Base de dados : MEDLINE
Pesquisa : A11.870.740.800 [Categoria DeCS]
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  1 / 169 MEDLINE  
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[PMID]:28215870
[Au] Autor:Calero-Bernal R; Mauroo NF; Hui SW; Kuiken T; van de Bildt MW; de Jong AW; Osterhaus AD; Sims L; Gendron-Fitzpatrick A; Carmena D; Cerqueira-Cézar CK; Rosenthal BM; Dubey JP
[Ad] Endereço:United States Department of Agriculture, Agricultural Research Service, Beltsville Agricultural Research Center, Animal Parasitic Diseases Laboratory, Building 1001, Beltsville, MD 20705-2350, USA.
[Ti] Título:Acute fatal sarcocystosis hepatitis in an Indo-Pacific bottlenose dolphin (Tursiops aduncus) in Hong Kong.
[So] Source:Vet Parasitol;235:64-68, 2017 Feb 15.
[Is] ISSN:1873-2550
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Unlike most species in the genus Sarcocystis, Sarcocystis canis has a broad intermediate host range. Its life cycle is incompletely known and most reports are from the USA. Here we report fatal hepatitis in a 4year old male Indo-Pacific bottlenose dolphin (Tursiops aduncus) from Hong Kong associated with a S. canis-like infection. Diagnosis was made based on clinical presentation, histopathology, transmission electron microscopy (TEM), and molecular characterization. Microscopically, S. canis-like like infection was confined to the liver. Immature and mature schizonts were found in hepatocytes and the parasite was associated with generalized hepatic necrosis. By TEM, schizonts divided by endopolygeny, and merozoites lacked rhoptries. Molecular characterization of parasites present in liver and brain tissues at the cox1 gene showed a high degree of identity (97-98%) and clustered together with Sarcocystis canis, S. lutrae, S. arctica, S. speeri, S. turdusi, and S. rileyi in a phylogenetic study. This is the first report of S. canis-like infection from Asia.
[Mh] Termos MeSH primário: Golfinho Nariz-de-Garrafa/parasitologia
Hepatite Animal/parasitologia
Sarcocystis/isolamento & purificação
Sarcocistose/veterinária
[Mh] Termos MeSH secundário: Doença Aguda
Animais
Evolução Fatal
Hepatite Animal/diagnóstico
Hong Kong
Fígado/parasitologia
Fígado/patologia
Fígado/ultraestrutura
Masculino
Filogenia
Polimorfismo de Nucleotídeo Único/genética
Sarcocystis/classificação
Sarcocystis/genética
Sarcocystis/ultraestrutura
Sarcocistose/diagnóstico
Sarcocistose/parasitologia
Esquizontes
Análise de Sequência de DNA/veterinária
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170221
[St] Status:MEDLINE


  2 / 169 MEDLINE  
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[PMID]:28033565
[Au] Autor:Lindsay DS; Verma SK; Scott D; Dubey JP; von Dohlen AR
[Ad] Endereço:Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Faculty of Health Sciences, Virginia Tech, Blacksburg, VA 24061, USA. Electronic address: lindsayd@vt.edu.
[Ti] Título:Isolation, molecular characterization, and in vitro schizogonic development of Sarcocystis sp. ex Accipiter cooperii from a naturally infected Cooper's hawk (Accipiter cooperii).
[So] Source:Parasitol Int;66(2):106-111, 2017 Apr.
[Is] ISSN:1873-0329
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Raptors serve as the definitive host for several Sarcocystis species. The complete life cycles of only a few of these Sarcocystis species that use birds of prey as definitive hosts have been described. In the present study, Sarcocystis species sporocysts were obtained from the intestine of a Cooper's hawk (Accipiter cooperii) and were used to infect cell cultures of African green monkey kidney cells to isolate a continuous culture and describe asexual stages of the parasite. Two clones of the parasite were obtained by limiting dilution. Asexual stages were used to obtain DNA for molecular classification and identification. PCR amplification and sequencing were done at three nuclear ribosomal DNA loci; 18S rRNA, 28S rRNA, and ITS-1, and the mitochondrial cytochrome c oxidase subunit 1 (cox1) locus. Examination of clonal isolates of the parasite indicated a single species related to S. columbae (termed Sarcocystis sp. ex Accipiter cooperii) was present in the Cooper's hawk. Our results document for the first time Sarcocystis sp. ex A. cooperii occurs naturally in an unknown intermediate host in North America and that Cooper's hawks (A. cooperii) are a natural definitive host.
