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Sent on Wednesday, 2009 Apr 01Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
- 1: Antimicrob Agents Chemother. 2009 Mar 30. [Epub ahead of print]
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Topoisomerase I gene mutations at F270 in the large subunit and at N184 in the small subunit contribute to the resistance mechanism of unicellular parasite Leishmania donovani towards 3,3'-Diindolylmethane (DIM).
Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, 4, Raja S.C Mullick Road, Kolkata -700032, India; Biophysical Chemistry, Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland; Department of Medicinal Chemistry, Indian Institute of Chemical Biology; 4, Raja S.C Mullick Road, Kolkata -700032, India.
3,3'-Diindolylmethane (DIM), a novel Leishmania topoisomerase I (LdTOP1LS) poison induces programmed cell death in Leishmania parasites. Development of resistant parasites by adaptation with increasing concentrations of DIM generates random mutations in LdTOP1LS. Single nucleotide mutations result in amino acid substitutions of F270L and K430N in the large subunit and N184S in the small subunit of the enzyme. DIM failed to inhibit the catalytic activity of the recombinant mutant enzyme (LdTOP1DRLS). Transfection studies of the mutant genes showed that the mutated topoisomerase I confers DIM resistance to wild type Leishmania parasites. Site-directed mutagenesis studies revealed that there is a substantial level of resistance conferred by the F270L alone, however all the three mutations (F270L, K430N and N184S) together are required to reach a higher-resistant phenotype. DIM fails to stabilize the topo I-DNA covalent complexes in F270 mutant. Moreover, DIM cannot interfere the religation step in the catalytic cycle of recombinant mutant enzyme F270L. Taken together, these findings identify novel mutations in topoisomerase I that hinder topo I-DNA interaction, thereby modulating enzyme catalysis and confer resistance to DIM. These studies advance our understanding on the mechanism of cell poisoning by DIM and suggest the specific modification of the drug that may improve efficacy.
PMID: 19332675 [PubMed - as supplied by publisher]
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Related Articles
- An insight into the mechanism of inhibition of unusual bi-subunit topoisomerase I from Leishmania donovani by 3,3'-di-indolylmethane, a novel DNA topoisomerase I poison with a strong binding affinity to the enzyme. [Biochem J. 2008]
- Topoisomerase I amino acid substitutions, Gly185Arg and Asp325Glu, confer camptothecin resistance in Leishmania donovani. [Antimicrob Agents Chemother. 2005]
- Mitochondria-dependent reactive oxygen species-mediated programmed cell death induced by 3,3'-diindolylmethane through inhibition of F0F1-ATP synthase in unicellular protozoan parasite Leishmania donovani. [Mol Pharmacol. 2008]
- Differential induction of Leishmania donovani bi-subunit topoisomerase I-DNA cleavage complex by selected flavones and camptothecin: activity of flavones against camptothecin-resistant topoisomerase I. [Nucleic Acids Res. 2006]
- ReviewThe current status of camptothecin analogues as antitumor agents. [J Natl Cancer Inst. 1993]
- 2: Emerg Infect Dis. 2009 Apr;15(4):678-680.
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Leishmaniasis in Chaparé, Bolivia.
Universidad Mayor de San Simón, Cochabamba, Bolivia (E. Rojas, R. Parrado, R. Delgado, A.L. Garcia); London School of Hygiene and Tropical Medicine, London, UK (R. Reithinger); and George Washington University School of Medicine and Health Science, Washington, DC, USA (R. Reithinger).
To the Editor: In Bolivia, most cases of leishmaniasis are caused by Leishmania (Viannia) braziliensis (1). The parasite is transmitted zoonotically by several sandfly species and, when transmitted to humans, may cause cutaneous leishmaniasis (CL), and potentially, mucosal leishmaniasis (ML) (2).
PMID: 19331774 [PubMed - as supplied by publisher]
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Related Articles
- Leishmaniasis in Bolivia. II. The involvement of Psychodopygus yucumensis and Psychodopygus llanosmartinsi in the selvatic transmission cycle of Leishmania braziliensis braziliensis in a lowland subandean region. [Mem Inst Oswaldo Cruz. 1986]
- Cutaneous leishmaniasis in Bolivia. A study of 185 human cases from Alto Beni (La Paz Department). Isolation and isoenzyme characterization of 26 strains of Leishmania braziliensis braziliensis [corrected] [Trans R Soc Trop Med Hyg. 1987]
- [Cases of american cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis in the towns of Cosmópolis and Indaiatuba-region of Campinas, in São Paulo, Brazil] [Rev Soc Bras Med Trop. 1996]
- ReviewThe epidemiology and control of leishmaniasis in Andean countries. [Cad Saude Publica. 2000]
- ReviewNew world cutaneous leishmaniasis in travellers. [Lancet Infect Dis. 2006]
- 3: Emerg Infect Dis. 2009 Apr;15(4):626-32.
