New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is an incurable, progressive neurodegenerative disorder. AD is a complex and multifactorial disease that is responsible for 60-80% of dementia cases. Aging, genetic factors, and epigenetic changes are the main risk factors for AD.

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer's Pathogenesis.

The structural polymorphism and the physiological and pathophysiological roles of two important proteins, β-amyloid (Aβ) and tau, that play a key role in Alzheimer's disease (AD) are reviewed. Recent results demonstrate that monomeric Aβ has important physiological functions. Toxic oligomeric Aβ assemblies (AβOs) may play a decisive role in AD pathogenesis.

The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases.

Background: Widespread protein aggregation occurs in the living system under stress or during aging, owing to disturbance of endoplasmic reticulum (ER) proteostasis. Many neurodegenerative diseases may have a common mechanism: the failure of protein homeostasis. Perturbation of ER results in unfolded protein response (UPR).

[Improvement of the reliability of the cause of death diagnoses by co-operation of public health authorities and the Central Statistical Office in Hungary].

Introduction: The diagnosis of cause of death is based on the sequence of diagnoses declared by the physician who completes the death certificate that is processed by Central Statistical Office in Hungary. The validity control of the data requires the active involvement of the public health authority.

Aim: The authors analyzed the death certificates from Tolna county in order to elaborate and evaluate methods for cause of death data validity control.

Estimation of incidence, prevalence, and age-at-diagnosis of myasthenia gravis among adults by hospital discharge records.

Background: The Hungarian Health Insurance Fund, using appropriate information technology, covers all of the secondary care of the country and maintains a database of Hospital Discharge Records (HDR). Our study aimed to determine the incidence, average age-at-diagnosis (AaD), and prevalence of myasthenia gravis (MG) among adults and the regional heterogeneity of these measures to assess the potential usefulness of HDRs for monitoring.

Methods: The nationwide database of 336,679 HDRs from 2004 to 2009 was analyzed.

An archived serum sample as a clue for identifying the primary source of a nosocomial hepatitis C virus outbreak in a haemodialysis unit.

Due to an unexpected technical error, patients at a dialysis unit who were seronegative for hepatitis C virus (HCV) were temporarily transferred to another dialysis unit next to a ward reserved for HCV-seropositive patients. In the following 7 months, 17 patients were diagnosed as anti-HCV positive. The aim of the study was to reveal the cause of this nosocomial infection.

Ligand-specific regulation of the endogenous mu-opioid receptor by chronic treatment with mu-opioid peptide agonists.

Since the discovery of the endomorphins (EM), the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue, cis-1S,2R-aminocyclohexanecarboxylic acid(2)-endomorphin-2 (ACHC-EM2), had elevated mu-receptor affinity, selectivity, and proteolytic stability over the parent compound. In the present work, we have studied its antinociceptive effects and receptor regulatory processes.

Lack of regulatory changes of µ-opioid receptors by 14-methoxymetopon treatment in rat brain. Further evidence for functional selectivity.

Here we have studied regulatory changes of µ-opioid receptors accompanying in vivo 14-methoxymetopon treatments of rats. Previously, this ligand has been shown to be an extremely potent, centrally acting µ-opioid specific analgesic with low physical dependence, tolerance, respiratory depression, constipation and other side effects. Our work shows that it is a highly potent full agonist of µ-opioid receptor coupled G-protein signaling in vitro, alike the well-known opioid agonist, etorphine.

Intraneuronal β-amyloid and its interactions with proteins and subcellular organelles.

Amyloidogenic aggregation and misfolding of proteins are linked to neurodegeneration. The mechanism of neurodegeneration in Alzheimer's disease, which gives rise to severe neuronal death and memory loss, is not yet fully understood. The amyloid hypothesis remains the most accepted theory for the pathomechanism of the disease.

Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein.

