Assessment of potential genetic markers for diabetic foot ulcer among Moscow residents.

PURPOSE: Diabetic foot ulcer (DFU) is one of the most severe complications of type 2 diabetes, which is manifested in chronic skin ulcers of lower extremities. DFU treatment remains complex and expensive despite the availability of well-established protocols. Early prediction of potential DFU development at the onset of type 2 diabetes can greatly improve the aftermath of this complication. METHODS: To assess potential genetic markers for DFU, a group of diabetic patients from Moscow region with and without DFU was genotyped for a number of SNPs previously reported to be associated with the DFU. RESULTS: Obtained results did not confirm previously claimed association of rs1024611, rs3918242, rs2073618, rs1800629, rs4986790, rs179998, rs1963645 and rs11549465 (respectively, in MCP1, MMP9, TNFRSF11B, TNFα, TLR4, eNOS, NOS1AP and HIF1α genes) with the DFU. Surprisingly, the t allele of rs7903146 in the TCF7l2 gene known as one of the most prominent risk factors for type 2 diabetes has shown a protective effect on DFU with OR(95%) = 0.68(0.48-0.96). CONCLUSION: Non-replication of previously published SNP associations with DFU suggests that the role of genetic factors in the DFU onset is either highly variable in different populations or is not as significant as the role of non-genetic factors.

Retinoic acid co-treatment aggravates severity of dioxin-induced skin lesions in hairless mice via induction of inflammatory response.

Exposure to toxic halogenated polyaromatic hydrocarbons, of which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most potent, induces diverse skin pathologies in humans, including chloracne, hyperkeratosis, hamartomas, etc. While the toxic effects of TCDD have been extensively studied, effective approaches to their treatment are still lacking. Retinoids are commonly used in therapy of acneiform skin diseases. In vitro, retinoids elicit antagonistic effects on keratinocyte differentiation and proliferation, as compared to TCDD, suggesting their potential in treatment of TCDD-induced skin lesions. Nevertheless, the modulation of TCDD activity in skin by retinoids in vivo was never reported. We have used N-TERT keratinocyte cell line and hairless (hr) mice to determine if retinoic acid (RA) can lessen or reverse TCDD-induced effects in vitro and in vivo. RA co-treatment suppressed TCDD-induced changes in the expression of differentiation-associated genes and N-TERT keratinocyte viability in vitro. However, in hairless mice (in vivo), RA/TCDD co-treatment produced more severe effects, than treatment with either of the two compounds individually. RA/TCDD co-application to mouse skin strongly stimulated keratinocyte proliferation, resulting in dramatic epidermal hyperplasia. It has also led to massive immune cell infiltration into the dermis, and increased mRNA expression of inflammation markers, including IL1ß, IL6 and S100A7. Thus, retinoids not only appeared ineffective in treatment of TCDD-induced skin lesions in hairless mice, but also resulted in their exaggeration. These in vivo results question previous cell culture-based claims that RA may reduce TCDD-induced skin effects and caution against the reliance on in vitro data in TCDD toxicology research.

Expansion and evolution of the X-linked testis specific multigene families in the melanogaster species subgroup.

The testis specific X-linked genes whose evolution is traced here in the melanogaster species subgroup are thought to undergo fast rate of diversification. The CK2ßtes and NACßtes gene families encode the diverged regulatory ß-subunits of protein kinase CK2 and the homologs of ß-subunit of nascent peptide associated complex, respectively. We annotated the CK2ßtes-like genes related to CK2ßtes family in the D. simulans and D. sechellia genomes. The ancestor CK2ßtes-like genes preserved in D. simulans and D. sechellia are considered to be intermediates in the emergence of the D. melanogaster specific Stellate genes related to the CK2ßtes family. The CK2ßtes-like genes are more similar to the unique autosomal CK2ßtes gene than to Stellates, taking into account their peculiarities of polymorphism. The formation of a variant the CK2ßtes gene Stellate in D. melanogaster as a result of illegitimate recombination between a NACßtes promoter and a distinct polymorphic variant of CK2ßtes-like ancestor copy was traced. We found a close nonrandom proximity between the dispersed defective copies of DINE-1 transposons, the members of Helitron family, and the CK2ßtes and NACßtes genes, suggesting an involvement of DINE-1 elements in duplication and amplification of these genes.

The Y chromosome as a target for acquired and amplified genetic material in evolution.

The special properties of the Y chromosome stem form the fact that it is a non-recombining degenerate derivative of the X chromosome. The absence of homologous recombination between the X and the Y chromosome leads to gradual degeneration of various Y chromosome genes on an evolutionary timescale. The absence of recombination, however, also favors the accumulation of transposable elements on the Y chromosome during its evolution, as seen with both Drosophila and mammalian Y chromosomes. Alongside these processes, the acquisition and amplification of autosomal male benefit genes occur. This review will focus on recent studies that reveal the autosome-acquired genes on the Y chromosome of both Drosophila and humans. The evolution of the acquired and amplified genes on the Y chromosome is also discussed. Molecular and comparative analyses of Y-linked repeats in the Drosophila melanogaster genome demonstrate that there was a period of their degeneration followed by a period of their integration into RNAi silencing, which was beneficial for male fertility. Finally, the function of non-coding RNA produced by amplified Y chromosome genetic elements will be discussed.

An alien promoter capture as a primary step of the evolution of testes-expressed repeats in the Drosophila melanogaster genome.

Fertility of Drosophila melanogaster males is impaired due to the disruption of the silencing of the X-linked, testis-expressed, repeated Stellate (Ste) genes. Ste silencing is mediated by symmetric transcription of the paralogous Y-linked repeats and exerted by an RNA interference (RNAi) mechanism. Here we present a scenario for the origin of the Ste genes and their suppressors. The primary intermediate of their evolution emerged as a result of the acquisition of a preformed alien, testis-specific promoter. This intermediate is identified as a chimeric gene containing coding region of an autosomal gene for testis-specific protein kinase CK2. The 5' region of the chimera has been acquired from a member of a family of testis-expressed X-linked genes of unknown function. We propose that the evolution and amplification of the novel chimeric gene have led to the overproduction of the regulatory CK2 subunit in testes. The evolution of the Y-linked descendants of the primary intermediate resulted in the RNAi-mediated suppression of excessive expression of the X-linked paralogs. The newly detected "dead family" of cognate repeats on the Y chromosome has contributed to the evolution of Ste and its suppressors via gene conversion. Our results show that RNAi silencing, considered as a defense against viruses and transposable elements, may be involved in the evolution of eukaryotic genomes.