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1.
Nature ; 595(7866): 289-294, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34194041

RESUMO

The global decline in malaria has stalled1, emphasizing the need for vaccines that induce durable sterilizing immunity. Here we optimized regimens for chemoprophylaxis vaccination (CVac), for which aseptic, purified, cryopreserved, infectious Plasmodium falciparum sporozoites (PfSPZ) were inoculated under prophylactic cover with pyrimethamine (PYR) (Sanaria PfSPZ-CVac(PYR)) or chloroquine (CQ) (PfSPZ-CVac(CQ))-which kill liver-stage and blood-stage parasites, respectively-and we assessed vaccine efficacy against homologous (that is, the same strain as the vaccine) and heterologous (a different strain) controlled human malaria infection (CHMI) three months after immunization ( https://clinicaltrials.gov/ , NCT02511054 and NCT03083847). We report that a fourfold increase in the dose of PfSPZ-CVac(PYR) from 5.12 × 104 to 2 × 105 PfSPZs transformed a minimal vaccine efficacy (low dose, two out of nine (22.2%) participants protected against homologous CHMI), to a high-level vaccine efficacy with seven out of eight (87.5%) individuals protected against homologous and seven out of nine (77.8%) protected against heterologous CHMI. Increased protection was associated with Vδ2 γδ T cell and antibody responses. At the higher dose, PfSPZ-CVac(CQ) protected six out of six (100%) participants against heterologous CHMI three months after immunization. All homologous (four out of four) and heterologous (eight out of eight) infectivity control participants showed parasitaemia. PfSPZ-CVac(CQ) and PfSPZ-CVac(PYR) induced a durable, sterile vaccine efficacy against a heterologous South American strain of P. falciparum, which has a genome and predicted CD8 T cell immunome that differs more strongly from the African vaccine strain than other analysed African P. falciparum strains.


Assuntos
Anticorpos Neutralizantes/imunologia , Fígado/imunologia , Fígado/parasitologia , Vacinas Antimaláricas/imunologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/imunologia , Vacinas Atenuadas/imunologia , Adulto , Animais , Formação de Anticorpos/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Estágios do Ciclo de Vida/imunologia , Malária/sangue , Malária/imunologia , Malária/parasitologia , Malária/prevenção & controle , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/efeitos adversos , Vacinas Antimaláricas/química , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/crescimento & desenvolvimento , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo , Vacinação/efeitos adversos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/química
2.
Exp Parasitol ; 228: 108137, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34298076

RESUMO

Leishmaniasis is remaining as one of the important health problems of many countries around the world. The histopathology of the disease and the effects of the parasite on various tissues have not yet been fully elucidated. The current study aimed to evaluate the stereological features of the liver, spleen, and bone of hamsters infected with Leishmania infantum. In this experimental study, the L. infantum parasite was mass cultivated in a culture medium. Then, 15 golden hamsters were selected, of which 5 animals were considered as controls and another 10 animals were injected intravenously, with 1 × 108 promastigotes of L. infantum. Four months later, the hamsters were euthanized and impression smears were prepared from the liver and spleen. Moreover, pathology slides were prepared from the spleen, liver, and femur. The orientated method was used to obtain isotropic uniform random (IUR) sections. For stereological evaluation, the tissues were fixed with formalin buffer, and sections (4 and 25 µm thick) were prepared and stained with Heidenhain's AZAN trichrome and hematoxylin-eosin, respectively. The tissue samples were examined by stereological methods and all changes in the samples of the infected hamsters were compared with the control group. The number of hepatocyte and their nuclei volumes were significantly decreased in the Leishmania-infected group, compared to the control group. The number of Kupffer cells and their volume in the liver of the Leishmania-infected group was higher than that of the control group, and the differences were statistically significant. The volume of trabeculae and central arteries in the spleen of the Leishmania-infected group was lower than that of the control group and the number of lymphocytes and macrophages in the spleen of the Leishmania-infected group was increased compared to the control group. The trabecular volume and the number of osteoblasts and osteoclasts of the femur in Leishmania-infected animals decreased, whereas the volume of bone marrow was significantly raised. Leishmaniasis leads to changes in tissue structure and their function in the host by the involvement of various organs of the immune system including the liver, spleen, and bone. Understanding these changes are important in identifying the effective mechanisms of the parasite and host interaction.


Assuntos
Fêmur/patologia , Leishmania infantum/patogenicidade , Leishmaniose Visceral/patologia , Fígado/patologia , Baço/patologia , Animais , Cricetinae , Eosinófilos/patologia , Fêmur/parasitologia , Hepatócitos/patologia , Macrófagos do Fígado/patologia , Fígado/parasitologia , Macrófagos/patologia , Mesocricetus , Osteoblastos/patologia , Osteoclastos/patologia , Osteócitos/patologia , Baço/parasitologia
3.
Turkiye Parazitol Derg ; 45(2): 95-100, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34103284

