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1.
Mar Drugs ; 14(4)2016 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-27070627

RESUMO

Toxins that are secreted by cone snails are small peptides that are used to treat several diseases. However, their effects on parasites with human and veterinary significance are unknown. Toxoplasma gondii is an opportunistic parasite that affects approximately 30% of the world's population and can be lethal in immunologically compromised individuals. The conventional treatment for this parasitic infection has remained the same since the 1950s, and its efficacy is limited to the acute phase of infection. These findings have necessitated the search for new drugs that specifically target T. gondii. We examined the effects of the synthetic toxin cal14.1a (s-cal14.1a) from C. californicus on the tachyzoite form of T. gondii. Our results indicate that, at micromolar concentrations, s-cal14.1a lowers viability and inhibits host cell invasion (by 50% and 61%, respectively) on exposure to extracellular parasites. Further, intracellular replication decreased significantly while viability of the host cell was unaffected. Our study is the first report on the antiparasitic activity of a synthetic toxin of C. californicus.


Assuntos
Antiparasitários/farmacologia , Conotoxinas/farmacologia , Caramujo Conus/metabolismo , Parasitos/efeitos dos fármacos , Toxoplasma/efeitos dos fármacos , Animais , Antiparasitários/metabolismo , Linhagem Celular Tumoral , Conotoxinas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C
2.
Parasit Vectors ; 17(1): 142, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38500196

RESUMO

BACKGROUND: The protozoan parasite Toxoplasma gondii encodes dozens of phosphatases, among which a plant-like phosphatase absent from mammalian genomes named PPKL, which is involved in regulating brassinosteroid signaling in Arabidopsis, was identified in the genome. Among the Apicomplexa parasites, T. gondii is an important and representative pathogen in humans and animals. PPKL was previously identified to modulate the apical integrity and morphology of the ookinetes and parasite motility and transmission in another important parasite, Plasmodium falciparum. However, the exact function of PPKL in the asexual stages of T. gondii remains unknown. METHODS: The plant auxin-inducible degron (AID) system was applied to dissect the phenotypes of PPKL in T. gondii. We first analyzed the phenotypes of the AID parasites at an induction time of 24 h, by staining of different organelles using their corresponding markers. These analyses were further conducted for the parasites grown in auxin for 6 and 12 h using a quantitative approach and for the type II strain ME49 of AID parasites. To further understand the phenotypes, the potential protein interactions were analyzed using a proximity biotin labeling approach. The essential role of PPKL in parasite replication was revealed. RESULTS: PPKL is localized in the apical region and nucleus and partially distributed in the cytoplasm of the parasite. The phenotyping of PPKL showed its essentiality for parasite replication and morphology. Further dissections demonstrate that PPKL is required for the maturation of daughter parasites in the mother cells, resulting in multiple nuclei in a single parasite. The phenotype of the daughter parasites and parasite morphology were observed in another type of T. gondii strain ME49. The substantial defect in parasite replication and morphology could be rescued by genetic complementation, thus supporting its essential function for PPKL in the formation of parasites. The protein interaction analysis showed the potential interaction of PPKL with diverse proteins, thus explaining the importance of PPKL in the parasite. CONCLUSIONS: PPKL plays an important role in the formation of daughter parasites, revealing its subtle involvement in the proper maturation of the daughter parasites during division. Our detailed analysis also demonstrated that depletion of PPKL resulted in elongated tubulin fibers in the parasites. The important roles in the parasites are potentially attributed to the protein interaction mediated by kelch domains on the protein. Taken together, these findings contribute to our understanding of a key phosphatase involved in parasite replication, suggesting the potential of this phosphatase as a pharmaceutic target.


