| 1. |
- Hognert, Helena, 1973, et al.
(författare)
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Acute effects of transdermal 17beta-estradiol on hemostatic variables after 24-hour treatment.
- 2002
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Ingår i: Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. - 1076-0296. ; 8:3, s. 239-43
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate the acute effects of transdermal 17beta-estradiol (Estraderm) on plasma levels of coagulatory and fibrinolytic factors in postmenopausal normotensive and hypertensive women. Eleven normotensive and 13 hypertensive women were included in this placebo-controlled crossover study. In a randomized order each subject was treated with a patch of 100 microg 17beta-estradiol or placebo for 24 hours. Serum levels of tissue type plasminogen activator (tPA) activity, plasminogen activator inhibitor-I (PAI-1) activity, tPA antigen, PAI-I antigen, FVII, FX, and fibrinogen were assayed after both treatments. There was no significant difference in serum levels of hemostatic variables after treatment with estrogen compared to levels after placebo treatment in either of the groups. Nor was there any measurable difference when comparing hypertensive and normotensive subjects.
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| 2. |
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| 3. |
- Clemedson, Cecilia, et al.
(författare)
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Development of an in vitro test battery for the estimation of acute human systemic toxicity : An outline of the EDIT project. Evaluation-guided Development of New In Vitro Test Batteries
- 2002
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Ingår i: ATLA (Alternatives to Laboratory Animals). - 0261-1929. ; 30:3, s. 313-321
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the Evaluation-guided Development of new In Vitro Test Batteries (EDIT) multicentre programme is to establish and validate in vitro tests relevant to toxicokinetics and for organ-specific toxicity, to be incorporated into optimal test batteries for the estimation of human acute systemic toxicity. The scientific basis of EDIT is the good prediction of human acute toxicity obtained with three human cell line tests (R(2) = 0.77), in the Multicentre Evaluation of In Vitro Cytotoxicity (MEIC) programme. However, the results from the MEIC study indicated that at least two other types of in vitro test ought to be added to the existing test battery to improve the prediction of human acute systemic toxicity - to determine key kinetic events (such as biotransformation and passage through biological barriers), and to predict crucial organ-specific mechanisms not covered by the tests in the MEIC battery. The EDIT programme will be a case-by-case project, but the establishment and validation of new tests will be carried through by a common, step-wise procedure. The Scientific Committee of the EDIT programme defines the need for a specific set of toxicity or toxicokinetic data. Laboratories are then invited to perform the defined tests in order to provide the "missing" data for the EDIT reference chemicals. The results obtained will be evaluated against the MEMO (the MEIC Monograph programme) database, i.e. against human acute systemic lethal and toxicity data. The aim of the round-table discussions at the 19th Scandinavian Society for Cell Toxicology (SSCT) workshop, held in Ringsted, Denmark on 6-9 September 2001, was to identify which tests are the most important for inclusion in the MEIC battery, i.e. which types of tests the EDIT programme should focus on. It was proposed that it is important to include in vitro methods for various kinetic events, such as biotransformation, absorption in the gut, passage across the blood-brain barrier, distribution volumes, protein binding, and renal clearance/accumulation. Models for target organ toxicity were also discussed. Because several of the outlier chemicals (paracetamol, digoxin, malathion, nicotine, paraquat, atropine and potassium cyanide) in the MEIC in vivo-in vitro evaluation have a neurotoxic potential, it was proposed that the development within the EDIT target organ programme should initially be focused on the nervous system.
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| 4. |
- Filipsson, Helena L., 1973, et al.
(författare)
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Seasonal study of delta O-18 and delta C-13 in living (stained) benthic foraminifera from two Swedish fjords
- 2004
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Ingår i: Marine Micropaleontology. - : Elsevier BV. - 0377-8398. ; 53:1-2, s. 159-172
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Tidskriftsartikel (refereegranskat)abstract
- In a previous 16-month seasonal study on living (stained) benthic foraminifera from two fjords on the Swedish west coast, it was reported that foraminifera proliferated in response to phytodetritus input; the strongest response came from the opportunistic species Stainforthia fusiformis. In this study, our objective was to find out if that phytodetritus input resulted in a change in the carbon isotopic composition of the foraminiferal tests. We also wanted to examine if variations in salinity and temperature (due to seasonality or deep-water exchanges) were reflected in the delta(18)O values. From S. fusiformis that were obtained from the Havstens Fjord (20 m) and the Gullmar Fjord (119 m) during the 16-month study, we developed a time series of delta(18)O and delta(13)C. After the spring blooms in the Havstens and the Gullmar Fjord, decreases of about 0.2parts per thousand to 0.3parts per thousand in the foraminiferal delta(13)C values were noted; in the Gullmar Fjord after the autumn blooms, decreases of the same order were also noted. Comparing the Havstens and the Gullmar Fjord, we found a 1parts per thousand difference in both delta(13)C and delta(18)O; we attribute this to hydrographic differences between the two fjords. Using calculated values of delta(18)O, together with the measured ones, we noticed that S. fusiformis in the Gullmar Fjord seems to calcify close to equilibrium with respect to the oxygen isotopes. During autumn, water temperatures were relatively high in the Havstens Fjord, and foraminiferal abundance in the fjord was also high after a phytodetritus input; but, the measured delta(18)O values do not reflect these higher temperatures. This apparently contradictory combination of results might be explained by a varying delta(18)O composition of the water during the year, which counterbalances the temperature effect. (C) 2004 Published by Elsevier B.V.
