Biomedical subjects

Zsolt Török

Publications and source records attributed to Zsolt Török.

7 recordsLinked to original sources

PubMed2007

Membrane-regulated stress response: a theoretical and practical approach.

Anumber of observations have lent support to a model in which thermal stress is transduced into a signal at the level of the cellular membranes. Our alternative, but not exclusive, approach is based on the concept that the initial stress-sensing events are associated with the physical state and lipid composition of cellular membranes, i.e., the subtle alteration(s) of membrane fluidity, phase state, and/or microheterogeneity may operate as a cellular thermometer. In fact, various pathological states and aging are associated with typical "membrane defects" and simultaneous dysregulation of heat shock protein synthesis. The discovery of nonproteotoxic membrane-lipid interacting compounds, capable of modulating membrane microdomains engaged in primary stress sensing may be of paramount importance for the design of new drugs with the ability to induce or attenuate the level of particular heat shock proteins.

Animals↗

PubMed2005

Phospholipid vesicles increase the survival of freeze-dried human red blood cells.

In a previous report [Z. Török, G. Satpathy, M. Banerjee, R. Bali, E. Little, R. Novaes, H. Van Ly, D. Dwyre, A. Kheirolomoom, F. Tablin, J.H. Crowe, N.M. Tsvetkova, Preservation of trehalose loaded red blood cells by lyophilization, Cell Preservation Technol. 3 (2005) 96-111.], we presented a method for preserving human red blood cells (RBCs) by loading them with trehalose and then freeze-drying. We have now improved that method, based on the discovery that addition of phospholipid vesicles to the lyophilization buffer substantially reduces hemolysis of freeze-dried RBCs after rehydration. The surviving cells synthesize 2,3-DPG, have low levels of methemoglobin, and have preserved morphology. Among the lipid species we studied, unsaturated PCs were found to be most effective in suppressing hemoglobin leakage. RBC-vesicle interactions depend on vesicle size and structure; unilamellar liposomes with average diameter of less than 300 nm were more effective in reducing the hemolysis than multilamellar vesicles. Trehalose loaded RBCs demonstrated high survival and low levels of methemoglobin during 10 weeks of storage at 4 degrees C in the dry state when lyophilized in the presence of liposomes.

2,3-Diphosphoglycerate↗

PubMed2005

"Heat shock lipid" in cyanobacteria during heat/light-acclimation.

Parallel with the heat/light-induced thylakoid microdomain reorganization and thermal stabilization of photosynthesis we observed an increase in the level of the highly saturated monoglucosyldiacylglycerol (MGlcDG) in Synechocystis cells. The unusually high microviscosity obtained in thylakoid MGlcDG liposomes by monitoring DPH anisotropy was in good agreement with its exceptionally high acyl chain saturation. The MGlcDG membranes remained stable even at extreme high temperatures. Strikingly, in monolayer experiments, out of the five thylakoid polar lipids tested, MGlcDG expressed the strongest interaction with the thylakoid-stabilizing small Hsp from Synechocystis, Hsp17. The preferential interaction of Hsp17 with non-bilayer phase forming lipids supports our notion that sHsps counteract the formation of thermally induced local non-bilayer structures [Proc. Natl. Acad. Sci. USA 99 (2002) 13504] and thus implicated in microdomain organization and in the preservation of functional integrity of thylakoid membranes challenged by heat stress in the light. We also suggest that the highly saturated MGlcDG functions as a "heat shock lipid" and is of potential importance in the development of acquired thermotolerance of heat/light-primed cyanobacterial thylakoids.

Anisotropy↗

PubMed2005

Membrane fluidization triggers membrane remodeling which affects the thermotolerance in Escherichia coli.

Treatment of Escherichia coli with non-lethal doses of heat or benzyl alcohol (BA) causes transient membrane fluidization and permeabilization, and induces the rapid transcription of heat-shock genes in a sigma32-dependent manner. This early response is followed by a rapid adaptation (priming) of the cells to otherwise lethal elevated temperature, in strong correlation with an observed remodeling of the composition and alkyl chain unsaturation of membrane lipids. The acquisition of cellular thermotolerance in BA-primed cells is unrelated to protein denaturation and is not accompanied by the formation of major heat-shock proteins, such as GroEL and DnaK. This suggests that the rapid remodeling of membrane composition is sufficient for the short-term bacterial thermotolerance.

