Online Measurements during Simulated Atmospheric Aging Track the Strongly Increasing Oxidative Potential of Complex Combustion Aerosols Relative to Their Primary Emissions.

Oxidative potential (OP) is increasingly recognized as a more health-relevant metric than particulate matter (PM) mass concentration because of its response to varying chemical compositions. Given the limited research on the OP of complex combustion aerosols, the effects of aging processes on their OP remain underexplored. We used online instruments to track the evolution of OP [via dithiothreitol (DTT) assays] during the aging of wood burning and coal combustion emissions by hydroxyl-radical-driven photooxidation and dark ozonolysis.

Targeting cardiomyocyte ADAM10 ectodomain shedding promotes survival early after myocardial infarction.

After myocardial infarction the innate immune response is pivotal in clearing of tissue debris as well as scar formation, but exaggerated cytokine and chemokine secretion with subsequent leukocyte infiltration also leads to further tissue damage. Here, we address the value of targeting a previously unknown a disintegrin and metalloprotease 10 (ADAM10)/CX3CL1 axis in the regulation of neutrophil recruitment early after MI. We show that myocardial ADAM10 is distinctly upregulated in myocardial biopsies from patients with ischemia-driven cardiomyopathy.

Synthesis of C Labeled Vitamin D Metabolites for Their Use in LC-MS/MS: Valuable Tools for Cancer Research and Other Applications.

Background/aim: Simultaneous assessment of various vitamin D metabolites in human biofluids by liquid chromatography tandem mass spectrometry (LC-MS/MS) represents a new promising tool for the differential diagnosis of vitamin D-related diseases. Particularly, besides 25(OH)VD, low-abundant medicinally relevant vitamin D metabolites, such as 24,25(OH)VD, 1,25(OH)VD, and 1,24,25(OH)VD, along with their 3-epi-derivatives have to be considered.

Materials And Methods: The assessment of these metabolites by LC-MS/MS requires the development of calibration and reference standards, that is, their labeling with multiple deuterium-, or even better, C- atoms.

Novel approach to A-ring synthon for Pd-catalyzed synthesis of 1α-hydroxylated vitamin D metabolites.

A novel approach to an A-ring synthon for Pd-catalyzed synthesis of 1α-hydroxylated vitamin D metabolites is described. Key step is an asymmetric glyoxylate ene reaction to access a highly diastereomerically pure α-hydroxy ester. Subsequent stereospecific transformation to an anti-1,3-diol and appropriate chemical modifications at both ends of the acyclic precursor leads to a diastereomerically and enantiomerically pure silylated anti-1,3-diol enyne, serving as a versatile A-ring synthon for its use in vitamin D synthesis.

Sulfoximines as Rising Stars in Modern Drug Discovery? Current Status and Perspective on an Emerging Functional Group in Medicinal Chemistry.

Sulfoximines have been largely disregarded in medicinal chemistry for a long time. However, recently, they have risen to the apparent level of stardom on the drug discovery scene. Considering the outstanding properties of sulfoximines, this versatile functional group has advanced to implementation in several drug discovery programs.

Efficient synthesis of 3-TBDMS-11α,25-dihydroxyvitamin D and D ethers.

Vitamin D deficiency might cause a wide variety of human disorders. As a prerequisite for appropriate diagnosis and therapy, medicinally relevant vitamin D metabolites have to be assayed most accurately and with high specificity. It has been demonstrated, that vitamin D conjugates, linked via a hydroxyl group at C11, might be promising for the development of highly specific antibodies to be employed in competitive protein binding assays.

Highly regio- and stereoselective hydroxylation of vitamin D2 by CYP109E1.

Vitamin D2 is a form of vitamin D derived from mushrooms and plants which is structurally modified in the body due to the action of several enzymes. The resulting metabolites represent important compounds with potential bioactive properties. However, they are poorly studied and their availability is mostly limited.

Recent Developments Towards the Synthesis of Vitamin D Metabolites.

Due to latest advancements in the development of LC-MS/MS based assays and their applications in clinical chemistry, low abundant vitamin D metabolites can be detected at low concentration with high specificity. Consequently, there is a growing need for their synthesis as stable isotopically labeled compounds to be used as calibration and reference standards. Most commonly, ex chiral pool synthesis, starting with vitamin D, and palladium(0) catalyzed coupling reactions are applied in vitamin D synthesis.

Sarcoplasmic reticulum calcium leak contributes to arrhythmia but not to heart failure progression.

Increased sarcoplasmic reticulum (SR) Ca leak via the cardiac ryanodine receptor (RyR2) has been suggested to play a mechanistic role in the development of heart failure (HF) and cardiac arrhythmia. Mice treated with a selective RyR2 stabilizer, rycal S36, showed normalization of SR Ca leak and improved survival in pressure overload (PO) and myocardial infarction (MI) models. The development of HF, measured by echocardiography and molecular markers, showed no difference in rycal S36- versus placebo-treated mice.

An efficient synthesis of 1α,25-dihydroxyvitamin D LC-biotin.

In recent years the apparent impact of vitamin D deficiency on human health has gained increased awareness. Consequently, the development of appropriate assays to measure the status of medicinally most relevant vitamin D metabolites in human blood, serum or relevant tissue is continuously being improved. Particularly, assaying of 1α,25-dihydroxyvitamin D, in turn considered as the most active metabolite, is mainly indicated in disorders leading to calcaemia or those resulting from an impaired 1α-hydroxylation of 25-hydroxyvitamin D.

