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1.
PLoS Pathog ; 16(3): e1008435, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32210480

RESUMO

A striking feature of human visceral leishmaniasis (VL) is chronic inflammation in the spleen and liver, and VL patients present increased production levels of multiple inflammatory mediators, which contribute to tissue damage and disease severity. Here, we combined an experimental model with the transcriptional profile of human VL to demonstrate that the TLR4-IFN-ß pathway regulates the chronic inflammatory process and is associated with the asymptomatic form of the disease. Tlr4-deficient mice harbored fewer parasites in their spleen and liver than wild-type mice. TLR4 deficiency enhanced the Th1 immune response against the parasite, which was correlated with an increased activation of dendritic cells (DCs). Gene expression analyses demonstrated that IRF1 and IFN-ß were expressed downstream of TLR4 after infection. Accordingly, IRF1- and IFNAR-deficient mice harbored fewer parasites in the target organs than wild-type mice due to having an increased Th1 immune response. However, the absence of TLR4 or IFNAR increased the serum transaminase levels in infected mice, indicating the presence of liver damage in these animals. In addition, IFN-ß limits IFN-γ production by acting directly on Th1 cells. Using RNA sequencing analysis of human samples, we demonstrated that the transcriptional signature for the TLR4 and type I IFN (IFN-I) pathways was positively modulated in asymptomatic subjects compared with VL patients and thus provide direct evidence demonstrating that the TLR4-IFN-I pathway is related to the nondevelopment of the disease. In conclusion, our results demonstrate that the TLR4-IRF1 pathway culminates in IFN-ß production as a mechanism for dampening the chronic inflammatory process and preventing immunopathology development.


Assuntos
Fator Regulador 1 de Interferon/imunologia , Interferon beta/imunologia , Leishmania infantum/imunologia , Leishmaniose Visceral/imunologia , Células Th1/imunologia , Receptor 4 Toll-Like/imunologia , Animais , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Fator Regulador 1 de Interferon/genética , Interferon beta/genética , Leishmaniose Visceral/genética , Leishmaniose Visceral/patologia , Camundongos , Camundongos Knockout , Células Th1/patologia , Receptor 4 Toll-Like/genética
2.
Nutr Cancer ; 73(4): 642-651, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32406264

RESUMO

There is a strong correlation between obesity and cancer. Here, we investigated the influence of IL-6 and gut microbiota of obese mice in melanoma development. We first evaluated B16F10 melanoma growth in preclinical models for obesity: mice deficient for leptin (ob/ob) or adiponectin (AdpKO) and in wild-type mice (WT, C57BL/6J) fed a high-fat diet (HFD; 60% kcal from fat) for 12 weeks. The survival rates of ob/ob and HFD-fed mice were lower than those of their respective controls. AdpKO mice also died earlier than WT control mice. We then verified the involvement of IL-6 signaling in obese mice that were inoculated with melanoma cells. Both ob/ob and AdpKO mice had higher circulating IL-6 levels than wild-type mice. Melanoma tumor volumes in IL-6 KO mice fed an HFD were reduced compared to those of WT mice subjected to the same diet. Also evaluated the effect of microbiota in tumor development. Cohousing and fecal matter transfer experiments revealed that microbiota from ob/ob mice can stimulate tumor development in lean WT mice. Taken together, our data show that in some conditions IL-6 and the gut microbiota are key mediators that link obesity and melanoma.


Assuntos
Microbioma Gastrointestinal , Melanoma , Animais , Dieta Hiperlipídica/efeitos adversos , Interleucina-6 , Leptina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos
3.
Parasite Immunol ; 42(7): e12722, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32294247

RESUMO

Leishmaniasis is a neglected infectious disease with clinical presentations ranging from asymptomatic or mild symptoms to chronic infection and eventual death. The mechanisms of disease susceptibility and pathology have been extensively studied, but there are no steadfast rules regarding leishmaniasis. A Th1 response is usually associated with infection control, while a predominant Th2 response is detrimental to the patient. In this scenario, the enzymes arginase and inducible nitric oxide synthase represent two possible pathways of immune response. While the former contributes to parasite replication, the latter is crucial for its control. In the present review, we collected study results that associate arginase expression in patients and in experimental models with disease susceptibility/chronicity and show some proposed mechanisms that explain the role of arginase in maintaining Leishmania infection, including polyamine and thiol synthesis, tissue-resident macrophage (TRM) proliferation and activation and T-cell suppression and exhaustion.


