Репозиторий Университета

© 2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM) Microbial cells sense the presence of xenobiotics and, in response, upregulate genes involved in pleiotropic drug resistance (PDR). In yeast, PDR activation to a major extent relies on the transcription factor Pdr1. In addition, many xenobiotics induce oxidative stress, which may upregulate PDR independently of Pdr1 activity. Mitochondria are important sources of reactive oxygen species under stressful conditions. To evaluate the relevance of this redox pathway, we studied the activation of PDR in the yeast Candida glabrata, which we treated with a mitochondrially targeted antioxidant plastoquinonyl-decyl-triphenylphosphonium and dodecyltriphenylphosphonium (C12TPP) as a control. We found that both compounds induced activation of PDR genes and decreased the intracellular concentration of the PDR transporter substrate Nile red. Interestingly, the deletion of PDR transporter gene CDR1 inhibited the decrease in Nile red accumulation induced by antioxidant plastoquinonyl-decyl-triphenylphosphonium but not that by C12TPP. Moreover, antioxidant alpha-tocopherol inhibited C12TPP-mediated activation of PDR in Δcdr1 but not in the wild-type strain. Furthermore, pre-incubation of yeast cells with low concentrations of hydrogen peroxide induced a decrease in the intracellular concentration of Nile red in Δcdr1 and Δpdr1 as well as in control cells. Deletion of PDR1 inhibited the C12TPP-induced activation of CDR1 but not that of FLR1, which is a redox-regulated PDR transporter gene. It appears that disruption of the PDR1/CDR1 regulatory circuit makes auxiliary PDR regulation mechanisms crucial. Our data suggest that redox regulation of PDR is dispensable in wild-type cells because of redundancy in the activation pathways, but is manifested upon deletion of CDR1.

© 2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM) Microbial cells sense the presence of xenobiotics and, in response, upregulate genes involved in pleiotropic drug resistance (PDR). In yeast, PDR activation to a major extent relies on the transcription factor Pdr1. In addition, many xenobiotics induce oxidative stress, which may upregulate PDR independently of Pdr1 activity. Mitochondria are important sources of reactive oxygen species under stressful conditions. To evaluate the relevance of this redox pathway, we studied the activation of PDR in the yeast Candida glabrata, which we treated with a mitochondrially targeted antioxidant plastoquinonyl-decyl-triphenylphosphonium and dodecyltriphenylphosphonium (C12TPP) as a control. We found that both compounds induced activation of PDR genes and decreased the intracellular concentration of the PDR transporter substrate Nile red. Interestingly, the deletion of PDR transporter gene CDR1 inhibited the decrease in Nile red accumulation induced by antioxidant plastoquinonyl-decyl-triphenylphosphonium but not that by C12TPP. Moreover, antioxidant alpha-tocopherol inhibited C12TPP-mediated activation of PDR in Δcdr1 but not in the wild-type strain. Furthermore, pre-incubation of yeast cells with low concentrations of hydrogen peroxide induced a decrease in the intracellular concentration of Nile red in Δcdr1 and Δpdr1 as well as in control cells. Deletion of PDR1 inhibited the C12TPP-induced activation of CDR1 but not that of FLR1, which is a redox-regulated PDR transporter gene. It appears that disruption of the PDR1/CDR1 regulatory circuit makes auxiliary PDR regulation mechanisms crucial. Our data suggest that redox regulation of PDR is dispensable in wild-type cells because of redundancy in the activation pathways, but is manifested upon deletion of CDR1.

