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1371.
  • Zetterström, Per, 1980- (författare)
  • Misfolded superoxide dismutase-1 in amyotrophic lateral sclerosis
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Amyotrophic lateral sclerosis (ALS) is a disease in which the motor neurons die in a progressive manner, leading to paralysis and muscle wasting. ALS is always fatal, usually through respiratory failure when the disease reaches muscles needed for breathing. Most cases are sporadic, but approximately 5–10% are familial. The first gene to be linked to familial ALS encodes the antioxidant enzyme superoxide dismutase-1 (SOD1). Today, more than 160 different mutations in SOD1 have been found in ALS patients.  The mutant SOD1 proteins cause ALS by gain of a toxic property that should be common to all. Aggregates of SOD1 in motor neurons are hallmarks of ALS patients and transgenic models carrying mutant SOD1s, suggesting that misfolding, oligomerization, and aggregation of the protein may be involved in the pathogenesis. SOD1 is normally a very stable enzyme, but the structure has several components that make SOD1 sensitive to misfolding. The aim of the work in this thesis was to study misfolded SOD1 in vivo.Small amounts of soluble misfolded SOD1 were identified as a common denominator in transgenic ALS models expressing widely different forms of mutant SOD1, as well as wild-type SOD1. The highest levels of misfolded SOD1 were found in the vulnerable spinal cord. The amounts of misfolded SOD1 were similar in all the different models and showed a broad correlation with the lifespan of the different mouse strains. The misfolded SOD1 lacked the C57-C146 intrasubunit disulfide bond and the stabilizing zinc and copper ions, and was prinsipally monomeric. Forms with higher apparent molecular weights were also found, some of which might be oligomers. Misfolding-prone monomeric SOD1 appeared to be the principal source of misfolded SOD1 in the CNS. Misfolded SOD1 in the spinal cord was found to interact mainly with chaperones, with Hsc70 being the most important. Only a minor proportion of the Hsc70 was sequestered by SOD1, however, suggesting that chaperone depletion is not involved in ALS. SOD1 is normally found in the cytoplasm but can be secreted. Extracellular mutant SOD1 has been found to be toxic to motor neurons and glial cells. Misfolded SOD1 in the extracellular space could be involved in the spread of the disease between different areas of the CNS and activate glial cells known to be important in ALS. The best way to study the interstitium of the CNS is through the cerebrospinal fluid (CSF), 30% of which is derived from the interstitial fluid. Antibodies specific for misfolded SOD1 were used to probe CSF from ALS patients and controls for misfolded SOD1. We did find misfolded SOD1 in CSF, but at very low levels, and there was no difference between ALS patients and controls. This argues against there being a direct toxic effect of extracellular SOD1 in ALS pathogenesis.In conclusion, soluble misfolded SOD1 is a common denominator for transgenic ALS model mice expressing widely different mutant SOD1 proteins. The misfolded SOD1 is mainly monomeric, but also bound to chaperones, and possibly exists in oligomeric forms also. Misfolded SOD1 in the interstitium might promote spread of aggregation and activate glial cells, but it is too scarce to directly cause cytotoxicity.
1372.
  • Zetterström, Per, 1980-, et al. (författare)
  • Misfolded superoxide dismutase-1 in CSF from amyotrophic lateral sclerosis patients
  • 2011
  • Ingår i: Journal of Neurochemistry. - 0022-3042. ; 117:1, s. 91-99
  • Tidskriftsartikel (refereegranskat)abstract
    • Several of the superoxide dismutase-1 (SOD1) mutations linked to amyotrophic lateral sclerosis (ALS) lead to synthesis of structurally defective molecules, suggesting that any cytotoxic conformational species common for all mutations should be misfolded. SOD1 can be secreted and evidence from ALS model systems suggests that extracellular SOD1 may be involved in cytotoxicity. Three ELISAs specifically reacting with different sequence segments in misfolded SOD1 species were used for analysis of CSF from 38 neurological controls and from 96 ALS patients, 57 of whom were sporadic cases and 39 familial, including 22 patients carrying SOD1 mutations. Misfolded SOD1 was found in all samples. There were, however, no significant differences between patients with and without mutations, and between all the ALS patients and the controls. The estimated concentration of misfolded SOD1 in the interstitium of the CNS is a 1000 times lower than that required for appreciable cytotoxicity in model systems. The results argue against a direct cytotoxic role of extracellular misfolded SOD1 in ALS. Misfolded SOD1 in CSF cannot be used as a biomarker of ALS in patients with and without mutations in the enzyme.