Assuntos
Arginase/metabolismo , Leishmania/imunologia , Leishmaniose/imunologia , Macrófagos/imunologia , Óxido Nítrico Sintase Tipo II/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Humanos , Imunidade Inata/imunologia , Leishmaniose/parasitologia , Neutrófilos/imunologia , Células Th1/imunologia , Células Th2/imunologia
4.
J Infect Dis ; 217(2): 329-339, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29099934

RESUMO

Background: Paracoccidioides brasiliensis is equipped with an arsenal of virulence factors that are crucial for causing infection. Our group previously defined the NLRP3 inflammasome as a mediator of P brasiliensis-induced cell damage recognition and induction of effective Th1 immune responses. However, deficiency of caspase-1 only partially reduced interleukin (IL)-1ß levels. Methods: In this study, using chemical inhibitors as well as genetically modified mice, we identify an additional pathway for IL-1ß production in response to P brasiliensis infection. Results: Paracoccidioides brasiliensis initiated caspase-8-mediated IL-1ß production, an event that was necessary for transcriptional priming and posttranslational processing of pro-IL-1ß. Caspase-8 synergizes with the canonical NLRP3 inflammasome pathway to control caspase-1 processing and IL-1ß maturation, providing a regulatory role for caspase-8 in host resistance to in vivo P brasiliensis infection. Conclusions: Taken together, these findings revealed an important role for caspase-8 in the innate immune response of host cells to P brasiliensis infection, demonstrating a connected network between noncanonical and canonical inflammasomes to coordinate IL-1ß production during fungal challenge.


Assuntos
Caspase 1/metabolismo , Caspase 8/metabolismo , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Paracoccidioides/imunologia , Paracoccidioidomicose/imunologia , Animais , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/parasitologia , Redes Reguladoras de Genes , Imunidade Inata , Lectinas Tipo C/metabolismo , Macrófagos/imunologia , Macrófagos/parasitologia , Camundongos Endogâmicos C57BL
5.
Clin Immunol ; 190: 74-83, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28965882

RESUMO

To analyze the participation of the enzyme 5-lipoxygenase (5-LO) in skin repair, WT wounds were compared to those in 5-LO deficient mice (5-LO-/-), which presented faster closure and reduced inflammatory infiltrate in the skin, together with increased CD4 regulatory T cells markers in the draining lymph nodes. The 5-LO-/- wounds also had diminished TNF-α, CCL11, CCL7, CCL2, CXCL9, CCR1 and CXCR2 mRNA expression in the lesions, besides differential extracellular matrix remodeling. Furthermore, when cysteinyl leukotriene (cysLT) and leukotriene (LTB4) receptors were antagonized in WT mice, there was a remarkable reduction in TNF-α expression and faster skin healing, similarly to the findings in 5-LO-/- animals. Finally, our results suggested that 5-LO products, in special cysLT and LTB4, underline skin inflammation that follows skin injury and their neutralization may be an important strategy to improve cutaneous healing.


Assuntos
Araquidonato 5-Lipoxigenase/imunologia , Cisteína/imunologia , Citocinas/imunologia , Mediadores da Inflamação/imunologia , Leucotrieno B4/imunologia , Leucotrienos/imunologia , Cicatrização/imunologia , Animais , Araquidonato 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/metabolismo , Cisteína/metabolismo , Citocinas/genética , Citocinas/metabolismo , Feminino , Expressão Gênica/imunologia , Mediadores da Inflamação/metabolismo , Leucotrieno B4/metabolismo , Leucotrienos/metabolismo , Camundongos da Linhagem 129 , Camundongos Knockout , Pele/imunologia , Pele/metabolismo , Pele/patologia , Cicatrização/genética
7.
Inflammopharmacology ; 26(2): 403-411, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28168553

