Medical Sciences publications

Permanent URI for this collection

https://hdl.handle.net/2440/1089

Browse

Browsing Medical Sciences publications by Author "Abell, A."

Now showing 1 - 2 of 2
  • No Thumbnail Available
    ItemMetadata only
    New peptidomimetic boronates for selective inhibition of the chymotrypsin-like activity of the 26S proteasome
    (American Chemical Society, 2016) Zhang, X.; Adwal, A.; Turner, A.; Callen, D.; Abell, A.
    Proteasome is a large proteinase complex that degrades proteins via its three catalytic activities. Among these activities, the “chymotrypsin-like” activity has emerged as the focus of drug discovery in cancer therapy. Here, we report new peptidomimetic boronates that are highly specific for the chymotrypsin-like catalytic activity of the proteasome. These new specific proteasome inhibitors were demonstrated to have higher in vitro potency and selective cytotoxicity for cancer cells compared to benchmark proteasome inhibitors: bortezomib and carfilzomib. In breast cancer cell lines, treatment with 1a or 2a induced accumulation of the high molecular weight polyubiqutinated proteins at similar levels observed for bortezomib and carfilzomib, indicating that cancer cell death caused by 1a/2a is chiefly due to proteasome inhibition.
  • No Thumbnail Available
    ItemMetadata only
    Toll-Like Receptors change morphine-induced antinociception, tolerance and dependence: studies using male and female TLR and Signalling gene KO mice
    (Elsevier, 2022) Thomas, J.H.L.; Lui, L.; Abell, A.; Tieu, W.; Somogyi, A.A.; Bajic, J.E.; Hutchinson, M.R.
    Toll-like receptors (TLR) have been proposed as a site of action that alters opioid pharmacodynamics. However, a comprehensive assessment of acute opioid antinociception, tolerance and withdrawal behaviours in genetic null mutant strains with altered innate immune signalling has not been performed. Nor has the impact of genetic deletion of TLR2/4 on high-affinity opioid receptor binding. Here we show that diminished TLR signalling po- tentiates acute morphine antinociception equally in male and female mice. However, only male TIR8 null mutant mice showed reduced morphine analgesia. Analgesic tolerance was prevented in TLR2 and TLR4 null mutants, but not MyD88 animals. Withdrawal behaviours were only protected in TLR2 -/- mice. In silico docking simu- lations revealed opioid ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. There was no binding of [3H](-)-naloxone or [3H]diprenorphine to TLR4 in the concentrations explored. These data confirm that opioids have high efficacy activity at innate immune pattern recognition binding sites but do not bind to TLR4 and identify critical pathway and sex-specific effects of the complex innate immune signalling contributions to opioid pharmacodynamics. These data further support the behavioural importance of the TLR- opioid interaction but fail to demonstrate direct evidence for high-affinity binding of the TLR4 signalling complex to ligands.