Adaptation, Physiological↗

PubMed2004

Loading red blood cells with trehalose: a step towards biostabilization.

A method for freeze-drying red blood cells (RBCs) while maintaining a high degree of viability has important implications in blood transfusion and clinical medicine. The disaccharide trehalose, found in animals capable of surviving dehydration can aid in this process. As a first step toward RBC preservation, we present a method for loading RBCs with trehalose. The method is based on the thermal properties of the RBC plasma membranes and provides efficient uptake of the sugar at 37 degrees C in a time span of 7 h. The data show that RBCs can be loaded with trehalose from the extracellular medium through a combination of osmotic imbalance and the phospholipid phase transition, resulting in intracellular trehalose concentrations of about 40 mM. During the loading period, the levels of ATP and 2,3-DPG are maintained close to the levels of fresh RBCs. Increasing the membrane fluidity through the use of a benzyl alcohol results in a higher concentration of intracellular trehalose, suggesting the importance of the membrane physical state for the uptake of the sugar. Osmotic fragility data show that trehalose exerts osmotic protection on RBCs. Flow cytometry data demonstrate that incubation of RBCs in a hypertonic trehalose solution results in a fraction of cells with different complexity and that it can be removed by washing and resuspending the RBCs in an iso-osmotic medium. The data provide an important first step in long-term preservation of RBCs.

Benzyl Alcohol↗

PubMed2003

Heat shock protein coinducers with no effect on protein denaturation specifically modulate the membrane lipid phase.

The hydroxylamine derivative bimoclomol (BM) has been shown to activate natural cytoprotective homeostatic responses by enhancing the capability of cells to cope with various pathophysiological conditions. It exerts its effect in synergy with low levels of stress to induce the synthesis of members of major stress protein families. We show here that the presence of BM does not influence protein denaturation in the cells. BM and its derivatives selectively interact with acidic lipids and modulate their thermal and dynamic properties. BM acts as a membrane fluidizer at normal temperature, but it is a highly efficient membrane stabilizer, inhibiting the bilayer-nonbilayer phase transitions during severe heat shock. We suggest that BM and the related compounds modify those domains of membrane lipids where the thermally or chemically induced perturbation of lipid phase is sensed and transduced into a cellular signal, leading to enhanced activation of heat shock genes. BM may be a prototype for clinically safe membrane-interacting drug candidates that rebalance the level and composition of heat shock proteins.

3T3 Cells↗

PubMed2002

Small heat-shock proteins regulate membrane lipid polymorphism.

Thermal stress in living cells produces multiple changes that ultimately affect membrane structure and function. We report that two members of the family of small heat-shock proteins (sHsp) (alpha-crystallin and Synechocystis HSP17) have stabilizing effects on model membranes formed of synthetic and cyanobacterial lipids. In anionic membranes of dimyristoylphosphatidylglycerol and dimyristoylphosphatidylserine, both HSP17 and alpha-crystallin strongly stabilize the liquid-crystalline state. Evidence from infrared spectroscopy indicates that lipid/sHsp interactions are mediated by the polar headgroup region and that the proteins strongly affect the hydrophobic core. In membranes composed of the nonbilayer lipid dielaidoylphosphatidylethanolamine, both HSP17 and alpha-crystallin inhibit the formation of inverted hexagonal structure and stabilize the bilayer liquid-crystalline state, suggesting that sHsps can modulate membrane lipid polymorphism. In membranes composed of monogalactosyldiacylglycerol and phosphatidylglycerol (both enriched with unsaturated fatty acids) isolated from Synechocystis thylakoids, HSP17 and alpha-crystallin increase the molecular order in the fluid-like state. The data show that the nature of sHsp/membrane interactions depends on the lipid composition and extent of lipid unsaturation, and that sHsps can regulate membrane fluidity. We infer from these results that the association between sHsps and membranes may constitute a general mechanism that preserves membrane integrity during thermal fluctuations.

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