RESUMO

Objective: In the present study, preliminary outcomes of the in vivo assessment of a Leishmania donovani/L. infantum hybrid isolated from a hospitalised patient with visceral leishmaniasis in Manisa and identified through analysis of the Leishmania-specific ITS-1, hsp70 and cpb gene regions are presented in comparison with reference strains of L. donovani and L. infantum. Methods: Three different study groups [(SG); n=16 mice each] and a control group (n=8 mice) were established with female Balb/C mice weighing 25-30 g. Reference L. donovani (MHOM/IN/1980/DD8), reference L. infantum (MHOM/TN/1980/IP1) and a L. donovani/L. infantum hybrid (MHOM/TR/2014/CBVL-LI/ LD), stored in liquid nitrogen, were thawed, cultured and incubated at 25 °C. A 15-µL dose of 1x108/mL promastigotes of three strains was applied to the tail veins of mice in the SG. After the mice were sacrificed, the liver and spleen tissues were removed and stored for immunological, immunohistochemical and pathological analyses. Results: The presence of infection in the liver and spleen tissues of mice was detected both by a specific enzyme-linked immunosorbent assay test and from the recovery of Leishmania promastigotes from liver and spleen tissues in NNN medium. However, Leishmania amastigotes were not observed in the touch biopsy smears of livers or spleens in either of the SGs. In addition, no evidence of tissue damage was identified in the SGs after immunohistochemical staining (with antibodies against IL-9, CD-117, MBP, CD163, CD4, CD8 and CD31). Conclusion: The obtained results show that hybrid Leishmania and reference L. donovani and L. infantum strains reached the liver and spleens of Balb/C mice in SGs but were of no pathological consequence. Yet, these three Leishmania isolates caused skin lesions when applied subcutaneously in Balb/C mice in another study. The findings presented in this study will be reassessed upon completion of the project, once the final results are obtained.


Assuntos
Quimera , Leishmania donovani/isolamento & purificação , Leishmania infantum/isolamento & purificação , Leishmaniose Visceral/parasitologia , Animais , Quimera/genética , Citocinas/metabolismo , DNA Espaçador Ribossômico/genética , Feminino , Genes de Protozoários/genética , Humanos , Leishmania donovani/genética , Leishmania infantum/genética , Fígado/metabolismo , Fígado/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Baço/metabolismo , Baço/parasitologia
4.
Turkiye Parazitol Derg ; 45(2): 146-148, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34103293

RESUMO

A 65-year-old man, with signs of acute colon obstruction, was diagnosed with rectal tumour and liver hydatid cyst. Additionally, a focal liver lesion in segment 1 was detected. Moreover, physical examination revealed hepatomegaly and abdominal distension. Thus, rectal resection and small liver lesion biopsy was performed. Serological and pathohistological analyses showed concomitant presence of hydatid cyst and colorectal metastasis in the liver. Hence, the cyst was treated with anthelmintic therapy, and patient lived another year after the diagnosis. To the best of our knowledge, cases of concomitant hydatid cyst and colorectal liver metastasis has never been reported; thus, this article addresses a unique case of coexistence between these two serious liver diseases.


Assuntos
Neoplasias Colorretais/patologia , Equinococose Hepática/complicações , Neoplasias Hepáticas/secundário , Idoso , Animais , Anti-Helmínticos/uso terapêutico , Neoplasias Colorretais/complicações , Neoplasias Colorretais/cirurgia , Equinococose Hepática/diagnóstico , Equinococose Hepática/terapia , Echinococcus/isolamento & purificação , Humanos , Fígado/parasitologia , Fígado/patologia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Masculino
5.
PLoS Negl Trop Dis ; 15(5): e0009365, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33979343

RESUMO

BACKGROUND: In patients with hepatic cystic echinococcosis (CE), treatment effectiveness, outcomes, complications, and recurrence rate are controversial. Endocystectomy is a conservative surgical approach that adequately removes cyst contents without loss of parenchyma. This conservative procedure has been modified in several ways to prevent complications and to improve surgical outcomes. This systematic review aimed to evaluate the intraoperative and postoperative complications of endocysectomy for hepatic CE as well as the hepatic CE recurrence rate following endocystectomy. METHODS: A systematic search was made for all studies reporting endocystectomy to manage hepatic CE in PubMed, Web of Science, and Cochrane CENTRAL databases. Study quality was assessed using the methodological index for non-randomized studies (MINORS) criteria and the Cochrane revised tool to assess risk of bias in randomized trials (RoB2). The random-effects model was used for meta-analysis and the arscine-transformed proportions were used to determine complication-, mortality-, and recurrence rates. This study is registered with PROSPERO (number CRD42020181732). RESULTS: Of 3,930 retrieved articles, 54 studies reporting on 4,058 patients were included. Among studies reporting preoperative anthelmintic treatment (31 studies), albendazole was administered in all of them. Complications were reported in 19.4% (95% CI: 15.9-23.2; I2 = 84%; p-value <0.001) of the patients; biliary leakage (10.1%; 95% CI: 7.5-13.1; I2 = 81%; p-value <0.001) and wound infection (6.6%; 95% CI: 4.6-9; I2 = 27%; p-value = 0.17) were the most common complications. The post-endocystectomy mortality rate was 1.2% (95% CI: 0.8-1.8; I2 = 21%; p-value = 0.15) and the recurrence rate was 4.8% (95% CI: 3.1-6.8; I2 = 87%; p-value <0.001). Thirty-nine studies (88.7%) had a mean follow-up of more than one year after endocystectomy, and only 14 studies (31.8%) had a follow-up of more than five years. CONCLUSION: Endocystectomy is a conservative and feasible surgical approach. Despite previous disencouraging experiences, our results suggest that endocystectomy is associated with low mortality and recurrence.


