Wednesday, August 12, 2009

What's new for 'Trypanosomatids' in PubMed

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Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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PubMed Results
Items 1 -10 of 13

1: Free Radic Res. 2009 Aug 7:1-10. [Epub ahead of print]

Berberine chloride causes a caspase-independent, apoptotic-like death in Leishmania donovani promastigotes.

Saha P, Sen R, Hariharan C, Kumar D, Das P, Chatterjee M.

Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata, India.

Berberine chloride, a quarternary isoquinoline alkaloid, is a promising anti-leishmanial compound, IC(50) being 7.1 microM in L. donovani promastigotes. This leishmanicidal activity was initiated by its pro-oxidant effect, evidenced by enhanced generation of reactive oxygen intermediates that was accompanied by depletion of thiols; pre-incubation in N-acetyl cysteine, attenuated its cell viability, corroborating that generation of free radicals triggered its parasiticidal activity. Externalization of phosphatidylserine and elevation of intracellular calcium preceded depolarization of the mitochondrial membrane potential, which translated into an increase in the sub G(0)/G(1) population and was accompanied by DNA laddering, hallmarks of apoptosis. Berberine chloride failed to induce caspase activity and anti-leishmanial activity in the presence of a pan caspase inhibitor, Z-Val-Ala-DL-Asp (methoxy)-fluoromethylketone remained unchanged, which indicated that the apoptosis was caspase independent. Collectively, the data indicates that Berberine chloride triggers an apoptosis-like death following enhanced generation of reactive oxygen species, thus meriting further pharmacological investigations.

PMID: 19669998 [PubMed - as supplied by publisher]

2: Parasitol Res. 2009 Aug 11. [Epub ahead of print]

In vitro activity of the essential oil of Cymbopogon citratus and its major component (citral) on Leishmania amazonensis.

Santin MR, Dos Santos AO, Nakamura CV, Dias Filho BP, Ferreira IC, Ueda-Nakamura T.

Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brazil.

Leishmaniasis causes considerable mortality throughout the world, affecting more than 12 million people. Cymbopogon citratus (DC) Stapf, Family Poaceae, is a widely used herb in tropical countries and is also known as a source of ethnomedicines. In this study, the inhibitory effect and the morphological and ultrastructural alterations on Leishmania amazonensis by the essential oil (EO) of C. citratus and its main constituent, citral, were evaluated. The results showed that the antiproliferative activity of EO on promastigotes and axenic amastigotes, and intracellular amastigote forms of L. amazonensis was significantly better than citral, and indicated a dose-dependent effect. Neither compound showed a cytotoxic effect on macrophage strain J774G8. The promastigote forms of L. amazonensis underwent remarkable morphological and ultrastructural alterations compared with untreated cultures. These alterations were visible by light, scanning, and transmission electron microscopy of promastigotes treated with EO and citral at concentrations corresponding to the IC(50) (1.7 and 8.0 microg/ml) and IC(90) (3.2 and 25 microg/ml), respectively, after 72 h of incubation. This study revealed that citral-rich essential oil from C. citratus has promising antileishmanial properties, and is a good candidate for further research to develop a new anti-protozoan drug.

PMID: 19669793 [PubMed - as supplied by publisher]

3: Eukaryot Cell. 2009 Aug 7. [Epub ahead of print]

Trypanosomatid genomes contain several subfamilies of ingi-related retroposons.

Bringaud F, Berriman M, Hertz-Fowler C.

Centre de Résonance Magnétique des Systèmes Biologiques, UMR-5536 CNRS, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux, France; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.

Retroposons are ubiquitous transposable elements found in the genome of most eukaryotes, including trypanosomatids. The African and American trypanosomes (Trypanosoma brucei and T. cruzi) contain long autonomous retroposons of the ingi clade (Tbingi and L1Tc, respectively) and short non-autonomous truncated versions (TbRIME and NARTc, respectively), as well as degenerate ingi-related retroposons devoid of coding capacity (DIREs). In contrast, Leishmania major contains only remnants of extinct retroposons (LmDIREs) and of short non-autonomous heterogeneous elements (LmSIDERs). We now extend this comparative and evolutionary analysis of retroposons to the genomes of two other African trypanosomes (T. congolense and T. vivax) and another Leishmania spp. (L. braziliensis). Three new potentially functional retroposons of the ingi clade have been identified: Tvingi in T. vivax, Tcoingi and L1Tco in T. congolense. T. congolense is the first trypanosomatid containing two classes of potentially active retroposons of the ingi clade. We analysed sequences located upstream of these new long autonomous ingi-related elements, which code for the recognition site of the retroposons-encoded endonuclease. The closely related Tcoingi and Tvingi elements show the same conserved pattern indicating that the Tcoingi- and Tvingi-encoded endonucleases share site-specificity. Similarly, the conserved pattern previously identified upstream of L1Tc is also detected at the same relative position upstream of L1Tco elements. A phylogenetic analysis of all ingi-related retroposons identified so far, including DIREs, clearly shows that several distinct subfamilies have emerged and coexisted. Though in the course of the trypanosomatid evolution, only few have been maintained as active elements in modern trypanosomatid (sub)species.

