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Biomedical subjects

P Gergely

Publications and source records attributed to P Gergely.

At least 19 recordsLinked to original sources
PubMed2006

Lack of genetic association of the Toll-like receptor 4 (TLR4) Asp299Gly and Thr399Ile polymorphisms with spondylarthropathies in a Hungarian population.

OBJECTIVES: Bacteria have long been suggested as aetiological factors in the genetically susceptible host in spondylarthropathies, including ankylosing spondylitis (AS) and reactive arthritis (ReA). Variability of the Toll-like receptor 4 (TLR4) gene has been shown to play a role in the inflammatory response to certain bacterial infections. We investigated whether TLR4 Asp299Gly and Thr399Ile polymorphisms contribute to the genetic background of spondylarthropathies in a cohort of Hungarian patients with AS and ReA. METHODS: DNA was obtained from patients with AS (n=138), ReA (n=91) and ethnically matched healthy controls (n=140). Genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism analysis and the results were confirmed by direct sequencing. RESULTS: No significant differences in allele or genotype frequencies were observed between controls and either the AS patients or the ReA patients. Clinical characteristics of these groups were unrelated to the presence of any of these polymorphisms. CONCLUSIONS: Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms do not contribute to disease susceptibility in either AS or ReA. Functional abnormalities of the TLR4 signalling pathway suggested in spondylarthropathies seem not to be genetically determined by these two common polymorphisms.

Adult↗
PubMed2006

The analgesic effect of pamidronate is not caused by the elevation of beta endorphin level in Paget's disease--a controlled pilot study.

INTRODUCTION: Although an analgesic effect is an essential component of the mode of action of bisphosphonates, its physiological mechanisms are still unclear. Beta-endorphin release plays an important role in the analgesic effect of both calcitonin and raloxifene. As patients with Paget's disease receive large doses of bisphosphonates within relatively short time periods, we examined whether repeated pamidronate infusion therapy would cause measurable change in beta-endorphin levels MATERIALS & METHODS: Visual analog scale (VAS) scores of pain intensity, beta-endorphin levels, and alkaline phosphatase activity of 11 patients with Paget's disease (7 with the mono- and 4 with the polyostotic form) were determined at baseline, as well as after 3 and 6 infusions (on Days 6 and 12 of treatment, respectively). Eleven untreated patients with Paget's disease (7 with the mono- and 4 with the polyostotic form) served as controls. RESULTS: It was established that in the course of pamidronate infusion therapy BE levels remained constant, whereas the values in serum alkaline phosphatase and pain intensity scores were significantly reduced. CONCLUSIONS: Although high-dose pamidronate therapy does mitigate pain substantially (as demonstrated by the reduction of VAS scores), its analgesic action is probably unrelated to the enhancement of beta-endorphin release.

Aged↗
PubMed2005

Pathophysiologic role of oxidative stress-induced poly(ADP-ribose) polymerase-1 activation: focus on cell death and transcriptional regulation.

PARP-1 is a nuclear enzyme activated by DNA breaks. Activated PARP-1 cleaves NAD into nicotinamide and ADP-ribose and polymerizes the latter covalently coupled to nuclear acceptor proteins. Poly(ADP-ribosyl)ation has been implicated in the regulation of a diverse array of cellular processes ranging from DNA repair, chromatin organization, transcription, replication to protein degradation. On the 'dark side' of poly(ADP-ribosyl)ation, PARP-1 activation has been shown to contribute to tissue injury in shock, diabetes, myocardial or cerebral ischemia reperfusion and various forms of inflammation, as proven by pharmacological studies as well as experiments utilizing PARP-1 knockout animals. To our current knowledge, two mechanisms are responsible for the beneficial effects of PARP inhibitors in inflammatory, neurodegenerative and ischemia-reperfusion-based diseases: (i) inhibition of cell death caused by over-activation of PARP-1; (ii) inhibition of inflammatory signal transduction and production of inflammatory mediators. Here we review the possible regulatory mechanisms (e.g. calcium signaling, metabolism, density-dependent signaling, kinase cascades) of the PARP-1-mediated cell death pathway and discuss recent developments shedding new light on the complex role of PARP-1 in the regulation of the expression of inflammatory mediators.