Assuntos
Cistos/parasitologia , Cistos/cirurgia , Equinococose Hepática/cirurgia , Equinococose/cirurgia , Fígado/cirurgia , Albendazol/uso terapêutico , Animais , Anticestoides/uso terapêutico , Echinococcus granulosus , Humanos , Complicações Intraoperatórias/prevenção & controle , Fígado/parasitologia , Complicações Pós-Operatórias/prevenção & controle
6.
PLoS Negl Trop Dis ; 15(5): e0009423, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34014936

RESUMO

BACKGROUND: Nanotechnology has been manufactured from medicinal plants to develop safe, and effective antischistosmal alternatives to replace today's therapies. The aim of the study is to evaluate the prophylactic effect of ginger-derived nanoparticles (GNPs), and the therapeutic effect of ginger aqueous extract, and GNPs on Schistosoma mansoni (S. mansoni) infected mice compared to praziquantel (PZQ), and mefloquine (MFQ). METHODOLOGY/PRINCIPAL FINDINGS: Eighty four mice, divided into nine different groups, were sacrificed at 6th, 8th, and 10th week post-infection (PI), with assessment of parasitological, histopathological, and oxidative stress parameters, and scanning the worms by electron microscope. As a prophylactic drug, GNPs showed slight reduction in worm burden, egg density, and granuloma size and number. As a therapeutic drug, GNPs significantly reduced worm burden (59.9%), tissue egg load (64.9%), granuloma size, and number at 10th week PI, and altered adult worm tegumental architecture, added to antioxidant effect. Interestingly, combination of GNPs with PZQ or MFQ gave almost similar or sometimes better curative effects as obtained with each drug separately. The highest therapeutic effect was obtained when ½ dose GNPs combined with ½ dose MFQ which achieved 100% reduction in both the total worm burden, and ova tissue density as early as the 6th week PI, with absence of detected eggs or tissue granuloma, and preservation of liver architecture. CONCLUSIONS/SIGNIFICANCE: GNPs have a schistosomicidal, antioxidant, and hepatoprotective role. GNPs have a strong synergistic effect when combined with etiological treatments (PZQ or MFQ), and significantly reduced therapeutic doses by 50%, which may mitigate side effects and resistance to etiological drugs, a hypothesis requiring further research. We recommend extending this study to humans.


Assuntos
Gengibre/química , Nanopartículas/administração & dosagem , Extratos Vegetais/farmacologia , Esquistossomose mansoni/tratamento farmacológico , Administração Oral , Animais , Anti-Helmínticos/administração & dosagem , Quimioterapia Combinada , Granuloma , Fígado/parasitologia , Masculino , Mefloquina/administração & dosagem , Camundongos , Contagem de Ovos de Parasitas , Praziquantel/administração & dosagem , Profilaxia Pré-Exposição , Schistosoma mansoni/efeitos dos fármacos
7.
PLoS Negl Trop Dis ; 15(5): e0009444, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34033646

RESUMO

BACKGROUND: World Health Organization (WHO) guidelines for measuring global progress in schistosomiasis control classify individuals with Schistosoma spp. infections based on the concentration of excreted eggs. We assessed the associations between WHO infection intensity categories and morbidity prevalence for selected S. haematobium and S. mansoni morbidities in school-age children. METHODOLOGY: A total of 22,488 children aged 6-15 years from monitoring and evaluation cohorts in Burkina Faso, Mali, Niger, Uganda, Tanzania, and Zambia from 2003-2008 were analyzed using Bayesian logistic regression. Models were utilized to evaluate associations between intensity categories and the prevalence of any urinary bladder lesion, any upper urinary tract lesion, microhematuria, and pain while urinating (for S. haematobium) and irregular hepatic ultrasound image pattern (C-F), enlarged portal vein, laboratory-confirmed diarrhea, and self-reported diarrhea (for S. mansoni) across participants with infection and morbidity data. PRINCIPAL FINDINGS: S. haematobium infection intensity categories possessed consistent morbidity prevalence across surveys for multiple morbidities and participants with light infections had elevated morbidity levels, compared to negative participants. Conversely, S. mansoni infection intensity categories lacked association with prevalence of the morbidity measures assessed. CONCLUSIONS/SIGNIFICANCE: Current status infection intensity categories for S. haematobium were associated with morbidity levels in school-age children, suggesting urogenital schistosomiasis morbidity can be predicted by an individual's intensity category. Conversely, S. mansoni infection intensity categories were not consistently indicative of childhood morbidity at baseline or during the first two years of a preventive chemotherapy control program.