Optimization of Chemical Syntheses of Vitamin D C3-Epimers.

Due to the widespread impact of vitamin D on human health, the development of appropriate assays to detect deficiency of all vitamin D metabolites of pharmacological interest is being continuously improved. Although over 50 naturally-occurring metabolites of vitamin D are known to date, only very few are routinely detected in commercially available assays. This is particularly true regarding C3-epimers of vitamin D3 and D2, which not only may interfere in analytical measurements with other metabolites of interest, but also have controversial and not yet fully understood physiological functions.

Development of efficient chemical syntheses of vitamin D degradation products.

In recent years it has been recognized that vitamin D deficiency is associated with a wide range of diseases, including various types of cancers. Due to the enormous medical importance of vitamin D and its metabolites, their status in blood serum has to be accurately measured. Thus, the metabolites actually used as reference standards and also others of relevant biological activity have to be provided for validation and continuous improvement of appropriate diagnostic devices.

Synthetic retinal analogues modify the spectral and kinetic characteristics of microbial rhodopsin optogenetic tools.

Optogenetic tools have become indispensable in neuroscience to stimulate or inhibit excitable cells by light. Channelrhodopsin-2 (ChR2) variants have been established by mutating the opsin backbone or by mining related algal genomes. As an alternative strategy, we surveyed synthetic retinal analogues combined with microbial rhodopsins for functional and spectral properties, capitalizing on assays in C.

Development of a colorimetric and a fluorescence phosphatase-inhibitor assay suitable for drug discovery approaches.

Protein phosphatases (PP) are interesting drug targets. However, their ubiquitous presence and involvement in different, partially opposing signal pathways suggest that specificity may be achieved rather by targeting their interaction with subunits determining substrate specificity than the enzyme itself. An interesting subunit is phosphatase inhibitor-1 (I-1), which, in its protein kinase A-phosphorylated form (I-1(P)), inhibits the catalytic subunit of type 1 phosphatase (PP1c).

Combined Na(+)/Ca(2+) exchanger and L-type calcium channel block as a potential strategy to suppress arrhythmias and maintain ventricular function.

Background: L-type calcium channel (LTCC) and Na(+)/Ca(2+) exchanger (NCX) have been implicated in repolarization-dependent arrhythmias, but also modulate calcium and contractility. Although LTCC inhibition is negative inotropic, NCX inhibition has the opposite effect. Combined block may, therefore, offer an advantage for hemodynamics and antiarrhythmic efficiency, particularly in diseased hearts.

Chemical, biochemical and microbiological properties of a brominated nitrovinylfuran with broad-spectrum antibacterial activity.

A di-bromo substituted nitrovinylfuran with reported broad-spectrum antibacterial activity was found to be a potent inhibitor of MurA, a key enzyme in peptidoglycan biosynthesis. Further characterization of the compound was carried out to assess its reactivity towards thiol nucleophiles, its stability and degradation under aqueous conditions, inhibitory potential at other enzymes, and antibacterial and cytotoxic activity. Our results indicate that the nitrovinylfuran derivative is reactive towards cysteine residues in proteins, as demonstrated by the irreversible inhibition of MurA and bacterial methionine aminopeptidase.

Optimization of assay conditions for dengue virus protease: effect of various polyols and nonionic detergents.

The aim of this work was to perform a systematic study of the effect of nonionic detergents on the activity of the dengue virus NS2B-NS3 protease. To ensure a high activity of the protease, the assay procedures for the dengue virus and other flaviviral proteases published to date are performed in the presence of up to 35% glycerol, which does not represent the cellular physicochemical environment. In addition, the high viscosity of glycerol-containing solutions leads to various experimental problems in miniaturized assays.

Identification of terfenadine as an inhibitor of human CD81-receptor HCV-E2 interaction: synthesis and structure optimization.

Terfenadine (4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-(4-tert-butylphenyl)-butan-1-ol) was identified in a biological screening to be a moderate inhibitor (27% inhibition) of the CD81-LEL-HCV-E2 interaction. To increase the observed biological activity, 63 terfenadine derivates were synthesized via microwave assisted nucleophilic substitution. The prepared compounds were tested for their inhibitory potency by means ofa fluorescence labeled antibody assay using HUH7.

The dynamics of water-protein interaction studied by ultrafast optical Kerr-effect spectroscopy.

Changes in the ultrafast dynamics and terahertz Raman spectrum accompanying a helix-to-coil transition of a homo-polypeptide have been observed for the first time. Formation of the alpha-helix is associated with a shift to lower frequency of a broad Raman band attributable to solvent-peptide intermolecular hydrogen bonding. This band facilitates direct spectroscopic observation of so-called hydration water near a peptide and yields the first quantitative estimate of the time scale of the ultrafast dynamics in the solvation shell, which range from 0.

Synthesis and biochemical evaluation of (carbamoylalkenyl)phenyloxy carboxylic acid derivatives as non-steroidal 5 alpha-reductase inhibitors.

Several (carbamoylalkenyl)- and (carbamoylalkenyl)phenyloxy carboxylic acids (Table 1) and some of their ethyl esters (Table 2) were synthesized and evaluated in vitro as inhibitors of steroid 5 alpha-reductase. Inhibitors of this enzyme may be useful in treating dihydrotestosterone-related diseases such as prostate cancer and benign prostatic hyperplasia. Using an enzyme preparation obtained from human prostate carcinoma tissue, the inhibition values ranged from 0 to 57% at the given dose of 100 microM.