Animals↗
PubMed2004

Vitamin D receptor, oestrogen receptor-alpha and calcium-sensing receptor genotypes, bone mineral density and biochemical markers in Paget's disease of bone.

OBJECTIVES: The significance of genetic polymorphisms in the development of Paget's disease of bone is unclear at present. METHODS: We analysed the BsmI polymorphism of the vitamin D receptor (VDR) gene, the PvuII and XbaI polymorphisms of the oestrogen receptor-alpha (ER alpha) gene, and the A986S polymorphism of the calcium-sensing receptor (CaSR) gene in 69 pagetic patients and 120 healthy subjects. We also examined the relationship of these polymorphisms with lumbar spine and femoral neck BMD as well as with biochemical parameters (serum alkaline phosphatase, osteocalcin and parathyroid hormone) in Paget's disease. RESULTS: The XbaI and PvuII genotype distributions of the ER alpha gene were significantly different between patients with Paget's disease and control subjects (P<0.001). Also, the CaSR A986S genotype frequency was significantly different between pagetic patients and controls (P<0.01). No significant effect of gene polymorphisms on BMD or biochemical parameters of bone turnover was observed. CONCLUSION: Our results suggest that the ER alpha PvuII/XbaI and CaSR A986S polymorphisms may contribute to genetic susceptibility to Paget's disease. However, further studies are required to investigate the underlying pathomechanism and to replicate the associations.

Aged↗
PubMed2004

Abnormal cell-specific expressions of certain protein kinase C isoenzymes in peripheral mononuclear cells of patients with systemic lupus erythematosus: effect of corticosteroid application.

We have studied the expressions of various protein kinase C (PKC) isoenzymes in T cells and monocytes from patients with systemic lupus erythematosus (SLE), in comparison to those of healthy controls and patients with other immunological disorders. As measured by Western blotting, the levels of PKCbeta, delta, eta, epsilon, theta and zeta (but not of PKCalpha) significantly decreased in T cells of SLE patients. In monocytes, however, we observed marked suppressions only in the expressions of PKCdelta, epsilon and zeta but not in the expressions of other PKC isoforms. In vivo corticosteroid application, as well as in vitro steroid treatment of monocytes, elevated the expressions of most isoforms close to normal values; however, the decreased levels of PKCtheta and zeta were not affected by steroid application. These alterations were characteristic to SLE because we could not detect any changes in the PKC levels in mononuclear cells of primary Sjögren's syndrome and mixed connective tissue disease patients. These results suggest that impaired PKC isoenzyme pattern may exist in the T cells and monocytes of SLE patients. Furthermore, the clinically efficient glucocorticoid application in SLE can increase the expression of some members of PKC system.

Adrenal Cortex Hormones↗
PubMed2003

Effect of bisphosphonate treatment in patients with Paget's disease of the skull.

OBJECTIVES: Hearing loss has long been known to be a complication of Paget's disease of bone. The aim of this study was to investigate Paget's disease of the temporal bone with special attention to hearing loss. METHODS: Twenty-five patients with skull involvement were treated with either pamidronate or tiludronate. Imaging included radiography, quantitative bone scintigraphy (QBS), single photon emission computed tomography (SPECT) and high-resolution computed tomographic (HRCT) scanning. Audiometric assessment was also performed. RESULTS: Twenty-three of the 25 patients with skull involvement suffered from hearing loss. Bisphosphonate treatment resulted in a decreased serum total alkaline phosphatase (serum tAP) level and QBS ratio, and also seemed to improve the complaints of the patients. HRCT demonstrated involvement of the middle ear ossicles (n = 7), involvement of the petrous pyramids (n = 14), demineralization of the otic capsule (n = 10), porosis pericochlearis (n = 8), narrowing of the external auditory meatus (n = 12), mastoid process thickening (n = 5) and stapedial footplate thickening (n = 4). The audiometric examination did not show any significant changes 1 yr after bisphosphonate treatment. CONCLUSIONS: HRCT imaging is a well suited tool for demonstrating the complication of Paget's disease. QBS and measurement of serum tAP level may also be regarded as useful techniques for monitoring treatment. However, hearing may remain impaired in spite of the improved scintigraphy and laboratory parameters, therefore, audiometric assessment is also important in pagetic patients with skull involvement.

