Analysis of highly potent amidine containing inhibitors of serine proteases and their N-hydroxylated prodrugs (amidoximes).

The development of serine protease inhibitors often results in the discovery of new lead compounds containing strong basic amidine functions that usually suffer from poor absorption from the intestine. In order to improve oral bioavailability of these drugs, prodrug principles such as the conversion of amidines into amidoximes may be applied. In this work, two HPLC-based separation methods of serine protease inhibitors (amidines) and their N-hydroxylated prodrugs have been developed and characterised.

Pharmacokinetics of anti-psoriatic fumaric acid esters in psoriasis patients.

The aim of this study was to evaluate pharmacokinetic parameters of fumaric acid esters (FAE) in psoriasis patients for the first time. For this prupose new HPLC assays were developed. Additionally, physicochemical parameters of FAE were determined, allowing a better interpretation of the in vivo data.

International network of cancer genome projects.

The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

Modulating the NO generating system from a medicinal chemistry perspective: current trends and therapeutic options in cardiovascular disease.

An impaired nitric oxide (NO) bioavailability is well-recognized in the pathology of endothelial dysfunction or atherosclerosis, respectively, and characterized by a reduced NO biosynthesis, an accelerated inactivation and/or a decreased sensitivity to NO. Therefore, attempts to increase endogenous NO concentrations or to improve responses to NO stimulation have attracted great pharmaceutical interest for the treatment of several cardiovascular diseases. The biological system of the NO/cGMP cascade is very complex and highly regulated through diverse upstream and downstream molecular and cellular elements and feedback mechanisms.

Identification and epidemiology of severe respiratory disease due to novel swine-origin influenza A (H1N1) virus infection in Alberta.

Background: In March 2009, global surveillance started detecting cases of influenza-like illness in Mexico. By mid-April 2009, two pediatric patients were identified in the United States who were confirmed to be infected by a novel influenza A (H1N1) strain. The present article describes the first identified severe respiratory infection and the first death associated with pandemic H1N1 (pH1N1) in Canada.

Metabolism and distribution of two highly potent and selective peptidomimetic inhibitors of matriptase.

Matriptase is a serine protease expressed by several types of cancer cells and it participates in tumour growth and progression through the activation of hepatocyte growth factor (HGF) and urokinase-type plasminogen activator (uPA). The metabolism of two potent and selective peptidomimetic inhibitors of matriptase (CJ-1737 and CJ-672) was examined in vitro with enzyme preparations (9000g supernatants, microsomes, and plasma) from dog, pig, rat, and human. It was found that both compounds displayed interesting species-dependent differences.

Arylazoamidoximes and related compounds as NO-modulators.

Three amidinoarylhydrazines 1, three arylazoamidines 2, and nine arylazoamidoximes 3 have been synthesized and investigated for their potential to function as nitric oxide (NO) modulators. In-vitro studies demonstrated that 2 and 3 inhibited platelet aggregation (2c, IC(50 )= 3 microM) which could also be shown in vivo by inhibition of thrombus formation in arterioles (3a, 22%). Moreover, for all compounds antihypertensive effects were examined in vivo with SHR rats, with 2a being the most potent candidate by lowering blood pressure by 19%.

Effects of a physico-chemical treatment of a dredged sediment on its ecotoxicity after discharge in laboratory gravel pit microcosms.

In France, dredged sediments may be dumped into submerged gravel pits. As a consequence, adverse effects may be expected. In addition, groundwater quality may be impacted due to hydraulic communications with gravel pits.

Benefits and limits of sediment toxicity tests as an aid to decision-making.

With respect to the management of dredged sediments, a crucial issue is whether the removed materials (watered and/or processed) are disposed of or reused in an environmentally sound manner. In this context, the number of studies dealing with hazard or risk assessment has exponentially increased. This emphasis has resulted in the promotion and application of a very large variety of ecotoxicological tests.

A national collection of liver tumours: lessons learnt from 6 years of biobanking in France.

Eight liver centres in France have joined their effort to collect, preserve and distribute tissue samples from hepatocellular carcinomas, according to the recommendations for Biological Resources Centres (BRC) released by the Organisation for Economic Cooperation and Development (OECD), which were recently implemented in France. This led to the creation of a Liver cancer biobanks network which is recognized by the Ministry of research and the Ministry of health and sponsored by the main research agencies, namely Inserm and INCa. Samples are collected and stored locally, whereas related annotations are remotely collected within a central database.

Convenient access to biocompatible block copolymers from SG1-based aliphatic polyester macro-alkoxyamines.

SG1-based poly(d,l-lactide) (PLA) or poly(epsilon-caprolactone) (PCL) macro-alkoxyamines were synthesized and further used as macroinitiators for nitroxide-mediated polymerization (NMP) of 2-hydroxyethyl (meth)acrylate (HE(M)A) to obtain the corresponding PLA- or PCL-PHE(M)A block copolymers. First, a PLA-SG1 macro-alkoxyamine was prepared by 1,2-intermolecular radical addition (IRA) of the MAMA-SG1 (BlocBuilder) alkoxyamine onto acrylate end-capped PLA previously prepared by ring-opening polymerization. The NMP of HEA monomer from the PLA-SG1 macro-alkoxyamine appeared to be well controlled in the presence of free SG1 nitroxide, contrary to that of HEMA.

A refined characterisation of the NeoHepatocyte phenotype necessitates a reappraisal of the transdifferentiation hypothesis.

Under certain culture conditions human peripheral blood monocytes may be induced to express phenotypic markers of non-haematopoietic lineages, including hepatocyte-defining traits. One such example, the NeoHepatocyte, was previously shown to express a broad panel of hepatocyte-like marker antigens and metabolic activities, both in vitro and following engraftment in the liver of immunodeficient mice. In this report, a refined description of NeoHepatocytes, with regard to their expression of xenobiotic-metabolising enzymes, morphology, hepatocyte marker expression and cell surface phenotype, is presented in comparison with human macrophages in defined states of activation.

