Biomedical subjects

Péter Csermely

Publications and source records attributed to Péter Csermely.

At least 19 recordsLinked to original sources

PubMed2006

Chance and necessity in the evolution of minimal metabolic networks.

It is possible to infer aspects of an organism's lifestyle from its gene content. Can the reverse also be done? Here we consider this issue by modelling evolution of the reduced genomes of endosymbiotic bacteria. The diversity of gene content in these bacteria may reflect both variation in selective forces and contingency-dependent loss of alternative pathways. Using an in silico representation of the metabolic network of Escherichia coli, we examine the role of contingency by repeatedly simulating the successive loss of genes while controlling for the environment. The minimal networks that result are variable in both gene content and number. Partially different metabolisms can thus evolve owing to contingency alone. The simulation outcomes do preserve a core metabolism, however, which is over-represented in strict intracellular bacteria. Moreover, differences between minimal networks based on lifestyle are predictable: by simulating their respective environmental conditions, we can model evolution of the gene content in Buchnera aphidicola and Wigglesworthia glossinidia with over 80% accuracy. We conclude that, at least for the particular cases considered here, gene content of an organism can be predicted with knowledge of its distant ancestors and its current lifestyle.

Biological Evolution↗

PubMed2006

Changes of endoplasmic reticulum chaperone complexes, redox state, and impaired protein disulfide reductase activity in misfolding alpha1-antitrypsin transgenic mice.

Alpha1-antitrypsin (AAT) deficiency is characterized by the accumulation of the misfolded mutant, Z form of alpha1-antitrypsin (PiZ) inside the lumen of the hepatic endoplasmic reticulum (ER). Both human patients and PiZ transgenic mice have similar symptoms of hepatic failure culminating in cirrhosis and hepatocellular carcinoma. The involvement of molecular chaperones, as well as the relevance of oxidative stress in this disease is not characterized well yet. Here, we show that, in the PiZ transgenic mice, the 58-kDa protein disulfide isomerase (PDI), the most important oxidoreductase and chaperone of the endoplasmic reticulum, is in a complex with PiZ, which is accompanied by a decrease of protein disulfide reductase activity of the ER. PiZ transgenic mice have a shift toward a more reduced ER environment and an elevation of cytoplasmic chaperones and antioxidant enzymes. Our data suggest that lower availability of PDI and a decreased protein disulfide reductase activity of the ER along with a cytoplasmic stress may contribute to the toxic effects of PiZ aggregation.

Animals↗

PubMed2005

Uncoupled redox systems in the lumen of the endoplasmic reticulum. Pyridine nucleotides stay reduced in an oxidative environment.

The redox state of the intraluminal pyridine nucleotide pool was investigated in rat liver microsomal vesicles. The vesicles showed cortisone reductase activity in the absence of added reductants, which was dependent on the integrity of the membrane. The intraluminal pyridine nucleotide pool could be oxidized by the addition of cortisone or metyrapone but not of glutathione. On the other hand, intraluminal pyridine nucleotides were slightly reduced by cortisol or glucose 6-phosphate, although glutathione was completely ineffective. Redox state of microsomal protein thiols/disulfides was not altered either by manipulations affecting the redox state of pyridine nucleotides or by the addition of NAD(P)+ or NAD(P)H. The uncoupling of the thiol/disulfide and NAD(P)+/NAD(P)H redox couples was not because of their subcompartmentation, because enzymes responsible for the intraluminal oxidoreduction of pyridine nucleotides were distributed equally in smooth and rough microsomal subfractions. Instead, the phenomenon can be explained by the negligible representation of glutathione reductase in the endoplasmic reticulum lumen. The results demonstrated the separate existence of two redox systems in the endoplasmic reticulum lumen, which explains the contemporary functioning of oxidative folding and of powerful reductive reactions.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2005

Chaperone-related immune dysfunction: an emergent property of distorted chaperone networks.

Molecular chaperones (heat shock proteins) are important components of cellular networks, such as protein-protein and gene regulatory networks. Chaperones participate in the folding of immunologically important proteins, presentation of antigens and activation of the immune system. Here, we propose that chaperone-related immune dysfunction might be more general than was previously thought. Mutations and polymorphism of chaperones and the regulators of their synthesis, heat shock factor-1, chaperone diseases, sick chaperones and chaperone overload might all affect (mostly impairing) immune responses.

