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1.
Eur J Med Chem ; 185: 111780, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31655429

RESUMO

Two new series of pyrrolizine-5-carboxamides were synthesized and evaluated for their anticancer and anti-inflammatory activities. The new compounds exhibited potent cytotoxicity (IC50 = 0.10-22.96 µM) against three cancer (MCF-7, A2780 and HT29) cell lines with selectivity index in the range of 1-258. Moreover, these compounds also exhibited significant anti-inflammatory activity (18.13-44.51% inhibition of inflammation) mediated by inhibition of COX-1/2 with preferential inhibition of COX-2. The study of SAR revealed favorable cytotoxic outcomes of the aliphatic side chain and 4-thiazolidinone moiety at C6 of the pyrrolizine nucleus, while anti-inflammatory activities was improved with the (hetero)aromatic substituents. The IC50 values which inhibit COX-2 were higher than those needed to inhibit the growth of cancer cell lines. Mechanistic studies also revealed inhibition of multiple kinases by compounds 12, 19 and 22. Moreover, compounds 12, 14, 16 and 22 induced cell cycle arrest and apoptosis in MCF-7 cells. Docking studies revealed nice fitting of the new compounds into COX-1/2. Additionally, compounds 12, 19 and 22 also exhibited higher affinity for CDK2 than CAN508. To sum up, the above-mentioned data highlight these compounds as promising anti-inflammatory and anticancer agents.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Desenho de Fármacos , Edema/tratamento farmacológico , Pirrolidinas/farmacologia , Tiazolidinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HT29 , Humanos , Células MCF-7 , Masculino , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Relação Estrutura-Atividade , Tiazolidinas/química
2.
Parasitol Res ; 119(2): 763-770, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31863181

RESUMO

Cystic echinococcosis is a disease that affects both humans and animals, caused by cryptic species complex belonging to the platyhelminth Echinococcus granulosus sensu lato (s.l.). This disease is distributed worldwide, with E. granulosus sensu stricto (s.s.) being the most widespread of the species. High genetic variability has been demonstrated within E. granulosus s.s. studying single cyst per infected animal identifying a number of different haplotypes. However, few studies have addressed the genetic diversity of this parasite within a single intermediate host with multiple Echinococcus cysts. To date, it remains unknown if specific haplotypes of E. granulosus s.s. produce differences in biological features of the cyst. Here, we use the full length of the mitochondrial gene cox1 to determine E. granulosus s.s. haplotypes in samples from both cattle and sheep which harboured more than one cyst in different areas in Chile, where this parasite is endemic. We found 16 different haplotypes in 66 echinococcal cysts from 10 animals, and both cattle and sheep can harbour up to five different haplotypes of E. granulosus s.s. in the same animal. Regarding cyst fertility, five animals had both fertile and infertile Echinococcus cysts in both single and multiple haplotype infections. There was no association between haplotype and cyst fertility, size, or adventitial layer characteristics. Sampling and sequencing every Echinococcus cyst found in the intermediate host reveals a high molecular variability. We speculate that multiple haplotype infections could also suggest that intermediate hosts come from hyperendemic areas.


Assuntos
Doenças dos Bovinos/parasitologia , Equinococose/veterinária , Echinococcus granulosus/classificação , Doenças dos Ovinos/parasitologia , Animais , Bovinos , Chile , Ciclo-Oxigenase 1/genética , Equinococose/parasitologia , Echinococcus granulosus/genética , Echinococcus granulosus/isolamento & purificação , Fertilidade , Genes Mitocondriais/genética , Variação Genética/genética , Genótipo , Haplótipos , Humanos , Ovinos/genética
3.
Int J Mol Sci ; 21(1)2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31878290

RESUMO

Platelets and platelet microparticles (PMPs) play a key role in the pathophysiology of vascular disorders such as coronary artery disease and stroke. In atherosclerosis, for example, the disruption of the plaque exposes endogenous agonists such as collagen, which activates platelets. Platelet hyper-activation and the high levels of PMPs generated in such situations pose a thrombotic risk that can lead to strokes or myocardial infarctions. Interestingly, dietary polyphenols are gaining much attention due to their potential to mimic the antiplatelet activity of treatment drugs such as aspirin and clopidogrel that target the glycoprotein VI (GPVI)-collagen and cyclooxygenease-1 (COX-1)-thromboxane platelet activation pathways respectively. Platelet function tests such as aggregometry and flow cytometry used to monitor the efficacy of antiplatelet drugs can also be used to assess the antiplatelet potential of dietary polyphenols. Despite the low bioavailability of polyphenols, several in vitro and dietary intervention studies have reported antiplatelet effects of polyphenols. This review presents a summary of platelet function in terms of aggregation, secretion, activation marker expression, and PMP release. Furthermore, the review will critically evaluate studies demonstrating the impact of polyphenols on aggregation and PMP release.