PMID: 19666780 [PubMed - as supplied by publisher]

4: Proc Natl Acad Sci U S A. 2009 Aug 3. [Epub ahead of print]

Structure of the C-terminal domain of transcription factor IIB from Trypanosoma brucei.

Ibrahim BS, Kanneganti N, Rieckhof GE, Das A, Laurents DV, Palenchar JB, Bellofatto V, Wah DA.

Public Health Research Institute and Department of Biochemistry and Molecular Biology and.

In trypanosomes, the production of mRNA relies on the synthesis of the spliced leader (SL) RNA. Expression of the SL RNA is initiated at the only known RNA polymerase II promoter in these parasites. In the pathogenic trypanosome, Trypanosoma brucei, transcription factor IIB (tTFIIB) is essential for SL RNA gene transcription and cell viability, but has a highly divergent primary sequence in comparison to TFIIB in well-studied eukaryotes. Here we describe the 2.3 A resolution structure of the C-terminal domain of tTFIIB (tTFIIB(C)). The tTFIIB(C) structure consists of 2 closely packed helical modules followed by a C-terminal extension of 32 aa. Using the structure as a guide, alanine substitutions of basic residues in regions analogous to functionally important regions of the well-studied eukaryotic TFIIB support conservation of a general mechanism of TFIIB function in eukaryotes. Strikingly, tTFIIB(C) contains additional loops and helices, and, in contrast to the highly basic DNA binding surface of human TFIIB, contains a neutral surface in the corresponding region. These attributes probably mediate trypanosome-specific interactions and have implications for the apparent bidirectional transcription by RNA polymerase II in protein-encoding gene expression in these organisms.

PMID: 19666603 [PubMed - as supplied by publisher]

5: Proc Natl Acad Sci U S A. 2009 Aug 6. [Epub ahead of print]

Inoculation of killed Leishmania major into immune mice rapidly disrupts immunity to a secondary challenge via IL-10-mediated process.

Okwor I, Liu D, Beverley SM, Uzonna JE.

Parasite Vaccines Development Laboratory, Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, MB, R3E 0T5 Canada.

Recovery from natural or experimental Leishmania major infection, the causative agent of cutaneous leishmaniasis, results in development of durable immunity in mice and humans that is manifested as rapid control of parasite replication and resolution of cutaneous lesion after secondary challenge. This form of "infection-induced" immunity is thought to occur naturally in endemic areas and is generally considered the gold standard for any effective vaccine against cutaneous leishmaniasis. To determine factors that might heighten or abrogate infection-induced immunity, we investigated the impact of inoculating dead antigen in the form of killed Leishmania parasites to healed mice. We show that inoculation of killed parasites into mice that resolved their primary virulent L. major infection results in rapid and relatively sustained loss of infection-induced immunity. This loss of immunity was not due to the inability of killed parasites to induce inflammatory responses (such as delayed type hypersensitivity), but it was related to their failure to induce robust IFN-gamma response. Furthermore, inoculation of killed Leishmania parasites into healed mice led to rapid expansion of IL-10-producing CD4(+)CD25(+)Foxp3(+) T cells in lymph nodes draining the primary infection site. Treatment with anti-CD25 or anti-IL-10R mAb abolished killed parasite-induced loss of immunity. Our study suggests that vaccination with killed parasites could predispose naturally immune individuals to become susceptible to new infections and/or disease reactivation. This may account for the lack of efficacy of such vaccines in field trials in endemic regions. These findings have important implications for vaccine design and vaccination strategies against human cutaneous leishmaniasis.

PMID: 19666482 [PubMed - as supplied by publisher]

6: Vaccine. 2009 Aug 7. [Epub ahead of print]

The Chimerical Multi-Component Q protein from Leishmania in the absence of adjuvant protects dogs against an experimental Leishmania infantum infection.

