Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • Several groups studied CTD mouse models which largely mimick

    2022-06-29

    Several groups studied CTD mouse models, which largely mimicked the symptoms (i.e. impaired cognition and autistic-like behaviour) of the human disease (Kurosawa et al., 2012; Baroncelli et al., 2016; Stockebrand, 2018). The CRT-1 knockout mice showed a drastic deterioration in the GABAergic system, reduced hippocampal neurogenesis, prominent activation of microglia and altered oxidative metabolism (Baroncelli et al., 2016). This explains some of the epilepsy symptoms experienced by many CTD patients. To date, only Kurosawa and co-workers explored the possible therapeutic options for managing CTD, showing that, in L-365,260 to creatine itself, its analogue cyclocreatine enhanced cognitive abilities in mice with a brain-specific CRT-1 knock-out (Kurosawa et al., 2012). Our data suggest that 4-PBA may be an effective strategy for treating CTD. 4-PBA is administered in doses of up to 20 g/d and 0.5 g/kg/d for adults and children <20 kg, respectively. Therapeutic doses translate into plasma concentrations ≥1 mM. Thus, it may be justified to test 4-PBA in patients harbouring those mutations, which we found to be responsive when expressed in HEK293 cells. More importantly, our work provides a proof-of-principle that the folding deficiency of mutant hCRT-1 variants is amenable to pharmacological correction. This justifies the search for additional and possibly improved pharmacochaperones.
    Conflicts of interest
    Funding This work was supported by the Austrian Science Fund (project P31255-B27 to SS and P28179 to HK) and the Wiener Wissenschafts und Technologie Fonds (project WWTF LS17-026 to MF).
    Acknowledgement
    Introduction Absorption, distribution and bioavailability of many xenobiotics, including drugs, strongly depend on function of transporter proteins in different tissues and organs. Considerable scientific progress towards understanding the role of membrane transporters in drug pharmacokinetics as well as drug-drug interactions has led to the publication of guidelines by regulatory agencies, including the Food and Drug Administration (FDA) and European Medicines Agency (EMA). Those guidelines indicate the importance of inclusion of data on the transporters abundance in drug development process [1]. A substantial progress in protein analysis methods in the last decade, mainly utilizing mass-spectrometry-based assays, enabled absolute and accurate quantitation of drug transporters in tissue specimens, and substantially contributed to the definition of their biological functions [2]. A number of papers have been published, focusing on altered drug transporters content in various liver pathologies, i.e. viral hepatitis, hepatic cancer, alcoholic, immunological and cholestatic liver diseases, non-alcoholic steatohepatitis [[3], [4], [5], [6], [7]]. Those studies provided both mRNA expression information as well as semi-quantitative analysis of proteins (mainly Western blotting), and more recent ones, quantitative protein abundance data. Regardless the method used, final conclusions are usually drawn from comparisons of pathological liver specimens and control (considered as healthy) tissues. There are two main sources of the control liver samples used as the reference livers in published studies, i.e. donor livers [3,4]and non-tumorous tissue from metastatic livers [[5], [6], [7]], also applied for drug transporter investigations. Some of the studies included also a control group composed of both, liver tissue harvested during tumor resection and several liver biopsy specimens [8,9]. Non-tumorous tissue from cancer patients or liver samples from deceased organ donors constitute an accessible source of liver tissue for proteomic and functional studies, but may not reflect entirely the same functional liver state. Thus, the selection of the reference liver tissue may impact final conclusions in transporter expression/protein abundance, functional studies which provide drug transporter characteristics as well as data used for pharmacokinetic modelling [[10], [11], [12]]. Therefore, the present study aimed, for the first time, to characterize drug transporter expression and protein abundance in the two most frequently used types of reference liver tissues, namely liver tissue from organ donors and non-tumorous tissues from patients with metastatic (colon cancer) livers.