Aged↗
PubMed2003

Termination of disease-modifying antirheumatic drugs in rheumatoid arthritis and in psoriatic arthritis. A comparative study of 270 cases.

102 rheumatoid arthritis (RA) and 104 psoriatic arthritis (PsA) patients' records were analysed according to a standardised protocol. Using Cox regression, life-table analysis and log rank test, the effectiveness and toxicity of, and duration of disease modifying antirheumatic drug (DMARD) treatment were compared in RA and PsA. RA patients were treated with gold sodium thiomalate (GST), methotrexate (MTX) and sulphasalazine (SSZ) for a median duration of 35, 72 and 12 months respectively, whereas PsA patients were treated for 12, 12 and 17 months. The differences for GST and MTX were statistically significant (p=0.0043 and 0.0447). Drug toxicity was more frequently seen among patients with PsA (p=0.0023). No difference in efficacy could be proved. Results suggest that there is a significant difference between RA and PsA patients in terms of toxicity of these agents. Therefore, separate treatment strategies are needed, and earlier results with RA may not be directly applicable to PsA.

Antirheumatic Agents↗
PubMed2003

Prevalence of obesity in an elderly Hungarian population.

BACKGROUND: There are few cross-sectional population-based studies on obesity in Hungary. Aim of this study was to characterize the prevalence, associated diseases and metabolic laboratory parameters for obesity in men and women in Budapest, Hungary. METHODS: A random sample of 641 persons (307 males and 334 females) aged 50 years and over were recruited from a population register in Budapest. Subjects were interviewed, had height and weight measured in standard fashion. Those who were obese (BMI > 30.0 kg/m2) were matched individually with non-obese subjects. Altogether 101 pairs (48 women and 53 men pairs) were taking part and these subjects had blood taken for amount of serum glucose, lipids and uric acid. RESULTS: The mean age of men and women was 65.0 (SD = 9.1) years and 64.6 (SD = 8.9) years, respectively. The prevalence of obesity was 18.1% in men and 15.4% in women (p < 0.05). In both sexes the mean body mass index was higher at age of 50-64 years than at older ages [in men 27.2 (SD = 3.7) kg/m2 vs. 26.7 (SD = 3.3) kg/ m2, p = 0.286 and in women 26.7 (SD = 4.2) kg/m2 vs. 25.4 (SD = 4.0) kg/m2, p = 0.005]. Body mass index was higher in men than in women at all ages. In the case-control study the mean age of obese and non-obese individuals were 63.1 (SD = 7.8) years and 63.2 (SD = 7.9) years, respectively. Obesity was significantly associated with a history of diabetes mellitus (18 vs. 7%, p < 0.05) and hypertension (48 vs. 28%, p < 0.05). Compared to the non-obese, those who were obese had a higher level of serum uric acid (311 +/- 102 vs. 280 +/- 96 micromol/l, p < 0.05) and triglyceride (2.67 +/- 1.95 vs. 1.86 +/- 0.95 mmol/l, p < 0.05). CONCLUSION: The high prevalence of obesity both in elderly men and women and its strong association with chronic diseases causes economical and social burden for Hungary. Strategies and programs for weight maintenance as well as weight reduction must become a higher public health priority.

Age Distribution↗
PubMed2001

Partial protection by poly(ADP-ribose) polymerase inhibitors from nitroxyl-induced cytotoxity in thymocytes.

Nitroxyl (NO(-)/HNO), has been proposed to be one of the NO(*)-derived cytotoxic species. Although the biological effect of nitroxyl is largely unknown, it has been reported to cause DNA breakage and cytotoxicity. We have therefore investigated whether NO(-)/HNO-induced DNA single-strand breakage activates the nuclear nick sensor enzyme poly(ADP-ribose) polymerase (PARP) and whether PARP activation affects the mode of NO(-)/HNO- induced cell death. NO(-)/HNO generated from Angeli's salt (AS, sodium trioxodinitrate) (0-300 microM) induced DNA single-strand breakage, PARP activation, and a concentration-dependent cytotoxicity in murine thymocytes. AS-induced cell death was also accompanied by decreased mitochondrial membrane potential and increased secondary superoxide production. The cytotoxicity of AS, as measured by propidium iodide uptake, was abolished by electron acceptors potassium ferricyanide, TEMPOL, the intracellular calcium chelator BAPTA-AM, and by PARP inhibitors 3-aminobenzamide (3-AB) and PJ-34. The cytoprotective effect of 3-AB was paralleled by increased output of AS-induced apoptotic parameters such as phosphatidylserine exposure, caspase activation, and DNA fragmentation. No significant increase in tyrosine nitration could be observed in AS-treated thymocytes as opposed to peroxynitrite-treated cells, indicating that tyrosine nitration is not likely to contribute to NO(-)/HNO-induced cytotoxicity. Our results demonstrate that NO(-)/HNO-induced PARP activation shifts the default apoptotic cell death toward necrosis in thymocytes. However, as total PARP inhibition resulted only in 30% cytoprotection, PARP-independent mechanisms dominate NO(-)/HNO-induced cytotoxicity in thymocytes.