Carcelén J, Iniesta V, Fernández-Cotrina J, Serrano F, Parejo JC, Corraliza I, Gallardo-Soler A, Marañón F, Soto M, Alonso C, Gómez-Nieto C.

LeishmanCeres Laboratory (GLP Compliance certificated), Unidad de Parasitología y Enfermedades Parasitarias, Facultad de Veterinaria, Universidad de Extremadura, Avda. de la Universidad s/n, 10071 Cáceres, Spain.

The protective potential against Leishmania infection of the Leishmania chimerical Q protein administered as a single (Q) or double dose (Q+Q) without adjuvant was analyzed in a double-blind placebo controlled experiment in dogs. During vaccination the protein induced an intense early anti-Q response but no reactivity against total Leishmania infantum proteins was detected. Several end-points were taken into consideration. In the vaccinated animals the amount and intensity of clinical symptoms was lower than in the control group. Pathological signs of disease were observed in liver, kidney and spleen of all dogs from the control group in contrast to the normal appearance of the organs of the vaccinated animals. Vaccination was able to induce parasite clearance in most dogs. Only 1/7 dog was parasite DNA positive in skin in the Q group in contrast to 6/7 dogs in control and 4/7 in Q+Q. Significant anti-SLA clearance was observed in the vaccinated animals at the end of the study. Differences between control and vaccinated animals were also observed at the biochemical level, DTH and nitrite oxide production.

PMID: 19666153 [PubMed - as supplied by publisher]

7: Toxicol Appl Pharmacol. 2009 Aug 7. [Epub ahead of print]

Toxic effects of carvacrol, caryophyllene oxide and ascaridole from essential oil of Chenopodium ambrosioides on mitochondria.

Monzote L, Stamberg W, Staniek K, Gille L.

Parasitology Department, Institute of Tropical Medicine "Pedro Kouri", Apartado Postal No. 601, Marianao 13, Havana City, Cuba.

Chenopodium ambrosioides have been used for centuries in the Americas as a popular remedy for parasitic diseases. The essential oil of this plant possesses anthelmintic activity and is still used in some regions to treat parasitosis and leishmaniasis. However, the Chenopodium-oil caused also some fatalities, leading to its commercial disuse. In this work, we studied the mechanism of toxicity of the essential oil and its major pure ingredients (carvacrol, caryophyllene oxide and ascaridole, which was synthesized from alpha-terpinene) with respect to mammalian cells and mitochondria. We observed that all products, but especially caryophyllene oxide, inhibited the mitochondrial electron transport chain. This effect for carvacrol and caryophyllene oxide was mediated via direct complex I inhibition. Without Fe(2+), ascaridole was less toxic to mammalian mitochondria than other major ingredients. However, evidence for the formation of carbon-centered radicals in the presence of Fe(2+) was obtained by ESR spin-trapping. Furthermore, it was shown that Fe(2+) potentiated the toxicity of ascaridole on oxidative phosphorylation of rat liver mitochondria. The increase of the alpha-tocopherol quinone/ alpha-tocopherol ratio under these conditions indicated the initiation of lipid peroxidation by Fe(2+)-mediated ascaridole cleavage. Further ESR spin-trapping experiments demonstrated that in addition to Fe(2+), reduced hemin, but not mitochondrial cytochrome c can activate ascaridole, explaining why ascaridole in peritoneal macrophages from BALB/c mice exhibited a higher toxicity than in isolated mitochondria.

PMID: 19666043 [PubMed - as supplied by publisher]

8: Vet J. 2009 Aug 6. [Epub ahead of print]

Efficacy of an indirect immunofluorescence test in the diagnosis of canine leishmaniosis.

Figueiredo FB, Madeira MF, Menezes RC, Pacheco RS, Pires MQ, Furtado MC, Pinto AG, Schubach TM.

Laboratório de Pesquisa Clínica em Dermatozoonoses em Animais Domésticos, Instituto de Pesquisa Clínica Evandro Chagas, Fundação Oswaldo Cruz, Av. Brasil 4365, 21045-900 Rio de Janeiro, RJ, Brazil.

Of 146 dogs from a visceral leishmaniosis-endemic area that tested seronegative by indirect immunofluorescence (IIF) on blood samples collected on filter paper (IIFp), 51 (34.9%) and 10 (6.8%) tested positive by IIF on serum samples (IIFs) and enzyme immunoassay, respectively. Three samples (2.0%) tested positive by PCR. Leishmania chagasi was isolated from the skin of five (3.4%) dogs. Amastigote forms were identified in two of these five animals following histopathological and immunohistochemical examination. The findings highlight that detection methods such as IIFp can permit dogs infected with L. chagasi to remain undetected in endemic areas with attendant consequences for the epidemiology of infection both in the canine and human populations.