Assuntos
Parasitos , Toxoplasma , Humanos , Animais , Toxoplasma/fisiologia , Proteínas de Plantas/metabolismo , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Ácidos Indolacéticos/metabolismo , Mamíferos
3.
Front Immunol ; 14: 1268196, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37908369

RESUMO

In many infectious diseases, the pathogen-induced inflammatory response could result in protective immunity that should be regulated to prevent tissue damage and death. In fact, in Trypanosoma cruzi infection, the innate immune and the inflammatory response should be perfectly controlled to avoid significant lesions and death. Here, we investigate the role of Blimp-1 expression in T cells in resistance to T. cruzi infection. Therefore, using mice with Blimp-1 deficiency in T cells (CKO) we determined its role in the controlling parasites growth and lesions during the acute phase of infection. Infection of mice with Blimp-1 ablation in T cells resulted failure the cytotoxic CD8+ T cells and in marked Th1-mediated inflammation, high IFN-γ and TNF production, and activation of inflammatory monocyte. Interestingly, despite high nitric-oxide synthase activation (NOS-2), parasitemia and mortality in CKO mice were increased compared with infected WT mice. Furthermore, infected-CKO mice exhibited hepatic lesions characteristic of steatosis, with significant AST and ALT activity. Mechanistically, Blimp-1 signaling in T cells induces cytotoxic CD8+ T cell activation and restricts parasite replication. In contrast, Blimp-1 represses the Th1 response, leading to a decreased monocyte activation, less NOS-2 activation, and, consequently preventing hepatic damage and dysfunction. These data demonstrate that T. cruzi-induced disease is multifactorial and that the increased IFN-γ, NO production, and dysfunction of CD8+ T cells contribute to host death. These findings have important implications for the design of potential vaccines against Chagas disease.


Assuntos
Doença de Chagas , Trypanosoma cruzi , Animais , Camundongos , Linfócitos T CD8-Positivos , Inflamação/patologia , Transdução de Sinais
4.
Front Cell Infect Microbiol ; 11: 768124, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34778110

RESUMO

Chagas disease is a major public health problem, especially in the South and Central America region. Its incidence is related to poverty and presents a high rate of morbidity and mortality. The pathogenesis of Chagas disease is complex and involves many interactive pathways between the hosts and the Trypanosoma cruzi. Several factors have been implicated in parasite-host interactions, including molecules secreted by infected cells, lipid mediators and most recent, extracellular vesicles (EVs). The EVs of T. cruzi (EVsT) were reported for the first time in the epimastigote forms about 42 years ago. The EVsT are involved in paracrine communication during the infection and can have an important role in the inflammatory modulation and parasite escape mechanism. However, the mechanisms by which EVs employ their pathological effects are not yet understood. The EVsT seem to participate in the activation of macrophages via TLR2 triggering the production of cytokines and a range of other molecules, thus modulating the host immune response which promotes the parasite survival. Moreover, new insights have demonstrated that EVsT induce lipid body formation and PGE2 synthesis in macrophages. This phenomenon is followed by the inhibition of the synthesis of pro-inflammatory cytokines and antigen presentation, causing decreased parasitic molecules and allowing intracellular parasite survival. Therefore, this mini review aims to discuss the role of the EVs from T. cruzi as well as its involvement in the mechanisms that regulate the host immune response in the lipid metabolism and its significance for the Chagas disease pathophysiology.


Assuntos
Doença de Chagas , Vesículas Extracelulares , Trypanosoma cruzi , Doença de Chagas/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Imunidade , Metabolismo dos Lipídeos
5.
J Ethnopharmacol ; 273: 114019, 2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-33716084