RESUMO

Chemokines are a large family of proteins that, once associated to its receptor on leukocytes, stimulate their movement and migration from blood to tissues. Once in the tissue, immune cells trigger inflammation that, when uncontrolled, leads to fibrosis development. Among the immune cells, macrophages take a special role in fibrosis formation, since macrophage depletion reflects less collagen deposition. The majority of tissue macrophages is derived from monocytes, especially monocytes expressing the chemokine receptor CCR2. Here, we investigated the role of infiltrating CCR2+ cells in the development of fibrosis, and specifically, the dynamic of infiltration of these cells into kidneys under chronic obstructive lesion. Using liposome-encapsulated clodronate, we observed that macrophage depletion culminated in less collagen deposition and reduced chemokines milieu that were released in the damaged kidney after obstructive nephropathy. We also obstructed the kidneys of CCL3-/-, CCR2-/-, CCR4-/-, CCR5-/-, and C57BL/6 mice and we found that among all animals, CCR2-/- mice demonstrated the more robust protection, reflected by less inflammatory and Th17-related cytokines and less collagen formation. Next we evaluated the dynamic of CCR2+/rfp cell infiltration and we observed that they adhere onto the vessels at early stages of disease, culminating in increased recruitment of CCR2+/rfp cells at later stages. On the other hand, CCR2rfp/rfp animals exhibited less fibrosis formation and reduced numbers of recruited cells at later stages. We have experimentally demonstrated that inflammatory CCR2+ cells that reach the injured kidney at initial stages after tissue damage are responsible for the fibrotic pattern observed at later time points in the context of UUO.


Assuntos
Fibrose/patologia , Inflamação/patologia , Nefropatias/patologia , Rim/patologia , Monócitos/patologia , Receptores CCR2/metabolismo , Animais , Colágeno/metabolismo , Citocinas/metabolismo , Fibrose/metabolismo , Inflamação/metabolismo , Rim/metabolismo , Nefropatias/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo
8.
Mediators Inflamm ; 2016: 3694714, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27688600

RESUMO

Chemokines (CKs) and chemokine receptors (CKR) promote leukocyte recruitment into cardiac tissue infected by the Trypanosoma cruzi. This study investigated the long-term treatment with subantimicrobial doses of doxycycline (Dox) in association, or not, with benznidazole (Bz) on the expression of CK and CKR in cardiac tissue. Thirty mongrel dogs were infected, or not, with the Berenice-78 strain of T. cruzi and grouped according their treatments: (i) two months after infection, Dox (50 mg/kg) 2x/day for 12 months; (ii) nine months after infection, Bz (3,5 mg/kg) 2x/day for 60 days; (iii) Dox + Bz; and (iv) vehicle. After 14 months of infection, hearts were excised and processed for qPCR analysis of Th1 (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL11), Th2 (CCL1, CCL17, CCL24, and CCL26), Th17 (CCL20) CKs, Th1 (CCR5, CCR6, and CXCR3), and Th2/Th17 (CCR3, CCR4, and CCR8) CKR, as well as IL-17. T. cruzi infection increases CCL1, CCL2, CCL4, CCL5, CCL17, CXCL10, and CCR5 expression in the heart. Dox, Bz, or Dox + Bz treatments cause a reversal of CK and CKR and reduce the expression of CCL20, IL-17, CCR6, and CXCR3. Our data reveal an immune modulatory effect of Dox with Bz, during the chronic phase of infection suggesting a promising therapy for cardiac protection.

9.
Mediators Inflamm ; 2016: 9626427, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27872515

RESUMO

The prostaglandin, 15-deoxy Δ12,14-prostaglandin J2 (15d-PGJ2), is a lipid mediator that plays an important role in the control of chronic inflammatory disease. However, the role of prostanoid in rheumatoid arthritis (RA) is not well determined. We demonstrated the therapeutic effect of 15d-PGJ2 in an experimental model of arthritis. Daily administration of 15d-PGJ2 attenuated the severity of CIA, reducing the clinical score, pain, and edema. 15d-PGJ2 treatment was associated with a marked reduction in joint levels of proinflammatory cytokines. Although the mRNA expression of ROR-γt was profoundly reduced, FOXP3 was enhanced in draining lymph node cells from 15d-PGJ2-treated arthritic mice. The specific and polyclonal CD4+ Th17 cell responses were limited during the addition of prostaglandin to cell culture. Moreover, in vitro 15d-PGJ2 increased the expression of FOXP3, GITR, and CTLA-4 in the CD4+CD25- population, suggesting the induction of Tregs on conventional T cells. Prostanoid addition to CD4+CD25- cells selectively suppressed Th17 differentiation and promoted the enhancement of FOXP3 under polarization conditions. Thus, 15d-PGJ2 ameliorated symptoms of collagen-induced arthritis by regulating Th17 differentiation, concomitant with the induction of Tregs, and, consequently, protected mice from diseases aggravation. Altogether, these results indicate that 15d-PGJ2 may represent a potential therapeutic strategy in RA.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Antígenos CD4/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Prostaglandina D2/análogos & derivados , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Animais , Artrite Experimental/imunologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , PPAR gama/agonistas , PPAR gama/metabolismo , Prostaglandina D2/farmacologia , Prostaglandina D2/uso terapêutico
10.
J Infect Dis ; 211(6): 1015-26, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25274569