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| 5. |
- Gustafsson, Helena, et al.
(författare)
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Insulin-like growth factor type 1 prevents hyperglycemia-induced uncoupling protein 3 down-regulation and oxidative stress
- 2004
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 0360-4012 .- 1097-4547. ; 77:2, s. 285-291
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Tidskriftsartikel (refereegranskat)abstract
- Uncoupling proteins (UCPs) have been reported to decrease the mitochondrial production of reactive oxygen species (ROS) by lowering the mitochondrial inner membrane potential (MMP). We have previously shown that UCP3 expression is positively regulated by insulin-like growth factor-1 (IGF-1). The aim of this study was to investigate the role of UCPs in IGF-1-mediated protection from hyperglycemia-induced oxidative stress and neurodegeneration. Human neuroblastoma SH-SY5Y cells were differentiated with retinoic acid for 6 days, after which exposure to 8, 30, or 60 mM glucose with or without 10 nM IGF-1 was started. After 48-72 hr, the number of neurites per cell, UCP3 protein expression, MMP, and intracellular levels of ROS and total glutathione were examined. These studies showed that glucose concentration-dependently reduced the number of neurites per cell, with a 50% reduction at 60 mM. In parallel, the UCP3 protein expression was down-regulated, and the MMP was raised 3.5-fold, compared with those in cells incubated with 8 mM glucose. Also, the ROS levels were increased, showing a twofold maximum at 60 mM glucose. This was accompanied by a twofold elevation of total glutathione levels, confirming an altered cellular redox state. IGF-1 treatment prevented the glucose-induced neurite degeneration and UCP3 down-regulation. Furthermore, the MMP and the intracellular levels of ROS and glutathione were normalized to those of control cells. These data indicate that IGF-1 may protect from hyperglycemia-induced oxidative stress and neuronal injuries by regulating MMP, possibly by the involvement of UCP3.
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| 6. |
- Gustafsson, Helena, et al.
(författare)
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Insulin-like growth factor type 1 upregulates uncoupling protein 3.
- 2001
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Ingår i: Biochem Biophys Res Commun. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 287:5, s. 1105-11
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Tidskriftsartikel (refereegranskat)abstract
- In this study the expression of uncoupling protein 3 (UCP3) and its regulation by insulin-like growth factor 1 (IGF-I) and insulin in human neuroblastoma SH-SY5Y cells were characterized. Reverse transcriptase-PCR, Western blot, and immunofluorescence analysis showed that SH-SY5Y cells express UCP3 natively. IGF-I induced a time- and concentration-dependent induction of UCP3 protein reaching a twofold expression after 72 h with 10 nM IGF-I. Extremely high insulin concentrations (860 nM) and 10 nM trIGF-I, a truncated form of IGF-I with the same affinity for the IGF-I receptor as the full-length IGF-I, but with lower activity on the insulin receptor, also upregulated UCP3. We conclude that SH-SY5Y cells express UCP3 natively and that the expression is regulated by IGF-I via the IGF-I receptor. Copyright 2001 Academic Press.
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| 7. |
- Gustafsson, Helena, et al.
(författare)
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Signalling pathways for insulin-like growth factor type 1-mediated expression of uncoupling protein 3.
- 2004
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Ingår i: J Neurochem. - : Wiley. - 0022-3042 .- 1471-4159. ; 88:2, s. 462-8
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Tidskriftsartikel (refereegranskat)abstract
- Uncoupling protein 3 (UCP3) is a mitochondrial protein with antioxidant properties and its regulation by factors promoting cell-survival may be important for protection of, for instance, neurons in states of oxidative stress. In the present study, we investigated regulatory pathways for UCP3 expression mediated by the neuroprotective hormone insulin-like growth factor type 1 (IGF-1) in human neuroblastoma SH-SY5Y cells. Northern blot analysis and RT-PCR showed that treatment with 10 nm IGF-1 increased the UCP3 mRNA levels 2.5-fold after 5 h. Co-incubation with the phosphatidylinositol 3 (PI3)-kinase inhibitor LY294002 prohibited IGF-1-mediated induction of both UCP3 mRNA and protein in a concentration-dependent manner, with a complete blockage at 1 microm, as shown by RT-PCR and western blot analyses. The mitogen-activated protein (MAP) kinase kinase 1 (MKK1 or MEK) inhibitor PD98059 also decreased the UCP3 mRNA expression at 10 microm, however, this concentration only partly inhibited the protein expression. We conclude that IGF-1 enhanced UCP3 expression at transcriptional level, primarily through the PI3-kinase-dependent pathway and partly through the MAP kinase pathway.