Assuntos
Plaquetas/metabolismo , Polifenóis/metabolismo , Aterosclerose/metabolismo , Ciclo-Oxigenase 1/metabolismo , Citometria de Fluxo , Humanos , Testes de Função Plaquetária
4.
J Helminthol ; 94: e110, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31843028

RESUMO

Human strongyloidiasis is a deleterious gastrointestinal disease mainly caused by Strongyloides stercoralis infection. We aimed to study the possible transmission of S. stercoralis between humans and pet animals. We isolated Strongyloides from humans and domestic dogs in the same rural community in north-east Thailand and compared the nucleotide sequences of derived worms using portions of the mitochondrial cytochrome c oxidase subunit 1 (cox1) and 18S ribosomal RNA (18S rRNA) genes. Twenty-eight sequences from the 18S rRNA gene were obtained from worms derived from humans (n = 23) and dogs (n = 5), and were identical with S. stercoralis sequences (from Thailand, Cambodia, Lao PDR and Myanmar) published in the GenBank database. The 28 cox1 sequences from humans and dogs showed high similarity to each other. The available published cox1 sequences (n = 150), in combination with our 28 sequences, represented 68 haplotypes distributed among four clusters. The 28 samples from the present study represented eight haplotypes including four new haplotypes. Dogs and humans shared the same haplotypes, suggesting the possibility of zoonotic transmission from pet dogs to humans. This is of concern since dogs and humans live in close association with each other.


Assuntos
Reservatórios de Doenças/veterinária , Doenças do Cão/parasitologia , Doenças do Cão/transmissão , Variação Genética , Estrongiloidíase/transmissão , Zoonoses/transmissão , Animais , Ciclo-Oxigenase 1/genética , DNA de Helmintos/genética , Reservatórios de Doenças/parasitologia , Cães/parasitologia , Características da Família , Fezes/parasitologia , Haplótipos , Humanos , Masculino , Animais de Estimação/parasitologia , Filogenia , RNA Ribossômico 18S/genética , População Rural , Strongyloides stercoralis/genética , Estrongiloidíase/epidemiologia , Estrongiloidíase/parasitologia , Tailândia/epidemiologia , Zoonoses/parasitologia
5.
BMC Neurol ; 19(1): 291, 2019 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-31735164

RESUMO

BACKGROUND: Mutations of cyclooxygenase gene (COX gene) may increase the susceptibility of ischemic stroke. We investigated five variants (rs5788, rs1330344, rs3842788, rs20417, and rs689466) of two COX genes in order to explaining the association between these polymorphisms and we also investigated the association between these variants and ischemic stroke risk to determine whether gene-gene interaction between these genes increases the susceptibility of ischemic stroke or its subtypes. METHODS: A total of 1981 study subjects (1078 cases and 903 control subjects) were recruited. The interaction of multiple factors was investigated using Multifactor Dimensionality Reduction. The additive effect of single nucleotide polymorphisms on ischemic stroke or its subtypes were analyzed by multiple factor logistic regression. RESULTS: At COX-1(rs1330344), AA genotype carriers had a lower susceptibility of ischemic stroke (OR = 0.657, 95%CI = 0.437-0.988, P = 0.044), and A allele carriers had a lower susceptibility of ischemic stroke (OR = 0.812, 95%CI = 0.657-0.978, P = 0.029). At COX-1(rs3842788), AA genotype carriers had a higher susceptibility of ischemic stroke (OR = 5.203, 95% CI = 1.519-5.159, P = 0.016). At COX-2 (rs689466), AA genotype carriers had a higher susceptibility of large-artery atherosclerosis (OR = 1.404, 95% CI = 1.019-1.934, P = 0.038). COX-1(rs1330344, rs3842788) and COX-2 rs689466 interacted in SVO, but had no additive effect with ischemic stroke and other subtypes. CONCLUSIONS: At rs1330344, AA genotype may reduce the susceptibility of ischemic stroke. At rs3842788, AA genotype may increase the susceptibility of ischemic stroke. At rs689466, AA genotype may increase the susceptibility of large-artery atherosclerosis (LAA). COX - 1(rs1330344, rs3842788) and COX-2 rs689466 interacted in small vessel occlusion (SVO), but had no additive effect with ischemic stroke and other subtypes.


Assuntos
Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Predisposição Genética para Doença/genética , Acidente Vascular Cerebral/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Aterosclerose/enzimologia , Aterosclerose/genética , Isquemia Encefálica/enzimologia , Isquemia Encefálica/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/enzimologia
6.
Life Sci ; 239: 117039, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31704447