Assuntos
Fígado/parasitologia , Esquistossomose Urinária/patologia , Esquistossomose mansoni/patologia , Sistema Urinário/parasitologia , Adolescente , África ao Sul do Saara/epidemiologia , Animais , Quimioprevenção , Criança , Diarreia , Feminino , Humanos , Fígado/patologia , Masculino , Morbidade , Contagem de Ovos de Parasitas , Schistosoma haematobium , Schistosoma mansoni , Esquistossomose mansoni/tratamento farmacológico , Sistema Urinário/patologia
8.
BMC Vet Res ; 17(1): 191, 2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-33985499

RESUMO

BACKGROUND: Tetratrichomonas gallinarum is parasitic protozoa with a wide host range. However, its lethal infection is rare reported. CASE PRESENTATION: Here, we described the first lethal cases of T. gallinarum infection in black swans in China. Five black swans died within a week in succession without obvious symptoms except mild diarrhea. At necropsy, severe lesions were observed in caeca with thickened caecal walls and hemorrhages in the mucosa. A large number of moving trophozoites were found in the contents of the cecum by microscopic examination. The livers were enlarged with multiple bleeding spots on the surface. Histopathology of the livers showed mononuclear cell infiltration and moderate hyperplasia of fibrous tissue. The histopathology of the cecum showed that the villi of the cecum were edematous. Finally, the presence of T. gallinarum was determined by specific PCR andin-situ hybridization assay. Additionally, common pathogens that can cause similar symptoms were excluded. CONCLUSIONS: The death of the black swan was caused by T. gallinarum, suggesting that the parasite might be a new threat to the Cygnus birds.


Assuntos
Doenças das Aves/parasitologia , Infecções Protozoárias em Animais/patologia , Trichomonadida/isolamento & purificação , Animais , Anseriformes , Doenças das Aves/patologia , Doenças do Ceco/parasitologia , Doenças do Ceco/patologia , China , Hibridização In Situ/veterinária , Fígado/parasitologia , Fígado/patologia , Reação em Cadeia da Polimerase/veterinária , Trichomonadida/genética
9.
Mol Biochem Parasitol ; 244: 111375, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34023299

RESUMO

Malaria parasites exhibit a complex lifecycle, requiring extensive asexual replication in the liver and blood of the vertebrate host, and in the haemocoel of the insect vector. Yet, they must also undergo a single round of sexual reproduction, which occurs in the vector's midgut upon uptake of a blood meal. Sexual reproduction is obligate for infection of the vector and thus, is essential for onwards transmission to new hosts. Sex in malaria parasites involves several bottlenecks in parasite number, making the stages involved attractive targets for blocking disease transmission. Malaria parasites have evolved a suite of adaptations ("strategies") to maximise the success of sexual reproduction and transmission, which could undermine transmission-blocking interventions. Yet, understanding parasite strategies may also reveal novel opportunities for such interventions. Here, we outline how evolutionary and ecological theories, developed to explain reproductive strategies in multicellular taxa, can be applied to explain two reproductive strategies (conversion rate and sex ratio) expressed by malaria parasites within the vertebrate host.


Assuntos
Gametogênese , Estágios do Ciclo de Vida/genética , Malária/parasitologia , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium chabaudi/crescimento & desenvolvimento , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium knowlesi/crescimento & desenvolvimento , Animais , Coevolução Biológica , Culicidae/parasitologia , Eritrócitos/parasitologia , Feminino , Interações Hospedeiro-Parasita/genética , Humanos , Insetos Vetores/parasitologia , Fígado/parasitologia , Malária/transmissão , Masculino , Plasmodium berghei/genética , Plasmodium berghei/metabolismo , Plasmodium chabaudi/genética , Plasmodium chabaudi/metabolismo , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Plasmodium knowlesi/genética , Plasmodium knowlesi/metabolismo , Reprodução Assexuada , Razão de Masculinidade
10.
PLoS Med ; 18(5): e1003567, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34038421

RESUMO

BACKGROUND: Plasmodium vivax has been proposed to infect and replicate in the human spleen and bone marrow. Compared to Plasmodium falciparum, which is known to undergo microvascular tissue sequestration, little is known about the behavior of P. vivax outside of the circulating compartment. This may be due in part to difficulties in studying parasite location and activity in life. METHODS AND FINDINGS: To identify organ-specific changes during the early stages of P. vivax infection, we performed 18-F fluorodeoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) at baseline and just prior to onset of clinical illness in P. vivax experimentally induced blood-stage malaria (IBSM) and compared findings to P. falciparum IBSM. Seven healthy, malaria-naive participants were enrolled from 3 IBSM trials: NCT02867059, ACTRN12616000174482, and ACTRN12619001085167. Imaging took place between 2016 and 2019 at the Herston Imaging Research Facility, Australia. Postinoculation imaging was performed after a median of 9 days in both species (n = 3 P. vivax; n = 4 P. falciparum). All participants were aged between 19 and 23 years, and 6/7 were male. Splenic volume (P. vivax: +28.8% [confidence interval (CI) +10.3% to +57.3%], P. falciparum: +22.9 [CI -15.3% to +61.1%]) and radiotracer uptake (P. vivax: +15.5% [CI -0.7% to +31.7%], P. falciparum: +5.5% [CI +1.4% to +9.6%]) increased following infection with each species, but more so in P. vivax infection (volume: p = 0.72, radiotracer uptake: p = 0.036). There was no change in FDG uptake in the bone marrow (P. vivax: +4.6% [CI -15.9% to +25.0%], P. falciparum: +3.2% [CI -3.2% to +9.6%]) or liver (P. vivax: +6.2% [CI -8.7% to +21.1%], P. falciparum: -1.4% [CI -4.6% to +1.8%]) following infection with either species. In participants with P. vivax, hemoglobin, hematocrit, and platelet count decreased from baseline at the time of postinoculation imaging. Decrements in hemoglobin and hematocrit were significantly greater in participants with P. vivax infection compared to P. falciparum. The main limitations of this study are the small sample size and the inability of this tracer to differentiate between host and parasite metabolic activity. CONCLUSIONS: PET/MRI indicated greater splenic tropism and metabolic activity in early P. vivax infection compared to P. falciparum, supporting the hypothesis of splenic accumulation of P. vivax very early in infection. The absence of uptake in the bone marrow and liver suggests that, at least in early infection, these tissues do not harbor a large parasite biomass or do not provoke a prominent metabolic response. PET/MRI is a safe and noninvasive method to evaluate infection-associated organ changes in morphology and glucose metabolism.