The disordered tubulin polymerization promoting protein (TPPP/p25) was found to be co-enriched in neuronal and glial inclusions with α-synuclein in Parkinson disease and multiple system atrophy, respectively; however, co-occurrence of α-synuclein with β-amyloid (Aβ) in human brain inclusions has been recently reported, suggesting the existence of mixed type pathologies that could result in obstacles in the correct diagnosis and treatment. Here we identified TPPP/p25 as an interacting partner of the soluble Aβ oligomers as major risk factors for Alzheimer disease using ProtoArray human protein microarray. The interactions of oligomeric Aβ with proteins involved in the etiology of neurological disorders were characterized by ELISA, surface plasmon resonance, pelleting experiments, and tubulin polymerization assay.

A comprehensive study on the putative δ-opioid receptor (sub)types using the highly selective δ-antagonist, Tyr-Tic-(2S,3R)-β-MePhe-Phe-OH.

The goal of our work was a throughout characterization of the pharmacology of the TIPP-analog, Tyr-Tic-(2S,3R)-β-MePhe-Phe-OH and see if putative δ-opioid receptor subtypes can be distinguished. Analgesic latencies were assessed in mouse tail-flick assays after intrathecal administration. In vitro receptor autoradiography, binding and ligand-stimulated [(35)S]GTPγS functional assays were performed in the presence of putative δ(1)-(DPDPE: agonist, BNTX: antagonist), δ(2)-(agonist: deltorphin II, Ile(5,6)-deltorphin II, antagonist: naltriben) and μ-(DAMGO: agonist) opioid ligands.

Long-lasting, distinct changes in central opioid receptor and urinary bladder functions in models of schizophrenia in rats.

Ketamine treatments and social isolation of rats reflect certain features of schizophrenia, among them altered pain sensitivity. To study the underlying mechanisms of these phenomena, rats were either housed individually or grouped for 33 days after weaning, and treated with either ketamine or saline for 14 days. After one month re-socialization, the urinary bladder capacity by ultrasound examination in the anesthetized animals, and changes of μ-opioid receptors by saturation binding experiments using a specific μ-opioid agonist [(3)H]DAMGO were determined.

Pharmacology of a new tritiated endomorphin-2 analog containing the proline mimetic cis-2-aminocyclohexanecarboxylic acid.

As part of ongoing work aimed at generating proteolytically stable, readily applicable, radiolabeled endomorphin-2 (EM-2) analogs for elucidation of the topological requirements of peptide binding to μ-opioid receptors, we report here on the synthesis, radiolabeling, binding kinetics and binding site distribution of an EM-2 analog in which Pro(2) is replaced by 2-aminocyclohexanecarboxylic acid, ACHC. [(3)H][(1S,2R)ACHC](2)EM-2 (specific activity 63.49Ci × mmol(-1)) bound specifically to its binding sites with high affinity (K(D) = 0.

CB1 receptor-independent actions of SR141716 on G-protein signaling: coapplication with the mu-opioid agonist Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol unmasks novel, pertussis toxin-insensitive opioid signaling in mu-opioid receptor-Chinese hamster ovary cells.

The CB(1) cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716) has been shown by many investigators to inhibit basal G-protein activity, i.e., to display inverse agonism at high concentrations.

New endomorphin analogues containing alicyclic beta-amino acids: influence on bioactive conformation and pharmacological profile.

Endomorphins were subjected to a number of structural modifications in a search for their bioactive conformations. The alicyclic beta-amino acids cis-(1 S,2 R)ACPC/ACHC, cis-(1 R,2 S)ACPC/ACHC, trans-(1 S,2 S)ACPC/ACHC, and trans-(1 R,2 R)ACPC/ACHC were introduced into endomorphins to examine the conformational effects on the bioactivity. Use of a combination of receptor binding techniques, (1)H NMR, and molecular modeling allowed the conclusion that Pro (2) substitution by these residues causes changes in structure, proteolytic stability, and pharmacological activity.

Mucoadhesive behaviour of emulsions containing polymeric emulsifier.

Over the last two decades the attention has been focused on mucoadhesive dosage forms as a possibility to improve the residence time on a specified region of the body. In addition to bioadhesivity, controlled drug release from the dosage form is also desirable. Pemulen TR1 and Pemulen TR2 are cross-linked block copolymers of poly(acrylic acid) and hydrophobic long-chain methacrylates.