[Mh] Termos MeSH primário: Doenças das Aves/parasitologia
Falcões/parasitologia
Sarcocystis/genética
Sarcocystis/isolamento & purificação
Sarcocistose/veterinária
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Cercopithecus aethiops
Clonagem Molecular
Ciclo-Oxigenase 1/genética
DNA Ribossômico/genética
Microscopia Eletrônica de Transmissão
Oocistos/ultraestrutura
Filogenia
Reação em Cadeia da Polimerase/veterinária
RNA Ribossômico/genética
Reprodução Assexuada/fisiologia
Sarcocystis/classificação
Sarcocystis/crescimento & desenvolvimento
Sarcocistose/parasitologia
Esquizontes/crescimento & desenvolvimento
Esquizontes/ultraestrutura
Análise de Sequência de DNA
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Ribosomal); 0 (RNA, Ribosomal); EC 1.14.99.1 (Cyclooxygenase 1)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170413
[Lr] Data última revisão:
170413
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161230
[St] Status:MEDLINE


  3 / 169 MEDLINE  
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[PMID]:27799215
[Au] Autor:Ke H; Morrisey JM; Qu S; Chantarasriwong O; Mather MW; Theodorakis EA; Vaidya AB
[Ad] Endereço:Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA hangjun.ke@drexelmed.edu.
[Ti] Título:Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity.
[So] Source:Antimicrob Agents Chemother;61(1), 2017 Jan.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Caged Garcinia xanthones (CGXs) constitute a family of natural products that are produced by tropical/subtropical trees of the genus Garcinia CGXs have a unique chemical architecture, defined by the presence of a caged scaffold at the C ring of a xanthone moiety, and exhibit a broad range of biological activities. Here we show that synthetic CGXs exhibit antimalarial activity against Plasmodium falciparum, the causative parasite of human malaria, at the intraerythrocytic stages. Their activity can be substantially improved by attaching a triphenylphosphonium group at the A ring of the caged xanthone. Specifically, CR135 and CR142 were found to be highly effective antimalarial inhibitors, with 50% effective concentrations as low as ∼10 nM. CGXs affect malaria parasites at multiple intraerythrocytic stages, with mature stages (trophozoites and schizonts) being more vulnerable than immature rings. Within hours of CGX treatment, malaria parasites display distinct morphological changes, significant reduction of parasitemia (the percentage of infected red blood cells), and aberrant mitochondrial fragmentation. CGXs do not, however, target the mitochondrial electron transport chain, the target of the drug atovaquone and several preclinical candidates. CGXs are cytotoxic to human HEK293 cells at the low micromolar level, which results in a therapeutic window of around 150-fold for the lead compounds. In summary, we show that CGXs are potent antimalarial compounds with structures distinct from those of previously reported antimalarial inhibitors. Our results highlight the potential to further develop Garcinia natural product derivatives as novel antimalarial agents.
[Mh] Termos MeSH primário: Antimaláricos/farmacologia
Garcinia/química
Xantonas/farmacologia
[Mh] Termos MeSH secundário: Antimaláricos/química
Antimaláricos/uso terapêutico
Células HEK293
Seres Humanos
Mitocôndrias/efeitos dos fármacos
Estrutura Molecular
Parasitemia/tratamento farmacológico
Parasitemia/parasitologia
Plasmodium falciparum/efeitos dos fármacos
Esquizontes/efeitos dos fármacos
Relação Estrutura-Atividade
Trofozoítos/efeitos dos fármacos
Xantonas/química
Xantonas/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimalarials); 0 (Xanthones)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161102
[St] Status:MEDLINE


  4 / 169 MEDLINE  
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[PMID]:27934832
[Au] Autor:Sharma S; Kaitholia K; Mishra N; Srivastava B; Pillai CR; Valecha N; Anvikar AR
[Ad] Endereço:Department of Epidemiology and Clinical Research, National Institute of Malaria Research, Sector-8, New Delhi, India.
[Ti] Título: sensitivity pattern of chloroquine and artemisinin in .
[So] Source:Indian J Med Microbiol;34(4):509-512, 2016 Oct-Dec.