Assuntos
Medula Óssea/parasitologia , Glucose/metabolismo , Fígado/parasitologia , Malária Falciparum/parasitologia , Malária Vivax/parasitologia , Baço/parasitologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Feminino , Humanos , Fígado/metabolismo , Fígado/patologia , Imageamento por Ressonância Magnética , Malária Falciparum/patologia , Malária Falciparum/fisiopatologia , Malária Vivax/patologia , Malária Vivax/fisiopatologia , Masculino , Plasmodium falciparum , Plasmodium vivax , Tomografia por Emissão de Pósitrons , Estudos Prospectivos , Queensland , Coluna Vertebral/metabolismo , Coluna Vertebral/parasitologia , Coluna Vertebral/patologia , Baço/metabolismo , Baço/patologia , Adulto Jovem
11.
Viruses ; 13(5)2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925701

RESUMO

Hepatitis viruses and liver-stage malaria are within the liver infections causing higher morbidity and mortality rates worldwide. The highly restricted tropism of the major human hepatotropic pathogens-namely, the human hepatitis B and C viruses and the Plasmodium falciparum and Plasmodium vivax parasites-has hampered the development of disease models. These models are crucial for uncovering the molecular mechanisms underlying the biology of infection and governing host-pathogen interaction, as well as for fostering drug development. Bioengineered cell models better recapitulate the human liver microenvironment and extend hepatocyte viability and phenotype in vitro, when compared with conventional two-dimensional cell models. In this article, we review the bioengineering tools employed in the development of hepatic cell models for studying infection, with an emphasis on 3D cell culture strategies, and discuss how those tools contributed to the level of recapitulation attained in the different model layouts. Examples of host-pathogen interactions uncovered by engineered liver models and their usefulness in drug development are also presented. Finally, we address the current bottlenecks, trends, and prospect toward cell models' reliability, robustness, and reproducibility.


Assuntos
Bioengenharia , Técnicas de Cultura de Células , Suscetibilidade a Doenças , Hepatite/etiologia , Hepatite/metabolismo , Hepatócitos/metabolismo , Animais , Bioengenharia/métodos , Modelos Animais de Doenças , Descoberta de Drogas , Hepatite/tratamento farmacológico , Hepatite/patologia , Hepatite Viral Humana/etiologia , Hepatite Viral Humana/metabolismo , Hepatite Viral Humana/patologia , Hepatócitos/parasitologia , Hepatócitos/virologia , Interações Hospedeiro-Patógeno , Humanos , Fígado/metabolismo , Fígado/parasitologia , Fígado/virologia , Hepatopatias Parasitárias/etiologia , Hepatopatias Parasitárias/metabolismo , Hepatopatias Parasitárias/patologia
12.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808062

RESUMO

The liver is well recognized as a non-immunological visceral organ that is involved in various metabolic activities, nutrient storage, and detoxification. Recently, many studies have demonstrated that resident immune cells in the liver drive various immunological reactions by means of several molecular modulators. Understanding the mechanistic details of interactions between hepatic host immune cells, including Kupffer cells and lymphocytes, and various hepatic pathogens, especially viruses, bacteria, and parasites, is necessary. MicroRNAs (miRNAs), over 2600 of which have been discovered, are small, endogenous, interfering, noncoding RNAs that are predicted to regulate more than 15,000 genes by degrading specific messenger RNAs. Several recent studies have demonstrated that some miRNAs are associated with the immune response to pathogens in the liver. However, the details of the underlying mechanisms of miRNA interference in hepatic host-pathogen interactions still remain elusive. In this review, we summarize the relationship between the immunological interactions of various pathogens and hepatic resident immune cells, as well as the role of miRNAs in the maintenance of liver immunity against pathogens.