Animals↗

PubMed2005

FAD oxidizes the ERO1-PDI electron transfer chain: the role of membrane integrity.

The molecular steps of the electron transfer in the endoplasmic reticulum from the secreted proteins during their oxidation are relatively unknown. We present here that flavine adenine dinucleotide (FAD) is a powerful oxidizer of the oxidoreductase system, Ero1 and PDI, besides the proteins of rat liver microsomes and HepG2 hepatoma cells. Inhibition of FAD transport hindered the action of FAD. Microsomal membrane integrity was mandatory for all FAD-related oxidation steps downstream of Ero1. The PDI inhibitor bacitracin could inhibit FAD-mediated oxidation of microsomal proteins and PDI, but did not hinder the FAD-driven oxidation of Ero1. Our data demonstrated that Ero1 can utilize FAD as an electron acceptor and that FAD-driven protein oxidation goes through the Ero1-PDI pathway and requires the integrity of the endoplasmic reticulum membrane. Our findings prompt further studies to elucidate the membrane-dependent steps of PDI oxidation and the role of FAD in redox folding.

Animals↗

PubMed2005

Diabetic changes in the redox status of the microsomal protein folding machinery.

Changes in assisted protein folding are largely unexplored in diabetes. In the present studies, we have identified a reductive shift in the redox status of rat liver microsomes after 4 weeks of streptozotocin-induced diabetes. This change was reflected by a significant increase in the total- and protein-sulfhydryl content, as well as in the free sulfhydryl groups of the major protein disulfide isomerases (PDIs), the 58 kDa PDI and the 57 kDa ERp57 but not other chaperones. A parallel decrease of the protein-disulfide oxidoreductase activity was detected in the microsomal fraction of diabetic livers. The oxidant of PDI, Ero1-Lalpha showed a more oxidized status in diabetic rats. Our results reveal major changes in the redox status of the endoplasmic reticulum and its redox chaperones in diabetic rats, which may contribute to the defective protein secretion of the diabetic liver.

Animals↗

PubMed2005

Multiple weak hits confuse complex systems: a transcriptional regulatory network as an example.

Robust systems, like the molecular networks of living cells, are often resistant to single hits such as those caused by high-specificity drugs. Here we show that partial weakening of the Escherichia coli and Saccharomyces cerevisiae transcriptional regulatory networks at a small number (3-5) of selected nodes can have a greater impact than the complete elimination of a single selected node. In both cases, the targeted nodes have the greatest possible impact; still, the results suggest that in some cases broader specificity compounds or multitarget drug therapies may be more effective than individual high-affinity, high-specificity ones. Multiple but partial attacks mimic well a number of in vivo scenarios and may be useful in the efficient modification of other complex systems.

Computer Simulation↗

PubMed2005

Molecular chaperones as regulatory elements of cellular networks.

Molecular chaperones help hundreds of signaling molecules to keep their activation-competent state, and regulate various signaling processes ranging from signaling at the plasma membrane to transcription. Besides these specific regulatory roles, recent studies have revealed that chaperones act as genetic buffers stabilizing the phenotypes of various cells and organisms. This may be related to their low affinity for the proteins they interact with, which means that they represent weak links in protein networks. Chaperones may uncouple protein, signaling, membrane, organelle and transcriptional networks during stress, which gives the cell additional protection. The same networks are preferentially remodeled in various diseases and aging, which may help us to design novel therapeutic and anti-aging strategies.

Animals↗

PubMed2005

The efficiency of multi-target drugs: the network approach might help drug design.

Despite considerable progress in genome- and proteome-based high-throughput screening methods and rational drug design, the number of successful single-target drugs did not increase appreciably during the past decade. Network models suggest that partial inhibition of a surprisingly small number of targets can be more efficient than the complete inhibition of a single target. This and the success stories of multi-target drugs and combinatorial therapies led us to suggest that systematic drug-design strategies should be directed against multiple targets. We propose that the final effect of partial, but multiple, drug actions might often surpass that of complete drug action at a single target. The future success of this novel drug-design paradigm will depend not only on a new generation of computer models to identify the correct multiple targets and their multi-fitting, low-affinity drug candidates but also on more-efficient in vivo testing.

Computational Biology↗

PubMed2005

Heat shock proteins as emerging therapeutic targets.