RESUMO

AIMS: Obesity is a risk factor for endothelial dysfunction, the severity of which is likely to vary depending on extent and impact of adiposity on the vasculature. This study investigates the roles of cyclooxygenase isoforms and thromboxane receptor activities in the differential endothelial dilatory capacities of arteries derived from omental and subcutaneous adipose tissues in obesity. MAIN METHODS: Small arteries were isolated from omental and subcutaneous adipose tissues obtained from consented morbidly obese patients (n = 65, BMI 45 ±â€¯6 kg m-2 [Mean ±â€¯SD]) undergoing bariatric surgery. Relaxation to acetylcholine was studied by wire myography in the absence or presence of indomethacin (10 µM, cyclooxygenase inhibitor), FR122047 (1 µM, cyclooxygenase-1 inhibitor), Celecoxib (4 µM, cyclooxygenase-2 inhibitor), Nω-Nitro-L-arginine methyl ester (L-NAME, 100 µM, nitric oxide synthase inhibitor) or combination of apamin (0.5 µM) and charybdotoxin (0.1 µM) that together inhibit endothelium-derived hyperpolarizing factor (EDHF). Contractions to U46619 (thromboxane A2 mimetic) were also studied. KEY FINDINGS: Acetylcholine relaxation was significantly attenuated in omental compared with subcutaneous arteries from same patients (p < 0.01). Indomethacin (p < 0.01) and FR122047 (p < 0.001) but not Celecoxib significantly improved the omental arteriolar relaxation. Cyclooxygenase-1 mRNA and U46619 contractions were both increased in omental compared with subcutaneous arteries (p < 0.05). L-NAME comparably inhibited acetylcholine relaxation in both arteries, while apamin+charybdotoxin were less effective in omental compared with subcutaneous arteries. SIGNIFICANCE: The results show that the depot-specific reduction in endothelial dilatory capacity of omental compared with subcutaneous arteries in obesity is in large part due to altered cyclooxygenase-1 and enhanced thromboxane receptor activities, which cause EDHF deficiency.


Assuntos
Ciclo-Oxigenase 1/metabolismo , Artéria Gastroepiploica/efeitos dos fármacos , Receptores de Tromboxanos/metabolismo , Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/metabolismo , Adulto , Apamina/farmacologia , Artérias/efeitos dos fármacos , Celecoxib/farmacologia , Charibdotoxina/farmacologia , Ciclo-Oxigenase 1/fisiologia , Inibidores de Ciclo-Oxigenase/farmacologia , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Endotélio Vascular/efeitos dos fármacos , Feminino , Artéria Gastroepiploica/metabolismo , Humanos , Indometacina/farmacologia , Masculino , Pessoa de Meia-Idade , Relaxamento Muscular/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Obesidade Mórbida/metabolismo , Omento/irrigação sanguínea , Omento/metabolismo , Receptores de Tromboxanos/fisiologia , Vasodilatação/efeitos dos fármacos
7.
Zootaxa ; 4623(2): zootaxa.4623.2.8, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31716265

RESUMO

The Moluccan net-winged beetle fauna remains poorly studied and here, new species of Schizotrichalus Kleine, 1926 and Eniclases Waterhouse, 1879 are reported from Halmahera. Using morphological traits and cox1 mitochondrial DNA sequences, we propose two new species, Eniclases kusyi sp. nov. and Schizotrichalus halmaherensis sp. nov., and redescribe E. moluccanus Kleine, 1930. New molecular data confirm morphology-based sister relationships between Schizotrichalus and Eniclases and the analysis identifies the combined area of the present-day Halmahera and New Guinea as an ancestral area of these genera. Now, Halmahera and New Guinea are quite similar in respect of the number of trichaline genera. Concerning the size of islands and the recent origin of the nowadays northern Moluccas, these results are unexpected and thus the general validity of this distribution pattern should be confirmed with other groups of beetles.


Assuntos
Besouros , Animais , Ciclo-Oxigenase 1 , DNA Mitocondrial , Nova Guiné , Filogenia
8.
Parasit Vectors ; 12(1): 489, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623642

RESUMO

BACKGROUND: Ticks and tick-borne diseases are a major impediment to livestock production worldwide. Cattle trade and transnational transhumance create risks for the spread of ticks and tick-borne diseases and threaten cattle production in the absence of an effective tick control program. Few studies have been undertaken on cattle ticks in the Central African region; therefore, the need to assess the occurrence and the spatial distribution of tick vectors with the aim of establishing a baseline for monitoring future spread of tick borne-diseases in the region is urgent. RESULTS: A total of 7091 ixodid ticks were collected during a countrywide cross-sectional field survey and identified using morphological criteria. Of these, 4210 (59.4%) ticks were Amblyomma variegatum, 1112 (15.6%) Rhipicephalus (Boophilus) microplus, 708 (10.0%) Rhipicephalus (Boophilus) decoloratus, 28 (0.4%) Rhipicephalus (Boophilus) annulatus, 210 (3.0%) Hyalomma rufipes, 768 (10.8%) Hyalomma truncatum, and 19 (0.3%) Rhipicephalus sanguineus. Three ticks of the genus Hyalomma spp. and 33 of the genus Rhipicephalus spp. were not identified to the species level. Cytochrome c oxidase subunit 1 (cox1) gene sequencing supported the data from morphological examination and led to identification of three additional species, namely Hyalomma dromedarii, Rhipicephalus sulcatus and Rhipicephalus pusillus. The finding of the invasive tick species R. microplus in such large numbers and the apparent displacement of the indigenous R. decoloratus is highly significant since R. microplus is a highly efficient vector of Babesia bovis. CONCLUSIONS: This study reports the occurrence and current geographical distribution of important tick vectors associated with cattle in Cameroon. It appears that R. microplus is now well established and may be displacing native Rhipicephalus (Boophilus) species, such as R. decoloratus. This calls for an urgent response to safeguard the livestock sector in western central Africa.