Assuntos
Interações Hospedeiro-Patógeno/genética , Fígado/microbiologia , Fígado/parasitologia , Fígado/virologia , MicroRNAs/genética , Animais , Regulação da Expressão Gênica , Hepatite/genética , Vírus de Hepatite/patogenicidade , Humanos , Fígado/imunologia , Abscesso Hepático/genética , Abscesso Hepático/microbiologia , Doença Inflamatória Pélvica/genética , Peritonite/genética , Peritonite/microbiologia
13.
Acta Trop ; 219: 105917, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33839085

RESUMO

In this study, the role of nitric oxide (NO) in the pathogenesis of hydatidosis and the interaction with effects of anthelmintic drugs, albendazole and praziquantel, were examined in larval infection caused by protoscolices obtained from hydatid cysts of sheep liver in Albino Balb/c mice. Animals were divided into ten groups including controls and infected groups. Larval infection was established with intraperitoneal injection of protoscolices. Eight months after infection with protoscolices, the infected animals were divided into 6 groups. The infected animals were given a selective inhibitor of inducible nitric oxide synthase (iNOS) L-N6-(1-Iminoethyl) lysine-hydrochloride (L-NIL), NO donor sodium nitroprusside (SNP), albendazole and praziquantel as anthelmintic drugs for 7 days. In addition, control groups were composed of intact group, control, anthelmintic drugs + L-NIL, and anthelmintic drugs + SNP. The liver and blood samples were taken for cytological, histological, immunohistochemical and biochemical analyses 7 days after treatments at the end of experiment. The animals injected with protoscolices showed histopathological changes including inflammation areas, infiltration and accumulation of leukocytes, dilation of sinusoids, and damage in endothelial cells and hepatocytes at light microscopy. Electron microscopy were revealed severe damage in sinusoidal endothelial cells, leukocytes especially eosinophils in sinusoid lumens and disorganization in endoplasmic reticulum and nuclear membrane. Endothelial nitric oxide synthase (eNOS) and iNOS reactions were increased in the tissue. Anthelmintic drugs decreased inflammation areas and damages; however, it did not change NOS reactions in the animals given protoscolices. L-NIL and SNP diminished both iNOS and eNOS reactions. Unlike the group administered the inhibitor, SNP treated group exhibited less inflammation areas. Combination of these substances and drugs resulted in decreased inflammation areas. eNOS and iNOS reactions decreased in the drugs and SNP administered group, while only iNOS reaction was decreased in L-NIL given infection group. In addition, the infected groups which received SNP displayed expanded sinusoids and hepatocytes with vacuoles, intriguingly. While levels of serum nitrite/nitrate elevated only in the infection group given drugs and SNP, it decreased in the L-NIL administered group. Tissue level of malondialdehyde increased in infection groups with drugs and SNP. In conclusion, the results indicated that NO plays an important role in the pathogenesis of hydatidosis.


Assuntos
Albendazol/farmacologia , Echinococcus granulosus/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Fígado/parasitologia , Lisina/farmacologia , Óxido Nítrico/metabolismo , Praziquantel/farmacologia , Animais , Interações Medicamentosas , Echinococcus granulosus/metabolismo , Echinococcus granulosus/fisiologia , Injeções , Larva/efeitos dos fármacos , Larva/metabolismo , Larva/fisiologia , Fígado/efeitos dos fármacos , Camundongos , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Ovinos
14.
J Parasitol ; 107(2): 309-319, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33886960

RESUMO

Toxoplasma gondii infections are common in humans and animals worldwide. The ingestion of food or water contaminated with oocysts excreted by infected cats or ingestion of uncooked or undercooked meat containing tissue cysts of T. gondii are the 2 major modes of transmission of T. gondii. Deer are a popular game. Recently, outbreaks of clinical toxoplasmosis were reported in humans in North America linked to ingestion of undercooked venison. Here, we review prevalence, persistence of infection, clinical disease, epidemiology, and public health risks of T. gondii infections in deer and other cervids for the past decade. Estimates of worldwide serological prevalence are summarized individually for each species of deer, elk, moose, and caribou. Genetic diversity of 112 viable isolates of T. gondii from cervids is discussed, including its public health significance. Prevalence of T. gondii in deer is very high. Any part of a deer, including liver, spleen, and muscles, should be cooked thoroughly before human consumption.


Assuntos
Cervos/parasitologia , Carne/parasitologia , Toxoplasma/isolamento & purificação , Toxoplasmose Animal/epidemiologia , Toxoplasmose Animal/transmissão , Toxoplasmose/etiologia , Aborto Animal/epidemiologia , Animais , Anticorpos Antiprotozoários/sangue , Culinária/métodos , Culinária/normas , DNA de Protozoário/análise , Genótipo , Humanos , Fígado/parasitologia , Músculos/parasitologia , Prevalência , Baço/parasitologia , Toxoplasma/classificação , Toxoplasma/genética , Toxoplasma/imunologia , Toxoplasmose/epidemiologia , Toxoplasmose/transmissão , Estados Unidos/epidemiologia
15.
Biochem Biophys Res Commun ; 549: 61-66, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33667710

