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Sent on Wednesday, 2010 Apr 14Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | PLoS Negl Trop Dis. 2010 Apr 6;4(4):e651.Structural Characterization of CYP51 from Trypanosoma cruzi and Trypanosoma brucei Bound to the Antifungal Drugs Posaconazole and Fluconazole.Chen CK, Leung SS, Guilbert C, Jacobson MP, McKerrow JH, Podust LM.Department of Pharmaceutical Chemistry, University of California, San Francisco, California, United States of America. AbstractBACKGROUND: Chagas Disease is the leading cause of heart failure in Latin America. Current drug therapy is limited by issues of both efficacy and severe side effects. Trypansoma cruzi, the protozoan agent of Chagas Disease, is closely related to two other major global pathogens, Leishmania spp., responsible for leishmaniasis, and Trypansoma brucei, the causative agent of African Sleeping Sickness. Both T. cruzi and Leishmania parasites have an essential requirement for ergosterol, and are thus vulnerable to inhibitors of sterol 14alpha-demethylase (CYP51), which catalyzes the conversion of lanosterol to ergosterol. Clinically employed anti-fungal azoles inhibit ergosterol biosynthesis in fungi, and specific azoles are also effective against both Trypanosoma and Leishmania parasites. However, modification of azoles to enhance efficacy and circumvent potential drug resistance has been problematic for both parasitic and fungal infections due to the lack of structural insights into drug binding. METHODOLOGY/PRINCIPAL FINDINGS: We have determined the crystal structures for CYP51 from T. cruzi (resolutions of 2.35 A and 2.27 A), and from the related pathogen T. brucei (resolutions of 2.7 A and 2.6 A), co-crystallized with the antifungal drugs fluconazole and posaconazole. Remarkably, both drugs adopt multiple conformations when binding the target. The fluconazole 2,4-difluorophenyl ring flips 180 degrees depending on the H-bonding interactions with the BC-loop. The terminus of the long functional tail group of posaconazole is bound loosely in the mouth of the hydrophobic substrate binding tunnel, suggesting that the major contribution of the tail to drug efficacy is for pharmacokinetics rather than in interactions with the target. CONCLUSIONS/SIGNIFICANCE: The structures provide new insights into binding of azoles to CYP51 and mechanisms of potential drug resistance. Our studies define in structural detail the CYP51 therapeutic target in T. cruzi, and offer a starting point for rationally designed anti-Chagasic drugs with improved efficacy and reduced toxicity. |
| PMID: 20386598 [PubMed - in process] | |
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| 2. | Antimicrob Agents Chemother. 2010 Apr 12. [Epub ahead of print]A Non-azole CYP51 Inhibitor Cures Chagas Disease in a Mouse Model of Acute Infection.Doyle PS, Chen CK, Johnston JB, Hopkins SD, Leung SS, Jacobson MP, Engel JC, McKerrow JH, Podust LM.Sandler Center for Basic Research in Parasitic Diseases, and Department of Pharmaceutical Chemistry, University of California, San Francisco, California, 94158, USA. AbstractChagas Disease, the leading cause of heart failure in Latin America, is caused by the kinetoplastid protozoan Trypanosoma cruzi. The sterols of T. cruzi resemble those of fungi, both in composition and biosynthesis. Azole inhibitors of sterol 14alpha-demethylase (CYP51) successfully treat fungal infections in humans and efforts are underway to adapt the success of anti-fungal azoles posaconazole and ravuconazole as second-use agents for Chagas Disease. However, to address concerns about the use of azoles in Chagas Disease, including drug resistance and cost, rational design of non-azole CYP51 inhibitors can provide promising alternative drug chemotypes. We report the curative effect of the non-azole CYP51 inhibitor LP10 in an acute mouse model of T. cruzi infection. Mice treated with an oral dose of 40 mg LP10/kg BID for 30 days, initiated 24 hours post infection, showed no signs of acute disease and had histologically normal tissues after 6 months. A very stringent test of cure showed that 4/5 mice had negative PCR for T. cruzi, and parasites were amplified by hemoculture in only two treated mice. These results compare favorably with those reported for posaconazole. Electron microscopy and GC-MS analysis of sterol composition confirmed that treatment with LP10 blocked the 14alpha-demethylation step and induced breakdown of parasite cell membranes culminating in severe ultrastructural and morphological alterations and death of the clinically relevant amastigote stage of the parasite. |
