Tacrine-flurbiprofen hybrids as multifunctional drug candidates for the treatment of Alzheimer's disease.

Five tacrine-flurbiprofen hybrid compounds (3a-e) were synthesized as multi-target-directed compounds for the treatment of Alzheimer's disease. Compared to tacrine, two compounds (3d and 3e) showed better acetylcholinesterase (AChE) inhibitory activity and others (3b-e) better or the same butyrylcholinesterase (BuChE) inhibitory activity. Notably, 3d showed a mixed-type inhibitory action for AChE, indicating a "dual-binding site action" of both toward the catalytic active site (CAS) and the peripheral anionic site (PAS), whereas for BuChE, a competitive inhibitory action was observed.

Berberine acts as a natural inhibitor of Wnt/β-catenin signaling--identification of more active 13-arylalkyl derivatives.

Aberrant activation of the canonical Wnt/β-catenin signaling pathway has been reported for numerous tumors of different origins. In most cases, mutations in components of the Wnt signaling pathway or in β-catenin itself were detected which ultimately induce a genetic program that promotes cell proliferation and attenuates apoptosis. Thus, targeting of Wnt/β-catenin signaling is of specific therapeutic interest.

Old wine in new pipes? Treatment of advanced non-small cell lung cancer with trofosfamide.

Background: The aim of this retrospective study was to examine the effect of oral trofosfamide in patients with advanced non-small cell lung cancer (NSCLC).

Patients And Methods: Patients with histologically or cytologically proven NSCLC, who had received at least 2 other therapies, were enrolled. The primary clinical end point was progression-free survival (PFS); secondary end points included overall survival (OS), response rate and toxicity.

High capacity for leukotriene biosynthesis in peripheral blood during pregnancy.

Pregnancy is accompanied by major immunological changes to maintain both tolerance for the fetus and immune competence. Leukotrienes are powerful 5-lipoxygenase-derived inflammatory mediators and the characteristics of leukotriene-related diseases (e.g.

Stereospecific micellar electrokinetic chromatography assay of methionine sulfoxide reductase activity employing a multiple layer coated capillary.

A micellar electrokinetic chromatography method for the analysis of the l-methionine sulfoxide diastereomers employing a successive multiple ionic-polymer layer coated fused-silica capillary was developed and validated in order to investigate the stereospecificity of methionine sulfoxide reductases. The capillary coating consisted of a first layer of hexadimethrine and a second layer of dextran sulfate providing a stable strong cathodic EOF and consequently highly repeatable analyte migration times. The methionine sulfoxide diastereomers, methionine as product as well as β-alanine as internal standard were derivatized by dabsyl chloride and separated using a 35 mM sodium phosphate buffer, pH 8.

Potent inhibition of human 5-lipoxygenase and microsomal prostaglandin E₂ synthase-1 by the anti-carcinogenic and anti-inflammatory agent embelin.

Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone) possesses anti-inflammatory and anti-carcinogenic properties in vivo, and these features have been related to interference with multiple targets including XIAPs, NFκB, STAT-3, Akt and mTOR. However, interference with these proteins requires relatively high concentrations of embelin (IC₅₀>4 μM) and cannot fully explain its bioactivity observed in several functional studies. Here we reveal human 5-lipoxygenase (5-LO) and microsomal prostaglandin E₂ synthase (mPGES)-1 as direct molecular targets of embelin.

Perichromism: a powerful tool for probing the properties of cellulose and its derivatives.

This overview is concerned with the use of certain dyes (perichromic indicators, hereafter designated as "probes") in order to determine the properties of cellulose, its solutions and solid derivatives. It is arranged as follows: (i) the properties of cellulose and its derivatives that are relevant to their applications are listed; (ii) a general discussion is presented on how perichromism can be employed in order to gain information on the medium where the probe is present; (iii) the results of perichromism, as applied to cellulose, cellulose solutions, and derivative films are discussed.

Capillary electrophoretic enzyme assays.

In the past years, capillary electrophoresis has become a frequently used technique for enzyme assays due to the high separation efficiency and versatility as well as small sample size and low consumption of chemicals. The capillary electrophoresis assays can be divided into two general categories: pre-capillary (or offline) assays and in-capillary (or online) assays. In pre-capillary assays, the incubation is performed offline and substrate(s) and product(s) are subsequently analyzed by capillary electrophoresis.

Randomized placebo-controlled intervention with n-3 LC-PUFA-supplemented yoghurt: effects on circulating eicosanoids and cardiovascular risk factors.

Background & Aims: The study examined the value of n-3 LC-PUFA-enriched yogurt as means of improving cardiovascular health.