RESUMO

The glyoxalase system is a ubiquitous detoxification pathway of methylglyoxal, a cytotoxic byproduct of glycolysis. Actively proliferating cells, such as cancer cells, depend on their energy metabolism for glycolysis. Therefore, the glyoxalase system has been evaluated as a target of anticancer drugs. The malaria sporozoite, which is the infective stage of the malaria parasite, actively proliferates and produces thousands of merozoites within 2-3 days in hepatocytes. This is the first step of infection in mammalian hosts. The glyoxalase system appears to play an important role in this active proliferation stage of the malaria parasite in hepatocytes. In this study, we aimed to dissect the role of the glyoxalase system in malaria parasite proliferation in hepatocytes to examine its potential as a target of malaria prevention using a reverse genetics approach. The malaria parasite possesses a glyoxalase system, comprised of glyoxalases and GloI-like protein, in the cytosol and apicoplast. We generated cytosolic glyoxalase II (cgloII) knockout, apicoplast targeted glyoxalase gloII (tgloII) knockout, and cgloII and tgloII double-knockout parasites and performed their phenotypic analysis. We did not observe any defects in the cgloII or tgloII knockout parasites. In contrast, we observed approximately 90% inhibition of the liver-stage proliferation of cgloII and tgloII double-knockout parasites in vivo. These findings suggest that although the glyoxalase system is dispensable, it plays an important role in parasite proliferation in hepatocytes. Additionally, the results indicate a complementary relationship between the cytosolic and apicoplast glyoxalase pathways. We expect that the parasite utilizes a system similar to that observed in cancer cells to enable its rapid proliferation in hepatocytes; this process could be targeted in the development of novel strategies to prevent malaria.


Assuntos
Lactoilglutationa Liase/metabolismo , Estágios do Ciclo de Vida , Fígado/parasitologia , Redes e Vias Metabólicas , Plasmodium berghei/enzimologia , Plasmodium berghei/crescimento & desenvolvimento , Animais , Feminino , Técnicas de Inativação de Genes , Malária/parasitologia , Malária/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Parasitos/metabolismo
16.
Acta Trop ; 218: 105909, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33789153

RESUMO

Schistosomiasis is an infectious disease caused by helminth parasites of the genus Schistosoma; it is transmitted in over 78 countries. The main strategy for schistosomiasis control is treatment of infected people with praziquantel (PZQ). As PZQ-resistant strains have emerged, new anti-schistosomal agents have become necessary. We evaluated the in vitro and in vivo effect of P-MAPA, an aggregated polymer of protein magnesium ammonium phospholinoleate-palmitoleate anhydride with immunomodulatory properties; it is produced by Aspergillus oryzae fermentation. In vitro, P-MAPA (5, 50, and 100 µg/mL) damaged the Schistosoma mansoni tegument, causing thorn losses and tuber destruction in male worms and peeling and erosion in females after 24-h incubation. In vivo, P-MAPA (5 and 100 mg/kg, alone and combined with PZQ - 50 mg/kg) reduced the number of eggs by up to 69.20% in the liver and 88.08% in the intestine. Furthermore, granulomas were reduced up to 83.13%, and there was an increase in the number of dead eggs and a reduction of serum aspartate aminotransferase levels. These data suggest that P-MAPA activity can help improve schistosomiasis treatment and patients' quality of life.


Assuntos
Ácidos Linoleicos/farmacologia , Ácidos Oleicos/farmacologia , Praziquantel/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Animais , Feminino , Granuloma/tratamento farmacológico , Granuloma/patologia , Humanos , Fatores Imunológicos/farmacologia , Intestinos/parasitologia , Fígado/parasitologia , Fígado/patologia , Masculino , Camundongos , Compostos Organofosforados , Esquistossomicidas/farmacologia
17.
PLoS Negl Trop Dis ; 15(3): e0009013, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33651812

RESUMO

BACKGROUND: There is a continued need to develop effective and safe treatments for visceral leishmaniasis (VL). Preclinical studies on pharmacokinetics and pharmacodynamics of anti-infective agents, such as anti-bacterials and anti-fungals, have provided valuable information in the development and dosing of these agents. The aim of this study was to characterise the pharmacokinetic and pharmacodynamic properties of the anti-leishmanial drugs AmBisome and miltefosine in a preclinical disease model of VL. METHODOLOGY / PRINCIPAL FINDINGS: BALB/c mice were infected with L. donovani (MHOM/ET/67/HU3) amastigotes. Groups of mice were treated with miltefosine (orally, multi-dose regimen) or AmBisome (intravenously, single dose regimen) or left untreated as control groups. At set time points groups of mice were killed and plasma, livers and spleens harvested. For pharmacodynamics the hepatic parasite burden was determined microscopically from tissue impression smears. For pharmacokinetics drug concentrations were measured in plasma and whole tissue homogenates by LC-MS. Unbound drug concentrations were determined by rapid equilibrium dialysis. Doses exerting maximum anti-leishmanial effects were 40 mg/kg for AmBisome and 150 mg/kg (cumulatively) for miltefosine. AmBisome displayed a wider therapeutic range than miltefosine. Dose fractionation at a total dose of 2.5 mg/kg pointed towards concentration-dependent anti-leishmanial activity of AmBisome, favouring the administration of large doses infrequently. Protein binding was >99% for miltefosine and amphotericin B in plasma and tissue homogenates. CONCLUSION / SIGNIFICANCE: Using a PK/PD approach we propose optimal dosing strategies for AmBisome. Additionally, we describe pharmacokinetic and pharmacodynamic properties of miltefosine and compare our findings in a preclinical disease model to available knowledge from studies in humans. This approach also presents a strategy for improved use of animal models in the drug development process for VL.