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1373.
  • Zetterström, Per, 1980-, et al. (författare)
  • Proteins that bind to misfolded mutant superoxide dismutase-1 in spinal cords from transgenic ALS model mice
  • 2011
  • Ingår i: Journal of Biological Chemistry. - American Society for Biochemistry and Molecular Biology. - 0021-9258. - 1083-351X (Electronic) 0021-9258 (Linking) ; 286:23, s. 20130-20136
  • Tidskriftsartikel (refereegranskat)abstract
    • Mutant superoxide dismutase-1 (SOD1) has an unidentified toxic property that provokes ALS. Several ALS-linked SOD1 mutations cause long C-terminal truncations, which suggests that common cytotoxic SOD1 conformational species should be misfolded and that the C-terminal end cannot be involved. The cytotoxicity may arise from interaction of cellular proteins with misfolded SOD1 species. Here we specifically immunocaptured misfolded SOD1 by the C-terminal end, from extracts of spinal cords from transgenic ALS model mice. Associated proteins were identified with proteomic techniques. Two transgenic models expressing SOD1s with contrasting molecular properties were examined: the stable G93A mutant, which is abundant in the spinal cord with only a tiny subfraction misfolded, and the scarce disordered truncation mutant G127insTGGG. For comparison, proteins in spinal cord extracts with affinity for immobilized apo G93A mutant SOD1 were determined. Two-dimensional gel patterns with a limited number of bound proteins were found, which were similar for the two SOD1 mutants. Apart from neurofilament light, the proteins identified were all chaperones and by far most abundant was Hsc70. The immobilized apo G93A SOD1, which would populate a variety of conformations, was found to bind to a considerable number of additional proteins. A substantial proportion of the misfolded SOD1 in the spinal cord extracts appeared to be chaperone-associated. Still, only about 1% of the Hsc70 appeared to be associated with misfolded SOD1. The results argue against the notion that chaperone depletion is involved in ALS pathogenesis in the transgenic models and in humans carrying SOD1 mutations.
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1374.
  • Zhang, Jin-Yan, et al. (författare)
  • Dimethylsulfoxide-soluble Smoking Particles and Nicotine Affect Vascular Contractibility
  • 2009
  • Ingår i: Archives of Pharmacal Research. - Pharmaceutical Society of Korea. - 1976-3786. ; 32:10, s. 1475-1481
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim is to study the effect of dimethylsulfoxide-soluble smoking particles (DSP) and nicotine on the contractility of rat mesenteric artery. The superior mesenteric artery segments were cultured with DSP or nicotine for 24 h. The vascular contractibility was recorded with myograph system. DSP 0.4 mL/L and nicotine 0.48 and 0.96 mg/L shifted the concentration-contractile curves induced by sarafotoxin 6c, a selective agonist for ETB receptor toward the left with increased E-max. DSP 0.4 mL/L and nicotine 0.96 mg/L shifted ETA receptor-mediated the concentration-contractile curves toward the left with increased E-max. However, nicotine 0.06 mg/L which is the equivalent concentration of nicotine in DSP 0.4 mL/L did not affect the curves and the E-max mediated with ETA receptor and ETB receptor. DSP 0.2 and 0.4 mL/L shifted the concentration-contractile curves induced by noradrenaline toward the right with decreased E-max. Neither did nicotine 0.06 and 0.96 mg/L. Both DSP and nicotine shifted the concentration-contractile curves induced by 5-hydroxytryptamine (5-HT) toward the right parallely. DSP changed the phenotypes towards an increased efficacy of ETA receptor and ETB receptor, and a reduced efficacy of 5-HT receptor and alpha-adrenocceptor. The effects of DSP on ETB receptor, ETA receptor and alpha-adrenocceptor were independent of nicotine. The effect on 5-HT receptor was responsible to nicotine.
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1375.
  • Zhang, Yao, et al. (författare)
  • Boswellic acid inhibits expression of acid sphingomyelinase in intestinal cells.
