Genotoxic and genoprotective effects of 1,4-dihydropyridine derivatives: a brief review.

This review summarises current knowledge about the genotoxic and genoprotective effects of 1,4-dihydropyridines (DHP) with the main focus on the water-soluble 1,4-DHPs. Most of these water-soluble compounds manifest very low calcium channel blocking activity, which is considered "unusual" for 1,4-DHPs. Glutapyrone, diludine, and AV-153 decrease spontaneous mutagenesis and frequency of mutations induced by chemical mutagens.

Neutrophil cytosolic factor 2 (NCF2) gene polymorphism is associated with juvenile-onset systemic lupus erythematosus, but probably not with other autoimmune rheumatic diseases in children.

Background: Genetic variations of neutrophil cytosolic factor 2 (NCF2), a subunit of NADPH oxidase, are usually associated with chronic granulomatous disease, and their relationship with autoimmune disorders through the defective NADPH oxidase function during phagocytosis is suggested. Our study aimed to explore whether there is an association between the non-synonymous single nucleotide polymorphism in the NCF2 gene (rs17849502, NC_000001.11:g.

AGER gene variant as a risk factor for juvenile idiopathic arthritis.

Background: The AGER gene encodes a cell surface multiligand receptor of advanced glycation end-products that is also capable of binding other molecules and is involved in numerous pathways related to inflammation, apoptosis, immunity and so on. In the present study, we aimed to investigate whether the AGER rs1035798 (G>A) intronic polymorphism, showing an association with multiple sclerosis and rheumatoid arthritis in adults, is related to juvenile idiopathic arthritis (JIA).

Methods: Caucasian children from the Belarusian population were enrolled in the study.

Polymorphism of Proteasomal Genes Can Be a Risk Factor for Systemic Autoimmune Diseases in Children.

The study aimed to assess the involvement of three proteasomal genes, , , and , in autoimmune pathogenesis by analyzing associations between single nucleotide polymorphisms and systemic rheumatic diseases with a different autoimmune component: juvenile idiopathic arthritis (JIA), the juvenile form of systemic lupus erythematosus, and Kawasaki's disease (KD). Our results showed that the (rs1048990) polymorphism can be a risk factor for JIA (false discovery rate ≤ 0.090), while (rs2348071) has a tendency to be nonspecific and is shared with JIA and other autoimmune diseases, including KD, an illness with very low autoimmune activity and high autoinflammation.

Time-course of micronucleated erythrocytes in response to whole-body gamma irradiation in a model mammalian species, the bank vole (Clethrionomys glareolus, Schreber).

The time course of the formation of micronucleated polychromatic (MNPCEs) and normochromatic erythrocytes (MNNCEs) in the bone marrow of the bank vole (Clethrionomys glareolus, Schreber), a model mouse-like species, was studied using the standard micronucleus test at 0, 6, 12, 18, 24, 30, 36 and 48 hr following whole-body acute γ-irradiation at a dose of 0.5 Gy. Based on the existing literature on laboratory mice, it was suggested that such a dose will not have significant effect on erythroid cell proliferation in the bank vole and hence on the time course of the rise of micronucleated cells.

Modulation of cellular defense processes in human lymphocytes in vitro by a 1,4-dihydropyridine derivative.

The aim of this pilot study was to assess whether a compound of the beta-carbonyl-1,4-dihydropyridine series (AV-153 or sodium 3,5-bis-ethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine-4-carboxylate), which has high efficiency in stimulating DNA repair, can simultaneously modulate apoptosis in human cells. Peripheral blood lymphocytes of healthy donors were used in this study. DNA strand-break rejoining was assessed with the alkaline comet assay after a 3-h incubation of lymphocytes in the presence of a wide range of concentrations of AV-153 (10(-10)-10(-5) M).

Inhibition of poly(ADP-ribose) polymerase activity affects its subcellular localization and DNA strand break rejoining.

Poly(ADP-ribose) polymerase (PARP) plays a crucial role in DNA repair. Modulation of its activity by stimulation or inhibition is considered as a potentially important strategy in clinical practice, especially to sensitize tumor cells to chemo- and radiotherapy through inhibition of DNA repair. Here we studied the effect of the three PARP inhibitors, 5-iodo-6-amino-benzopyrone (INH(2)BP), 1,5-isoquinolinediol (1,5-dihydroxyisoquinolinediol (1,5-IQD) and 8-hydroxy-2-methylquinazolin-4-[3H]one (NU1025), and for two of them the efficiency in slowing the rejoining of DNA strand breaks induced by H(2)O(2) was compared.

Changes in poly(ADP-ribose) level modulate the kinetics of DNA strand break rejoining.

ADP-ribose polymers are rapidly synthesized in cell nuclei by the poly(ADP-ribose) polymerases PARP-1 and PARP-2 in response to DNA strand interruptions, using NAD(+) as precursor. The level of induced poly(ADP-ribose) formation is proportional to the level of DNA damage and can be decreased by NAD(+) or PARP deficiency, followed by poor DNA repair and genomic instability. Here we studied the correlation between poly(ADP-ribose) level and DNA strand break repair in lymphoblastoid Raji cells.

Transgenerational accumulation of radiation damage in small mammals chronically exposed to Chernobyl fallout.

The purpose of this investigation has been the analysis of the long-term development of biological damage in natural populations of a model mammalian species, the bank vole (Clethrionomys glareolus, Schreber), which were chronically exposed to low doses of ionizing radiation over 22 animal generations within 10 years following the Chernobyl accident. The time course of the biological end-points (chromosome aberrations in bone marrow cells and embryonic lethality) was compared with the time course of the whole-body absorbed dose rate from external and internal exposure in the studied populations inhabiting monitoring sites in Belarus with different ground deposition of radionuclides. The yield of chromosome aberrations and, in lesser degree, embryonic lethality was associated with the radionuclide contamination of the monitoring areas in a dose-dependent manner.

A 1,4-dihydropyridine derivative reduces DNA damage and stimulates DNA repair in human cells in vitro.

Compounds of the 1,4-dihydropyridine (1,4-DHP) series have been shown to reduce spontaneous, alkylation- and radiation-induced mutation rates in animal test systems. Here we report studies using AV-153, the 1,4-DHP derivative that showed the highest antimutagenic activity in those tests, to examine if it modulates DNA repair in human peripheral blood lymphocytes and in two human lymphoblastoid cell lines, Raji and HL-60. AV-153 caused a 50% inhibition of growth (IC50) of Raji and HL-60 cells at 14.