Animals↗
PubMed2001

Synthesis of and a comparative study on the inhibition of muscle and liver glycogen phosphorylases by epimeric pairs of d-gluco- and d-xylopyranosylidene-spiro-(thio)hydantoins and N-(d-glucopyranosyl) amides.

D-Gluco- and D-xylopyranosylidene-spiro-hydantoins and -thiohydantoins were prepared from the parent sugars in a six-step, highly chemo-, regio-, and stereoselective procedure. In the key step of the syntheses C-(1-bromo-1-deoxy-beta-D-glycopyranosyl)formamides were reacted with cyanate ion to give spiro-hydantoins with a retained configuration at the anomeric center as the major products. On the other hand, thiocyanate ions gave spiro-thiohydantoins with an inverted anomeric carbon as the only products. On the basis of radical inhibition studies, a mechanistic rationale was proposed to explain this unique stereoselectivity and the formation of C-(1-hydroxy-beta-D-glycopyranosyl)formamides as byproducts. Enzyme assays with a and b forms of muscle and liver glycogen phosphorylases showed spiro-hydantoin 12 and spiro-thiohydantoin 14 to be the best and equipotent inhibitors with K(i) values in the low micromolar range. The study of epimeric pairs of D-gluco and D-xylo configurated spiro-hydantoins and N-(D-glucopyranosyl)amides corroborated the role of specific hydrogen bridges in binding the inhibitors to the enzyme.

Amides↗
PubMed2001

Synthesis of new cyclitol compounds that influence the activity of phosphatidylinositol 4-kinase isoform, PI4K230.

The synthesis, chemical derivatization, and investigation of the inhibitory properties of novel cyclitol derivatives on the phosphatidylinositol 4-kinase enzymes PI4K55 and PI4K230 involved in the phosphatidylinositol cycle are reported. Some of the prepared cyclitol derivatives (i.e. 9, 11, 12, and 14) proved to be very powerful and specific irreversible inhibitors of PI4K230 at or below a concentration of 1 mM.

Animals↗
PubMed2001

Functional analysis of the Neurospora crassa PZL-1 protein phosphatase by expression in budding and fission yeast.

The gene pzl-1 from the filamentous fungus Neurospora crassa encodes a putative Ser/Thr protein phosphatase that is reminiscent of the Ppz1/Ppz2 and Pzh1 phosphatases from Saccharomyces cerevisiae and Schizosaccharomyces pombe, respectively. The entire PZL-1 protein, as well as its carboxyl-terminal domain, have been expressed in Escherichia coli as active protein phosphatases. To characterize its cellular role, PZL-1 was also expressed in Sz. pombe and in S. cerevisiae. Expression of PZL-1 in S. cerevisiae from the PPZ1 promoter was able to rescue the altered sensitivity to caffeine and lithium ions of a ppz1 strain. Furthermore, high copy number expression of PZL-1 alleviated the lytic phenotype of a S. cerevisiae slt2/mpk1 mitogen-activated protein (MAP) kinase mutant, similarly to that described for PPZ1, and mimicked the effects of high levels of Ppz1 on cell growth. Expression of PZL-1 in fission yeast from a weak version of the nmt1 promoter fully rescued the growth defect of a pzh1Delta strain in high potassium, but only partially complemented the sodium-hypertolerant phenotype. Strong overexpression of the N. crassa phosphatase in Sz. pombe affected cell growth and morphology. Therefore, PZL-1 appears to fulfil every known function carried out by its S. cerevisiae counterpart, despite the marked divergence in sequence within their NH(2)-terminal moieties.