RESUMO

Interleukin 17 (IL-17) is an inflammatory cytokine that plays a protective role against intracellular parasites. The role of IL-17 during Leishmania infection remains controversial and poorly defined. We evaluated whether IL-17 participates in the host immune response to Leishmania infantum. IL-17A is present in sera from patients with visceral leishmaniasis and decreases after successful treatment. In C57BL/6 infected mice, higher production of IL-17A coincided with the peak of parasitism. Il17ra(-/-) mice were more susceptible to infection and also exhibited reduced inflammatory infiltration and interferon γ (IFN-γ)-expressing CD4+ T-cell frequencies than wild-type mice. The frequencies of FoxP3+ CD4+ T cells and interleukin 10 (IL-10)-expressing CD4+ T cells were increased in Il17ra(-/-) mice. We also demonstrated that IL-17A acts synergistically with IFN-γ to potentiate NO production and leishmanicidal activity in infected macrophages. Therefore, our results indicate that L. infantum induces IL-17A production, which promotes the control of parasite replication by strengthening T-helper type 1 responses and NO production and prevents regulatory T-cell and IL-10-expressing T-cell expansion.


Assuntos
Interferon gama/fisiologia , Interleucina-17/fisiologia , Leishmania infantum/imunologia , Leishmaniose Visceral/imunologia , Adolescente , Adulto , Animais , Células Cultivadas , Criança , Pré-Escolar , Feminino , Humanos , Imunidade Celular , Leishmaniose Visceral/sangue , Leishmaniose Visceral/parasitologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/parasitologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/parasitologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/parasitologia , Adulto Jovem
11.
Tetrahedron ; 71(39): 7344-7353, 2015 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-26435551

RESUMO

Reaction of 2-(2-(2-azidoethoxy)ethoxy)ethyl 6-O-(prop-2-ynyl)-ß-d-galactopyranoside (7) under CuAAC conditions gives rise to mixed cyclic and linear triazole-linked oligomers, with individual compounds up to d.p. 5 isolable, along with mixed larger oligomers. The linear compounds resolve en bloc from the cyclic materials by RP HPLC, but are separable by gel permeation chromatography. The triazole-linked oligomers-pseudo-galactooligomers-were demonstrated to be acceptor substrates for the multi-copy cell surface trans-sialidase of the human parasite Trypanosoma cruzi. In addition, these multivalent TcTS ligands were able to block macrophage invasion by T. cruzi.

12.
Mediators Inflamm ; 2015: 983782, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26063981

RESUMO

Chronic periodontitis is a multifactorial inflammatory disease that affects supporting structures of the teeth. Although the gingival response is largely described, little is known about the immune changes in the alveolar bone and neighboring tissues that could indicate periodontal disease (PD) activity. Then, in this study we identified the ongoing inflammatory changes and novel biomarkers for periodontitis in the tissues directly affected by the destructive disease in PD patients. Samples were collected by osteotomy in 17 control subjects during extraction of third molars and 18 patients with advanced PD, in which alveoloplasty was necessary after extraction of teeth with previous extensive periodontal damage. Patients presented mononuclear cells infiltration in the connective tissue next to the bone and higher fibrosis area, along with increased accumulation of IL-17(+) and TRAP(+) cells. The levels of TNF-α and MMP-2 mRNA were also elevated compared to controls and a positive and significant correlation was observed between TNF-α and MMP-2 mRNA expression, considering all samples evaluated. In conclusion, nongingival tissues neighboring large periodontal pockets present inflammatory markers that could predict ongoing bone resorption and disease spreading. Therefore, we suggested that the detailed evaluation of these regions could be of great importance to the assessment of disease progression.