Assuntos
Doenças dos Bovinos/epidemiologia , Doenças dos Bovinos/parasitologia , Infestações por Carrapato/veterinária , Carrapatos/fisiologia , Agricultura , Animais , Camarões/epidemiologia , Bovinos , Sequência Consenso , Estudos Transversais , Ciclo-Oxigenase 1/genética , Demografia , Feminino , Masculino , Filogenia , Prevalência , Alinhamento de Sequência/veterinária , Razão de Masculinidade , Infestações por Carrapato/epidemiologia , Infestações por Carrapato/parasitologia , Doenças Transmitidas por Carrapatos/epidemiologia , Doenças Transmitidas por Carrapatos/veterinária , Carrapatos/classificação , Carrapatos/crescimento & desenvolvimento
9.
Parasit Vectors ; 12(1): 496, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640777

RESUMO

Strongyloidiasis is a soil-borne helminthiasis, which, in spite of the up to 370 million people currently estimated to be infected with its causing agent, the nematode Strongyloides stercoralis, is frequently overlooked. Recent molecular taxonomic studies conducted in Southeast Asia and Australia, showed that dogs can carry the same genotypes of S. stercoralis that also infect humans, in addition to a presumably dog-specific Strongyloides species. This suggests a potential for zoonotic transmission of S. stercoralis from dogs to humans. Although natural S. stercoralis infections have not been reported in any host other than humans, non-human primates and dogs, other as yet unidentified animal reservoirs cannot be excluded. Molecular studies also showed that humans carry rather different genotypes of S. stercoralis. As a result, their taxonomic status and the question of whether they differ in their pathogenic potential remains open. It would therefore be very important to obtain molecular genetic/genomic information about S. stercoralis populations from around the world. One way of achieving this (with little additional sampling effort) would be that people encountering S. stercoralis in the process of their diagnostic work preserve some specimens for molecular analysis. Here we provide a guideline for the isolation, preservation, genotyping at the nuclear 18S rDNA and the mitochondrial cox1 loci, and for whole genome sequencing of single S. stercoralis worms. Since in many cases the full analysis is not possible or desired at the place and time where S. stercoralis are found, we emphasize when and how samples can be preserved, stored and shipped for later analysis. We hope this will benefit and encourage researchers conducting field studies or diagnostics to collect and preserve S. stercoralis for molecular genetic/genomic analyses and either analyze them themselves or make them available to others for further analysis.


Assuntos
Genoma , Preservação Biológica/métodos , Strongyloides stercoralis/genética , Strongyloides stercoralis/isolamento & purificação , Estrongiloidíase/parasitologia , Animais , Ciclo-Oxigenase 1/genética , DNA de Helmintos/química , DNA de Helmintos/isolamento & purificação , Doenças do Cão/parasitologia , Doenças do Cão/transmissão , Cães , Fezes/parasitologia , Feminino , Técnicas de Genotipagem , Humanos , Larva/fisiologia , Masculino , Microesferas , Reação em Cadeia da Polimerase , RNA Ribossômico 18S/genética , Solo/parasitologia , Strongyloides stercoralis/anatomia & histologia , Strongyloides stercoralis/fisiologia , Estrongiloidíase/transmissão , Fatores de Tempo , Sequenciamento Completo do Genoma
10.
Parasit Vectors ; 12(1): 492, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31639027

RESUMO

BACKGROUND: Water mites are among the most diverse organisms inhabiting freshwater habitats and are considered as substantial part of the species communities in springs. As parasites, Hydrachnidia influence other invertebrates and play an important role in aquatic ecosystems. In Europe, 137 species are known to appear solely in or near springheads. New species are described frequently, especially with the help of molecular species identification and delimitation methods. The aim of this study was to verify the mainly morphology-based taxonomic knowledge of spring-inhabiting water mites of central Europe and to build a genetic species identification library. METHODS: We sampled 65 crenobiontic species across the central Alps and tested the suitability of mitochondrial (cox1) and nuclear (28S) markers for species delimitation and identification purposes. To investigate both markers, distance- and phylogeny-based approaches were applied. The presence of a barcoding gap was tested by using the automated barcoding gap discovery tool and intra- and interspecific genetic distances were investigated. Furthermore, we analyzed phylogenetic relationships between different taxonomic levels. RESULTS: A high degree of hidden diversity was observed. Seven taxa, morphologically identified as Bandakia concreta Thor, 1913, Hygrobates norvegicus (Thor, 1897), Ljania bipapillata Thor, 1898, Partnunia steinmanni Walter, 1906, Wandesia racovitzai Gledhill, 1970, Wandesia thori Schechtel, 1912 and Zschokkea oblonga Koenike, 1892, showed high intraspecific cox1 distances and each consisted of more than one phylogenetic clade. A clear intraspecific threshold between 5.6-6.0% K2P distance is suitable for species identification purposes. The monophyly of Hydrachnidia and the main superfamilies is evident with different species clearly separated into distinct clades. cox1 separates water mite species but is unsuitable for resolving higher taxonomic levels. CONCLUSIONS: Water mite species richness in springs is higher than has been suggested based on morphological species identification alone and further research is needed to evaluate the true diversity. The standard molecular species identification marker cox1 can be used to identify species but should be complemented by a nuclear marker, e.g. 28S, to resolve taxonomic relationships. Our results contribute to the taxonomical knowledge on spring inhabiting Hydrachnida, which is indispensable for the development and implementation of modern environment assessment methods, e.g. metabarcoding, in spring ecology.


