Oxidative Stress-Mediated Overexpression of Uracil DNA Glycosylase in Leishmania donovani Confers Tolerance against Antileishmanial Drugs
Autor: | Anshul Mishra, Pravin K. Jha, Sushmita Das, Kislay K. Sinha, Ajay Kumar, Mohd. Imran Khan, Prolay Das, Pradeep Das |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Aging Article Subject 030106 microbiology Leishmania donovani Biology medicine.disease_cause Biochemistry Microbiology 03 medical and health sciences parasitic diseases medicine lcsh:QH573-671 lcsh:Cytology Leishmaniasis Cell Biology General Medicine Base excision repair medicine.disease Leishmania biology.organism_classification 030104 developmental biology Visceral leishmaniasis DNA glycosylase Uracil-DNA glycosylase Oxidative stress |
Zdroj: | Oxidative Medicine and Cellular Longevity, Vol 2018 (2018) |
ISSN: | 1942-0994 1942-0900 |
Popis: | Leishmania donovaniis an intracellular protozoan parasite that causes endemic tropical disease visceral leishmaniasis (VL). Present drugs used against this fatal disease are facing resistance and toxicity issues. Survival of leishmania inside the host cells depends on the parasite’s capacity to cope up with highly oxidative environment. Base excision repair (BER) pathway inL. donovaniremains unexplored. We studied uracil DNA glycosylase (UNG), the key enzyme involved in BER pathway, and found that the glycosylase activity of recombinant LdUNG (Leishmania donovaniUNG) expressed inE. coliis in sync with the activity of the parasite lysate under different reaction conditions. Overexpression of UNG in the parasite enhances its tolerance towards various agents which produce reactive oxygen species (ROS) and shows a higher infectivity in macrophages. Surprisingly, exposure of parasite to amphotericin B and sodium antimony gluconate upregulates the expression of UNG. Further, we found that the drug resistant parasites isolated from VL patients show higher expression of UNG. Mechanisms of action of some currently used drugs include accumulation of ROS. Our findings strongly suggest that targeting LdUNG would be an attractive therapeutic strategy as well as potential measure to tackle the problem of drug resistance in the treatment of leishmaniasis. |
Databáze: | OpenAIRE |
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