Assuntos
Periodontite Crônica/metabolismo , Interleucina-17/genética , Metaloproteinase 2 da Matriz/genética , Fator de Necrose Tumoral alfa/genética , Adulto , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análise , Fator de Crescimento Transformador beta/genética
13.
J Oral Pathol Med ; 43(10): 754-60, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25060152

RESUMO

BACKGROUND: Actinic cheilitis (AC) is an oral potentially malignant lesion which is the counterpart of actinic keratosis of the skin and has potential to develop into squamous cell carcinoma. Regulatory T cells (Tregs) have a critical role in modulating the antitumor immune responses. The presence of regulatory T cells in potentially malignant lesions has not been described. We chose investigate the involvement of regulatory T cells in potentially malignant lesions. METHODS: The frequency, phenotype, and activity of CD4+CD25+ T cells isolated from blood and lesion of AC patients were analyzed by flow cytometry. Cytokines were quantified by ELISA. Data were compared with samples from healthy subjects. RESULTS: The frequency and suppressor activity of circulating CD4+CD25+ T cells was similar in AC patients and control subjects. However, the frequencies of IL-10-positive Tregs were higher in AC patients, and these cells inhibited interferon-gamma (IFN-γ) and increased interleukin (IL)-10 productions in co-cultures. Furthermore, CD4+CD25+ T cells accumulate in AC lesions. Lesions-derived regulatory T cells suppressed lymphocyte proliferation and pro-inflammatory cytokine production. Moreover, high levels of IL-10 and transforming growth factor-ß (TGF-ß), and low IFN-γ were detected in the potentially malignant lesions. CONCLUSION: Therefore, our data show that Tregs accumulate in AC lesions, and these cells could be suppressing immune responses in a potentially malignant microenvironment.


Assuntos
Queilite/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD4/análise , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Proliferação de Células , Queilite/sangue , Queilite/patologia , Humanos , Mediadores da Inflamação/imunologia , Interferon gama/análise , Interleucina-10/análise , Subunidade alfa de Receptor de Interleucina-2/análise , Leucócitos Mononucleares/imunologia , Neoplasias Labiais/imunologia , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Pessoa de Meia-Idade , Fenótipo , Lesões Pré-Cancerosas/imunologia , Linfócitos T Reguladores/patologia , Fator de Crescimento Transformador beta/análise , Microambiente Tumoral/imunologia
14.
Mediators Inflamm ; 2014: 291024, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25132730

RESUMO

Macrophages play a special role in the onset of several diseases, including acute and chronic kidney injuries. In this sense, tubule interstitial nephritis (TIN) represents an underestimated insult, which can be triggered by different stimuli and, in the absence of a proper regulation, can lead to fibrosis deposition. Based on this perception, we evaluated the participation of macrophage recruitment in the development of TIN. Initially, we provided adenine-enriched food to WT and searched for macrophage presence and action in the kidney. Also, a group of animals were depleted of macrophages with the clodronate liposome while receiving adenine-enriched diet. We collected blood and renal tissue from these animals and renal function, inflammation, and fibrosis were evaluated. We observed higher expression of chemokines in the kidneys of adenine-fed mice and a substantial protection when macrophages were depleted. Then, we specifically investigated the role of some key chemokines, CCR5 and CCL3, in this TIN experimental model. Interestingly, CCR5 KO and CCL3 KO animals showed less renal dysfunction and a decreased proinflammatory profile. Furthermore, in those animals, there was less profibrotic signaling. In conclusion, we can suggest that macrophage infiltration is important for the onset of renal injury in the adenine-induced TIN.


Assuntos
Injúria Renal Aguda/metabolismo , Adenina/toxicidade , Quimiocina CCL3/metabolismo , Rim/metabolismo , Macrófagos/metabolismo , Receptores CCR5/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/genética , Animais , Quimiocina CCL3/genética , Citometria de Fluxo , Rim/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Nefrite Intersticial/metabolismo , Receptores CCR5/genética
15.
Bioorg Med Chem Lett ; 23(16): 4597-601, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23850203

RESUMO

The 1,4-dihydro-4-oxoquinoline ribonucleoside, Neq135, is the first low micromolar trypanosomatidae inhibitor to show good ligand efficiency (0.28 kcal mol(-1)atom(-1)) and good ligand lipophilicity efficiency (0.37 kcal mol(-1)atom(-1)) when acting against Trypanosoma cruzi glyceraldehyde 3-phosphate dehydrogenase (TcGAPDH). This and other six ribonucleosides were synthesized using our in-house technology, and assayed against the GAPDH NAD(+) site using isothermal titration calorimetry (ITC). Compound Neq135 had acceptable in vitro cytotoxicity, inhibited TcGAPDH with a Ki(app) value of 16 µM and killed the trypomastigote form of Trypanosoma cruzi Tulahuen strain with a concentration similar to that displayed by the control drug benznidazole. Neq135 is tenfold lower kinetic affinity against hGAPDH and does not kill Balb-c fibroblast nor spleen mouse cells. These results emphasize the possibility of integrating ligand- and target-based designs to uncover potent and selective TcGAPDH inhibitors that expands the opportunity for further medicinal chemistry endeavor towards NAD(+) TcGAPDH site.