Assuntos
Biodiversidade , Ácaros/classificação , Nascentes Naturais/parasitologia , Animais , Áustria , Teorema de Bayes , Ciclo-Oxigenase 1/genética , DNA/química , DNA/isolamento & purificação , Água Doce/parasitologia , Alemanha , Funções Verossimilhança , Ácaros/anatomia & histologia , Ácaros/genética , Filogenia , Reação em Cadeia da Polimerase , RNA Ribossômico 28S/genética , Alinhamento de Sequência , Suíça
11.
Korean J Parasitol ; 57(4): 423-427, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31533410

RESUMO

Coenurosis is an important zoonotic helminthic disease caused by the larval stage of the tapeworm Taenia multiceps. This parasite typically infects the brain of the intermediate hosts, including sheep, goat, cattle and even humans. We report a case of T. multiceps infection in a yak confirmed by clinical symptoms, morphological characteristics, and molecular and phylogenetic analyses. The coenurus was thin-walled, whitish, and spherical in shape with a diameter of 10 cm. The parasite species was identified as T. multiceps by PCR amplification and sequencing of the 18S rRNA, cox1 and nad1 genes. Three gene sequences all showed high homology (all above 97%) with the reference sequences from different hosts. Moreover, phylogenetic reconstructions with the 3 published Taenia gene sequences confirmed that the Qinghai yak isolate was closely related to T. multiceps. Although there are advanced diagnosis and treatment methods for coenurosis, early infection is difficult to diagnose. Importantly, the findings of yak infection case should not be ignored due to its zoonotic potential.


Assuntos
Doenças dos Bovinos/parasitologia , Neurocisticercose/veterinária , Taenia/genética , Animais , Bovinos , Ciclo-Oxigenase 1/genética , Eletroforese em Gel de Ágar/veterinária , Masculino , NAD/genética , Neurocisticercose/parasitologia , Filogenia , Reação em Cadeia da Polimerase/veterinária , RNA Ribossômico 18S/genética , Alinhamento de Sequência/veterinária , Análise de Sequência de DNA/veterinária , Taenia/classificação , Taenia/isolamento & purificação , Tibet
12.
Int J Mol Sci ; 20(18)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487817

RESUMO

Cyclooxygenases (COXs), including COX-1 and -2, are enzymes essential for lipid mediator (LMs) syntheses from arachidonic acid (AA), such as prostaglandins (PGs). Furthermore, COXs could interplay with other enzymes such as lipoxygenases (LOXs) and cytochrome P450s (CYPs) to regulate the signaling of LMs. In this study, to comprehensively analyze the function of COX-1 and -2 in regulating the signaling of bioactive LMs in skeletal muscle, mouse primary myoblasts and C2C12 cells were transfected with specific COX-1 and -2 siRNAs, followed by targeted lipidomic analysis and customized quantitative PCR gene array analysis. Knocking down COXs, particularly COX-1, significantly reduced the release of PGs from muscle cells, especially PGE2 and PGF2α, as well as oleoylethanolamide (OEA) and arachidonoylethanolamine (AEA). Moreover, COXs could interplay with LOXs to regulate the signaling of hydroxyeicosatetraenoic acids (HETEs). The changes in LMs are associated with the expression of genes, such as Itrp1 (calcium signaling) and Myh7 (myogenic differentiation), in skeletal muscle. In conclusion, both COX-1 and -2 contribute to LMs production during myogenesis in vitro, and COXs could interact with LOXs during this process. These interactions and the fine-tuning of the levels of these LMs are most likely important for skeletal muscle myogenesis, and potentially, muscle repair and regeneration.