Catalytic Domain↗
PubMed2001

Okadaic acid-induced inhibition of protein phosphatase 2A enhances chondrogenesis in chicken limb bud micromass cell cultures.

The role of major cellular serine/threonine-specific protein phosphatases, protein phosphatase 1 and 2A, was investigated during chicken cartilage differentiation under in vitro conditions. Activity of protein phosphatase 2A decreased parallel to differentiation of chondrogenic cells, whereas activity of protein phosphatase 1 remained unchanged as assayed in the supernatants of the homogenised chicken limb bud micromass cell cultures. When okadaic acid, a potent inhibitor of protein phosphatase 1 and 2A was applied in 20 nM concentration for 4 h during the second and third culturing days, it significantly increased the size of metachromatic cartilage areas measured in 6-day-old colonies. Following okadaic acid treatments, a significant inhibition in the activity of protein phosphatase 2A was found, while the activity of protein phosphatase 1 was unaffected as measured an days 2 and 3. TRITC-phalloidin labelling demonstrated that okadaic acid disorganised actin filaments and induced rounding of chondrogenic cells. This deterioration of actin filaments was reversible. Electron microscopy and biochemical analysis of colonies revealed that the ultrastructure and major components of cartilage matrix remained unchanged under the effect of okadaic acid. Okadaic acid-treatment applied to cultures containing predominantly differentiated chondrocytes (after day 4) did not influence the cartilage formation. 3H-thymidine and bromodeoxyuridine incorporation-assays demonstrated enhanced cell proliferation in the okadaic acid-treated colonies compared to that of the untreated ones. Our results indicate, for the first time, that protein phosphatase 2A is involved in the regulation of chondrogenesis. Inhibition of protein phosphatase 2A with okadaic acid may result in increased chondrogenesis via modulation of proliferation and cytoskeletal organisation, as well as via alteration of protein kinase A-signaling pathway of the chondrogenic cells.

Actin Cytoskeleton↗
PubMed2001

Effect of silibinin and vitamin E on restoration of cellular immune response after partial hepatectomy.

Our aim was to study the antioxidant and immunomodulatory effect of silibinin and vitamin E on the early postoperative course in rats that had undergone a partial hepatectomy (PHX). Male Wistar rats that were treated with silibinin (50 mg/b.w.kg i.p.) and/or vitamin E (500 mg/b.w.kg p.o.) were randomised to undergo 70% PHX. At 72 h after operation, Concanavalin A (Con-A) induced lymphocyte proliferation, and lipopolysaccharide (LPS) induced interleukin-1 (IL-1) mitogenicity and tumour necrosis factor-alpha (TNF-alpha) cytotoxicity were measured in the spleen. In addition, total free radical scavenger capacity of the liver was analysed. In PHX animals, Con-A induced lymphocyte proliferation was significantly decreased, and both LPS induced IL-1 and TNF-alpha activity were significantly increased as compared to Sham treated animals. Treatment with silibinin and vitamin E synergistically restored both lymphocyte proliferation (P<0.01) and cytokine activity (P<0.001) in PHX animals. In addition, silibinin and vitamin E synergistically (P<0.001) restored total hepatic free radical scavenger capacity as well as serum levels of AST and gammaGT, that were all markedly decreased in PHX animals. Our results suggest that preoperative treatment with silibinin and/or vitamin E modulates the cellular immunoresponse and restores impaired liver function following PHX, presumably through their antioxidant capacity. This may explain their beneficial effects on the postoperative course of liver repair.

Animals↗
PubMed2001

The ATP-binding site of brain phosphatidylinositol 4-kinase PI4K230 as revealed by 5'-p-fluorosulfonylbenzoyladenosine.

