Background: Necroptosis is a regulated signaling pathway leading to necrotic cell death. Results: Genetic mapping identified that down-regulation of the deubiquitinase CYLD confers resistance to necroptosis in a wild-derived mouse strain. Conclusion: Different strains of inbred mice regulate cell death pathways using distinct mechanisms. Significance: Genetic diversity of wild-derived mice underlies phenotypic diversity, which can identify novel mechanisms of regulation in cell death signaling.

The transcript levels of circadian rhythm genes CLOCK, BMAL1, and PER1 in buccal epithelial cells of the patients with essential arterial hypertension was analyzed in relation to polymorphic variants of CLOCK and BMAL1 genes. These levels were assessed with realtime PCR method at daily hours 9, 13, and 17. The significant differences were revealed in transcript levels of the examined genes in patients with various genotypes at the polymorphic markers 3111TC and 257TG regulatory regions of CLOCK gene. The study detected no significant differences among the carriers of various genotypes at polymorphic markers 862TC and 2121GA of CLOCK gene and 56445TC of BMAL1 gene.

The level of TNFα and IL6 in the blood plasma of patients with rheumatoid arthritis (RA) who received antiinflammatory therapy with methotrexate (MT) was significantly lower than in the patients without MT treatment. The level of caspase 6 and 9 gene transcripts in peripheral blood lymphocytes in patients with rheumatoid arthritic diagnosed for the first time and in patients with MT treatment were not significantly different. At the same time, the level of caspase 3 mRNA expression was significantly higher in the cells of the RA patients with MT therapy compared to the patients without MT therapy.

Association of TNF gene polymorphism -308G>A with the development of nonalcoholic steatohepatitis in the Russian population was revealed. Carriers of allele A of the TNF gene marker -308G>A have significantly higher risk of nonalcoholic steatohepatitis development: OR=1.69 (1.05; 2.71). Allele A carriage by this marker predicts an increase in the basal HDL level and a decrease in LDL and IL-10 levels in the blood of healthy subjects. Patients with nonalcoholic steatohepatitis, differing by the TNF gene -308G>A marker genotype, differ by the time course of the markers of hepatocellular damage (ALT, AST), activity of hepatocyte apoptosis (tissue polypeptide-specific antigen), and activation of specific humoral immunity (γ-globulin) in response to therapy with ursodeoxycholic acid in a dose of 10-15 mg/kg over 4-6 weeks. Carriers of allele A of the TNF gene polymorphic marker -308G>A are more sensitive to ursodeoxycholic acid therapy than carriers of GG genotype.

Association of IL6R gene polymorphic variant rs2228145(C>A) with the development of nonalcoholic steatohepatitis in Karelia residents is detected. The risk of nonalcoholic steatohepatitis is more than 2-fold higher in carriers of CC genotype by rs2228145 polymorphic marker than in carriers of other genotypes. Plasma levels of IL-6 and the content of IL6R gene transcripts in the peripheral blood leukocytes are higher in patients with nonalcoholic steatohepatitis than in normal subjects. No relationships between rs2228145 polymorphism and the level of IL-6 and content of IL6 and IL6R mRNA were detected. Gene IL6R polymorphic variant rs2228145(C>A) seems to be involved in genetic predisposition of the population of Karelia to nonalcoholic steatohepatitis. However, biochemical and molecular mechanisms underlying the relationship of rs2228145 with the development of nonalcoholic steatohepatitis are not yet studied.