Assuntos
Desenho de Fármacos , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/antagonistas & inibidores , Ribonucleosídeos/síntese química , Ribonucleosídeos/farmacologia , Tripanossomicidas , Trypanosoma cruzi/efeitos dos fármacos , 4-Quinolonas/síntese química , 4-Quinolonas/química , 4-Quinolonas/farmacologia , Animais , Células 3T3 BALB , Fibroblastos/efeitos dos fármacos , Concentração Inibidora 50 , Camundongos , Nitroimidazóis/química , Nitroimidazóis/farmacologia , Ribonucleosídeos/química , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Tripanossomicidas/farmacologia
16.
Data Brief ; 46: 108811, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36582994

RESUMO

This dataset is related to the article "Insight Into the Long Noncoding RNA and mRNA Coexpression Profile in the Human Blood Transcriptome Upon Leishmania infantum Infection" by S.R. Maruyama, C.A. Fuzo, A.E.R. Oliveira, L.A. Rogerio, N.T. Takamiya, G. Pessenda, E.V. de Melo, A.M. da Silva, A.R. Jesus, V. Carregaro, H.I. Nakaya, R.P. Almeida and J.S. da Silva. Frontiers in Immunology, 2022. Through the reuse of raw sequencing data, we generated original dataset by performing a dual RNA-seq mapping procedure to survey the parasite transcripts found in RNA-seq samples from blood of visceral leishmaniasis patients. Diseased patients with active infection displayed the highest number of reads mapped to L. infantum genome. Even after six months later of the treatment, when the patients were considered cured, parasite reads were still detected. Parasite reads were also detected in asymptomatic individuals. The original dual RNA-seq alignment read count data provided here can be further explored to evaluate either host or parasite transcripts.

17.
Arch Dermatol Res ; 315(3): 481-490, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36042041

RESUMO

Transcriptional factor B lymphocyte-induced maturation protein 1 (Blimp-1) is pivotally implicated in T helper 17 (Th17) cell differentiation. This study investigated expression of the Blimp-1 protein, positive regulatory domain 1 (PRDM1), and cytokine genes in psoriasis (PsO). Affected (AS-PsO) and non-affected skin (nAS-PsO) samples were used to assess gene and protein expressions by reverse transcription-quantitative PCR (RT-qPCR), and immunostaining and confocal microscopy, respectively; the normalised public transcriptomic data permitted differential gene expression analyses. On RT-qPCR, PRDM1 and IL17A transcripts showed higher expression in AS-PsO than in nAS-PsO (n = 34) (p < 0.001; p < 0.0001, respectively). Confocal microscopy showed Blimp-1 protein expression in epidermal layer keratinocytes in AS-PsO, but not in nAS-PsO. Bioinformatic analysis of the transcriptomic dataset GSE13355 corroborated the increased PRDM1, signal transducer and activator of transcription 3 (STAT3), IL12B, TNF, IL17A, IL6, IL1B, IL22, and IL10 gene expression in AS-PsO, when compared to normal skin and nAS-PsO (p < 0.001). PRDM1 expression correlated positively (p < 0.0001) with that of IL17A (r = 0.7), IL1B (r = 0.67), IL12B (r = 0.6), IL6 (r = 0.59), IL22 (r = 0.53), IL23A (r = 0.47), IL21 (r = 0.47), IL27 (r = 0.34), IL23R (r = 0.32), S100 calcium binding protein A9 (r = 0.63), and lipocalin 2 (r = 0.50), and negatively with that of TGFB1 (r = - 0.28) and RORC (r = - 0.60). Blimp-1 may be critical in the pathogenesis of PsO dysregulation involving the Th17 inflammatory pathway. This knowledge may accelerate the development of new treatments.