PMID: 19665398 [PubMed - as supplied by publisher]

9: BMC Genomics. 2009 Aug 7;10(1):370. [Epub ahead of print]

The steady-state transcriptome of the four major life-cycle stages of Trypanosoma cruzi.

Minning TA, Weatherly DB, Atwood J 3rd, Orlando R, Tarleton RL.

ABSTRACT: BACKGROUND: Chronic chagasic cardiomyopathy is a debilitating and frequently fatal outcome of human infection with the protozoan parasite, Trypanosoma cruzi. Microarray analysis of gene expression during the T. cruzi life-cycle could be a valuable means of identifying drug and vaccine targets based on their appropriate expression patterns, but results from previous microarray studies in T. cruzi and related kinetoplastid parasites have suggested that the transcript abundances of most genes in these organisms do not vary significantly between life-cycle stages. RESULTS: In this study, we used whole genome, oligonucleotide microarrays to globally determine the extent to which T. cruzi regulates mRNA relative abundances over the course of its complete life-cycle. In contrast to previous microarray studies in kinetoplastids, we observed that relative transcript abundances for over 50% of the genes detected on the T. cruzi microarrays were significantly regulated during the T. cruzi life-cycle. The significant regulation of 25 of these genes was confirmed by quantitative reverse-transcriptase PCR (qRT-PCR). The T. cruzi transcriptome also mirrored published protein expression data for several functional groups. Among the differentially regulated genes were members of paralog clusters, nearly 10% of which showed divergent expression patterns between cluster members. CONCLUSION: Taken together, these data support the conclusion that transcript abundance is an important level of gene expression regulation in T. cruzi. Thus, microarray analysis is a valuable screening tool for identifying stage-regulated T. cruzi genes and metabolic pathways.

PMID: 19664227 [PubMed - as supplied by publisher]

10: Clin Exp Immunol. 2009 Sep;157(3):377-84.

The skin homing receptor cutaneous leucocyte-associated antigen (CLA) is up-regulated by Leishmania antigens in T lymphocytes during active cutaneous leishmaniasis.

Mendes-Aguiar Cde O, Gomes-Silva A, Nunes E Jr, Pereira-Carvalho R, Nogueira RS, Oliveira-Neto Mde P, Bertho AL, Da-Cruz AM.

Laboratório de Interdisciplinar de Pesquisas Médicas, Núcleo de Análise e Sorting, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.

The cutaneous leucocyte-associated antigen receptor (CLA) can direct Leishmania-specific T lymphocytes towards inflamed skin lesions. Homing receptors [CLA, lymphocyte-associated antigen 1 (LFA-1) or CD62L] were analysed in lymphocytes from blood and cutaneous leishmaniasis (CL) lesions. CL patients with active lesions (A-CL) presented lower levels of T lymphocytes expressing the CLA(+) phenotype (T CD4(+) = 10.4% +/- 7.5% and T CD8(+) = 5.8% +/- 3.4%) than did healthy subjects (HS) (T CD4(+) = 19.3% +/- 13.1% and T CD8(+) = 21.6% +/- 8.8%), notably in T CD8(+) (P < 0.001). In clinically cured patients these percentages returned to levels observed in HS. Leishmanial antigens up-regulated CLA in T cells (CLA(+) in T CD4(+) = 33.3% +/- 14.1%; CLA(+) in T CD8(+) = 22.4% +/- 9.4%) from A-CL but not from HS. An enrichment of CLA(+) cells was observed in lesions (CLA(+) in T CD4(+) = 45.9% +/- 22.5%; CLA(+) in T CD8(+) = 46.4% +/- 16.1%) in comparison with blood (CLA(+) in T CD4(+) = 10.4% +/- 7.5%; CLA(+) in T CD8(+) = 5.8% +/- 3.4%). Conversely, LFA-1 was highly expressed in CD8(+) T cells and augmented in CD4(+) T from peripheral blood of A-CL patients. In contrast, CD62L was not affected. These results suggest that Leishmania antigens can modulate molecules responsible for migration to skin lesions, potentially influencing the cell composition of inflammatory infiltrate of leishmaniasis or even the severity of the disease.

PMID: 19664146 [PubMed - in process]

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