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- Bergemalm, Daniel, 1977-, et al.
(författare)
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Overloading of stable and exclusion of unstable human superoxide dismutase-1 variants in mitochondria of murine amyotrophic lateral sclerosis models
- 2006
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Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 26:16, s. 4147-4154
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Tidskriftsartikel (refereegranskat)abstract
- Mutants of human superoxide dismutase-1 (hSOD1) cause amyotrophic lateral sclerosis (ALS), and mitochondria are thought to be primary targets of the cytotoxic action. The high expression rates of hSOD1s in transgenic ALS models give high levels of the stable mutants G93A and D90A as well as the wild-type human enzyme, significant proportions of which lack Cu and the intrasubunit disulfide bond. The endogenous murine SOD1 (mSOD1) also lacks Cu and is disulfide reduced but is active and oxidized in mice expressing the low-level unstable mutants G85R and G127insTGGG. The possibility that the molecular alterations may cause artificial loading of the stable hSOD1s into mitochondria was explored. Approximately 10% of these hSOD1s were localized to mitochondria, reaching levels 100-fold higher than those of mSOD1 in control mice. There was no difference between brain and spinal cord and between stable mutants and the wild-type hSOD1. mSOD1 was increased fourfold in mitochondria from high-level hSOD1 mice but was normal in those with low levels, suggesting that the Cu deficiency and disulfide reduction cause mitochondrial overloading. The levels of G85R and G127insTGGG mutant hSOD1s in mitochondria were 100- and 1000-fold lower than those of stable mutants. Spinal cords from symptomatic mice contained hSOD1 aggregates covering the entire density gradient, which could contaminate isolated organelle fractions. Thus, high hSOD1 expression rates can cause artificial loading of mitochondria. Unstable low-level hSOD1s are excluded from mitochondria, indicating other primary locations of injury. Such models may be preferable for studies of ALS pathogenesis.
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| 2. |
- Berkenstam, Anders, et al.
(författare)
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The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans
- 2008
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 105:2, s. 663-667
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Tidskriftsartikel (refereegranskat)abstract
- Atherosclerotic cardiovascular disease is a major problem despite the availability of drugs that influence major risk factors. New treatments are needed, and there is growing interest in therapies that may have multiple actions. Thyroid hormone modulates several cardiovascular risk factors and delays atherosclerosis progression in humans. However, use of thyroid hormone is limited by side effects, especially in the heart. To overcome this limitation, pharmacologically selective thyromimetics that mimic metabolic effects of thyroid hormone and bypass side effects are under development. In animal models, such thyromimetics have been shown to stimulate cholesterol elimination through LDL and HDL pathways and decrease body weight without eliciting side effects. We report here studies on a selective thyromimetic [KB2115, (3-[[3,5-dibromo-4- [4-hydroxy-3-(1-methylethyl)-phenoxy]-phenyl]-amino]-3-oxopropanoic acid)] in humans. In moderately overweight and hypercholesterolemic subjects KB2115 was found to be safe and well tolerated and elicited up to a 40% lowering of total and LDL cholesterol after 14 days of treatment. Bile acid synthesis was stimulated without evidence of increased cholesterol production, indicating that KB2115 induced net cholesterol excretion. KB2115 did not provoke detectable effects on the heart, suggesting that the pharmacological selectivity observed in animal models translates to humans. Thus, selective thyromimetics deserve further study as agents to treat dyslipidemia and other risk factors for atherosclerosis. © 2007 by The National Academy of Sciences of the USA.
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| 3. |
- Rehnmark, Stefan, 1956-
(författare)
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Adrenergic regulation of proliferation and differentiation in brown adipose tissue
- 1991
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Brown adipose tissue constitutes an interesting model for studies of cell proliferation and cellular differentiation. Cold exposure of an animal induces recruitment of the tissue; this is accompanied by a marked increase in the mitogenic activity within the tissue and an increased expression of the genes coding for lipoprotein lipase and the uncoupling protein thermogenin. Stimulation of DNA synthesis in mouse brown adipose tissue invivo is here suggested to be a ß-adrenergically mediated process.In-vitro studies of the lipoprotein lipase gene in brown fat cell cultures revealed that the expression of this gene was under control of ß-adrenergic receptors of the ß3-receptor subtype. The increased gene expression was apparently not mediated through elevations of the cytosolic cAMP level. A localized cAMP signal is proposed.The brown fat cell culture system was further developed, to allow precursor cells to differentiate to the degree that functional resemblance to brown adipose tissue was obtained; especially, the only biochemical parameter which qualitatively distinguishes brown adipose tissue from white adipose tissue (i.e. the presence of thermogenin) was induced. It was found that thermogenin gene expression was under the control of both a)- and ßadrenergic receptors. A synergism between the adrenergic signal, thyroxine and insulin was also observed. Thermogenin itself was synthesized and targeted to the mitochondrial inner membrane, demonstrating the functional competence of these cultured cells.In-vivo studies of thermogenin gene expression in cold-exposed rats revealed that while there was only a transient increase in the transcription rate of the gene, the level of thermogenin mRNA was maintained at an elevated level for at least four days in cold. A prolongation of thermogenin mRNA half-life during sustained cold stimulation is suggested.It was concluded that the adrenergic signalling pathway allows for a multitude of cellular responses, either alone or through interaction with different signal transduction systems, and maybe also through specific localization of the signal in space.
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