[Is] ISSN:1998-3646
[Cp] País de publicação:India
[La] Idioma:eng
[Ab] Resumo:Artemisinin (ART) and its derivatives form the mainstay of antimalarial therapy. Emergence of resistance to them poses a potential threat to future malaria control and elimination on a global level. It is important to know the mechanism of action of drug and development of drug resistance. We put forwards probable correlation between the mode of action of chloroquine (CQ) and ART. Modified trophozoite maturation inhibition assay, WHO Mark III assay and molecular marker study for CQ resistance at K76T codon in Plasmodium falciparum CQ-resistant transporter gene were carried out on cultured P. falciparum. On comparing trophozoite and schizont growth for both CQ-sensitive (MRC-2) and CQ-resistant (RKL-9) culture isolates, it was observed that the clearance of trophozoites and schizonts was similar with both drugs. The experiment supports that CQ interferes with heme detoxification pathway in food vacuoles of parasite, and this may be correlated as one of the plausible mechanisms of ART.
[Mh] Termos MeSH primário: Antimaláricos/farmacologia
Artemisininas/farmacologia
Cloroquina/farmacologia
Plasmodium falciparum/efeitos dos fármacos
[Mh] Termos MeSH secundário: Plasmodium falciparum/crescimento & desenvolvimento
Esquizontes/efeitos dos fármacos
Esquizontes/crescimento & desenvolvimento
Trofozoítos/efeitos dos fármacos
Trofozoítos/crescimento & desenvolvimento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimalarials); 0 (Artemisinins); 886U3H6UFF (Chloroquine); 9RMU91N5K2 (artemisinine)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161210
[St] Status:MEDLINE
[do] DOI:10.4103/0255-0857.195365


  5 / 169 MEDLINE  
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[PMID]:27780272
[Au] Autor:Rovira-Graells N; Aguilera-Simón S; Tintó-Font E; Cortés A
[Ad] Endereço:ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Barcelona, Catalonia, Spain.
[Ti] Título:New Assays to Characterise Growth-Related Phenotypes of Plasmodium falciparum Reveal Variation in Density-Dependent Growth Inhibition between Parasite Lines.
[So] Source:PLoS One;11(10):e0165358, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The growth phenotype of asexual blood stage malaria parasites can influence their virulence and also their ability to survive and achieve transmission to the next host, but there are few methods available to characterise parasite growth parameters in detail. We developed a new assay to measure growth rates at different starting parasitaemias in a 96-well format and applied it to characterise the growth of Plasmodium falciparum lines 3D7-A and 3D7-B, previously shown to have different invasion rates and to use different invasion pathways. Using this simple and accurate assay we found that 3D7-B is more sensitive to high initial parasitaemia than 3D7-A. This result indicates that different parasite lines show variation in their levels of density-dependent growth inhibition. We also developed a new assay to compare the duration of the asexual blood cycle between different parasite lines. The assay is based on the tight synchronisation of cultures to a 1 h parasite age window and the subsequent monitoring of schizont bursting and formation of new rings by flow cytometry. Using this assay we observed differences in the duration of the asexual blood cycle between parasite lines 3D7 and HB3. These two new assays will be useful to characterise variation in growth-related parameters and to identify growth phenotypes associated with the targeted deletion of specific genes or with particular genomic, transcriptomic or proteomic patterns. Furthermore, the identification of density-dependent growth inhibition as an intrinsic parasite property that varies between parasite lines expands the repertoire of measurable growth-related phenotypic traits that have the potential to influence the outcome of a malarial blood infection.
[Mh] Termos MeSH primário: Parasitemia/parasitologia
Plasmodium falciparum/crescimento & desenvolvimento
[Mh] Termos MeSH secundário: Eritrócitos/parasitologia
Citometria de Fluxo
Genômica
Seres Humanos
Estágios do Ciclo de Vida
Malária Falciparum/diagnóstico
Malária Falciparum/parasitologia
Merozoítos/fisiologia
Análise em Microsséries
Parasitemia/diagnóstico
Fenótipo
Plasmodium falciparum/fisiologia
Proteômica
Esquizontes/crescimento & desenvolvimento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170614
[Lr] Data última revisão:
170614
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0165358


  6 / 169 MEDLINE  
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[PMID]:27425600
[Au] Autor:Engelbrecht D; Coetzer TL
[Ad] Endereço:Wits Research Institute for Malaria, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa. Electronic address: DewaldtEngelbrecht@gmail.com.
[Ti] Título:Plasmodium falciparum exhibits markers of regulated cell death at high population density in vitro.