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sulfadiazine and pyrimethamine are the two drugs used as part of the standard therapy for toxoplasmosis, however; they may cause adverse side effects and fail to prevent relapse in many patients, rendering infected individuals at risk of reactivation upon becoming immunocompromised. Extracts from various parts of Annona muricata have been widely used medicinally for the management, control and/or treatment of several human diseases, acting against parasites that cause diseases in humans. AIM OF THE STUDY: This study was performed to investigate the action of the ethanolic extract of A. muricata (EtOHAm) and its fractions in the control of the apicomplexan parasite Toxoplasma gondii in vitro and in vivo, and the effect of EtOHAm on the inflammatory response and lipid profile alteration induced by in vivo T. gondii infection. MATERIALS AND METHODS: The cytotoxicity of EtOHAm and its fractions ethyl acetate (EtOAcAm), n-butanol (BuOHAm), aqueous (H2OAm), hexane (HexAm) and dichloromethane (CH2Cl2Am) was evaluated in NIH/3T3 fibroblasts using the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The cells were infected with T. gondii, treated with the extracts, and parasite proliferation was analyzed. For the in vivo experiments, C57BL/6 mice were orally infected with T. gondii and, treated with different concentrations of extract fractions that were effective in vitro (EtOHAm, EtOAcAm, HexAm and CH2Cl2Am). Tissue parasitism, histological alterations, systemic cytokine and lipid profile were investigated. RESULTS: EtOHAm, EtOAcAm, BuOHAm, H2OAm presented low cytotoxicity until doses of 200 µg/mL, while HexAm and CH2Cl2Am presented toxicity from doses of 100µg/mL. EtOHAm, HexAm and CH2Cl2Am decreased the parasitism in vitro, presenting a therapeutic index of 2.62, 2.44, and 2.96, respectively. In vivo, EtOHAm, HexAm and CH2Cl2Am improved the survival rate of infected animals, however, only EtOHAm was able to decrease the parasitism in the small intestine and lung. Additionally, EtOHAm decreased the systemic interferon (IFN)-γ and tumor necrosis factor (TNF) systemically in infected mice, and was able to maintain the triglycerides and very-low-density lipoprotein (VLDL) lipid fractions at similar levels to uninfected animals. Although treatment with EtOHAm could not control the inflammation induced by oral infection in the tissues analyzed, it was able to preserve the number of goblet cells in the small intestine. CONCLUSIONS: Ethanolic A. muricata leaf extract could be considered as a good candidate for the development of a complementary/alternative therapy against toxoplasmosis, and also as an anti-inflammatory alternative for decreasing TNF and IFN-γ concentrations and lipid fractions in specific diseases.


Assuntos
Annona/química , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Toxoplasma/efeitos dos fármacos , Toxoplasmose Animal/tratamento farmacológico , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Fitoterapia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química
6.
Vet Parasitol ; 268: 16-20, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30981301

RESUMO

Neospora caninum is an intracellular parasite that causes neosporosis in cattle. Bovine neosporosis is considered a major cause of bovine abortion worldwide. Rapid replication of N. caninum tachyzoites within host cells is responsible for the acute phase of N. caninum infection. Evidence shows that the host immune response plays an essential role in recognizing and regulating the replication of invading pathogens. Nucleotide-binding oligomerization domain receptors (NLRs) are a class of cytoplasmic sensors that can sense pathogens and induce the formation of the inflammasome complex. Activation of the inflammasome promotes restriction of microbial replication. Our previous study revealed NLRP3 inflammasome activation in N. caninum-infected murine macrophages. However, the role of inflammasome activity in N. caninum-infected bovine cells is unknown. To address this question, a bovine peritoneal macrophage cell line was used to investigate the role of inflammasome activation in regulating intracellular N. caninum replication. The results showed that inflammasome mediated activation of caspase-1 occurs in N. caninum-infected bovine macrophages, and caspase-1-dependent cell death was considered to be induced in N. caninum-infected bovine macrophages because N. caninum induced cell death decreased following pretreatment with zVAD-fmk and VX765. Meanwhile, the inhibition of caspase-1 in N. caninum-infected bovine macrophages led to the presence of more parasites in the parasitophorous vacuole. In contrast, inflammasome activation induced by ATP treatment in N. caninum-infected bovine macrophages contributed to the clearance of N. caninum. In addition, pyroptotic cell supernatant collected from ATP-stimulated bovine macrophages also impaired the ability of this parasite to infect new cells. In conclusion, this study is the first report on the role of the bovine inflammasome in restraining intracellular N. caninum replication and suggests that the bovine inflammasome may be a potential target for future development of drugs or vaccines against N. caninum infection in cattle.