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High incidence of diseases endemic to the Amazon region of Brazil, 2001-2006.
University of Brasília, Brasília, Brazil (G. Penna); Serra dos Orgãos Education Foundation, Rio de Janeiro, Brazil (L.F. Pinto, D. Soranz); and Federal Ministry of Health, Brasília (R. Glatt).
In Brazil, reportable diseases are the responsibility of the Secretariat of Health Surveillance of the Brazilian Federal Ministry of Health. During 2001-2006, to determine incidence and hospitalization rates, we analyzed 5 diseases (malaria, leishmaniasis [cutaneous and visceral], dengue fever, leprosy, and tuberculosis) that are endemic to the Amazon region of Brazil. Data were obtained from 773 municipalities in 3 regions. Although incidence rates of malaria, leishmaniasis, tuberculosis, and leprosy are decreasing, persons in lower socioeconomic classes with insufficient formal education are affected more by these diseases and other health inequalities than are other population groups in the region.
PMID: 19331758 [PubMed - in process]
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Related Articles
- Dengue and dengue hemorrhagic fever, Brazil, 1981-2002. [Emerg Infect Dis. 2005]
- [Community participation and control of endemic diseases in Brazil: problems and possibilities] [Cad Saude Publica. 1998]
- Community participation in health activities in an Amazon community of Brazil. [Bull Pan Am Health Organ. 1978]
- ReviewImmunogenetics of leishmanial and mycobacterial infections: the Belem Family Study. [Philos Trans R Soc Lond B Biol Sci. 1997]
- ReviewDengue and dengue hemorrhagic fever epidemics in Brazil: what research is needed based on trends, surveillance, and control experiences? [Cad Saude Publica. 2005]
- 4: Parasitol Int. 2009 Mar;58(1):110-3. Epub 2008 Dec 16.
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Establishment of an in vitro transgene expression system in epimastigotes of Trypanosoma congolense.
National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido 080-8555, Japan.
Trypanosoma congolense epimastigote forms (EMFs) adhere to the tsetse fly proboscis, proliferate, and differentiate into animal-infective metacyclic forms (MCFs). This differentiation step, called metacyclogenesis, is indispensable for the cyclical transmission of the parasite. Although an in vitro metacyclogenesis culture system was established several decades ago, few genetic tools have been utilized to investigate the molecular mechanisms underlying T. congolense metacyclogenesis. This study established a transgene expression system using an in vitro derived EMF of T. congolense IL3000, and the transgenic EMF successfully underwent metacyclogenesis in vitro. The newly constructed expression vector pSAK was designed for integration into the alpha-beta tubulin locus, which is tandemly arranged in the T. congolense genome. The expression cassette of pSAK/enhanced green fluorescent protein (eGFP) was transfected into the EMF by electroporation. An EMF expressing eGFP was successfully generated and differentiated into an MCF that constitutively expressed eGFP. The in vitro metacyclogenesis system in combination with the transgenic EMF technique will be important tools to investigate the molecular mechanisms of metacyclogenesis.
PMID: 19135170 [PubMed - indexed for MEDLINE]
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Related Articles
- Identification and molecular characterization of a novel stage-specific surface protein of Trypanosoma congolense epimastigotes. [Mol Biochem Parasitol. 2008]
- The requirement for epimastigote attachment during division and metacyclogenesis in Trypanosoma congolense. [Parasitol Res. 1988]
- Novel species specific antigens of trypanosoma congolense and their different localization among life-cycle stages. [J Vet Med Sci. 2000]
- Cell culture and animal infection with distinct Trypanosoma cruzi strains expressing red and green fluorescent proteins. [Int J Parasitol. 2008]
- ReviewStage-specific gene expression during Trypanosoma cruzi metacyclogenesis. [Genet Mol Res. 2003]
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