[So] Source:Parasitol Int;65(6 Pt A):715-727, 2016 Dec.
[Is] ISSN:1873-0329
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The asexual erythrocytic cycle of the protozoan parasite Plasmodium falciparum is responsible for the pathogenesis of malaria and causes the overwhelming majority of malaria deaths. Rapidly increasing parasitaemia during this 48hour cycle threatens the survival of the human host and the parasite prior to transmission of the slow-maturing sexual stages to the mosquito host. The parasite may utilise regulated cell death (RCD) to control the burden of infection on the host and thus aid its own survival and transmission. The occurrence of RCD in P. falciparum remains a controversial topic. We provide strong evidence for the occurrence of an apoptosis-like phenotype of RCD in P. falciparum under conditions of high parasite density. P. falciparum was maintained in vitro and stressed by allowing growth to an unrestricted peak parasitaemia. Cell death markers, including morphological changes, DNA fragmentation, mitochondrial polarisation and phosphatidylserine externalisation were used to characterise parasite death at the time of peak parasitaemia and 24h later. At peak parasitaemia, mitochondrial depolarisation was observed, together with phosphatidylserine externalisation in both parasitised- and neighbouring non-infected erythrocytes. DNA fragmentation coincided with a decline in parasitaemia. Fewer merozoites were observed in mature schizonts at peak parasitaemia. Growth recovery to near-peak parasitaemia was noted within two intraerythrocytic cycles. The combination and chronological order of the biochemical markers of cell death suggest the occurrence of an apoptosis-like phenotype. The identification of a RCD pathway in P. falciparum may provide novel drug targets, particularly if the pathway differs from the host machinery.
[Mh] Termos MeSH primário: Morte Celular/fisiologia
Eritrócitos/parasitologia
Malária Falciparum/parasitologia
Parasitemia/patologia
Plasmodium falciparum/crescimento & desenvolvimento
[Mh] Termos MeSH secundário: Animais
Culicidae/parasitologia
Fragmentação do DNA
Seres Humanos
Merozoítos/metabolismo
Mitocôndrias/fisiologia
Fosfatidilserinas/metabolismo
Plasmodium falciparum/genética
Plasmodium falciparum/patogenicidade
Densidade Demográfica
Esquizontes/crescimento & desenvolvimento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Phosphatidylserines)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170327
[Lr] Data última revisão:
170327
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160719
[St] Status:MEDLINE


  7 / 169 MEDLINE  
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[PMID]:27348424
[Au] Autor:Morse D; Webster W; Kalanon M; Langsley G; McFadden GI
[Ad] Endereço:School of BioSciences, University of Melbourne, Melbourne, VIC, 3010, Australia.
[Ti] Título:Plasmodium falciparum Rab1A Localizes to Rhoptries in Schizonts.
[So] Source:PLoS One;11(6):e0158174, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Over-expression of a GFP-PfRab1A fusion protein in Plasmodium falciparum schizonts produces a punctate pattern of fluorescence typical of rhoptries, secretory organelles involved in host cell invasion. The GFP-positive bodies were purified by a combination of differential and density gradient centrifugation and their protein content determined by MS/MS sequencing. Consistent with the GFP rhoptry-like pattern of transgenic parasites, four of the 19 proteins identified have been previously described to be rhoptry-associated and another four are ER or ER-associated proteins. Confirmation that GFP-PfRab1A decorates rhoptries was obtained by its co-localization with Rap1 and Ron4 in late phase schizonts. We conclude that PfRab1A potentially regulates vesicular traffic from the endoplasmic reticulum to the rhoptries in Apicomplexa parasites.
[Mh] Termos MeSH primário: Plasmodium falciparum/metabolismo
Proteínas de Protozoários/metabolismo
Esquizontes/metabolismo
Proteínas rab1 de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Clonagem Molecular
Plasmodium falciparum/genética
Transporte Proteico
Proteômica/métodos
Proteínas de Protozoários/genética
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/metabolismo
Proteínas rab1 de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protozoan Proteins); 0 (Recombinant Fusion Proteins); EC 3.6.5.2 (rab1 GTP-Binding Proteins)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170724
[Lr] Data última revisão:
170724
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160628
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0158174


  8 / 169 MEDLINE  
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[PMID]:27078044
[Au] Autor:Cai C; Carey KA; Nedosekin DA; Menyaev YA; Sarimollaoglu M; Galanzha EI; Stumhofer JS; Zharov VP
[Ad] Endereço:Arkansas Nanomedicine Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205.
