suggested that this is an area where the legislator should intervene without delay. Especially, the market would benefit from certainty concerning the right of an agent to represent creditors in court proceedings, and the enforceability of non-action undertakings of individual creditors. Importantly, if an agent is able to collect funds from a common borrower in and outside of bankruptcy, an agreed waterfall would become enforceable in practice.
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| 6. |
- Hägg, Daniel, 1974, et al.
(författare)
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Augmented levels of CD44 in macrophages from atherosclerotic subjects: a possible IL-6-CD44 feedback loop?
- 2007
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 190:2, s. 291-7
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Tidskriftsartikel (refereegranskat)abstract
- The cell-adhesion molecule CD44 likely participates in atherosclerosis development. We have shown previously that pro-inflammatory cytokines affect CD44 expression. Therefore, this work examined the role of elevated CD44 levels in human macrophages. Macrophages from human atherosclerotic subjects (n=15) showed elevated levels of CD44 transcript and protein (1.5-fold) compared to matched controls (n=15) (P=0.050 and 0.044, respectively). To test whether genetic factors influence CD44 expression, two single nucleotide polymorphisms in the CD44 gene were analyzed but these were not associated with coronary artery disease. We also examined the potential connection between plasma cytokine levels and CD44 expression. In atherosclerotic subjects, elevated CD44 expression correlates (P=0.012) with enhanced macrophage IL-6 secretion (3.13+/-2.5 pg/mL versus 0.32+/-0.16 pg/mL in controls, P=0.021). Additionally, CD44-deficient mice exhibit less circulating IL-6 than wild-type controls (9.8+/-0.7 pg/mL versus 14.3+/-0.7 pg/mL; P=0.032). Furthermore, IL-6 augments CD44 expression in primary human macrophages after 24 h (P=0.038) and 48 h (P=0.015). Taken together, our data show an IL-6-CD44 feedback loop in macrophages. Such a positive feedback loop may aggravate atherosclerosis development.
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| 7. |
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| 8. |
- Krettek, Alexandra, 1968, et al.
(författare)
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CD44 - a new cardiovascular drug target or merely an innocent bystander?
- 2009
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Ingår i: Cardiovascular & hematological disorders drug targets. - : ingentaconnect. - 2212-4063. ; 9:4, s. 293-302
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Tidskriftsartikel (refereegranskat)abstract
- CD44, short for cluster of differentiation 44, is an adhesion molecule of the hyaluronate receptor family. Expressed on the surface of most vertebrate cells, it functions as a receptor for several extracellular matrix components, e.g., hyaluronan, collagen, laminin, fibronectin, and osteopontin. CD44 has in recent years been intensively studied in connection with different forms of cancer, where CD44 may regulate invasiveness and tumor progression. Although major functions involve adhesion and migration, CD44 also affects leukocyte homing and recruitment, phagocytosis, matrix remodeling, proliferation, and apoptosis. As such, CD44 is an interesting putative molecule in cardiovascular drug therapy. Accumulating evidence from human studies point to CD44 as involved in inflammatory diseases such as atherosclerosis and human abdominal aneurysms. To date, several animal studies have shown that the role of CD44 in atherogenesis may vary depending on experimental model. In this Review, we trace CD44 and its potential role in the context of cardiovascular diseases by highlighting both human and animal studies that may help us understand; is CD44 a new cardiovascular drug target or merely an innocent bystander?
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| 9. |
- Morin, Eric, et al.
(författare)
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VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival
- 2018
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Ingår i: Journal of Pathology. - : John Wiley & Sons. - 0022-3417 .- 1096-9896. ; 246:3, s. 311-322
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Tidskriftsartikel (refereegranskat)abstract
- Unstable and dysfunctional tumor vasculature promotes cancer progression and spread. Signal transduction by the pro-angiogenic vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) is modulated by VEGFA-dependent complex formation with neuropilin 1 (NRP1). NRP1 expressed on tumor cells can form VEGFR2/NRP1 trans-complexes between tumor cells and endothelial cells which arrests VEGFR2 on the endothelial surface, thus interfering with productive VEGFR2 signaling. In mouse fibrosarcoma, VEGFR2/NRP1 trans-complexes correlated with reduced tumor vessel branching and reduced tumor cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) strongly expressed NRP1 on both tumor cells and endothelial cells, in contrast to other common cancer forms. Using proximity ligation assay, VEGFR2/NRP1 trans-complexes were identified in human PDAC tumor tissue, and its presence was associated with reduced tumor vessel branching, reduced tumor cell proliferation, and improved patient survival after adjusting for other known survival predictors. We conclude that VEGFR2/NRP1 trans-complex formation is an independent predictor of PDAC patient survival.