Assuntos
Doenças dos Bovinos/imunologia , Coccidiose/imunologia , Inflamassomos/imunologia , Macrófagos Peritoneais/parasitologia , Trifosfato de Adenosina/farmacologia , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Caspase 1/metabolismo , Bovinos , Proliferação de Células , Células Cultivadas , Citoplasma/parasitologia , Dipeptídeos/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Neospora , para-Aminobenzoatos/farmacologia
7.
Front Microbiol ; 9: 499, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29616011

RESUMO

During Chagas disease, the Trypanosoma cruzi can induce some changes in the host cells in order to escape or manipulate the host immune response. The modulation of the lipid metabolism in the host phagocytes or in the parasite itself is one feature that has been observed. The goal of this mini review is to discuss the mechanisms that regulate intracellular lipid body (LB) biogenesis in the course of this parasite infection and their meaning to the pathophysiology of the disease. The interaction host-parasite induces LB (or lipid droplet) formation in a Toll-like receptor 2-dependent mechanism in macrophages and is enhanced by apoptotic cell uptake. Simultaneously, there is a lipid accumulation in the parasite due to the incorporation of host fatty acids. The increase in the LB accumulation during infection is correlated with an increase in the synthesis of PGE2 within the host cells and the parasite LBs. Moreover, the treatment with fatty acid synthase inhibitor C75 or non-steroidal anti-inflammatory drugs such as NS-398 and aspirin inhibited the LB biogenesis and also induced the down modulation of the eicosanoid production and the parasite replication. These findings show that LBs are organelles up modulated during the course of infection. Furthermore, the biogenesis of the LB is involved in the lipid mediator generation by both the macrophages and the parasite triggering escape mechanisms.

9.
Int J Parasitol ; 48(7): 531-542, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29476866

RESUMO

African apes are endemically infected with numerous Plasmodium spp. including close relatives of human Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. Although these ape parasites are not believed to pose a zoonotic threat, their ability to colonise humans has not been fully explored. In particular, it remains unknown whether ape parasites are able to initiate exo-erythrocytic replication in human hepatocytes following the bite of an infective mosquito. Since animal studies have shown that liver stage infection can result in the excretion of parasite nucleic acids into the bile, we screened faecal samples from 504 rural Cameroonians for Plasmodium DNA. Using pan-Laverania as well as P. malariae- and P. vivax-specific primer sets, we amplified human P. falciparum (n = 14), P. malariae (n = 1), and P. ovale wallikeri (n = 1) mitochondrial sequences from faecal DNA of 15 individuals. However, despite using an intensified PCR screening approach we failed to detect ape Laverania, ape P. vivax or ape P. malariae parasites in these same subjects. One faecal sample from a hunter-gatherer contained a sequence closely related to the porcupine parasite Plasmodium atheruri. Since this same faecal sample also contained porcupine mitochondrial DNA, but a matching blood sample was Plasmodium-negative, it is likely that this hunter-gatherer consumed Plasmodium-infected bushmeat. Faecal Plasmodium detection was not secondary to intestinal bleeding and/or infection with gastrointestinal parasites, but indicative of blood parasitaemia. Quantitative PCR identified 26-fold more parasite DNA in the blood of faecal Plasmodium-positive than faecal Plasmodium-negative individuals (P = 0.01). However, among blood-positive individuals only 10% - 20% had detectable Plasmodium sequences in their stool. Thus, faecal screening of rural Cameroonians failed to uncover abortive ape Plasmodium infections, but detected infection with human parasites, albeit with reduced sensitivity compared with blood analysis.


Assuntos
DNA de Protozoário/isolamento & purificação , Fezes/parasitologia , Hominidae/parasitologia , Malária/veterinária , Plasmodium/classificação , Zoonoses , Animais , Camarões/epidemiologia , Humanos , Malária/epidemiologia , Malária/parasitologia , Filogenia , Plasmodium/genética
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