Monotonicity of interleukin-1 receptor-ligand binding with respect to antagonist in the presence of decoy receptor

We consider the interaction between interleukin-1 IL-1, its receptor IL-1RI, the receptor antagonist IL-1Ra and a decoy receptor (or trap) that binds both with the ligand and the antagonist. We study how the interaction between IL-1Ra and the decoy receptor influences the effect of either reagent on reducing the equilibrium concentration of the receptor-ligand complex. We obtain that, given a certain relationship among the equilibrium constants and the total concentrations of solutes, IL-1Ra can reverse the effect of the decoy receptor of decreasing the equilibrium concentration of the receptor-ligand complex. This finding derives from a mathematical result applicable to any reversible chemical reaction system comprising four species arranged in a square such that each species binds its two immediate neighbors. The result gives the monotonicity of the equilibrium concentrations of the complex species as functions of the total concentrations of the simple species.     

Effect of α-crystallin on thermal aggregation of glycogen phosphorylase <Emphasis Type="Italic">b</Emphasis> from rabbit skeletal muscle

Thermal aggregation of rabbit skeletal muscle glycogen phosphorylase b (Phb) has been investigated using dynamic light scattering under conditions of a constant rate of temperature increase (1 K/min). The linear behavior of the dependence of the hydrodynamic radius on temperature for Phb aggregation is consistent with the idea that thermal aggregation of proteins proceeds in the kinetic regime wherein the rate of aggregation is limited by diffusion of the interacting particles (the regime of "diffusion-limited cluster-cluster aggregation"). In the presence of alpha-crystallin, a protein exhibiting chaperone-like activity, the dependence of the hydrodynamic radius on temperature follows the exponential law; this suggests that the aggregation process proceeds in the kinetic regime where the sticking probability for colliding particles becomes lower than unity (the regime of "reaction-limited cluster-cluster aggregation"). Based on analysis of the ratio between the light scattering intensity and the hydrodynamic radius of Phb aggregates, it has been concluded that the addition of alpha-crystallin results in formation of smaller size starting aggregates. The data on differential scanning calorimetry indicate that alpha-crystallin interacts with the intermediates of the unfolding process of the Phb molecule. The proposed scheme of thermal denaturation and aggregation of Phb includes the stage of reversible dissociation of dimers of Phb into monomers, the stage of the formation of the starting aggregates from the denatured monomers of Phb, and the stage of the sticking of the starting aggregates and higher order aggregates. Dissociation of Phb dimer into monomers at elevated temperatures has been confirmed by analytical ultracentrifugation.     

Design and testing of a new photosensitizer based on an ytterbium porphyrazine complex

The ytterbium tetraphenyltetracyanoporphyrazine complex (YbPz) has been studied as a potential photosensitizer for fluorescence diagnostics and photodynamic therapy of cancer. A water-miscible formulation of YbPz has been prepared using PEG 6000. The new compound shows intense absorption and fluorescence in the “optical window” of biological tissues (absorption maximum ∼590 nm, emission maximum ∼625 nm). Fluorescence enhancement (a 50-fold increase in YbPz quantum yield) is observed in blood serum. In cultured human cancer cells, YbPz quickly accumulates around the nuclei, presumably in lysosomes. The distribution and pharmacokinetics of YbPz in mice have been investigated by a novel method of in vivo transillumination fluorescence imaging. The highest level of YbPz in grafted mouse cervical carcinoma is maintained from 3 to 6 h after i.v. injection, its half-life in the tumor being ∼24 h. However, the selectivity of YbPz for the tumor vs. normal tissue is not high enough. Most of the drug is cleared from the body (mainly via liver and intestine) in two days. Conventional ex vivo methods (confocal microscopy and point spectroscopic measurements) have revealed the largest content of YbPz in the intestine, liver, tumor, and skin. In general, the optical characteristics of YbPz as well as the features of its interaction with biological objects make it a promising candidate drug for photodynamic therapy and/or fluorescence diagnostics of cancer, though searching for formulations with higher tumor selectivity remains a topical task.     

Synthesis of caged 2,3,3a,7a-tetrahydro-3,6-methanobenzofuran-7(6H)-ones: Evaluating the minimum structure for apoptosis induction by gambogic acid

We have reported the discovery of gambogic acid (GA) as a potent apoptosis inducer and the identification of transferrin receptor as its molecular target. In order to understand the basic pharmacophore of GA for inducing apoptosis and to discover novel and simplified derivatives as potential anti-cancer agents, we explored the synthesis of caged 2,3,3a,7a-tetrahydro-3,6-methanobenzofuran-7(6H)-ones (4-oxatricyclo[4.3.1.0]decan-2-ones). Three types of 2,3,3a,7a-tetrahydro-3,6-methanobenzofuran-7(6H)-ones based on xanthone, 2-phenylchromene-4-one and benzophenone, were synthesized using a Claisen/Diels-Alder reaction cascade. All the reactions produced the targeted caged compound as well as its neo-isomer. The caged compounds based on xanthone and 2-phenylchromene-4-one were found to maintain the apoptosis inducing and cell growth inhibiting activity of GA, although with less potency. The caged compounds based on benzophenone were found to be inactive. Our study determined the minimum structure of GA for its apoptosis inducing activity, which could lead to the development of simple derivatives as potential anti-cancer drugs.     

Phytopathogenic fungus Fusarium cerealis in Russia

The fungus Fusarium cerealis is described, which had not been previously identified in Russia. F. cerealis was isolated from wheat and barley roots and grains, as well as from the leaves of thistle collected in the Far Eastern, North Caucasus, and Central regions. F. cerealis strains may be misidentified as F. culmorum or F. graminearum, since the morphological characteristics of these fungi are similar.     

Genetic Analysis of Pleiotropic Effects of pho85 Mutations in Yeast Saccharomyces cerevisiae

The cyclin-dependent phosphoprotein kinase Pho85p is involved in the regulation of metabolism and cell cycle in the yeast Saccharomyces cerevisiae. It is known that mutations in the PHO85gene lead to constitutive synthesis of Pho5p acidic phosphatase, a delay in cell growth on media containing nonfermentable carbon sources, sensitivity to high temperature, and other phenotypic effects. A lack of growth at 37°C and on a medium with alcohol as the carbon source was shown to be associated with the rapid accumulation of nuclear ts and mitochondrial [rho ^– ] mutations occurring in the background of gene PHO85 inactivation. Thus, Pho85p seems to play an important role in the maintenance of yeast genome stability.