  • 2009
  • Ingår i: Lipids in Health and Disease. - BioMed Central. - 1476-511X. ; 8:Dec 1
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Boswellic acid is a type of triterpenoids with antiinflammatory and antiproliferative properties. Sphingomyelin metabolism generates multiple lipid signals affecting cell proliferation, inflammation, and apoptosis. Upregulation of acid sphingomyelinase (SMase) has been found in several inflammation-related diseases such as inflammatory bowel diseases, atherosclerosis, and diabetes. METHODS: The present study is to examine the effect of 3-acetyl-11-keto-beta-boswellic acids (AKBA), a potent boswellic acid, on acid SMase activity and expression in intestinal cells. Both transformed Caco-2 cells and non-transformed Int407 cells were incubated with AKBA. After incubation, the change of acid SMase activity was assayed biochemically, the enzyme protein was examined by Western blot, and acid SMase mRNA was quantified by qPCR. RESULTS: We found that AKBA decreased acid SMase activity in both intestinal cell lines in dose and time dependent manners without affecting the secretion of the enzyme to the cell culture medium. The effect of AKBA was more effective in the fetal bovine serum-free culture medium. Among different types of boswellic acid, AKBA was the most potent one. The inhibitory effect on acid SMase activity occurred only in the intact cells but not in cell-free extract in the test tubes. At low concentration, AKBA only decreased the acid SMase activity but not the quantity of the enzyme protein. However, at high concentration, AKBA decreased both the mass of acid SMase protein and the mRNA levels of acid SMase in the cells, as demonstrated by Western blot and qPCR, respectively. Under the concentrations decreasing acid SMase activity, AKBA significantly inhibited cell proliferation. CONCLUSION: We identified a novel inhibitory effect of boswellic acids on acid SMase expression, which may have implications in human diseases and health.
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1376.
  • Zhang, Yao, et al. (författare)
  • Crucial role of alkaline sphingomyelinase in sphingomyelin digestion: A study on the enzyme knockout mice.
  • 2010
  • Ingår i: Journal of Lipid Research. - American Society for Biochemistry and Molecular Biology. - 1539-7262. ; 52:4, s. 771-781
  • Tidskriftsartikel (refereegranskat)abstract
    • Alkaline sphingomyelinase (alk-SMase) hydrolyses sphingomyelin (SM) to ceramide in the gut. To evaluate physiological importance of the enzyme, we generated alk-SMase knockout (KO) mice by Cre-LoxP system and studied SM digestion. Both wild type (WT) and the KO mice were fed 3H-palmitic acid labeled SM together with milk SM by gavage. The lipids in intestinal content, intestinal tissues, serum and liver were analysed by TLC. In KO mice, non-digested 3H-SM in the intestinal content increased by 6 fold and the formation of 3H-ceramide decreased markedly, resulting in 98% reduction of 3H-ceramide/3H-SM ratio 1 h after gavage. The absorbed 3H-palmitic acid portion was decreased by 95%. After three hours, a small increase in 3H-ceramide was identified in distal intestine in KO mice. In feces 3H-SM was increased by 243% and ceramide decreased by 74% in the KO mice. The KO mice also showed significantly decreased radioactivity in liver and serum. Furthermore alkaline phosphatase activity in the mucosa was reduced by 50%, and histological comparison of two female littermates preliminarily suggested mucosal hypertrophy in KO mice. The study provides definite proofs for crucial roles of alk-SMase in SM digestion and points to possible roles in regulating mucosal growth and alkaline phosphatase function.
1377.
  •  
1378.
  • Zheng, Jianpu, et al. (författare)
  • Vasodilation effect of atropine on rat mesenteric artery
  • 2005
  • Ingår i: Yao Xue Xue Bao. - Chinese Electronic Periodical Services. - 0513-4870. ; 40:5, s. 402-405
  • Tidskriftsartikel (refereegranskat)abstract
    • AIM: To study the vasodilation effect of atropine and its mechanism. METHODS: Isometric tension was recorded in isolated rat super mesenteric arteries precontracted by noradrenaline (NE) to study the vasodilation effect of atropine, and to investigate the role of endothelial cell and vascular smooth muscle cell on vasodilation. RESULTS: Atropine was shown to significantly dilate the endothelium-intact and endothelium-denuded arteries precontracted by NE. Nomega-Nitro-L-arginine methyl ester (L-NAME, nitric oxide synthase inhabitor), indomethacin (cyclooxygenase inhibitor), propranolol (general beta adrenoceptor antagonist) and glibenclamide (ATP sensitive potassium channel inhibitor) showed no effect on vasodilation of atropine. Atropine did not affect the concentration-contraction curve of K+. However, atropine suppressed the contraction induced by NE and CaCl2, but not that by caffeine in the Ca+ -free Krebs solution. CONCLUSION: Atropine showed significant vasodilation effect which may derive, in part, from endothelium. Besides, atropine could inhibit the receptor-mediated Ca2+ -influx and Ca2+ -release, which was inferred to the mechanism of atropine on vasodilation.