Assuntos
Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Desenvolvimento Muscular , Mioblastos Esqueléticos/metabolismo , Transdução de Sinais , Animais , Linhagem Celular , Células Cultivadas , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Lipoxigenase/genética , Lipoxigenase/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mioblastos Esqueléticos/citologia , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo
13.
PLoS Negl Trop Dis ; 13(9): e0007609, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31525192

RESUMO

Strongyloidiasis is a neglected tropical disease caused by the human infective nematodes Strongyloides stercoralis, Strongyloides fuelleborni fuelleborni and Strongyloides fuelleborni kellyi. Previous large-scale studies exploring the genetic diversity of this important genus have focused on Southeast Asia, with a small number of isolates from the USA, Switzerland, Australia and several African countries having been genotyped. Consequently, little is known about the global distribution of geographic sub-variants of these nematodes and the genetic diversity that exists within the genus Strongyloides generally. We extracted DNA from human, dog and primate feces containing Strongyloides, collected from several countries representing all inhabited continents. Using a genotyping assay adapted for deep amplicon sequencing on the Illumina MiSeq platform, we sequenced the hyper-variable I and hyper-variable IV regions of the Strongyloides 18S rRNA gene and a fragment of the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene from these specimens. We report several novel findings including unique S. stercoralis and S. fuelleborni genotypes, and the first identifications of a previously unknown S. fuelleborni infecting humans within Australia. We expand on an existing Strongyloides genotyping scheme to accommodate S. fuelleborni and these novel genotypes. In doing so, we compare our data to all 18S and cox1 sequences of S. fuelleborni and S. stercoralis available in GenBank (to our knowledge), that overlap with the sequences generated using our approach. As this analysis represents more than 1,000 sequences collected from diverse hosts and locations, representing all inhabited continents, it allows a truly global understanding of the population genetic structure of the Strongyloides species infecting humans, non-human primates, and domestic dogs.


Assuntos
Variação Genética , Strongyloides/genética , Estrongiloidíase/genética , Animais , Ciclo-Oxigenase 1/genética , Cães , Fezes/parasitologia , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças Negligenciadas , Primatas , RNA Ribossômico 18S/genética , Análise de Sequência de DNA , Strongyloides/classificação , Strongyloides stercoralis/genética , Estrongiloidíase/epidemiologia , Estrongiloidíase/veterinária
14.
Life Sci ; 236: 116865, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31525428

RESUMO

AIMS: Endothelial dysfunction is one of the earliest symptoms in septic patients and plays an important role in the cardiovascular alterations. However, the endothelial mechanisms involved in the impaired sympathetic regulation of the cardiovascular system are not clear. This study aimed to determine the role of the endocardial endothelium (EE) in the cardiac ß-adrenergic (ß-AR) remodeling at the early phase of endotoxemic shock. MAIN METHODS: Rats received either lipopolysaccharide (LPS) or saline (control) intravenously. Three hours later, ß-AR cardiac contractility was evaluated on papillary muscles with or without a functional EE. KEY FINDINGS: Isoproterenol-induced contractility was strongly increased in papillary muscles from LPS rats. A similar increase was observed with a ß1-AR stimulation, whereas ß2-AR and ß3-AR produced similar contractility in control and LPS treatments. The removal of the EE did not modify ß1-AR-induced contractility in controls, whereas it abolished the increased ß1-AR response in LPS-treated muscles. In LPS-treated papillary muscle, the increased ß1-AR-induced contractility was not modified by pretreatment with a NOS inhibitor or an endothelin receptor antagonist. Conversely, the increased ß1-AR-induced contractility was abolished by indomethacin, a non-selective cyclooxygenase (COX) inhibitor, as well as by selective inhibitors of COX1 and COX2. An early treatment with indomethacin improved the survival of LPS rat. SIGNIFICANCE: Our results suggest that the EE is involved in the increased cardiac ß1-AR contractility in the early phase of endotoxemic shock. This effect is mediated through the activation of COX1 and COX2 and suggests these may be novel putative therapeutic targets during endotoxemic shock.


Assuntos
Ciclo-Oxigenase 1/metabolismo , Endotélio Vascular/fisiopatologia , Endotoxemia/fisiopatologia , Proteínas de Membrana/metabolismo , Contração Miocárdica , Músculos Papilares/fisiopatologia , Receptores Adrenérgicos beta 1/metabolismo , Animais , Modelos Animais de Doenças , Endotoxemia/induzido quimicamente , Lipopolissacarídeos/toxicidade , Masculino , Ratos , Ratos Sprague-Dawley
15.
Parasit Vectors ; 12(1): 392, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391113

RESUMO

BACKGROUND: Cystic echinococcosis (CE) is a zoonosis caused by cestodes of Echinococcus granulosus (sensu lato) complex. In Nigeria, reports on the prevalence of CE, although limited, have been found to vary with location and host with higher prevalence and fertility rate observed in camels than other livestock. Until now, information regarding the molecular characteristics, genetic population structure, and genotypes of Echinococcus is lacking. Therefore, this study was aimed at addressing these gaps in knowledge. METHODS: We describe the genetic status of 31 Echinococcus isolates collected from slaughtered livestock (camels, cattle and goats) based on the full-length mitochondrial cytochrome c oxidase subunit 1 (cox1) and NADH dehydrogenase subunit 1 (nad1) genes. RESULTS: The resulting nucleotide sequences via the NCBI BLAST algorithm and Bayesian phylogeny of cox1 and cox1-nad1 genes using MrBayes v.3.1.2 showed that all isolates were clearly E. canadensis (G6/G7) and were 99-100% identical to previously reported G6/G7 haplotypes across Europe, Asia, North and East Africa. CONCLUSIONS: Although, the G1 genotype is believed to be responsible for the majority of global CE burden, reports from a number of West African countries including Nigeria suggest that E. canadensis G6/G7 genotype could be the major causative agent of CE in the subregion. This study provides for the first time insight into the genetic population structure of Echinococcus species as well as implications for CE control in Nigeria.