[Ti] Título:In vivo photoacoustic flow cytometry for early malaria diagnosis.
[So] Source:Cytometry A;89(6):531-42, 2016 Jun.
[Is] ISSN:1552-4930
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In vivo photoacoustic (PA) flow cytometry (PAFC) has already demonstrated a great potential for the diagnosis of deadly diseases through ultrasensitive detection of rare disease-associated circulating markers in whole blood volume. Here, we demonstrate the first application of this powerful technique for early diagnosis of malaria through label-free detection of malaria parasite-produced hemozoin in infected red blood cells (iRBCs) as high-contrast PA agent. The existing malaria tests using blood smears can detect the disease at 0.001-0.1% of parasitemia. On the contrary, linear PAFC showed a potential for noninvasive malaria diagnosis at an extremely low level of parasitemia of 0.0000001%, which is ∼10(3) times better than the existing tests. Multicolor time-of-flight PAFC with high-pulse repetition rate lasers at wavelengths of 532, 671, and 820 nm demonstrated rapid spectral and spatial identification and quantitative enumeration of individual iRBCs. Integration of PAFC with fluorescence flow cytometry (FFC) provided real-time simultaneous detection of single iRBCs and parasites expressing green fluorescence proteins, respectively. A combination of linear and nonlinear nanobubble-based multicolor PAFC showed capability to real-time control therapy efficiency by counting of iRBCs before, during, and after treatment. Our results suggest that high-sensitivity, high-resolution ultrafast PAFC-FFC platform represents a powerful research tool to provide the insight on malaria progression through dynamic study of parasite-cell interactions directly in bloodstream, whereas portable hand-worn PAFC device could be broadly used in humans for early malaria diagnosis. © 2016 International Society for Advancement of Cytometry.
[Mh] Termos MeSH primário: Eritrócitos/parasitologia
Citometria de Fluxo/métodos
Hemeproteínas/análise
Malária/diagnóstico
Parasitemia/diagnóstico
Técnicas Fotoacústicas/instrumentação
Plasmodium yoelii/crescimento & desenvolvimento
[Mh] Termos MeSH secundário: Animais
Computadores de Mão
Orelha/irrigação sanguínea
Orelha/parasitologia
Diagnóstico Precoce
Citometria de Fluxo/instrumentação
Genes Reporter
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Hemeproteínas/biossíntese
Hemeproteínas/química
Interações Hospedeiro-Parasita
Lasers
Malária/parasitologia
Camundongos
Camundongos Endogâmicos C57BL
Parasitemia/parasitologia
Técnicas Fotoacústicas/métodos
Plasmodium yoelii/patogenicidade
Esquizontes/química
Esquizontes/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hemeproteins); 147336-22-9 (Green Fluorescent Proteins); 39404-00-7 (hemozoin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160415
[St] Status:MEDLINE
[do] DOI:10.1002/cyto.a.22854


  9 / 169 MEDLINE  
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[PMID]:27060339
[Au] Autor:Tay CL; Jones ML; Hodson N; Theron M; Choudhary JS; Rayner JC
[Ad] Endereço:Malaria Programme, Wellcome Trust Sanger Institute, Cambridge, UK.
[Ti] Título:Study of Plasmodium falciparum DHHC palmitoyl transferases identifies a role for PfDHHC9 in gametocytogenesis.
[So] Source:Cell Microbiol;18(11):1596-1610, 2016 Nov.
[Is] ISSN:1462-5822
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Palmitoylation is the post-translational reversible addition of the acyl moiety, palmitate, to cysteine residues of proteins and is involved in regulating protein trafficking, localization, stability and function. The Aspartate-Histidine-Histidine-Cysteine (DHHC) protein family, named for their highly conserved DHHC signature motif, is thought to be responsible for catalysing protein palmitoylation. Palmitoylation is widespread in all eukaryotes, including the malaria parasite, Plasmodium falciparum, where over 400 palmitoylated proteins are present in the asexual intraerythrocytic schizont stage parasites, including proteins involved in key aspects of parasite maturation and development. The P. falciparum genome includes 12 proteins containing the conserved DHHC motif. In this study, we adapted a palmitoyl-transferase activity assay for use with P. falciparum proteins and demonstrated for the first time that P. falciparum DHHC proteins are responsible for the palmitoylation of P. falciparum substrates. This assay also reveals that multiple DHHCs are capable of palmitoylating the same substrate, indicating functional redundancy at least in vitro. To test whether functional redundancy also exists in vivo, we investigated the endogenous localization and essentiality of a subset of schizont-expressed PfDHHC proteins. Individual PfDHHC proteins localized to distinct organelles, including parasite-specific organelles such as the rhoptries and inner membrane complex. Knock-out studies identified individual DHHCs that may be essential for blood-stage growth and others that were functionally redundant in the blood stages but may have functions in other stages of parasite development. Supporting this hypothesis, disruption of PfDHHC9 had no effect on blood-stage growth but reduced the formation of gametocytes, suggesting that this protein could be exploited as a transmission-blocking target. The localization and stage-specific expression of the DHHC proteins may be important for regulating their substrate specificity and thus may provide a path for inhibitor development.