Design: Fifty three mildly hypertriacylglycerolemic subjects (TAG ≥ 1.7 mmol/L) participated in a randomized, placebo-controlled, double-blind, parallel designed study.

Histone deacetylase 6 (HDAC6) plays a crucial role in p38MAPK-dependent induction of heme oxygenase-1 (HO-1) in response to proteasome inhibition.

The proteasome is responsible for the degradation of polyubiquitinated proteins. Inhibition of the proteasome leads to an accumulation of polyubiquitinated proteins and thus to an impairment of the cellular protein homeostasis. To prevent cellular damage on proteasome inhibition there is an up-regulation of several heat shock proteins (Hsps), including Hsp27, Hsp70, and heme oxygenase-1 (HO-1).

Breakdown of the FLT3-ITD/STAT5 axis and synergistic apoptosis induction by the histone deacetylase inhibitor panobinostat and FLT3-specific inhibitors.

Activating mutations of the class III receptor tyrosine kinase FLT3 are the most frequent molecular aberration in acute myeloid leukemia (AML). Mutant FLT3 accelerates proliferation, suppresses apoptosis, and correlates with poor prognosis. Therefore, it is a promising therapeutic target.

Significance of amino acid substitutions in the thymidine kinase gene of herpes simplex virus type 1 for resistance.

The analysis of the viral thymidine kinase (TK) genotype is of rising significance for testing resistance of herpes simplex virus (HSV) to antivirals especially acyclovir. However, numerous of the described amino acid (aa) substitutions are diagnostically less conclusive because of the pronounced natural polymorphism of this gene. In this study, several aa substitutions in the TK sequence of HSV-1 with unclear significance for resistance were analyzed by expression of recombinant TK proteins and determination of enzymatic activity on the basis of an enzyme linked immunosorbent assay using bromodeoxyuridine (BrdU) as TK substrate.

Proteinase-activated receptor 2 (PAR(2)) in cholangiocarcinoma (CCA) cells: effects on signaling and cellular level.

In this study, we demonstrate functional expression of the proteinase-activated receptor 2 (PAR(2)), a member of a G-protein receptor subfamily in primary cholangiocarcinoma (PCCA) cell cultures. Treatment of PCCA cells with the serine proteinase trypsin and the PAR(2)-selective activating peptide, furoyl-LIGRLO-NH(2), increased migration across a collagen membrane barrier. This effect was inhibited by a PAR(2)-selective pepducin antagonist peptide (P2pal-18S) and it was also blocked with the Met receptor tyrosine kinase (Met) inhibitors SU 11274 and PHA 665752, the MAPKinase inhibitors PD 98059 and SL 327, and the Stat3 inhibitor Stattic.

A transplantable phosphorylation probe for direct assessment of G protein-coupled receptor activation.

The newly developed multireceptor somatostatin analogs pasireotide (SOM230), octreotide and somatoprim (DG3173) have primarily been characterized according to their binding profiles. However, their ability to activate individual somatostatin receptor subtypes (sst) has not been directly assessed so far. Here, we transplanted the carboxyl-terminal phosphorylation motif of the sst(2) receptor to other somatostatin receptors and assessed receptor activation using a set of three phosphosite-specific antibodies.

Perioperative chemotherapy with docetaxel, cisplatin and capecitabine (DCX) in gastro-oesophageal adenocarcinoma: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO){dagger}.

Background: This prospective multicentre phase II trial assessed the feasibility and efficacy of perioperative chemotherapy with docetaxel, cisplatin and capecitabine (DCX) in patients with gastro-oesophageal adenocarcinoma.

Methods: Patients with curatively resectable adenocarcinoma of the stomach, the gastro-oesophageal junction or the lower third of the oesophagus were enrolled. Patients received docetaxel 75 mg/m(2) plus cisplatin 60 mg/m(2) (day 1), followed by oral capecitabine 1875 mg/m(2) divided into two doses (days 1-14) every 3 weeks.

Biosynthesis, extraction, purification, and analysis of trisporoid sexual communication compounds from mated cultures of Blakeslea trispora.

The zygomycete Blakeslea trispora produces high amounts of the general zygomycete β-carotene-derived sexual signal compounds, the trisporoids. These can be isolated from the culture medium and purified by extraction with organic solvents followed by thin layer chromatography. Concentration is determined spectrophotometrically using specific extinction coefficients established for some members of this compound family.

Block Copolymers of Poly(2-oxazoline)s and Poly(meth)acrylates: A Crossover between Cationic Ring-Opening Polymerization (CROP) and Reversible Addition-Fragmentation Chain Transfer (RAFT).