| PMID: 20385875 [PubMed - as supplied by publisher] | |
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| 3. | Nucleic Acids Res. 2010 Apr 12. [Epub ahead of print]Genome-wide analysis of mRNA abundance in two life-cycle stages of Trypanosoma brucei and identification of splicing and polyadenylation sites.Siegel TN, Hekstra DR, Wang X, Dewell S, Cross GA.Laboratory of Molecular Parasitology, Laboratory of Living Matter and Genomics Resource Center, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. AbstractTranscription of protein-coding genes in trypanosomes is polycistronic and gene expression is primarily regulated by post-transcriptional mechanisms. Sequence motifs in the untranslated regions regulate mRNA trans-splicing and RNA stability, yet where UTRs begin and end is known for very few genes. We used high-throughput RNA-sequencing to determine the genome-wide steady-state mRNA levels ('transcriptomes') for approximately 90% of the genome in two stages of the Trypanosoma brucei life cycle cultured in vitro. Almost 6% of genes were differentially expressed between the two life-cycle stages. We identified 5' splice-acceptor sites (SAS) and polyadenylation sites (PAS) for 6959 and 5948 genes, respectively. Most genes have between one and three alternative SAS, but PAS are more dispersed. For 488 genes, SAS were identified downstream of the originally assigned initiator ATG, so a subsequent in-frame ATG presumably designates the start of the true coding sequence. In some cases, alternative SAS would give rise to mRNAs encoding proteins with different N-terminal sequences. We could identify the introns in two genes known to contain them, but found no additional genes with introns. Our study demonstrates the usefulness of the RNA-seq technology to study the transcriptional landscape of an organism whose genome has not been fully annotated. |
| PMID: 20385579 [PubMed - as supplied by publisher] | |
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| 4. | Rev Bras Parasitol Vet. 2010 Jan-Mar;19(1):73-4.Seroprevalen ce of anti-Leishmania spp. antibodies in rural dogs from the city of Monte Negro, State of Rondônia, Brazil.Aguiar DM, Oliveira TM, Cavalcante GT, Labruna MB, Camargo LM, Machado RZ, Gennari SM.Departamento de Clínica Médica Veterinária,Faculdade de Agronomia e Medicina Veterinária,Universidade Federal de Mato Grosso UFMTAv. Fernando Corrêa da Costa, s/n, CEP 78060-900 Cuiabá - MT, Brazil. danmoura@ufmt.br. AbstractThe present study assessed the prevalence of anti-Leishmania spp. antibodies in dogs from the city of Monte Negro, State of Rondônia, Brazil. ELISA (NE >/= 3) and IFAT (>/=1:40) were used to evaluate 161 serum samples collected from rural dogs from Monte Negro. Forty-five (27.9%) dogs were positive by ELISA tests and five (3.1%) were positive by IFAT. The present study showed for the first time the frequency of exposure to Leishmania spp. in dogs in the State of Rondônia, Amazon Region. |
| PMID: 20385065 [PubMed - in process] | |
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| 5. | Rev Bras Parasitol Vet. 2010 Jan-Mar;19(1):64-6.Surveillance of canine visceral leishmaniasis in a disease-free area.Frehse MS, Júnior HG, Ullmann LS, Camossi LG, Machado JG, Langoni H, Biondo AW, Molento MB.Departamento de Medicina Veterinária, Universidade Federal do Paraná UFPRRua dos Funcionários, 1540, CEP 80035-050, Juvevê, Curitiba - PR, Brazil. molento@ufpr.br. AbstractLeishmaniasis is an important re-emergent parasitosis worldwide, particularly in tropical countries. There are no reports of autochthonous disease in the State of Paraná, southern Brazil. No surveillance has been carried out in the most populated areas such as the city of Curitiba and its surroundings. The purpose of the present study was to determine the seroprevalence of visceral leishmaniasis in dogs at the Center for Zoonosis Control of São José dos Pinhais, Paraná, before euthanasia. Enzyme-linked immunosorbent assay (ELISA) and immunofluorescence antibody test (IFAT) were used to detect antibody levels against Leishmania sp. in dog sera. Imprints of the popliteal lymph nodes that were also randomly collected from 50 dogs with suspected clinical signs of visceral leishmaniasis, and evaluated under light microscopy for the detection of amastigote forms, were negative. A total of 364 dog samples were tested. The results showed only one positive sample (0.0027%) by ELISA test but negative by IFAT, however, the dog had no clinical signs. Random surveillance of dog populations from several districts of a metropolitan area may be a means of preventing Leishmania spreading. Based on our results, the city of Curitiba and its metropolitan area were considered at low risk for visceral leishmaniasis. |
| PMID: 20385062 [PubMed - in process] | |
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| 6. | Rev Bras Parasitol Vet. 2010 Jan-Mar;19(1):41-5.Monitoring of Lutzomyia longipalpis Lutz & Neiva, 1912 in an area of intense transmission of visceral leishmaniasis in Rio Grande do Norte, Northeast Brazil.Amóra SS, Bevilaqua CM, Dias Ede C, Feijó FM, Oliveira PG, Peixoto GC, Alves ND, Oliveira LM, Macedo IT.Laboratório de Doenças Parasitárias,Programa de Pós-Graduação em Ciências Veterinárias PPGCV,Universidade Estadual do Ceará UECE, Campus do Itaperi,Av. Paranjana, 1700, Fortaleza, CEP 60740-000, Brazil. claudiamlb@yahoo.com.br. AbstractUrban increase of visceral leishmaniasis (VL) in Brazil is associated with the adaptation of its vector, Lutzomyia longipalpis, to environments modified by humans. The present study reports the results of an entomological monitoring of L. longipalpis and the effect of environmental variables on its population density. Sandflies were captured in the municipality of Mossoró, State of Rio Grande do Norte, Northeastern Brazil, from January 2005 to December 2006. Two CDC light traps were placed monthly for four consecutive nights in the peridomicile of selected households. Data analysis was based on the chi-square test and linear regression. A total of 2,087 sandflies were captured, 99.86% of which were L. longipalpis. A higher proportion of females were captured (p < 0.05). Monthly analysis of the variables temperature, relative humidity and rainfall did not show a significant influence on population density. However, there were seasonal differences: approximately 70% of sand flies were captured during the rainy season (p < 0.05). The predominant species, L. longipalpis, is present in substantial number, representing a public health risk. Therefore, because of higher prevalence during the rainy season, we recommend intensified VL control measures before and during this season to reduce the risk of disease transmission. |
| PMID: 20385058 [PubMed - in process] | |
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| 7. | Rev Bras Parasitol Vet. 2010 Jan-Mar;19(1):34-40.[Canine Visceral Leishmaniasis diagnosis by immunohistochemistry and PCR in skin tissues in association with RI FI and ELISA-test.][Article in Portuguese] Queiroz NM, Assis JD, Oliveira TM, Machado RZ, Nunes CM, Starke-Buzetti WA.Departamento de Biologia e Zootecnia, Universidade Estadual Paulista UNESP,Júlio de Mesquita Filho, Campus de Ilha Solteira,Passeio Monção, 226, CEP 15385-000 Ilha Solteira, SP, Brazil. starke@bio.feis.unesp.br. AbstractThe purpose of the present study was to evaluate the immunohistochemistry (IMHC) and PCR (Polymerase Chain Reaction) tests for Canine Visceral Leishmaniasis (CVL) diagnosis and compare the results with serological tests such as the indirect fluorescence antibody test (IFAT), ELISA and a parasitological test (microscopic direct examination of the parasite stained with haematoxylin and eosin - HE). For this study, samples of healthy or lesion skin tissues were obtained from 34 CVL naturally infected dogs classified in three groups: asymptomatic, oligosymptomatic and polisymptomatic. Not only lesion (56.5%) but also healthy skins (31.8%) were positives by IMHC and confirmed by PCR in 97.8% of skin samples. In asymptomatic group, 87.5% dogs were negatives by serological tests, but positives by IMHC in 50% and by PCR in 100%. In oligosymptomatic group, 100%, 85.7% and 28.6% of dogs were positives, respectively by PCR, serological and IMHC tests. In addition, 91.7% of polisymptomatic dogs were serum positive and had intact parasites in the skin. In general, PCR showed higher positivity (100%). The efficiency of each test varied with the evolution of the disease. IMHC may be used to confirm the results of the serology and PCR in inconclusive cases after HE and IMHC. The association of techniques proposed in this study may increase the positivity and contributed to the control of this canine disease. |
