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Sökning: WFRF:(Holmgren B) > (2020-2021)

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1.
  • Tokarew, JM, et al. (författare)
  • Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites
  • 2021
  • Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 141:5, s. 725-754
  • Tidskriftsartikel (refereegranskat)abstract
    • The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions and that these are reflected in its posttranslational modifications. We found that in post mortem human brain, including in the Substantia nigra, parkin is largely insoluble after age 40 years; this transition is linked to its oxidation, such as at residues Cys95 and Cys253. In mice, oxidative stress induces posttranslational modifications of parkin cysteines that lower its solubility in vivo. Similarly, oxidation of recombinant parkin by hydrogen peroxide (H2O2) promotes its insolubility and aggregate formation, and in exchange leads to the reduction of H2O2. This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. In prkn-null mice, H2O2 levels are increased under oxidative stress conditions, such as acutely by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin exposure or chronically due to a second, genetic hit; H2O2 levels are also significantly increased in parkin-deficient human brain. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at the primate-specific residue Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation in vitro. By probing sections of adult, human midbrain from control individuals with epitope-mapped, monoclonal antibodies, we found specific and robust parkin reactivity that co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these complementary redox effects may augment oxidative stress during ageing in dopamine-producing cells of mutant PRKN allele carriers, thereby enhancing the risk of Parkinson’s-linked neurodegeneration.
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2.
  • Holmgren, Christina M, et al. (författare)
  • Out-of-hospital cardiac arrest : Causes according to autopsy and electrocardiography - Analysis of 781 patients with neither hospital care nor prescribed medication during the preceding two years.
  • 2020
  • Ingår i: Resuscitation. - : Elsevier BV. - 0300-9572 .- 1873-1570. ; 150, s. 65-71
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: There is a knowledge gap regarding aetiology of and potential for predicting out-of-hospital cardiac arrest (OHCA) among individuals who are healthy before the event.AIM: To describe causes of OHCA and the potential for predicting OHCA in apparently healthy patients.METHODS: Patients were recruited from the Swedish Register of Cardiopulmonary Resuscitation from November 2007 to January 2011. Inclusion criteria were: OHCA with attempted CPR but neither dispensed prescription medication nor hospital care two years before the event The register includes the majority of patients suffering OHCA in Sweden where cardiopulmonary resuscitation (CPR) was attempted. Medication status was defined by linkage to the Swedish Prescribed Drug Register. Cause of death was assessed based on autopsy and the Swedish Cause of Death Register. Prediction of OHCA was attempted based on available electrocardiograms (ECG) before the OHCA event.RESULTS: Altogether 781 individuals (16% women) fulfilled the inclusion criteria. Survival to 30 days was 16%. Autopsy rate was 72%. Based on autopsy, 70% had a cardiovascular aetiology and 59% a cardiac aetiology. An ECG recording before the event was found in 23% of cases. The ECG was abnormal in 22% of them.CONCLUSION: Among OHCA victims who appeared to be healthy prior to the event, the cause was cardiovascular in the great majority according to autopsy findings. A minority had a preceding abnormal ECG that could have been helpful in avoiding the event.
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3.
  • Holmgren, Gustav, 1983-, et al. (författare)
  • Characterization of Human Induced Pluripotent Stem Cell-Derived Hepatocytes with Mature Features and Potential for Modeling Metabolic Diseases
  • 2020
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 21:2
  • Tidskriftsartikel (refereegranskat)abstract
    • There is a strong anticipated future for human induced pluripotent stem cell-derived hepatocytes (hiPS-HEP), but so far, their use has been limited due to insufficient functionality. We investigated the potential of hiPS-HEP as an in vitro model for metabolic diseases by combining transcriptomics with multiple functional assays. The transcriptomics analysis revealed that 86% of the genes were expressed at similar levels in hiPS-HEP as in human primary hepatocytes (hphep). Adult characteristics of the hiPS-HEP were confirmed by the presence of important hepatocyte features, e.g., Albumin secretion and expression of major drug metabolizing genes. Normal energy metabolism is crucial for modeling metabolic diseases, and both transcriptomics data and functional assays showed that hiPS-HEP were similar to hphep regarding uptake of glucose, low-density lipoproteins (LDL), and fatty acids. Importantly, the inflammatory state of the hiPS-HEP was low under standard conditions, but in response to lipid accumulation and ER stress the inflammation marker tumor necrosis factor alpha (TNF alpha) was upregulated. Furthermore, hiPS-HEP could be co-cultured with primary hepatic stellate cells both in 2D and in 3D spheroids, paving the way for using these co-cultures for modeling non-alcoholic steatohepatitis (NASH). Taken together, hiPS-HEP have the potential to serve as an in vitro model for metabolic diseases. Furthermore, differently expressed genes identified in this study can serve as targets for future improvements of the hiPS-HEP.
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