To combine the advantages of poly(2-oxazoline)s (POx) and controlled radical polymerization (CRP) techniques, the cationic ring-opening polymerization (CROP) of 2-methyl-2-oxazoline (MeOx), 2-ethyl-2-oxazoline (EtOx), and 2--nonyl-2-oxazoline (NonOx) were terminated with a carboxylic acid functionalized chain transfer agent (CTA). The obtained PEtOx with a high degree of functionalization (DF) was used as macro-CTA for the reversible addition-fragmentation chain transfer (RAFT) polymerization of various vinylic monomers (styrene (St), methyl acrylate (MA), -butyl acrylate (BuA), acrylic acid (AA), ,-dimethyl acrylamide (DMAAm), and ,-dimethylaminoethylacrylate (DMAEA)) resulting in well-defined block copolymers. Thus, in this work we report a versatile route to combine poly(2-oxazoline)s prepared via CROP with RAFT polymerization for the synthesis of novel block copolymers.

Advanced glycation end products and β(2)-microglobulin as predictors of carpal tunnel syndrome in hemodialysis patients.

Background/aims: Carpal tunnel syndrome (CTS) is a common clinical presentation of dialysis-related amyloidosis. It was determined whether β(2)-microglobulin (β2M) and advanced glycation end products in serum are predictors of CTS in dialysis patients.

Methods: A total of 385 hemodialysis patients were screened for CTS.

Chaperones, but not oxidized proteins, are ubiquitinated after oxidative stress.

After oxidative stress, proteins that are oxidatively modified are degraded by the 20S proteasome. However, several studies have documented an enhanced ubiquitination of yet unknown proteins. Because ubiquitination is a prerequisite for degradation by the 26S proteasome in an ATP-dependent manner this raises the question whether these proteins are also oxidized and, if not, what proteins need to be ubiquitinated and degraded after oxidative conditions.

Positive effect of eplerenone treatment on endothelial progenitor cells in patients with chronic heart failure.

Background: Endothelial progenitor cells (EPCs) are known to play a significant role in reendothelialization and vascular repair. Recently, a mineralocorticoid receptor was demonstrated to be expressed by EPCs. The study aimed to evaluate a potential influence of eplerenone treatment on the total number of EPCs in patients with chronic heart failure.

Amino-functionalized cellulose nanoparticles: preparation, characterization, and interactions with living cells.

Spherical nanoparticles with sizes from 80 to 200 nm are obtained by self-assembly of highly functionalized 6-deoxy-6-(ω-aminoalkyl)aminocellulosecarbamates. The particles are very stable, nontoxic, and possess primary amino groups that are accessible to further modifications in aqueous suspension. The particles can be labeled with rhodamine B isothiocyanate without changing their size, stability, and shape.

Rapid and sensitive determination of protein-nitrotyrosine by ELISA: Application to human plasma.

3-Nitrotyrosine (3NT) is known as an important indicator of nitrosative stress and has been linked to various diseases. Our aim was to develop an indirect ELISA (enzyme-linked immunosorbent assay) method suitable for the detection of protein-bound 3NT in clinical plasma and serum samples. Nitrated protein standards and reduced protein standards were prepared.

Protein oxidative modification in the aging organism and the role of the ubiquitin proteasomal system.

Living in an oxygen containing environment is automatically connected to oxidative stress. Beside lipids and nucleic acids, especially proteins are very susceptible for oxidative modifications. These oxidative modifications comprise alterations of single amino acids, like the formation of protein carbonyls and methionine sulfoxide, or the aggregation of whole proteins.

Impact of stable PGI₂ analog iloprost on early graft viability after liver transplantation: a pilot study.

Background: Ischemia/reperfusion injury after liver transplantation (LT) may be associated with primary graft dysfunction (PDF) or non-function. Prostaglandins were demonstrated to be beneficial in reducing ischemic injury by improving microcirculation and protecting endothelial cells. The aim of this study was to analyze the effect of the continuously administered prostaglandin I(2) analog iloprost on allograft function after LT.

Acids with an equivalent taste lead to different erosion of human dental enamel.

Objectives: The consumption of acidic soft drinks may lead to demineralization and softening of human dental enamel, known as dental erosion. The aims of this in vitro study were to determine: (i) if different acids with a similar sensorial acidic taste lead to different hardness loss of enamel and (ii) if the fruit acids tartaric, malic, lactic or ascorbic acid lead to less hardness loss of enamel than citric or phosphoric acid when their concentration in solution is based on an equivalent sensorial acidic taste.

Methods: Enamel samples of non-erupted human third molars were treated with acidic solutions of tartaric (TA), malic (MA), lactic (LA), ascorbic (AA), phosphoric (PA) and citric (CA) acids with a concentration that gave an equivalent sensorial acidic taste.