Chaperones (stress proteins) are essential proteins to help the formation and maintenance of the proper conformation of other proteins and to promote cell survival after a large variety of environmental stresses. Therefore, normal chaperone function is a key factor for endogenous stress adaptation of several tissues. However, altered chaperone function has been associated with the development of several diseases; therefore, modulators of chaperone activities became a new and emerging field of drug development. Inhibition of the 90 kDa heat shock protein (Hsp)90 recently emerged as a very promising tool to combat various forms of cancer. On the other hand, the induction of the 70 kDa Hsp70 has been proved to be an efficient help in the recovery from a large number of diseases, such as, for example, ischemic heart disease, diabetes and neurodegeneration. Development of membrane-interacting drugs to modify specific membrane domains, thereby modulating heat shock response, may be of considerable therapeutic benefit as well. In this review, we give an overview of the therapeutic approaches and list some of the key questions of drug development in this novel and promising therapeutic approach.

HSP90 Heat-Shock Proteins↗

PubMed2004

Enhancement of complement-induced cell lysis: a novel mechanism for the anticancer effects of Hsp90 inhibitors.

Molecular chaperones (heat shock proteins, Hsp-s) play a pleiotropic role in immunological functions. Hsp-s participate in the presentation of peptide antigens, folding of several immunologically important proteins, such as the MHC, and in the maintenance of the activation-competent conformation of key signaling molecules (mostly serine/threonine and tyrosine kinases) of B and T cells activation. The most abundant cytoplasmic chaperone, Hsp90, is in the center of these processes. In recent years Hsp90 inhibitors emerged as very promising anticancer agents. Not surprisingly, Hsp90 inhibitors behave as immunosuppressants, and also cause an induction of superoxide production. Here we extend our previous data by showing the enhancement of complement-induced lysis of several types of tumor cells after Hsp90 inhibition. This novel mechanism may significantly contribute to the anticancer effects of Hsp90 inhibitors in vivo.

Antineoplastic Agents↗

PubMed2004

Hsp90 isoforms: functions, expression and clinical importance.

The 90 kDa heat shock protein, Hsp90, is a main functional component of an important cytoplasmic chaperone complex, and it is involved in various cellular processes, such as cell proliferation, differentiation and apoptosis. Identification of Hsp90 as a molecular target of various anticancer drugs highlighted its importance from the clinical point of view. Here we summarize the current knowledge of various Hsp90 isoforms regarding their genomic location, molecular evolution, functional differences, differential induction after various environmental stresses and in pathological conditions as well as the growing importance of discriminating between Hsp90 isoforms in clinical practice.

Animals↗

PubMed2004

Inhibition of Hsp90: a new strategy for inhibiting protein kinases.

The 90-kDa heat shock protein (Hsp90) is a ubiquitous, evolutionarily highly conserved, molecular chaperone in the eukaryotic cytosol. Hsp90, together with a number of other chaperones, promotes the conformational maturation of a large variety of protein kinases. Inhibition of Hsp90 function results in the collapse of the metastable conformation of most of these kinases and leads to their proteolytic elimination by the proteasome. Numerous natural and synthetic Hsp90 inhibitors have been developed in recent years. Some of these inhibitors are also involved in sensitizing tumor cells to pro-apoptotic insults, hence serve as anti-cancer drugs. Here we review these novel protein kinase inhibitors and their emerging role in various cellular processes, apart from their inhibition of Hsp90 protein function. We focus not only on Hsp90-tumor progression, but also on cytoarchitecture, as the higher levels of cellular organization need constant remodeling, where the role of Hsp90 requires investigation. Our last major aspect deals with protein oxidation, since several Hsp90 inhibitors exert pro-oxidant effects.

Animals↗

PubMed2004

[New steroid hormone family: endogenous cardiac glycosides and their role in physiologic and pathologic conditions].

