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
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • GSTP has an antiapoptotic activity that is mediated

    2022-09-09

    GSTP1 has an antiapoptotic activity that is mediated by the inhibitory interaction with JNK1. Our data suggest that GSTP1 treatment is associated with a significant down-regulation of caspase expression. This might explain the reduction in infarct-related cardiomyocyte death and saving the cardiomyocyte structure observed in the AZ505 ditrifluoroacetate of GSTP1-treated rats. Similarly, the inhibition of MAPK in the infarcted myocardium by GSTP1 might reduce the activation of signals essential for cardiomyocyte apoptosis; such as detoxification of reactive oxygen species.14, 32 Together, the acute inhibition of p38-mediating cardiomyocyte apoptosis and proinflammatory mechanisms early after MI by GSTP-1 might result in salvage of cardiomyocytes in the infarct zone and reduction of the initial infarct size. This in turn may contribute to long-term preservation of ventricular mass and function during the post-MI remodeling stage seen in the present study. An important clinical aspect of acute post-MI intervention is whether long-term benefits can be achieved. A major determinant of early and late survival in MI patients is reduction of the initial infarct size and preservation of LV ejection fraction that reduces the incidence of ventricular arrhythmias and progression to HF.33, 34 Our findings indicate that 1-time GSTP1 treatment markedly attenuates all of the features of maladaptive remodeling seen after large infarcts, significantly improving LV structural and functional parameters at 21 days after treatment. It is also important to note that both treatment and control groups had a similar LV cardiac function before treatment, suggesting that the beneficial effects were mediated by GSTP1 treatment. The present study has limitations. First, the single dose of GSTP1 used here was selected based on studies comparing pharmacokinetics of GSTP1 in rats with the available data of a mouse inflammation model. Therefore, dose-adjusting studies might be necessary in clinical trials. Also, the rate of administration might vary in human subjects. Second, GSTP1 was administered 2 hours after MI in this study. Whether delayed administration of GSTP1 would provide similar long-term beneficial effects regarding inflammation, apoptosis, and survival is unclear. Finally, the GSTP1 used here was a recombinant human protein which had a high homology with rat GSTP1 and was therefore unlikely to cause adverse immunologic effects, which it did not. The potential emergence of such adverse effects in humans needs controlled trials.
    Acknowledgment
    Disclosures
    Introduction The role of oxidative stress in the etiology of various neurodegenerative disorders including stroke (Zhang et al., 2007), Alzheimer’s (Dmitriev, 2007) and Parkinson’s disease (Liang et al., 2007) is well accepted. 4-Hydroxytrans-2-nonenal (4-HNE), a long-chain alpha, beta unsaturated aldehyde is generated by the oxidation of ω−6 polyunsaturated fatty acids and is one of the many products produced during lipid peroxidation (Sakai et al., 2006). Physiological concentration of 4-HNE ranges from 0.1 to 3μM, whereas high concentrations of 4-HNE (10μM to 5mM) have been reported following toxic insults (Uchida, 2003). 4-HNE at higher concentrations is known to cause necrotic cell death in a number of cell types including PC12 (Piga et al., 2007), HepG2 (Gallagher et al., 2007), V79 (Li et al., 2006), cerebellar granule neurons (Arakawa et al., 2007), human osteosarcoma cells (Sunjic et al., 2005) and primary cultures of normal human osteoblasts (Borovic et al., 2007). Lower concentrations of 4-HNE have also been reported to influence cell proliferation (Zhang et al., 2007), inhibit the synthesis of nucleic acids and proteins (Wonisch et al., 1998), affect the stimulation of neutrophil chemotaxis (Yu and Ran, 2006) and phospholipases (Natarajan et al., 1997) and activate stress signaling pathways (Chen et al., 2005). Recently, it has been shown by us and others that cytotoxic concentrations of 4-HNE in PC12 cells alter the sensitivity of dopamine (DA)-D2, cholinergic-muscarinic, benzodiazepine and serotonin (5-HT)2A receptors (Abdul and Butterfield, 2007, Siddiqui et al., 2008). HNE induced genotoxicity and its association with intracellular GSH/GST systems in the cells of human origin mainly HT29, colon tumor cells (Knoll et al., 2005) and K562, erythroleukemia cells (Yadav et al., 2008) have also been reported. Protective potential of glutathione transferase both in neuronal cultured cells (Xie et al., 2001) and cells of non-neuronal origin (Zhang et al., 2002, Dabrowski et al., 2006) against 4-HNE exposure has also been reported. Although a number of studies have been carried out to investigate the pathophysiology of 4-HNE induced neurotoxicity and neurodegeneration, the cellular events influenced by 4-HNE are poorly understood. The present study has therefore been carried out to investigate 4-HNE induced oxidative stress in PC12 cells, a widely preferred cell line for understanding the mechanism of neuronal functions and neurotoxicity (Sutton et al., 2007, Dickinson et al., 2007). The study has also been planned in an attempt to evaluate the usefulness of PC12 cells as in vitro tool for understanding the mechanism of 4-HNE induced neurotoxicity.