Assuntos
Equinococose/veterinária , Echinococcus granulosus/genética , Filogenia , Matadouros , Animais , Ciclo-Oxigenase 1/genética , Equinococose/epidemiologia , Variação Genética , Genética Populacional , Genótipo , Haplótipos , Gado/parasitologia , NADH Desidrogenase/genética , Nigéria/epidemiologia
16.
Eur J Pharmacol ; 861: 172609, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421091

RESUMO

Paracetamol (acetaminophen), is a centrally-acting antipyretic analgesic drug, which can also lower body temperature. Despite a century of clinical use, its mechanism of pharmacological action has not been completely elucidated. Previously, we demonstrated significant attenuation in the paracetamol induced hypothermia in parallel with its inhibitory action on the synthesis of brain prostaglandin E2 (PGE2) in cyclooxygenase-1 (COX-1) knockout mice in comparison to wild-type mice. The above reported pharmacological actions by paracetamol were completely retained in COX-2 knockout mice. We thus concluded that the mechanism of hypothermic action of paracetamol is dependent on inhibition of a COX-1 gene-derived enzyme. In the current investigation, we provide further support for this notion by demonstrating that the paracetamol-induced hypothermia is not mediated through inhibition of COX-1 as neither the COX-1 selective inhibitor, SC560, nor the COX-1/COX-2 dual inhibitor, indomethacin, induced hypothermia at pharmacologically active doses in mice. In addition, using a COX-2-dependent and PGE2-mediated model of endotoxin-induced fever, paracetamol induced anti-pyretic and hypothermic actions in COX-1 wild-type mice. These effects were fully or partially attenuated in COX-1 knockout mice after prophylactic or therapeutic administration, respectively. Therapeutically-administered paracetamol also reduced hypothalamic PGE2 biosynthesis in febrile COX-1 wild-type mice, but not in febrile COX-1 knockout mice. In conclusion, we provide further evidence which suggests that the hypothermic and now anti-pyretic actions of paracetamol are mediated through inhibition of a COX-1 variant enzyme.


Assuntos
Acetaminofen/farmacologia , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Febre/tratamento farmacológico , Técnicas de Inativação de Genes , Hipotermia Induzida , Mutação , Acetaminofen/uso terapêutico , Animais , Ciclo-Oxigenase 1/deficiência , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Ciclo-Oxigenase/uso terapêutico , Dinoprostona/metabolismo , Febre/enzimologia , Febre/genética , Febre/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
17.
Syst Parasitol ; 96(7): 575-584, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31364030

RESUMO

Branchellion spindolaorum n. sp. (Hirudinida: Piscicolidae) is described based on specimens found parasitising the giant electric ray Narcine entemedor Jordan & Starks off the coast of Oaxaca, Mexico. The new species can be clearly distinguished from the other species of Branchellion Savigny, 1822 by the presence of 30 pairs of lateral branchiae and 10 pairs of pulsatile vesicles. The definition of the genus Branchellion is expanded to include species with either 30, 31 or 33 pairs of foliaceous (plate-like) lateral branchiae in the urosome. In addition, we provide for the first time for the genus, scanning electron micrographs of the secondary suckers located on the ventral surface of the posterior sucker. Additionally, partial DNA sequences of the mitochondrial cytochrome c oxidase subunit 1 (cox1) were generated and compared with homologous sequences of other species of the genus. Branchellion spindolaorum n. sp. represents the fourth species of the genus known in the Eastern Pacific and the first record of a leech parasitising N. entemedor.


Assuntos
Elasmobrânquios/parasitologia , Sanguessugas/classificação , Sanguessugas/fisiologia , Animais , Ciclo-Oxigenase 1/genética , Sanguessugas/genética , Sanguessugas/ultraestrutura , México , Especificidade da Espécie
18.
PLoS Negl Trop Dis ; 13(8): e0007241, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31430282

RESUMO

Strongyloidiasis is caused by the human infective nematodes Strongyloides stercoralis, Strongyloides fuelleborni subsp. fuelleborni and Strongyloides fuelleborni subsp. kellyi. The zoonotic potential of S. stercoralis and the potential role of dogs in the maintenance of strongyloidiasis transmission has been a topic of interest and discussion for many years. In Australia, strongyloidiasis is prevalent in remote socioeconomically disadvantaged communities in the north of the continent. Being an isolated continent that has been separated from other regions for a long geological period, description of diversity of Australian Strongyloides genotypes adds to our understanding of the genetic diversity within the genus. Using PCR and amplicon sequencing (Illumina sequencing technology), we sequenced the Strongyloides SSU rDNA hyper-variable I and hyper-variable IV regions using Strongyloides-specific primers, and a fragment of the mtDNA cox1 gene using primers that are broadly specific for Strongyloides sp. and hookworms. These loci were amplified from DNA extracted from Australian human and dog faeces, and one human sputum sample. Using this approach, we confirm for the first time that potentially zoonotic S. stercoralis populations are present in Australia, suggesting that dogs represent a potential reservoir of human strongyloidiasis in remote Australian communities.