Assuntos
Anfotericina B/farmacocinética , Antiprotozoários/farmacocinética , Leishmaniose Visceral/tratamento farmacológico , Fosforilcolina/análogos & derivados , Anfotericina B/uso terapêutico , Animais , Antiprotozoários/uso terapêutico , Quimioterapia Combinada , Proteínas de Homeodomínio/genética , Humanos , Fígado/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Carga Parasitária , Fosforilcolina/farmacocinética , Fosforilcolina/uso terapêutico , Ligação Proteica/fisiologia
18.
PLoS Negl Trop Dis ; 15(3): e0009200, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33657133

RESUMO

Control of the neglected tropical disease schistosomiasis relies almost entirely on praziquantel (PZQ) monotherapy. How PZQ clears parasite infections remains poorly understood. Many studies have examined the effects of PZQ on worms cultured in vitro, observing outcomes such as muscle contraction. However, conditions worms are exposed to in vivo may vary considerably from in vitro experiments given the short half-life of PZQ and the importance of host immune system engagement for drug efficacy in animal models. Here, we investigated the effects of in vivo PZQ exposure on Schistosoma mansoni. Measurement of pro-apoptotic caspase activation revealed that worm death occurs only after parasites shift from the mesenteric vasculature to the liver, peaking 24 hours after drug treatment. This indicates that PZQ is not directly schistocidal, since PZQ's half-life is ~2 hours in humans and ~30 minutes in mice, and focuses attention on parasite interactions with the host immune system following the shift of worms to the liver. RNA-Seq of worms harvested from mouse livers following sub-lethal PZQ treatment revealed drug-evoked changes in the expression of putative immunomodulatory and anticoagulant gene products. Several of these gene products localized to the schistosome esophagus and may be secreted into the host circulation. These include several Kunitz-type protease inhibitors, which are also found in the secretomes of other blood feeding animals. These transcriptional changes may reflect mechanisms of parasite immune-evasion in response to chemotherapy, given the role of complement-mediated attack and the host innate/humoral immune response in parasite elimination. One of these isoforms, SmKI-1, has been shown to exhibit immunomodulatory and anti-coagulant properties. These data provide insight into the effect of in vivo PZQ exposure on S. mansoni, and the transcriptional response of parasites to the stress of chemotherapy.


Assuntos
Anti-Helmínticos/farmacologia , Praziquantel/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Animais , Anti-Helmínticos/administração & dosagem , Feminino , Fígado/parasitologia , Camundongos , Doenças Negligenciadas , Praziquantel/administração & dosagem , Schistosoma mansoni/genética , Schistosoma mansoni/imunologia , Schistosoma mansoni/metabolismo , Esquistossomose mansoni/imunologia
19.
Exp Parasitol ; 224: 108098, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33713659

RESUMO

Molecular diagnostics are powerful tools for disease detection but are typically confined to the laboratory environment due to the cumbersome methods required to extract nucleic acids from biological samples. Accurate diagnosis is essential for early detection of parasitic worm infections and for monitoring control programs, particularly during new transmission outbreaks to limit infection spread. We optimized the recently developed DNA dipstick technology to purify Schistosoma japonicum DNA from different life stages in <60 s. We successfully detected DNA from adult worms, eggs and infected snails. The speed and simplicity of this method enables the point-of-care detection of S. japonicum.


Assuntos
DNA de Helmintos/isolamento & purificação , Schistosoma japonicum/isolamento & purificação , Esquistossomose Japônica/diagnóstico , Animais , Fígado/parasitologia , Camundongos , Técnicas de Diagnóstico Molecular , Técnicas de Amplificação de Ácido Nucleico , Testes Imediatos , Reação em Cadeia da Polimerase em Tempo Real , Schistosoma japonicum/genética , Esquistossomose Japônica/prevenção & controle , Caramujos/parasitologia
20.
Exp Parasitol ; 224: 108097, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33736972

RESUMO

The quest for the development of a novel antimalarial drug informed the decision to subject phytol to in vivo trials following a demonstration of therapeutic potential against chloroquine sensitive strain of Plasmodium falciparum under in vitro condition. On this basis, the in vivo anti-Plasmodium berghei activity of phytol including the ameliorative effects of the compound on P. berghei-associated anaemia and organ damage were investigated. Mice were infected with chloroquine-sensitive strain of P. berghei and were treated with phytol at a dose of 10 and 20 mg/kg body weight (BW) for four days. The levels of parasitemia, packed cell volume and redox sensitive biomarkers of liver, brain and spleen tissues were determined. Our result revealed that phytol significantly (p < 0.05) suppressed the multiplication of P. berghei in a dose-dependent manner. Additionally, the phytol significantly (p < 0.05) ameliorated the P. berghei-induced anaemia and brain damage. Data from the present study demonstrated that phytol has suppressive effect on P. berghei and could ameliorate some P. berghei-induced pathological changes.


Assuntos
Malária/tratamento farmacológico , Fitol/uso terapêutico , Plasmodium berghei/efeitos dos fármacos , Análise de Variância , Anemia/tratamento farmacológico , Anemia/parasitologia , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Encéfalo/parasitologia , Encéfalo/patologia , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Hematócrito , Fígado/parasitologia , Fígado/patologia , Malária/sangue , Malária/parasitologia , Malária/patologia , Masculino , Camundongos , Oxirredução/efeitos dos fármacos , Parasitemia/tratamento farmacológico , Fitol/farmacologia , Distribuição Aleatória , Baço/parasitologia , Baço/patologia
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