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| 8. |
- Gustafsson, Helena, 1975-
(författare)
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Uncoupling Proteins : Regulation by IGF-1 and Neuroprotection during Hyperglycemia in Vitro
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diabetic neuropathy is believed to arise due to oxidative stress following hyperglycemic situations. Uncoupling proteins (UCPs) constitute a subgroup of mitochondrial transporter proteins with putative antioxidant properties. By dissipating the proton gradient over the mitochondrial inner membrane, these proteins reduce the mitochondrial inner membrane potential (MMP), and thereby, the mitochondrial production of reactive oxygen species (ROS) is decreased. In this thesis I have examined the regulation of UCP2, UCP3, and UCP4 by the neuroprotective hormone insulin-like growth factor type 1 (IGF-1). I have also investigated the possible involvement of UCP3 in IGF-1-mediated neuroprotection following high glucose treatments. All studies were performed using human neuroblastoma SH-SY5Y cells as an in vitro cell model. The major findings were as follows: i. Native SH-SY5Y cells expressed UCP2, UCP3, and UCP4. ii. UCP3 was upregulated by IGF-1 via activation of the IGF-1 receptor. IGF-1 increased UCP3 mRNA and protein levels primarily via activation of the “classical” anti-apoptotic phosphatidyl inositol 3 (PI3)-kinase signaling pathway, as shown by incubation with specific inhibitors of the PI3-kinase and mitogen activated protein (MAP) kinase signaling pathways. iii. UCP2 and UCP4 protein levels were only marginally or not at all regulated by IGF-1. These UCPs are probably not involved in IGF-1-mediated neuroprotection. iv. High glucose concentrations reduced the UCP3 protein levels in highly differentiated SH-SY5Y cells. Concomitantly, the MMP and the levels of ROS and glutathione increased, whereas the number of neurites per cell was reduced. This supports an antioxidant and neuroprotective role of UCP3 v. IGF-1 prevented the glucose-induced reduction in UCP3 protein levels. In parallel, the effects on MMP, levels of ROS and glutathione, and number of neurites per cell were abolished or significantly reduced. These data suggest that UCP3 is involved in IGF-1-mediated neuroprotection.
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| 9. |
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| 10. |
- Svanborg, Catharina, et al.
(författare)
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HAMLET kills tumor cells by an apoptosis-like mechanism--cellular, molecular, and therapeutic aspects.
- 2003
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Ingår i: Advances in Cancer Research. - 0065-230X. ; 88, s. 1-29
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Forskningsöversikt (refereegranskat)abstract
- HAMLET (human α-lactalbumin made lethal to tumor cells) is a protein-lipid complex that induces apoptosis-like death in tumor cells, but leaves fully differentiated cells unaffected. This review summarizes the information on the in vivo effects of HAMLET in patients and tumor models, on the tumor cell biology, and on the molecular characteristics of the complex. HAMLET limits the progression of human glioblastomas in a xenograft model and removes skin papillomas in patients. This broad anti-tumor activity includes >40 different lymphomas and carcinomas and apoptosis is independent of p53 or bcl-2. In tumor cells, HAMLET enters the cytoplasm, translocates to the perinuclear area, and enters the nuclei, where it accumulates. HAMLET binds strongly to histones and disrupts the chromatin organization. In the cytoplasm, HAMLET targets ribosomes and activates caspases. The formation of HAMLET relies on the propensity of α-lactalbumin to alter its conformation when the strongly bound Ca2+ ion is released and the protein adopts the apo-conformation that exposes a new fatty acid binding site. Oleic acid (C18:1,9 cis) fits this site with high specificity, and stabilizes the altered protein conformation. The results illustrate how protein folding variants may be beneficial, and how their formation in peripheral tissues may depend on the folding change and the availability of the lipid cofactor. One example is the acid pH in the stomach of the breast-fed child that promotes the formation of HAMLET This mechanism may contribute to the protective effect of breastfeeding against childhood tumors. We propose that HAMLET should be explored as a novel approach to tumor therapy.
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