[Gel-emulsion systems. II. Stability].

Viscosity, elastic character of gel emulsions containing polymeric emulsifiers and change of droplet size distribution under storage were studied. The quantitative change of free (non-bound) water and immobilized one in microgel form, and that of the evaporation rate under storage were examined. The phenomena were divided into two groups: change of i) macrostructure, and ii) microstructure.

[Gel-emulsion systems. I. Physical-chemical characterisation].

Emulsion gels prepared with polyacrylic acid-alkyl acrylate diblock copolymer surfactants were studied. It was supposed that the polymer surfactants surrounding the oil droplets formed a microgel structure and this structure stabilized the emulsions sterically. This assumption was verified by thermoanalytic investigation.

Reciprocal inhibition of G-protein signaling is induced by CB(1) cannabinoid and GABA(B) receptor interactions in rat hippocampal membranes.

Cannabinoid CB(1) and the metabotropic GABA(B) receptors have been shown to display similar pharmacological effects and co-localization in certain brain regions. Previous studies have reported a functional link between the two systems. As a first step to investigate the underlying molecular mechanism, here we show cross-inhibition of G-protein signaling between GABA(B) and CB(1) receptors in rat hippocampal membranes.

Characterization of the interaction between Abeta 1-42 and glyceraldehyde phosphodehydrogenase.

Advances in the understanding of AD pathogenesis have recently provided strong support for a modified Abeta protein cascade hypothesis, stating that several different Abeta assemblies contribute to the triggering of a complex pathological cascade leading to neurodegeneration. Both in vitro and in vivo, Abeta rapidly forms fibrils (fAbeta), which are able to interact with various molecular partners, including proteins, lipids and proteoglycans. In a previous study aimed to identify some of these molecular partners of fAbeta, we demonstrated that the GAPDH was specifically coprecipitated with fAbeta.

Synthesis and pharmacological characterization of a novel, highly potent, peptidomimetic delta-opioid radioantagonist, [3H]Tyr-Tic-(2S,3R)-beta-MePhe-Phe-OH.

[(3)H]Tyr-Tic-(2S,3R)-beta-MePhe-Phe-OH (where Tic: 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) with a specific radioactivity of 53.7 Ci/mmol was synthesized and characterized in receptor binding assays at 25 degrees C in rat brain membranes. The specific binding was saturable and displayed high affinity, with a K(D) of 0.

An assessment of the interactions between diclofenac sodium and ammonio methacrylate copolymer using thermal analysis and Raman spectroscopy.

The objective of the work was to assess the possible interactions between the model drug diclofenac sodium (DS) and the water-insoluble ammonio methacrylate copolymer (AMC). Films with different drug/polymer ratios were therefore prepared by the solvent casting method and investigated as a preformulation study towards sustained release microparticles. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were used to investigate the dispersed/dissolved state of the DS in the preparation, the thermal stability and the properties of DS-containing AMC films; and Raman spectroscopy was used to confirm the possible interactions between DS and AMC.

[Hepatitis A outbreak in Transdanubia (Hungary): molecular connections and epidemiological conclusions - 2006].

Introduction: Hepatitis A virus (HAV) is one of the most important cause of fecally transmitted acute infectious hepatitis worldwide. In Hungary, beside the sporadic HAV infections, outbreaks also occur, particularly in Northeast part of the country where the subgenotype IA is endemic. The reported number of HAV cases was less than 10 per year in Southwest Hungary.

Synthesis, radiolabeling and receptor binding of [3H][(1S,2R)ACPC2]endomorphin-2.

Previously, we have shown that substitution of Pro(2) for cis-2-aminocyclopentanecarboxylic acid, ACPC in endomorphin-2 results in an analogue with greatly augmented proteolytic stability, high mu-opioid receptor affinity and selectivity. We now report the synthesis and biochemical characterization of [(3)H][(1S,2R)ACPC(2)]endomorphin-2 with a specific activity of 1.41 TBq/mmol (38.