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Träfflista för sökning "WFRF:(Svensson Maria K) ;pers:(Johansson Lars)"

Sökning: WFRF:(Svensson Maria K) > Johansson Lars

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1.
  • Ladds, Marcus J. G. W., et al. (författare)
  • A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
  • 2018
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.
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2.
  • Svensson, Maria K., et al. (författare)
  • Alterations in heart rate variability during everyday life are linked to insulin resistance. A role of dominating sympathetic over parasympathetic nerve activity?
  • 2016
  • Ingår i: Cardiovascular Diabetology. - : Springer Science and Business Media LLC. - 1475-2840. ; 15
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: To evaluate the role of the autonomic nervous system (ANS) in the development of insulin resistance (IR) and assess the relationship between IR and activity of ANS using power spectrum analysis of heart rate variability (HRV).Subjects and methods: Twenty-three healthy first-degree relatives of patients with type 2 diabetes (R) and 24 control subjects without family history of diabetes (C) group-matched for age, BMI and sex were included. Insulin sensitivity (M value) was assessed by hyperinsulinemic (56 mU/m2/min) euglycemic clamp. Activity of the ANS was assessed using power spectrum analysis of HRV in long-term recordings, i.e., 24-h ECG monitoring, and in short-term recordings during manoeuvres activating the ANS. Computed tomography was performed to estimate the amount and distribution of abdominal adipose tissue.Results: Insulin sensitivity (M value, mg/kg lbm/min) did not differ significantly between the R and C groups. Total spectral power (Ptot) and very low-frequency (PVLF) power was lower in R than C during 24 h ECG-recordings (p = 0.02 and p = 0.03). The best fit multiple variable linear regression model (r2 = 0.37, p < 0.001 for model) indicated that body composition (BMI) and long-term low to high frequency (LF/HF) power ratio (std β = −0.46, p = 0.001 and std β = −0.28, p = 0.003, respectively) were significantly and independently associated with the M value.Conclusion: Altered heart rate variability, assessed by power spectrum analysis, during everyday life is linked to insulin resistance. The data suggest that an increased ratio of sympathetic to parasympathetic nerve activity, occurring via both inherited and acquired mechanisms, could potentially contribute to the development of type 2 diabetes.
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