Assuntos
Genótipo , Strongyloides/genética , Strongyloides/isolamento & purificação , Estrongiloidíase/fisiopatologia , Estrongiloidíase/veterinária , Ancylostomatoidea , Animais , Austrália/epidemiologia , Ciclo-Oxigenase 1 , DNA Mitocondrial/genética , DNA Ribossômico/genética , Doenças do Cão/epidemiologia , Doenças do Cão/parasitologia , Cães , Fezes/parasitologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Strongyloides/classificação , Estrongiloidíase/epidemiologia , Estrongiloidíase/transmissão , Inquéritos e Questionários
19.
Parasit Vectors ; 12(1): 410, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439012

RESUMO

BACKGROUND: Currently, knowledge regarding the phlebotomine sand fly (Diptera: Psychodidae) fauna of Turkey is restricted to regions with endemic leishmaniasis. However, rapidly changing environmental and social conditions highlight concerns on the possible future expansion of sand fly-borne diseases in Turkey, promoting risk assessment through biosurveillance activities in non-endemic regions. Traditional morphological approaches are complicated by extensive cryptic speciation in sand flies, thus integrated studies utilizing DNA markers are becoming increasingly important for correct sand fly identification. This study contributes to the knowledge of the sand fly fauna in understudied regions of Turkey, and provides an extensive DNA barcode reference library of expertly identified Turkish sand fly species for the first time. METHODS: Fly sampling was conducted at 101 locations from 29 provinces, covering all three biogeographical regions of Turkey. Specimens were morphologically identified using available keys. Cytochrome c oxidase I (cox1) barcode sequences were analyzed both for morphologically distinct species and those specimens with cryptic identity. A taxon identity tree was obtained using Neighbor Joining (NJ) analysis. Species boundaries among closely related taxa evaluated using ABGD, Maximum Likelihood (ML) and haplotype network analyses. Sand fly richness of all three biogeographical regions were compared using nonparametric species richness estimators. RESULTS: A total of 729 barcode sequences (including representatives of all previously reported subgenera) were obtained from a total of 9642 sand fly specimens collected in Turkey. Specimens belonging to the same species or species complex clustered together in the NJ tree, regardless of their geographical origin. The species delimitation methods revealed the existence of 33 MOTUs, increasing the previously reported 28 recorded sand fly species by 17.8%. The richest sand fly diversity was determined in Anatolia, followed by the Mediterranean, and then the Black Sea regions of the country. CONCLUSIONS: A comprehensive cox1 reference library is provided for the sand fly species of Turkey, including the proposed novel taxa discovered herein. Our results have epidemiological significance exposing extensive distributions of proven and suspected sand fly vectors in Turkey, including those areas currently regarded as non-endemic for sand fly-borne disease.


Assuntos
Código de Barras de DNA Taxonômico , Proteínas de Insetos/genética , Insetos Vetores/classificação , Phlebotomus/classificação , Animais , Ciclo-Oxigenase 1/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Feminino , Geografia , Insetos Vetores/genética , Masculino , Phlebotomus/genética , Turquia
20.
J Helminthol ; 94: e79, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31462333

RESUMO

Intraspecific diversity in parasites with heteroxenous life cycles is guided by reproduction mode, host vagility and dispersal, transmission features and many other factors. Studies of these factors in Digenea have highlighted several important patterns. However, little is known about intraspecific variation for digeneans in the marine Arctic ecosystems. Here we analyse an extended dataset of partial cox1 and nadh1 sequences for Tristriata anatis (Notocotylidae) and confirm the preliminary findings on its distribution across Eurasia. Haplotypes are not shared between Europe and the North Pacific, suggesting a lack of current connection between these populations. Periwinkle distribution and anatid migration routes are consistent with such a structure of haplotype network. The North Pacific population appears ancestral, with later expansion of T. anatis to the North Atlantic. Here the parasite circulates widely, but the direction of haplotype transfer from the north-east to the south-west is more likely than the opposite. In the eastern Barents Sea, the local transmission hotspot is favoured.


Assuntos
Variação Genética , Genética Populacional , Haplótipos , Trematódeos/genética , Animais , Regiões Árticas , Ciclo-Oxigenase 1/genética , DNA Mitocondrial , Europa (Continente) , Estágios do Ciclo de Vida , NAD/genética , Filogenia , Filogeografia , Análise de Sequência de DNA
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