Assuntos
Interleucina-6 , Psoríase , Humanos , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Queratinócitos , Psoríase/genética , Psoríase/patologia , Pele , Células Th17/patologia
18.
Int J Infect Dis ; 133: 85-88, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37182549

RESUMO

We report a refractory and relapsed visceral leishmaniasis case in a male child patient followed from 2016 to 2020, whose clinical isolates from multiple relapses were analyzed at the genome level. To the best of our knowledge, it is the first report that both visceral leishmaniasis and non-ulcerated cutaneous leishmaniasis have concomitantly manifested in the same patient. Importantly, sequence analysis revealed that the patient was co-infected with Leishmania infantum and a Crithidia-related parasite, which was previously found in a fatal case of visceral leishmaniasis from the same endemic region.


Assuntos
Coinfecção , Leishmania infantum , Leishmaniose Cutânea , Leishmaniose Visceral , Criança , Humanos , Masculino , Leishmaniose Visceral/complicações , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/tratamento farmacológico , Leishmania infantum/genética , Brasil/epidemiologia , Coinfecção/diagnóstico , Leishmaniose Cutânea/parasitologia , Crithidia
19.
Trop Med Infect Dis ; 8(8)2023 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-37624343

RESUMO

Visceral leishmaniasis (VL) is a neglected disease considered a serious public health problem, especially in endemic countries. Several studies have discovered monoxenous trypanosomatids (Leptomonas and Crithidia) in patients with VL. In different situations of leishmaniasis, investigations have examined cases of co-infection between Leishmania spp. and Crithidia spp. These coinfections have been observed in a wide range of vertebrate hosts, indicating that they are not rare. Diagnostic techniques require improvements and more robust tools to accurately detect the causative agent of VL. This study aimed to develop a real-time quantitative dye-based PCR (qPCR) assay capable of distinguishing Leishmania infantum from Crithidia-related species and to estimate the parasite load in samples of VL from humans and animals. The primer LinJ31_2420 targets an exclusive phosphatase of L. infantum; the primer Catalase_LVH60-12060_1F targets the catalase gene of Crithidia. Therefore, primers were designed to detect L. infantum and Crithidia sp. LVH60A (a novel trypanosomatid isolated from VL patients in Brazil), in samples related to VL. These primers were considered species-specific, based on sequence analysis using genome data retrieved from the TriTryp database and the genome assembling of Crithidia sp. LVH60A strain, in addition to experimental and clinical data presented herein. This novel qPCR assay was highly accurate in identifying and quantifying L. infantum and Crithidia sp. LVH60A in samples obtained experimentally (in vitro and in vivo) or collected from hosts (humans, dogs, cats, and vectors). Importantly, the screening of 62 cultured isolates from VL patients using these primers surprisingly revealed that 51 parasite cultures were PCR+ for Crithidia sp. In addition, qPCR assays identified the co-infection of L. infantum with Crithidia sp. LVH60A in two new VL cases in Brazil, confirming the suspicion of co-infection in a previously reported case of fatal VL. We believe that the species-specific genes targeted in this study can be helpful for the molecular diagnosis of VL, as well as for elucidating suspected co-infections with monoxenous-like trypanosomatids, which is a neglected fact of a neglected disease.

20.
ScientificWorldJournal ; 2012: 525947, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22666132

RESUMO

Dengue fever is a noncontagious infectious disease caused by dengue virus (DENV). DENV belongs to the family Flaviviridae, genus Flavivirus, and is classified into four antigenically distinct serotypes: DENV-1, DENV-2, DENV-3, and DENV-4. The number of nations and people affected has increased steadily and today is considered the most widely spread arbovirus (arthropod-borne viral disease) in the world. The absence of an appropriate animal model for studying the disease has hindered the understanding of dengue pathogenesis. In our study, we have found that immunocompetent C57BL/6 mice infected intraperitoneally with DENV-1 presented some signs of dengue disease such as thrombocytopenia, spleen hemorrhage, liver damage, and increase in production of IFNγ and TNFα cytokines. Moreover, the animals became viremic and the virus was detected in several organs by real-time RT-PCR. Thus, this animal model could be used to study mechanism of dengue virus infection, to test antiviral drugs, as well as to evaluate candidate vaccines.


Assuntos
Dengue/imunologia , Modelos Animais de Doenças , Imunocompetência , Animais , Linfócitos T CD4-Positivos/imunologia , Citocinas/imunologia , Dengue/patologia , Vírus da Dengue/genética , Vírus da Dengue/isolamento & purificação , Ensaio de Imunoadsorção Enzimática , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Baço/imunologia , Baço/patologia , Carga Viral
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