The role of vitamin E in metabolism and reception of vitamin D

It was found that calcium exchange disturbances under vitamin E deficiency is due to changes in the metabolism of vitamin D. In vitamin E-deficient rats the serum blood levels of hydroxyvitamin D (25-OHD) showed no significant changes, whereas the concentration of the hormonal form of 1.25-hydroxyvitamin D [1.25(OH)2D], decreased by 40%. In vitro studies showed that the 25-hydroxylase D3 activity in the livers of rats with E-avitaminosis had a tendency to decrease (by 22%), whereas that of 24-hydroxylase dropped drastically (by 52%). The serum blood levels of the parathyroid hormone (PTH) and kidney levels of cAMP under E-avitaminosis were significantly lowered. Preincubation of kidney slices with the adenylate cyclase activator, forskolin, increased the activity of 1-OHase in about the same degree as that in vitamin E-rich rats. The free radical scavenger, BHT, added to kidney slices suppressed the activity of the both enzymes; this finding testifies to the low O2-binding affinity of these monooxygenases. The content of 1.25(OH)2D3 receptors occupied in vivo in the kidneys of vitamin E-deficient rats decreased 2.5-fold; however, the binding of 1.25(OH)2D3-receptor complexes to heterologous DNA was unaffected thereby. The vitamin deficiency in vivo results in the inhibition of vitamin D metabolism in the liver and kidney concomitant with the formation of active metabolites and decreases the concentration of hormone-receptor complexes in target tissues.     

The role of cytochrome b 5 structural domains in interaction with cytochromes P450

To understand the role of the structural elements of cytochrome b ₅ in its interaction with cytochrome P450 and the catalysis performed by this heme protein, we carried out comparative structural and functional analysis of the two major mammalian forms of membrane-bound cytochrome b ₅ — microsomal and mitochondrial, designed chimeric forms of the heme proteins in which the hydrophilic domain of one heme protein is replaced by the hydrophilic domain of another one, and investigated the effect of the highly purified native and chimeric heme proteins on the enzymatic activity of recombinant cytochromes P4503A4 and P45017A1 (CYP3A4 and CYP17A1). We show that the presence of a hydrophobic domain in the structure of cytochrome b ₅ is necessary for its effective interaction with its redox partners, while the nature of the hydrophobic domain has no significant effect on the ability of cytochrome b ₅ to stimulate the activity of cytochrome P450-catalyzed reactions. Thus, the functional properties of cytochrome b ₅ are mainly determined by the structure of the hemebinding domain.     

Polymethoxylated flavones induce Ca(2+)-mediated apoptosis in breast cancer cells

Flavonoids, polyphenolic phytochemicals which include flavones and isoflavones, are present in the common human diet. It has been suggested that these compounds may exert anticancer activity; however, the mechanisms involved remain unknown. We have recently shown (Sergeev, 2004, Biochem Biophys Res Commun 321: 462-467) that isoflavones can activate the novel apoptotic pathway mediated by cellular Ca(2+). Here, we report that polymethoxyflavones (PMFs) derived from sweet orange (Citrus sinensis L.) inhibit growth of human breast cancer cells via Ca(2+)-dependent apoptotic mechanism. The treatment of MCF-7 breast cancer cells with 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (5-OH-HxMF) and 3'-hydroxy-5,6,7,4'-tetramethoxyflavone (3'-OH-TtMF) induced a sustained increase in concentration of intracellular Ca(2+) ([Ca(2+)](i)) resulting from both depletion of the endoplasmic reticulum Ca(2+) stores and Ca(2+) influx from the extracellular space. This increase in [Ca(2+)](i) was associated with the activation of the Ca(2+)-dependent apoptotic proteases, mu-calpain and caspase-12, as evaluated with the calpain and caspase-12 peptide substrates and antibodies to active (cleaved) forms of the enzymes. Corresponding non-hydroxylated PMFs, 3,5,6,7,8,3',4'-heptamethoxyflavone (HpMF) and 5,6,7,3',4'-pentamethoxyflavone (PtMF), were dramatically less active in inducing Ca(2+)-mediated apoptosis. Our results strongly suggest that the cellular Ca(2+) modulating activity of flavonoids underlies their apoptotic mechanism and that hydroxylation of PMFs is critical for their ability to induce an increase in [Ca(2+)](i) and, thus, activate Ca(2+)-dependent apoptotic proteases.     