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| 10. |
- Sjöberg, Sara, 1979
(författare)
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A role of CD44 in atherosclerosis? Studies in mice and humans
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atherosclerosis is an inflammatory disease that can lead to clinical complications such as myocardial infarction and stroke. Expressed in both vascular and inflammatory cells, adhesion molecule CD44 can be cleaved from the cell surface, and soluble CD44 can be detected in blood. CD44 mediates many inflammatory events, some possibly critical for atherogenesis. However, the role of CD44 in atherosclerosis remains incompletely understood. Therefore, this thesis aimed to investigate the role of CD44 in atherogenesis. No association between soluble CD44 in serum and atherosclerosis, cardiovascular risk factors, and diabetes was determined, suggesting that soluble CD44 is not a suitable biomarker for atherosclerosis. In contrast, macrophages from patients with subclinical atherosclerosis showed enhanced levels of CD44 compared to healthy controls. CD44 expression associated with increased interleukin-6 secretion, and macrophages treated with interleukin-6 exhibited augmented CD44 expression. To further examine the potential role of CD44 in atherosclerosis in vivo, low-density lipoprotein receptor-deficient (LDLr-/-) mice with or without CD44 expression were used. A bone marrow transplantation in LDLr-/- mice to obtain a mouse model with CD44-deficiency on bone marrow-derived cells was also performed. Surprisingly, and in contrast to published data on CD44 in apolipoprotein-deficient mice, CD44-deficiency in LDLr-/- mice resulted in no or very modest reduction of lesion development. However, both mast cells and T cells, two cell types involved in lesion instability and rupture, decreased due to CD44-deficiency in advanced lesions. Furthermore, altered CD44 expression may influence the extrinsic coagulation cascade and therefore may affect thrombus formation. Taken together, CD44 expression increased in macrophages from subjects with atherosclerosis. However, its soluble counterpart did not associate with subclinical atherosclerosis and did not hold promise as potential biomarker. Since altered CD44 expression affects cell composition, it may contribute to lesion stability.
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| 11. |
- Sjöberg, Sara, 1979, et al.
(författare)
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CD44-deficiency on hematopoietic cells limits T-cell number but does not protect against atherogenesis in LDL receptor-deficient mice
- 2009
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Ingår i: Atherosclerosis. - : Elsevier. - 0021-9150 .- 1879-1484. ; 206:2, s. 369-374
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Vascular and inflammatory cells express adhesion molecule CD44. We demonstrated previously that enhanced CD44 localizes in human atherosclerotic lesions. Apolipoprotein E/cd44 double-deficient mice and apolipoprotein E-deficient mice transplanted with CD44-deficient bone marrow (BM) exhibit reduced atherosclerosis. Since CD44 is a novel factor in atherogenesis, it is imperative that it is investigated in more than one animal model to conclusively determine its role in this particular disease pathology. To test the hypothesis that CD44 expressed by hematopoietic cells plays a critical role in atherogenesis in the low density lipoprotein (LDL) receptor-deficient mouse model, we performed BM reconstitution experiments.METHODS: Lethally irradiated LDL receptor-deficient mice were transplanted with either CD44-deficient or wild-type BM. Beginning 10 weeks after successful reconstitution, mice consumed a cholesterol-enriched atherogenic diet for 6 or 11 weeks.RESULTS: Surprisingly, CD44-deficiency on BM-derived inflammatory cells did not affect lesion size. Additionally, neither group displayed differences in smooth muscle cell, macrophage, collagen, or elastin content as well as lipoprotein levels. However, lesions in CD44-deficient BM-recipient mice contained fewer T-cells compared to wild-type BM mice. Interestingly, CD44-deficient T-cells expressed less chemokine receptor-5 mRNA. Furthermore, in vivo leukocyte adhesion decreased in CD44-deficient mice compared to wild-type mice.CONCLUSION: This study surprisingly revealed that atherogenesis does not require CD44 expression on hematopoietic cells in the LDL receptor-deficient mouse model. However, CD44 promotes T-cell recruitment, downregulates chemokine receptor-5, and participates critically in leukocyte adhesion in vivo. Consequently, the anti-atherogenic role of CD44 may require CD44-deficiency on cell types other than inflammatory cells in the LDL receptor-deficient mouse model.
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| 12. |
- Sjöberg, Sara, 1979, et al.
(författare)
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Circulating soluble CD44 is higher among women than men and is not associated with cardiovascular risk factors or subclinical atherosclerosis
- 2005
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Ingår i: Metabolism. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 54:2, s. 139-41
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, the associations between the plasma concentration of soluble CD44 (sCD44), sex, cardiovascular risk factors, and ultrasound-assessed measures of carotid atherosclerosis were examined in 2 groups of 61- and 64-year-old men and women from population-based samples. Women had higher levels of circulating sCD44 than men. There were no associations between sCD44 and cardiovascular risk factors or subclinical atherosclerosis.
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