The ATP-binding site of purified bovine brain phosphatidylinositol 4-kinase 230 (PI4K230) was studied by its reaction with 5'-p-fluorosulfonylbenzoyladenosine (FSBA), an ATP-like alkylating reagent. Four hundred to eight hundred micromolar FSBA inactivated PI4K230 specifically with apparently first-order kinetics and resulted in 50% loss of enzyme activity in 36--130 min. The specificity of the reaction with FSBA was demonstrated by the lack of inactivation with 5'-p-fluorosulfonylbenzoyl chloride and by protection with ATP and ATP analogues against inactivation. Most ATP analogues competed with FSBA inactivation in order of their increasing hydrophobicity, parallel to their inhibitory potency in activity measurements. The specific binding of FSBA to PI4K230 was demonstrated also by Western-blot experiments. These results suggest that FSBA-reactive group(s) involved in the enzyme activity are located near to the ATP-binding site in a hydrophobic region of native PI4K230. Experiments with site-directed mutagenesis indicate that the conserved Lys-1792 plays essential role in the enzyme activity and serves as one target of affinity labelling by FSBA. Prevention of both Lys-1792-directed and Lys-1792-independent binding of FSBA by Cibacron Blue 3GA suggest that these sites are located spatially close to each other.

1-Phosphatidylinositol 4-Kinase↗
PubMed2001

Peroxynitrite production, DNA breakage, and poly(ADP-ribose) polymerase activation in a mouse model of oxazolone-induced contact hypersensitivity.

Peroxynitrite-induced poly(ADP-ribose) polymerase activation has been implicated in the pathogenesis of various inflammatory conditions. Here we have investigated whether peroxynitrite and poly(ADP-ribose) polymerase may play a role in the pathophysiology of the elicitation phase of contact hypersensitivity. We have detected nitrotyrosine, DNA breakage, and poly(ADP-ribose) polymerase activation in the epidermis of mice in an oxazolone-induced contact hypersensitivity model. As tyrosine nitration is mostly mediated by peroxynitrite, a nitric-oxide-derived cytotoxic oxidant capable of causing DNA breakage, we have applied peroxynitrite directly on mouse skin and showed poly(ADP-ribose) polymerase activation in keratinocytes and in some scattered dermal cells. We have also investigated the cellular effects of peroxynitrite in HaCaT cells, a human keratinocyte cell line. We found that peroxynitrite inhibited cell proliferation and at higher concentrations also caused cytotoxicity. Peroxynitrite activates poly(ADP-ribose) polymerase in HaCaT cells and poly(ADP-ribose) polymerase activation contributes to peroxynitrite-induced cytotoxicity, as indicated by the cytoprotective effect of the poly(ADP-ribose) polymerase inhibitor 3-aminobenzamide. The cytoprotective effect of 3-aminobenzamide cannot be attributed to inhibition of apoptosis, as apoptotic parameters (caspase activation and DNA fragmentation) were not reduced in the presence of 3-aminobenzamide in peroxynitrite-treated cells. Moreover, poly(ADP-ribose) polymerase inhibition by 3-aminobenzamide dose-dependently reduced interferon-induced intercellular adhesion molecule 1 expression as well as interleukin-1beta-induced interleukin-8 expression. Our results indicate that peroxynitrite and poly(ADP-ribose) polymerase regulate keratinocyte function and death in contact hypersensitivity.

Adjuvants, Immunologic↗
PubMed2001

Glucocorticosteroid dependent decrease in the activity of calcineurin in the peripheral blood mononuclear cells of patients with systemic lupus erythematosus.

OBJECTIVE: To compare the activity of calcineurin in the peripheral blood mononuclear cells (PBMC) of 32 patients with systemic lupus erythematosus (SLE) and 35 healthy controls. METHODS: The activity of calcineurin was assayed in the supernatants of sonicated mononuclear cells. RESULTS: There was no significant difference in the calcineurin activity of patients with SLE not taking glucocorticosteroids (GCS) compared with the healthy controls. On the other hand, the activity of calcineurin was reduced in patients with SLE taking GCS, correlating negatively with the dose of GCS. The stimulation of PBMC by phorbol ester and calcium ionophore decreased the calcineurin activity both in patients with SLE and in healthy controls. GCS could also reduce calcineurin activity in the mononuclear cells of healthy subjects in vitro. CONCLUSIONS: In patients with SLE the decrease in the calcineurin activity of PBMC depended on the dose of GCS used for treatment, and it was not a disease specific alteration. The higher the dose of GCS, the greater the inhibition of calcineurin activity. The reduction of calcineurin activity is a new element in the immunosuppressive effects of GCS during the treatment of patients with SLE.

Adolescent↗