[Mh] Termos MeSH primário: Aciltransferases/fisiologia
Plasmodium falciparum/fisiologia
Proteínas de Protozoários/fisiologia
[Mh] Termos MeSH secundário: Aciltransferases/química
Sequência de Aminoácidos
Eritrócitos/parasitologia
Células HEK293
Seres Humanos
Lipoilação
Ácido Palmítico/metabolismo
Processamento de Proteína Pós-Traducional
Proteínas de Protozoários/química
Esquizontes/fisiologia
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protozoan Proteins); 2V16EO95H1 (Palmitic Acid); EC 2.3.- (Acyltransferases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170605
[Lr] Data última revisão:
170605
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160410
[St] Status:MEDLINE
[do] DOI:10.1111/cmi.12599


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[PMID]:27054067
[Au] Autor:Roberts BF; Iyamu ID; Lee S; Lee E; Ayong L; Kyle DE; Yuan Y; Manetsch R; Chakrabarti D
[Ad] Endereço:Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
[Ti] Título:Spirocyclic chromanes exhibit antiplasmodial activities and inhibit all intraerythrocytic life cycle stages.
[So] Source:Int J Parasitol Drugs Drug Resist;6(1):85-92, 2016 Apr.
[Is] ISSN:2211-3207
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:We screened a collection of synthetic compounds consisting of natural-product-like substructural motifs to identify a spirocyclic chromane as a novel antiplasmodial pharmacophore using an unbiased cell-based assay. The most active spirocyclic compound UCF 201 exhibits a 50% effective concentration (EC50) of 350 nM against the chloroquine-resistant Dd2 strain and a selectivity over 50 using human liver HepG2 cells. Our analyses of physicochemical properties of UCF 201 showed that it is in compliance with Lipinski's parameters and has an acceptable physicochemical profile. We have performed a limited structure-activity-relationship study with commercially available chromanes preserving the spirocyclic motif. Our evaluation of stage specificities of UCF 201 indicated that the compound is early-acting in blocking parasite development at ring, trophozoite and schizont stages of development as well as merozoite invasion. SPC is an attractive lead candidate scaffold because of its ability to act on all stages of parasite's aexual life cycle unlike current antimalarials.
[Mh] Termos MeSH primário: Antimaláricos/química
Antimaláricos/farmacologia
Benzofuranos/farmacologia
Eritrócitos/parasitologia
Malária/tratamento farmacológico
Plasmodium falciparum/efeitos dos fármacos
Compostos de Espiro/farmacologia
[Mh] Termos MeSH secundário: Animais
Antimaláricos/síntese química
Antimaláricos/isolamento & purificação
Benzofuranos/uso terapêutico
Avaliação Pré-Clínica de Medicamentos
Estágios do Ciclo de Vida/efeitos dos fármacos
Malária/parasitologia
Merozoítos/efeitos dos fármacos
Merozoítos/crescimento & desenvolvimento
Camundongos Endogâmicos BALB C
Plasmodium berghei
Plasmodium falciparum/crescimento & desenvolvimento
Esquizontes/efeitos dos fármacos
Esquizontes/crescimento & desenvolvimento
Compostos de Espiro/uso terapêutico
Relação Estrutura-Atividade
Trofozoítos/efeitos dos fármacos
Trofozoítos/crescimento & desenvolvimento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antimalarials); 0 (Benzofurans); 0 (Spiro Compounds); 0 (UCF 201)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160408
[St] Status:MEDLINE
[do] DOI:10.1016/j.ijpddr.2016.02.004



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