Incorporation of neutral C-terminal residues in 3-amidinophenylalanine-derived matriptase inhibitors.

A novel series of matriptase inhibitors based on previously identified tribasic 3-amidinophenylalanine derivatives was prepared. The C-terminal basic group was replaced by neutral residues to reduce the hydrophilicity of the inhibitors. The most potent compound 22 inhibits matriptase with a K(i) value of 0.

[Fundamental and translational research on hepatocellular carcinoma in 2008: forces and priorities].

Hepatocellular carcinogenesis is usually the result of a muti-step process. It begins with an exposure to various risk factors; followed by the development of a chronic hepatitis and cirrhosis that is a pre-neoplastic step; and finally after the occurrence of an hepatocellular carcinoma (HCC), different molecular events control aggressiveness of the tumors. The aim of this work was to identify in the international context, forces and priorities of the fundamental and translational HCC research.

Synthesis and evaluation of pyrido[1,2-a]pyrimidines as inhibitors of nitric oxide synthases.

A series of new 3-aroylpyrido[1,2-a]pyrimidines were synthesized from aryl methyl ketones in a simple two-step procedure and evaluated as nitric oxide synthases (NOS) inhibitors. In order to perform a structure-activity relationship study, different aroyl groups were introduced in 3-position and methyl groups were introduced at different positions of the pyrimidine heterocycle. Compounds with a biphenyloyl, benzyloxybenzoyl or naphthoyl group displayed the highest inhibitory effects which were further increased by introduction of a methyl group in position 8 of the pyrido[1,2-a]pyrimidine moiety.

The fourth molybdenum containing enzyme mARC: cloning and involvement in the activation of N-hydroxylated prodrugs.

The recently discovered mammalian molybdoprotein mARC1 is capable of reducing N-hydroxylated compounds. Upon reconstitution with cytochrome b(5) and b(5) reductase, benzamidoxime, pentamidine, and diminazene amidoximes, N-hydroxymelagatran, guanoxabenz, and N-hydroxydebrisoquine are efficiently reduced. These substances are amidoxime/N-hydroxyguanidine prodrugs, leading to improved bioavailability compared to the active amidines/guanidines.

Structure-activity relationship of novel and known inhibitors of human dimethylarginine dimethylaminohydrolase-1: alkenyl-amidines as new leads.

Recent studies demonstrated that inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity could be a new strategy to indirectly affect nitric oxide (NO) formation by elevating N(omega)-methylated L-arginine (NMMA, ADMA) levels. This approach is an alternate strategy for the treatment of diseases associated with increased NO-concentrations. To date, three classes of potent inhibitors are known: (1) pentafluorophenyl sulfonates (IC(50)=16-58 microM, PaDDAH), which are also inhibitors for the arginine deiminase; (2) the most potent inhibitors are based on indolylthiobarbituric acid (IC(50)=2-17 microM, PaDDAH), which were identified by virtual modelling; and (3) L-arginine analogs, whose best representative is N(omega)-(2-methoxyethyl)-L-arginine (IC(50)=22 microM, rat DDAH).

Involvement of stearoyl-CoA desaturase in the reduction of amidoxime prodrugs.

1. This study investigates the enzymatic reduction of N-hydroxylated amidines by porcine adipose tissue and the possible involvement of stearoyl-CoA desaturase (SCD). 2.

A cryptic frizzled module in cell surface collagen 18 inhibits Wnt/beta-catenin signaling.

Collagens contain cryptic polypeptide modules that regulate major cell functions, such as cell proliferation or death. Collagen XVIII (C18) exists as three amino terminal end variants with specific amino terminal polypeptide modules. We investigated the function of the variant 3 of C18 (V3C18) containing a frizzled module (FZC18), which carries structural identity with the extracellular cysteine-rich domain of the frizzled receptors.

Initial phase 2 trial of a nicotinic agonist in schizophrenia.

Objective: Nicotinic acetylcholine receptors are possible therapeutic targets for schizophrenia, as shown by neurobiological and molecular evidence for deficiencies in expression of alpha(7)-nicotinic receptors. Patients' heavy smoking suggests attempted self-medication through this mechanism. The agent 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A) is a partial alpha(7)-nicotinic agonist and can be taken orally.

Search for flavor-changing-neutral-current d meson decays.

We study the flavor-changing-neutral-current process c-->u micro(+) micro(-) using 1.3 fb(-1) of pp[over ] collisions at square root s = 1.96 TeV recorded by the D0 detector operating at the Fermilab Tevatron Collider.

Inhibitory effects on cytochrome p450 enzymes of pentamidine and its amidoxime pro-drug.

Pentamidine is an antimicrobial drug, intravenously used in the treatment of trypanosomiasis, leishmaniasis or pneumocystis pneumonia. To elucidate potential drug interactions with pentamidine and N,N'-dihydroxypentamidine, respectively, the cytochrome P450 (CYP450) inhibitory properties of these compounds were determined. The study was performed in vitro by using human liver microsomes and marker substrates of several CYP450 isoenzymes.

Genomic insights into Mn(II) oxidation by the marine alphaproteobacterium Aurantimonas sp. strain SI85-9A1.

Microbial Mn(II) oxidation has important biogeochemical consequences in marine, freshwater, and terrestrial environments, but many aspects of the physiology and biochemistry of this process remain obscure. Here, we report genomic insights into Mn(II) oxidation by the marine alphaproteobacterium Aurantimonas sp. strain SI85-9A1, isolated from the oxic/anoxic interface of a stratified fjord.