Search

Background: The mitochondria-targeted hydrogen sulphide (H2S)-donor AP39 has previously been shown to exert cytoprotective effects in vitro by stimulation of mitochondrial respiration [1]. In vivo, AP39 improved haemodynamic and neurological outcome following cardiac arrest after pre- or early post-treatment administration [2,3]. Therefore, we tested the hypothesis whether AP39 has a beneficial impact in a resuscitated murine model of haemorrhagic shock. Methods and measurements: Anaesthetised and instrumented mice (C57BL/6J) underwent 1h of haemorrhage (mean arterial pressure (MAP)=35mmHg) and subsequently 4h of resuscitation comprising a bolus injection of 100nmol/kg AP39 (n=8) or vehicle (n=9), re-transfusion of shed blood together with lung-protective mechanical ventilation, fluid resuscitation and noradrenaline (NA) titrated to maintain MAP>50mmHg. Lung mechanics and gas exchange were assessed together with systemic haemodynamics, metabolism, and acid-base status. Blood and tissue samples were analysed for cytokine and chemokine levels, protein expression and high resolution respirometry to assess tissue mitochondrial activity (OxPHOS: maximal oxidative phosphorylation; LEAK: strong limitation of mitochondrial respiration due to ATP-synthase inhibition; ETS: maximal O2 consumption in the uncoupled state). Data are median (quartiles). Results: AP39 was associated with higher NA requirements to maintain haemodynamic stability which coincided with more pronounced metabolic acidosis and increased mortality rates. Local and systemic inflammation was decreased following AP39 treatment. In line, protein levels of the nitrosative stress marker (iNOS) were reduced in lung tissue whereas anti-inflammatory expression levels of HO-1 were increased. AP39 had no significant effect of AP39 on OxPHOS, LEAK or ETS in diaphragm, heart, kidney and liver.Conclusion: We were able to confirm the anti-inflammatory impact of AP39 in vivo. However, in contrast to the promising in vitro and in vivo data in cardiac arrest, AP39 had no beneficial effect on the outcome after murine haemorrhagic shock, possibly due to its timing and dose. In addition, the higher NA requirements, which may have resulted from AP39-related vasodilation [3], might have further offset beneficial effects on mitochondrial respiration.References: 1. Szcesny B, Nitric Oxide 2014, 41:120; 2. Ikeda K, Nitric Oxide 2015, 49-90; 3. Tomasova L, Nitric Oxide 2015, 46:131. Supported by the DFG (CRC1149, project B02).

Pluripotent stem cells are characterised by continuous self-renewal while maintaining the potential to differentiate into cells of all three germ layers. Regulatory networks of maintaining pluripotency have been described in great detail and, similarly, there is great knowledge on key players that regulate their differentiation. Interestingly, pluripotency has various shades with distinct developmental potential, an observation that coined the term of a ground state of pluripotency. A precise interplay of signalling axes regulates ground state conditions and acts in concert with a combination of key transcription factors. The balance between these transcription factors greatly influences the integrity of the pluripotency network and latest research suggests that minute changes in their expression can strengthen but also collapse the network. Moreover, recent studies reveal different facets of these core factors in balancing a controlled and directed exit from pluripotency. Thereby, subsets of pluripotency-maintaining factors have been shown to adopt new roles during lineage specification and have been globally defined towards neuroectodermal and mesendodermal sets of embryonic stem cell genes. However, detailed underlying insights into how these transcription factors orchestrate cell fate decisions remain largely elusive. Our group and others unravelled complex interactions in the regulation of this controlled exit. Herein, we summarise recent findings and discuss the potential mechanisms involved.