[Multidrug resistance P-glycoprotein inhibits the antiapoptotic action of mitochondria-targeted antioxidant SkQR1].

Mitochondria-targeted antioxidants of the SkQR1 family, being accumulated in energized mitochondria, protect cells from oxidative stress by increasing the level of reduced glutathione and decreasing the cell-damaging effect induced by hydrogen peroxide. Using various human transformed cell lines and SkQR1 (a fluorescent member of the SkQ family), we show that SkQRI is ejected from chemotherapy-resistant cells by P-glycoprotein - one of the main transport proteins determining multidrug resistance typical for many neoplastic cells. It is also shown that SkQR1 ejection is neutralized by P-glycoprotein inhibitors (verapamil and pluronic L61). In experiments on K562 cells, it was found that the subline sensitive to chemotherapy is protected by SkQRI from apoptotic action of hydrogen peroxide. Protection of the resistant subline occurs only after inhibition of P-glycoprotein.

[A locus involved in tuberculosis infection control in mice locates in the proximal part of the H2 complex].

One of genetic loci involved in tuberculosis (TB) infection control in mice is located within the segment of Chr. 17 occupied by the H2 complex, the mouse MHC. As far as this region includes approximately 40 Mb and contains hundreds of genes affecting immune responses and host-parasite interactions, narrowing the interval by genetic recombination is pre-requisite for identification of particular gene(s). We have developed a panel of recombinant congenic strains bearing different parts of the H2 complex from TB-susceptible I/St mice on the genetic background of TB-resistant C57BL/6 mice. By superposing the phenotype "severe vs. mild infectious course" against the chart of alleles inherited by these new strains from the two parental strains, we have mapped a locus involved in TB control within the segment 33.305-34.479 Mb (-1.1 Mb) of the Chr. 17. Such a location indicates that allelic variants of the prominent pro-inflammatory factor TNF do not affect TB course in our experimental system. This result was confirmed by the assessment of the TNF level in the lung tissue of infected mice of different strains. The QTL (quantitative trait locus) mapped in our study influences several important parameters of TB infection: multiplication of mycobacteria in the lungs, severity of lung pathology and regulation of the early inflammatory response.

[Multidrug resistance p-glycoprotein inhibits the antiapoptotic action of mitochondria-targeted antioxidant SkQR1].

Mitochondria-targeted antioxidants of the SkQRI family, being accumulated in energized mitochondria, protect cells from oxidative stress by increasing the level of reduced glutathione and decreasing the cell-damaging effect induced by hydrogen peroxide. Using various human transformed cell lines and SkQR1 (a fluorescent member of the SkQ family), we show that SkQR1 is ejected from chemotherapy-resistant cells by P-glycoprotein--one of the main transport proteins determining multidrug resistance typical for many neoplastic cells. It is also shown that SkQR1 ejection is neutralized by P-glycoprotein inhibitors (verapamil and pluronic L61). In experiments on K562 cells, it was found that the subline sensitive to chemotherapy is protected by SkQR1 from apoptotic action of hydrogen peroxide. Protection of the resistant subline occurs only after inhibition of P-glycoprotein.