Phosphocreatine Interacts with Phospholipids, Affects Membrane Properties and Exerts Membrane-Protective Effects

Tokarska‐Schlattner, Malgorzata; Epand, Richard M.; Meiler, Flurina; Zandomeneghi, Giorgia; Neumann, Dietbert; Widmer, Hans Rudolf; Meier, Beat H.; Epand, Richard M.; Saks, Valdur; Wallimann, Theo; Schlattner, Uwe

doi:10.1371/journal.pone.0043178

Cited by 70 publications

(40 citation statements)

References 78 publications

(109 reference statements)

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“…37 Decreased levels of phosphocreatine can be linked to diverse consequences for the cells, such as increased permeability of the plasma membrane. 45 In our study, increased levels of phosphocreatine induced by GO could probably be due to a cytoprotective mechanism triggered by cells to overcome the damage.…”

Section: Metabolomic Cell Profilementioning

confidence: 48%

Differential effects of graphene materials on the metabolism and function of human skin cells

et al. 2018

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Graphene-related materials (GRMs) such as graphene oxide (GO) and few-layer graphene (FLG) are used in multiple biomedical applications; however, there is still insufficient information available regarding their interactions with the main biological barriers such as skin. In this study, we explored the effects of GO and FLG on HaCaTs human skin keratinocytes, using NMR-based metabolomics and fluorescence microscopy to evaluate the global impact of each GRM on cell fate and damage. GO and FLG at low concentrations (5 μg mL-1) induced a differential remodeling of the metabolome, preceded by an increase in the level of radical oxygen species (ROS) and free cytosolic Ca2+. These changes are linked to a concentration-dependent increase in cell death by triggering apoptosis and necrosis, the latter being predominant at higher concentrations of the nanostructures. In addition, both compounds reduce the ability of HaCaT cells to heal wounds. Our results demonstrate that the GO and FLG used in this study, which mainly differ in their oxidation state, slightly trigger differential effects on HaCaTs cells, but with evident outcomes at the cellular and molecular levels. Their behavior as pro-apoptotic/necrotic substances and their ability to inhibit cell migration, even at low doses, should be considered in the development of future applications.

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Section: Metabolomic Cell Profilementioning

confidence: 48%

Differential effects of graphene materials on the metabolism and function of human skin cells

et al. 2018

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“…The NHCPB signal intensity S ( T m ) as a function of the mixing time T m reads

S ((), T_{normalm}) = C ([], e^{- R_{1 normalw} T_{m}} - e^{- ((), k_{normals normalw} + R_{1 normals}) T_{m}})

where R 1w is the longitudinal relaxation rate of the water pool, R 1s is the longitudinal relaxation rate of the solute pool (NHCPB), k sw is the chemical exchange rate between solute and water pool, and C is a constant proportional to the z magnetization of the water protons at the beginning of the mixing period and the concentration of the solute pool. A fit of Equation [1] to the measured NHCPB signal intensities S ( T m ) yields k sw + R 1s at a certain pH and temperature.…”

Section: Methodsmentioning

confidence: 99%

Amide proton transfer of carnosine in aqueous solution studied in vitro by WEX and CEST experiments

et al. 2015

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Amide protons of peptide bonds induce an important chemical exchange saturation transfer (CEST) contrast in vivo. As a simple in vitro model for a peptide amide proton CEST effect, we suggest herein the dipeptide carnosine. We show that the metabolite carnosine creates a CEST effect and we study the properties of the exchange of the amide proton (-NH) of the carnosine peptide bond (NHCPB) in model solutions for a pH range from 6 to 8.3 and a temperature range from T = 5 °C to 43 °C by means of CEST and water exchange spectroscopy (WEX) experiments on a 3 T whole-body MR tomograph. The dependence of the NHCPB chemical exchange rate k(sw) on pH and temperature T was determined using WEX. For physiological conditions (T = 37 °C, pH = 7.10) we obtained k(sw) = (47.07 ± 7.90)/s. With similar chemical shift and exchange properties to amide protons in vivo, carnosine forms a simple model system for optimization of CEST pulse sequences in vitro. The potential for direct detection of the metabolite carnosine in vivo is discussed.

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“…That we failed to observe protection from addition of exogenous creatine suggests that the phosphoryl group has functional significance [35] . Exogenous PCr has been shown to directly bind to phospholipid-containing membranes, altering structure and conformation of membrane phospholipids thus protecting membranes from permeabilization by doxorubicin-induced oxidative stress [36] , [37] .…”

Section: Discussionmentioning

confidence: 99%

Myocardial Creatine Levels Do Not Influence Response to Acute Oxidative Stress in Isolated Perfused Heart

et al. 2014

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BackgroundMultiple studies suggest creatine mediates anti-oxidant activity in addition to its established role in cellular energy metabolism. The functional significance for the heart has yet to be established, but antioxidant activity could contribute to the cardioprotective effect of creatine in ischaemia/reperfusion injury.ObjectivesTo determine whether intracellular creatine levels influence responses to acute reactive oxygen species (ROS) exposure in the intact beating heart. We hypothesised that mice with elevated creatine due to over-expression of the creatine transporter (CrT-OE) would be relatively protected, while mice with creatine-deficiency (GAMT KO) would fare worse.Methods and ResultsCrT-OE mice were pre-selected for creatine levels 20–100% above wild-type using in vivo 1H–MRS. Hearts were perfused in isovolumic Langendorff mode and cardiac function monitored throughout. After 20 min equilibration, hearts were perfused with either H2O2 0.5 µM (30 min), or the anti-neoplastic drug doxorubicin 15 µM (100 min). Protein carbonylation, creatine kinase isoenzyme activities and phospho-PKCδ expression were quantified in perfused hearts as markers of oxidative damage and apoptotic signalling. Wild-type hearts responded to ROS challenge with a profound decline in contractile function that was ameliorated by co-administration of catalase or dexrazoxane as positive controls. In contrast, the functional deterioration in CrT-OE and GAMT KO hearts was indistinguishable from wild-type controls, as was the extent of oxidative damage and apoptosis. Exogenous creatine supplementation also failed to protect hearts from doxorubicin-induced dysfunction.ConclusionsIntracellular creatine levels do not influence the response to acute ROS challenge in the intact beating heart, arguing against creatine exerting (patho-)physiologically relevant anti-oxidant activity.

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Phosphocreatine Interacts with Phospholipids, Affects Membrane Properties and Exerts Membrane-Protective Effects

Cited by 70 publications

References 78 publications

Differential effects of graphene materials on the metabolism and function of human skin cells

Differential effects of graphene materials on the metabolism and function of human skin cells

Amide proton transfer of carnosine in aqueous solution studied in vitro by WEX and CEST experiments

Myocardial Creatine Levels Do Not Influence Response to Acute Oxidative Stress in Isolated Perfused Heart

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