In the last two decades extensive study has been carried out on the isolation, identification and biosynthesis of the "endogenous digitalis-like compounds" whose physiological and pathophysiological functions are only starting to be understood. Besides ouabain (strophanthin) and digoxin, four further endogenous cardiac glycosides were isolated and identified so far. These compounds are found in almost all mammalian tissues, including blood plasma and urine, but with the highest concentrations in the adrenal gland, pituitary and hypothalamus. De novo biosynthesis of these glycosides occurs in zona fasciculata cells of adrenal glands, precursors such as progesterone, pregnenolone, and rhamnose increase the synthesis of the ouabain-like immunoreactive material. The secretion of these compounds from the adrenocortical cells are controlled by adrenerg mechanisms, as well as via the renin-angiotensin system. The hydrophobic cardiac glycosides are transported in blood as complexes bound to specific binding globulins. The identified endogenous cardiac glycosides fulfill all the postulated criterions of the hormones, so they represent a new class of steroid hormones. The cardiac glycosides influence the active sodium pump, indirectly the intracellular free calcium concentration and therefore exert a positive inotropic effect on cardiac muscle. Furthermore, in physiological concentrations they can regulate the cell growth and protein synthesis inducing activation of intracellular signal pathways. Under pathological conditions, however, when the concentration of these steroids are high, they play a crucial role in the development of different serious illnesses such as essential hypertension as well as congestive heart failure. Further intensive investigations are needed to clarify some contradictory details accumulated during the last few years in this field.

Cardiac Glycosides↗

PubMed2004

Photo-acoustic stimulation increases the amount of 70 kDa heat shock protein (Hsp70) in human whole saliva. A pilot study.

Long-term photo-acoustic stimulation leads to changes in the composition of saliva, which may have a key contribution to the effectivity of this technique in easing mucosal symptoms of psychosomatic patients. In the present study a significant (P <or= 0.01) increase in salivary 70 kDa heat shock protein, Hsp70 was demonstrated in human whole saliva after repeated photo-acoustic stimulation. Increased salivary chaperones may contribute to the effectivity of photo-acoustic stimulation, because of their cytoprotective extracellular actions.

Acoustic Stimulation↗

PubMed2004

[The effect of heat stimulation and mechanical stress (massage) of salivary glands on the secretory parameters of salivary Hsp70. A pilot study].

The presence of Hsp70 in human whole saliva was demonstrated in the authors' previous study. In the recent study the authors investigated, whether repeated, short-term heat and mechanical stimulation of the salivary glands can specifically modify the salivary Hsp70 concentration in the human whole saliva. Some other basic secretory parameters, like salivary secretion rate, total protein concentration and amylase activity of the whole saliva were also measured. Both kind of stimulation increased the secretory rate significantly (p < or = 0.05), during stimulation, but it decreased to control level in resting phases. Hsp70 concentration increased after the first stimulation in the case of mechanical stress and after the second stimulation in the case of heat stimulation. In contrast, a significant (p < or = 0.05) confluent increase of total protein concentration and amylase activity occurred after the first stimulation in the case of heat stimulation and after the second stimulation in the case of mechanical stress. Further investigations are needed to evaluate the durability and clinical importance of salivary changes following local heat and massage stimulation.

HSP70 Heat-Shock Proteins↗

PubMed2003

FAD transport and FAD-dependent protein thiol oxidation in rat liver microsomes.

The transport of FAD and its effect on disulfide bond formation was investigated in rat liver microsomal vesicles. By measuring the intravesicular FAD-accessible space, we observed that FAD permeates across the microsomal membrane and accumulates in the lumen. Rapid filtration experiments also demonstrated the uptake and efflux of the compound, which could be inhibited by atractyloside and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. FAD entering the lumen promoted the oxidation of protein thiols and increased the intraluminal oxidation of glucose-6-phosphate. These findings support the notion that, similar to yeast, free FAD may have a decisive role in the mechanism of oxidative protein folding in the endoplasmic reticulum lumen of mammalian cells.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed2003

Bimoclomol, a heat shock protein co-inducer, acts by the prolonged activation of heat shock factor-1.

The novel hydroxylamine derivative, bimoclomol, has been shown previously to act as a co-inducer of several heat shock proteins (Hsp-s), enhancing the amount of these proteins produced following a heat shock compared to heat shock alone. Here we show that the co-inducing effect of bimoclomol on Hsp expression is mediated via the prolonged activation of the heat shock transcription factor (HSF-1). Bimoclomol effects are abolished in cells from mice lacking HSF-1. Moreover, bimoclomol binds to HSF-1 and induces a prolonged binding of HSF-1 to the respective DNA elements. Since HSF-1 does not bind to DNA in the absence of stress, the bimoclomol-induced extension of HSF-1/DNA interaction may contribute to the chaperone co-induction of bimoclomol observed previously. These findings indicate that bimoclomol may be of value in targeting HSF-1 so as to induce up-regulation of protective Hsp-s in a non-stressful manner and for therapeutic benefit.

Animals↗