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1379.
  • Zhou, Li, et al. (författare)
  • Hydrolysis of the cubic liquid-crystalline phase of glyceryl monooleate by human pancreatic lipases
  • 2002
  • Ingår i: Conference on Lipid and Polymer-Lipid Systems, 2002,Chia Laguna, Italy,2002-10-01 - 2002-10-02. - Springer.
  • Konferensbidrag (refereegranskat)abstract
    • Glyceryl monooleate (GMO) and other unsaturated long-chain monoglycerides show peculiar phase behaviour characterised by the presence of one or more cubic liquid-crystalline phases. In the present study, hydrolysis of cubic lipid-water phases formed by GMO were determined. Human pancreatic carboxyl ester lipase (CEL), colipase-dependent lipase with colipase, human duodenal contents and rat pancreas homogenate were added and the release of free oleic acid from GMO was determined. It was found that pancreatic enzymes hydrolyse GMO cubic lipid-water phases in vitro. In the presence of concentrations of sodium taurocholate, sodium taourodeoxycholate or sodium glycocholate, above 3 mM, the hydrolysis by pancreatic enzymes was stimulated. The optimal pH for the hydrolysis of GMO by CEL was 7.5-8.5, by colipase-dependent lipase 6-9 with a peak at 6.5 and by rat pancreas homogenate 6-8.5 with a peak at 7.3. The hydrolysis of GMO with human duodenal content was slow but increased with time. These results indicated that pancreatic enzymes hydrolyse GMO in cubic lipid-water phases. The hydrolysis is effected by pH and the concentration of bile salts.
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1380.
  • Zhou, Li (författare)
  • Sources of Arachidonic Acid in Platelets, Bone, Marrow and Gastrointestinal Tract
  • 1999
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • This study investigates pathways by which the eicosanoid precursor pools in the platelets, bone marrow and the gastrointestinal (GI) mucosa are acquired and regulated, and in this context some aspects on the interaction between triglyceride (TG)-rich lipoproteins and platelets. 1. Platelets take up chylomicrons (CM) in vitro, the main part being sequestered in open canalicular system and not degraded, but do not exhibit any receptor mediated uptake and degradation of chylomicron remnants (CMR). Although CM, CMR and Intralipid affect agonist-induced platelet aggregation in vitro, CMs and CMRs are not an arachidonic acid (AA) source for platelets. The binding of prothrombin and protein S to postprandial TG-rich lipoproteins increased more after a meal rich in saturated fat than after a linoleate (LA) rich meal, which might increase platelet induced activation of these factors. 2. In rats plasma 2-arachidonyl-lysophosphatidylcholine (2-AA-LPC) supplies AA to several extrahepatic tissues, the quantitative importance being large in case of the small intestine. In guinea pigs, local desaturation-elongation of LA taken up as plasma free fatty acids (LA-FFA) is a major AA source. Bone marrow cells including megakaryocytes and the mucosa of GI tract produce much more AA than is exported from the liver. Therefore, we suggest that uptake and local interconversion of plasma LA-FFA and uptake of plasma 2-AA-LPC are two important alternative pathways for the supply of AA to extrahepatic tissues. Since platelets do not convert LA to d6-desaturase products, it is suggested that the build up of AA pools may be an integral part of the platelet formation in the bone marrow. 3. Fasting increases the rate of uptake and interconversion of plasma LA-FFA in both liver and extrahepatic tissues. The increase of plasma FFA concentration enhances the tissue uptake and this is linked to an increased rate of local interconversion of plasma LA-FFA. The concentration and composition of the plasma FFA pool as well as the regulation of desaturases activity in extrahepatic tissues during fasting is important determinants of eicosanoid precursor formation. 4. Our results challenge the common view that the liver is the main site of formation of AA which is then transported to other tissues mainly by lipoproteins. Our animal model can be used to study the rates of fatty acid desaturation and acylation in relation to enzyme activities and substrate availability in vivo.
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