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- Kovacs, T, et al.
(author)
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A conserved MTMR lipid phosphatase increasingly suppresses autophagy in brain neurons during aging
- 2022
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1, s. 21817-
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Journal article (peer-reviewed)abstract
- Ageing is driven by the progressive, lifelong accumulation of cellular damage. Autophagy (cellular self-eating) functions as a major cell clearance mechanism to degrade such damages, and its capacity declines with age. Despite its physiological and medical significance, it remains largely unknown why autophagy becomes incapable of effectively eliminating harmful cellular materials in many cells at advanced ages. Here we show that age-associated defects in autophagic degradation occur at both the early and late stages of the process. Furthermore, in the fruit fly Drosophila melanogaster, the myotubularin-related (MTMR) lipid phosphatase egg-derived tyrosine phosphatase (EDTP) known as an autophagy repressor gradually accumulates in brain neurons during the adult lifespan. The age-related increase in EDTP activity is associated with a growing DNA N6-adenine methylation at EDTP locus. MTMR14, the human counterpart of EDTP, also tends to accumulate with age in brain neurons. Thus, EDTP, and presumably MTMR14, promotes brain ageing by increasingly suppressing autophagy throughout adulthood. We propose that EDTP and MTMR14 phosphatases operate as endogenous pro-ageing factors setting the rate at which neurons age largely independently of environmental factors, and that autophagy is influenced by DNA N6-methyladenine levels in insects.
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- Fritz, T., et al.
(author)
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Effects of Nordic walking on cardiovascular risk factors in overweight individuals with type 2 diabetes, impaired or normal glucose tolerance
- 2013
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In: Diabetes/Metabolism Research Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 29:1, s. 25-32
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Journal article (peer-reviewed)abstract
- Background Physical activity remains a valuable prevention for metabolic disease. The effects of Nordic walking on cardiovascular risk factors were determined in overweight individuals with normal or disturbed glucose regulation. Methods We included 213 individuals, aged 60 +/- 5.3 years and with body mass index (BMI) of 30.2 +/- 3.8 kg/m(2); of these, 128 had normal glucose tolerance (NGT), 35 had impaired glucose tolerance (IGT) and 50 had type 2 diabetes mellitus (T2DM). Participants were randomized to unaltered physical activity or to 5 h per week of Nordic walking with poles, for a 4-month period. Dietary habits were unaltered. BMI, waist circumference, blood pressure, glucose tolerance, clinical chemistry, maximal oxygen uptake (peak VO2) and self-reported physical activity (questionnaire) were assessed at the time of inclusion and after 4 months. The participants in the exercise-intervention group kept a walking diary. Results In the NGT exercise group, self-reported physical activity increased markedly, and body weight (-2.0 +/- 3.8 kg), BMI (-0.8 +/- 1.4 kg/m(2)) and waist circumference (- 4.9 +/- 4.4 cm) (mean +/- SD) decreased. Exercise power output (12.9 +/- 9.9 W) and peak VO2 (2.7 +/- 2.8 mL/kg/min) increased in the IGT exercise group. More cardiovascular risk factors were improved after exercise intervention in people with NGT compared with those with IGT or T2DM. Exercise capacity improved significantly in all three groups of participants who reported at least 80% compliance with the scheduled exercise. Conclusions Nordic walking improved anthropometric measurements and exercise capacity. However, unsupervised Nordic walking may not provide a sufficient increase in exercise intensity to achieve ultimate health-promoting benefits on the cardiovascular parameters assessed in this study, particularly for those with disturbed glucose regulation. Copyright (C) 2012 John Wiley & Sons, Ltd.
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- Heffeter, P., et al.
(author)
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Ribonucleotide Reductase as One Important Target of [Tris(1,10- phenanthroline)lanthanum(III)] Trithiocyanate (KP772)
- 2009
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In: Current Cancer Drug Targets. - : Bentham Science Publishers Ltd.. - 1568-0096 .- 1873-5576. ; 9:5, s. 595-607
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Journal article (peer-reviewed)abstract
- KP772 is a new lanthanum complex containing three 1,10-phenathroline molecules. Recently, we have demonstrated that the promising in vitro and in vivo anticancer properties of KP772 are based on p53-independent G(0)G(1) arrest and apoptosis induction. A National Cancer Institute (NCI) screen revealed significant correlation of KP772 activity with that of the ribonucleotide reductase (RR) inhibitor hydroxyurea (HU). Consequently, this study aimed to investigate whether KP772 targets DNA synthesis in tumor cells by RR inhibition. Indeed, KP772 treatment led to significant reduction of cytidine incorporation paralleled by a decrease of deoxynucleoside triphosphate (dNTP) pools. This strongly indicates disruption of RR activity. Moreover, KP772 protected against oxidative stress, suggesting that this drug might interfere with RR by interaction with the tyrosyl radical in subunit R2. Additionally, several observations (e.g. increase of transferrin receptor expression and protective effect of iron preloading) indicate that KP772 interferes with cellular iron homeostasis. Accordingly, co-incubation of Fe(II) with KP772 led to generation of a coloured iron complex (Fe-KP772) in cell free systems. In electron paramagnetic resonance (EPR) measurements of mouse R2 subunits, KP772 disrupted the tyrosyl radical while Fe-KP772 had no significant effects. Moreover, coincubation of KP772 with iron-loaded R2 led to formation of Fe-KP772 suggesting chelation of RR-bound Fe(II). Summarizing, our data prove that KP772 inhibits RR by targeting the iron centre of the R2 subunit. As also Fe-KP772 as well as free lanthanum exert significant -though less pronounced- cytotoxic/static activities, additional mechanisms are likely to synergise with RR inhibition in the promising anticancer activity of KP772.
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