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Modification of expression of several genes encoding enzymes involved in radical production and DNA repair by a 1,4-DHP derivative glutapyrone was studied in intact rats and animals with streptozotocin diabetes mellitus. Glutapyrone stimulated iNosmRNA production in both kidneys and blood. The effect was stronger in kidneys of diabetic animals, however in blood the expression was down-regulated. The compound increased the Parp 1gene expression in kidneys of both intact and diabetic animals; in blood the effect was adverse. Expression of XDhgene was significantly increased by glutapyrone in kidneys of intact and diabetic animals. Administration of the compound to intact animals triggered significant increase of DNA damage in white blood cells assayed by comet assay; in diabetic animals no effect was produced. To explain discrepancies with the formerly described effects of glutapyrone on cultured cells, metabolism of the compound was studied. Glutapyrone is either oxidised or the residue of glutamic acid is removed, glutapyrone turns into AV-153, and the latter is metabolised to smaller compounds. Formation of AV-153, a DNA binder and genotoxic compound in high concentrations, can explain DNA damage in white blood cells and stimulation of DNA repair.

Diabetic cardiomyopathy increases the risk of heart failure and worsens prognosis for diabetes mellitus (DM) patients. Its development depends on many factors, including modification of nitric oxide production and impaired DNA repair. The goal of the present work was to study in vivoeffects of a 1,4-dihydropyridine AV-153, known as antimutagen and DNA-binder, on DNA integrity, and on the expression of several proteins involved in glucose transport, nitric oxide metabolism, and DNA repair in myocardium in diabetic rats. DM was induced in rats by streptozotocin (STZ) injection. Expression of proteins was studied by means of immunohistochemistry. Development of the STZ-induced DM significantly induced PARP1 and gamma H2AX histone, markers of DNA breakage, protein expression in heart tissue, while AV-153 administration decreased PARP1 and H2AX protein expression. In this model of diabetes, myocardial expression of iNOS was also significantly increased, but administration of AV-153 reduced it to normal levels. AV-153 also upregulated the expression of insulin-dependent GLUT4 and insulin-independent GLUT1 glucose transporters up to normal level in diabetic rats. Thus, AV-153 appears to be prospective for creation of a remedy for prevention of diabetic cardiomyopathy.

Association Study of Genetic Variants in the 14q11 - 14q13 Proteasomal Genes Cluster with Juvenile Idiopathic Arthritis (JIA) in Latvian PopulationThe possible role of proteasomes in the development of autoimmune diseases was hypothesised after discovery of the involvement of proteasomal LMP2 and LMP7 subunits in antigene processing. The objective of this study was to determine the association between allelic variants of the genes encoding proteasomal proteins PSME1, PSME2 and PSMA6 and juvenile idiopathic arthritis (JIA) in the Latvian population. One Indel G-4543CA-4544→GA and four SNPs related to the PSMA6 gene (A-2486→G and C-1910→T, upstream promoter, C-110→A of promoter, and C-8→G of 5'UTR), of two cSNP in PSME1 (G1457→A:Val104, exon 6 and C2536→A: Lys244→Thr, exon 11) and in PSME2 (C1153→G:Arg61→Gly, exon 4 and A1440→C:His89→Pro, exon 6) were geno-typed by means of primer-specific PCR, CAPS assay and/or sequencing in case/control study composed from the 156 JIA patients and 214 healthy individuals. Allele frequency and genotype distribution was similar in cases and controls for Indel, and SNPs A-2486→G, C-1910→T and C-8→G of PSMA6, as well as for all studied cSNPs in PSME1 and PSME2 genes. Differences in A-110allele and CG genotype frequencies were close to the statistically significant P level in JIA patients and healthy individuals, however, when an additive model was applied, the difference in the C-110→A locus turned out to be statistically significant. The results support the hypothesis of the possible association of PSMA6 gene allelic variants with JIA in the Latvian population.