| PMID: 20385057 [PubMed - as supplied by publisher] | |
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| 8. | Rev Bras Parasitol Vet. 2010 Jan-Mar;19(1):18-26.[Comparative study of diagnostic methods for visceral leishmaniasis in dogs from Ilha Solteira, SP.][Article in Portuguese] Assis JD, Queiroz NM, Silveira RD, Nunes CM, Oliveira TM, Junior AC, Neves MF, Machado RZ, Buzetti WA.Programa de Pós-graduação em Ciência Animal,Curso de Medicina Veterinária Preventiva e Produção Animal,Universidade Estadual Paulista UNESP Campus de Araçatuba,Rua Clóvis Pestana 93, Jardim D. Amélia, CEP 16.050-680, Araçatuba - SP, Brazil. jassis_assis@yahoo.com.br. AbstractThe purpose of the present work was a comparative study of diagnostic methods for Canine Visceral Leishmaniasis (CVL) using serological methods, enzyme-linked immunosorbent assay (ELISA) and indirect fluorescent antibody test (IFAT), histochemical (HE) and immunohistochemical (IMHC) tests using spleen, lymph node and liver canine tissues. In addition, Polymerase Chain Reaction (PCR) was done in blood and in tissues in order to compare and confirm no conclusive and negative diagnosis by the methods above. For this study, 34 dogs were divided according to clinical signs in asymptomatic, oligosymptomatic and polisymptomatic Leishmania-infected dogs euthanized by Zoonotic Disease Control Center (CCZ) from Ilha Solteira, SP, Brazil. The positivism indexes of ELISA, IMHC, IFAT and HE were 65.0, 62.0, 56.0 and 56.0%, respectively with the highest numbers of positive dogs in polisymptomatic (92.0%) followed by oligosymptomatic (57.0%) and asymptomatic dogs (12.5%). Furthermore, PCR confirmed the positive results and detected DNA in tissues from 100% of negative dogs and 89.0% suspects raising the animal positivism index up to 97.0%. In conclusion, PCR was the most sensitive and a valuable method for a definitive CVL diagnosis. |
| PMID: 20385055 [PubMed - as supplied by publisher] | |
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| 9. | Rev Bras Parasitol Vet. 2010 Jan-Mar;19(1):7-11.[In vitro insecticidal activity of seed neem oil on Lutzomyia longipalpis (Diptera: Psychodidae).][Article in Portuguese] Maciel MV, Morais SM, Bevilaqua CM, Silva RA, Barros RS, Sousa RN, Sousa LC, Machado LK, Brito ES, Souza-Neto MA.Programa de Pós-Graduação em Ciências Veterinárias,Laboratório de Doenças Parasitárias, Universidade Estadual do Ceará UECEAv. Paranjana, 1.700, CEP 60.740-000, Fortaleza, Ceará, Brazil. claudiamlb@yahoo.com.br. AbstractLutzomyia longipalpis is the main vector of visceral leishmaniasis in Brazil. The objective was to evaluate the effect of oil from (Azadirachta indica) neem seeds on eggs, larvae and adults of the vector. The insects were captured in the field and kept in the laboratory at +/- 27 degrees C and 80% relative humidity. Five treatments with different concentrations were performed using two negative controls (distilled water and Tween 80) and a positive control. The eggs were sprayed with the oil at different concentrations and the number of hatched larvae evaluated for 10 days. Mortality of larvae was observed to pupation and adult mortality was observed after 24, 48, and 72 hours. Statistical analysis was performed by Tukey test at 5% probability. The highest oil concentration of eggs obtained 65.16 +/- 3.24% efficacy for reducing egg hatching. The test with larvae showed 67.75 +/- 2.21% efficacy at a concentration of 100 mg.mL(1). In adults, the efficacy of the 100 mg.mL(1) concentration was 96.64 +/- 4.11% after 24 hours. The phytochemical analysis revealed the presence of triterpenes. These results demonstrate the potential use of this oil in the control of this vector. |
| PMID: 20385053 [PubMed - as supplied by publisher] | |
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