English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Plus

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Zendy Tools

Zendy Open

Background and Purpose  Valproic acid (VPA), a widely used epilepsy and bipolar disorder treatment, provides acute protection against haemorrhagic shock‐induced mortality in a range of  in vivo  models through an unknown mechanism. In the liver, this effect occurs with a concomitant protection against a decrease in GSK3β‐Ser 9  phosphorylation. Here, we developed an  in vitro  model to investigate this protective effect of VPA and define a molecular mechanism.    Experimental Approach  The human hepatocarcinoma cell line (Huh7) was exposed to conditions occurring during haemorrhagic shock (hypoxia, hypercapnia and hypothermia) to investigate the changes in GSK3β‐Ser 9  phosphorylation for a 4 h period following treatment with VPA, related congeners, PPAR agonists, antagonists and siRNA.    Key Results  Huh7 cells undergoing combined hypoxia, hypercapnia, and hypothermia reproduced the reduced GSK3β‐Ser 9  phosphorylation shown  in vivo  during haemorrhagic shock, and this change was blocked by VPA. The protective effect occurred through upstream PTEN and Akt signalling, and prevented downstream β‐catenin degradation while increasing histone 2/3 acetylation. This effect was reproduced by several VPA‐related compounds with known PPARγ agonist activity, independent of histone deacetylase (HDAC) inhibitory activity. Specific pharmacological inhibition (by T0070907) or knockdown of PPARγ blocked the protective effect of VPA against these signalling changes and apoptosis. In addition, specific activation of PPARγ using ciglitazone reproduced the changes induced by VPA in haemorrhagic shock‐like conditions.    Conclusion and Implications  Changes in GSK3β‐Ser 9  phosphorylation in  in vivo  haemorrhagic shock models can be modelled  in vitro , and this has identified a role for PPARγ activation in the protective role of VPA.

Valproic acid protects against haemorrhagic shock‐induced signalling changes via PPARγ activation in an in vitro model