Concepts of classic and modern biogeography: Contribution of Russian entomologists

The main stages and ways of development of insect biogeography in Russia are discussed. Three general research programs (studies of ranges, zones, and regions) are described. The role of the regional approach in biogeography is characterized. Some problems related to studies of insect ranges are evaluated, and the need for creating practical range maps is emphasized. The relationships between the insect distribution patterns and the life zones are discussed. The specific features of zonation in insect biogeography are noted. Special attention is paid to establishing the zones with unified population distribution patterns within a species range. The role of geozoological investigations and opportunities of modern information technologies are characterized relative to evaluation of general patterns of insect assemblage distribution. The problems of regionalization in insect biogeography are discussed. Three main approaches (intuitive, a priori, and a posteriori) are determined. Some advantages of using population and assemblage distribution patterns in regionalization are emphasized. The role and possibilities of insect biogeography studies for in the field of reconstruction of past and long-term forecasting are characterized.     

Interpreting the effect of vaccination on steady state infection in animals challenged with Simian immunodeficiency virus

A representative vaccinated macaque challenged with SIVmac251 establishes a persistent infection with a lower virus load, higher CTL frequencies, and much higher helper cell frequencies, than a representative control animal. The reasons for the difference are not fully understood. Here we interpret this effect using a mathematical model we developed recently to explain results of various experiments on virus and CTL dynamics in SIV-infected macaques and HIV-infected humans. The model includes two types of cytotoxic lymphocytes (CTLs) regulated by antigen-activated helper cells and directly by infected cells, respectively, and predicts the existence of two steady states with different viremia, helper cell and CTL levels. Depending on the initial level of CTL memory cells and helper cells, a representative animal ends up in either the high-virus state or the low-virus state, which accounts for the observed differences between the two animal groups. Viremia in the low-virus state is proportional to the antigen sensitivity threshold of helper cells. Estimating the infectivity ratio of activated and resting CD4 T cells at 200-300, the correct range for the critical memory cell percentage and the viremia peak suppression is predicted. However, the model does not explain why viremia in the “low-virus state” is surprisingly high , relative to vaccinated animals infected with SHIV, and broadly distributed among challenged animals. We conclude that the model needs an update explaining extremely low sensitivity of uninfected helper cells to antigen in vaccinated animals.     

Models to understand the population-level impact of mixed strain M. tuberculosis infections

Over the past decade, numerous studies have identified tuberculosis patients in whom more than one distinct strain of Mycobacterium tuberculosis is present. While it has been shown that these mixed strain infections can reduce the probability of treatment success for individuals simultaneously harboring both drug-sensitive and drug-resistant strains, it is not yet known if and how this phenomenon impacts the long-term dynamics for tuberculosis within communities. Strain-specific differences in immunogenicity and associations with drug resistance suggest that a better understanding of how strains compete within hosts will be necessary to project the effects of mixed strain infections on the future burden of drug-sensitive and drug-resistant tuberculosis. In this paper, we develop a modeling framework that allows us to investigate mechanisms of strain competition within hosts and to assess the long-term effects of such competition on the ecology of strains in a population. These models permit us to systematically evaluate the importance of unknown parameters and to suggest priority areas for future experimental research. Despite the current scarcity of data to inform the values of several model parameters, we are able to draw important qualitative conclusions from this work. We find that mixed strain infections may promote the coexistence of drug-sensitive and drug-resistant strains in two ways. First, mixed strain infections allow a strain with a lower basic reproductive number to persist in a population where it would otherwise be outcompeted if has competitive advantages within a co-infected host. Second, some individuals progressing to phenotypically drug-sensitive tuberculosis from a state of mixed drug-sensitive and drug-resistant infection may retain small subpopulations of drug-resistant bacteria that can flourish once the host is treated with antibiotics. We propose that these types of mixed infections, by increasing the ability of low fitness drug-resistant strains to persist, may provide opportunities for compensatory mutations to accumulate and for relatively fit, highly drug-resistant strains of M. tuberculosis to emerge.