© 2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM) Microbial cells sense the presence of xenobiotics and, in response, upregulate genes involved in pleiotropic drug resistance (PDR). In yeast, PDR activation to a major extent relies on the transcription factor Pdr1. In addition, many xenobiotics induce oxidative stress, which may upregulate PDR independently of Pdr1 activity. Mitochondria are important sources of reactive oxygen species under stressful conditions. To evaluate the relevance of this redox pathway, we studied the activation of PDR in the yeast Candida glabrata, which we treated with a mitochondrially targeted antioxidant plastoquinonyl-decyl-triphenylphosphonium and dodecyltriphenylphosphonium (C12TPP) as a control. We found that both compounds induced activation of PDR genes and decreased the intracellular concentration of the PDR transporter substrate Nile red. Interestingly, the deletion of PDR transporter gene CDR1 inhibited the decrease in Nile red accumulation induced by antioxidant plastoquinonyl-decyl-triphenylphosphonium but not that by C12TPP. Moreover, antioxidant alpha-tocopherol inhibited C12TPP-mediated activation of PDR in Δcdr1 but not in the wild-type strain. Furthermore, pre-incubation of yeast cells with low concentrations of hydrogen peroxide induced a decrease in the intracellular concentration of Nile red in Δcdr1 and Δpdr1 as well as in control cells. Deletion of PDR1 inhibited the C12TPP-induced activation of CDR1 but not that of FLR1, which is a redox-regulated PDR transporter gene. It appears that disruption of the PDR1/CDR1 regulatory circuit makes auxiliary PDR regulation mechanisms crucial. Our data suggest that redox regulation of PDR is dispensable in wild-type cells because of redundancy in the activation pathways, but is manifested upon deletion of CDR1.

© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. OBJECTIVES: Surgical interventional has been key in the treatment of tuberculosis (TB) for a long time. Its importance diminished after the emergence of chemotherapy. However, the spread of rapid multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB has led us to return to surgery to treat TB. Today, every second patient in Russia with destructive TB has either MDR or XDR TB, which is the reason for the low efficacy of conservative treatment. In 2015, treatment with drugs resulted in clinical recovery in only 29.8% of new cases of destructive TB acid-fast bacilli (AFB)+. METHODS: The author's data from 1999 to 2016 have been analysed. The author performed 5599 surgeries on patients with pulmonary TB aged from 1 to 87 years (mean age 34.6 years). The most common reasons for surgical treatment were fibrotic cavitary and cavitary pulmonary TB, tuberculoma with destruction, tuberculous pleural empyema, caseous pneumonia and intrathoracic lymph nodes. The strategy of early collapse therapy and the use of surgery to treat TB was proposed in the Penza region of Russia; the results were analysed to estimate the long-term outcomes of treatment. RESULTS: In 5599 surgeries, the full clinical effect was achieved in 93% of operated patients with MDR TB, in 92.1% of those with XDR TB and in 98% of patients without MDR or XDR resistance. According to the data from the Penza region, 3 years after surgery, 93.9% (149 of 159 cases) of the operated patients exhibited clinical recovery. CONCLUSIONS: Taking into account the data from the World Health Organization on the insufficient level of therapeutic success in the treatment of MDR and XDR pulmonary TB, surgical treatment is necessary in regions with a high frequency of drug-resistant cases.

© 2018 Tomsk National Research Medical Center of the Russian Academy of Sciences. All rights reserved. The purpose of the study was to present data on polymixin-based antibiotics with activity against infections caused by multidrug-resistant Gram-negative bacteria, such as Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Material and methods. The review includes data from clinical as well as in vitro studies for the period 1998–2017. The search for relevant sources was carried out in the Medline, Cochrane Library, Elibrary and other databases. Results. The analysis of the data showed the presence of synergism and additive activity of polymyxin in combination with carbapenems, rifampicin and azithromycin. However, experimental data showed no direct positive correlation between combination of polymyxim and azithromycin/ rifampicin. In clinical studies, in hospital-acquired pneumonia, including ventilator-associated pneumonia, the clinical response rate of polymyxin B combined with other antibiotics ranged from 38 % to 88 %. High nephro- and neurotoxicity of polymyxin observed in previous studies can be explained by a lack of understanding of its toxicodynamics or the use of an incorrect dose. Conclusion. Polymyxin B in combination with other antibiotics is a promising treatment against infectious complications caused by multidrug resistant Gram-negative bacteria.