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1.
Sci Rep ; 13(1): 7362, 2023 05 05.
Article in English | MEDLINE | ID: mdl-37147351

ABSTRACT

Vaccination with live attenuated Leishmania parasites such as centrin deleted Leishmania donovani (LdCen-/-) against visceral leishmaniasis has been reported extensively. The protection induced by LdCen-/- parasites was mediated by both CD4+ and CD8+ T cells. While the host immune mediators of protection are known, parasite determinants that affect the CD4+ and CD8+ T cell populations remain unknown. Parasite encoded inflammatory cytokine MIF has been shown to modulate the T cell differentiation characteristics by altering the inflammation induced apoptosis during contraction phase in experimental infections with Leishmania or Plasmodium. Neutralization of parasite encoded MIF either by antibodies or gene deletion conferred protection in Plasmodium and Leishmania studies. We investigated if the immunogenicity and protection induced by LdCen-/- parasites is affected by deleting MIF genes from this vaccine strain. Our results showed that LdCen-/-MIF-/- immunized group presented higher percentage of CD4+ and CD8+ central memory T cells, increased CD8+ T cell proliferation after challenge compared to LdCen-/- immunization. LdCen-/-MIF-/- immunized group presented elevated production of IFN-γ+ and TNF-α+ CD4+ T cells concomitant with a reduced parasite load in spleen and liver compared to LdCen-/-group following challenge with L. infantum. Our results demonstrate the role of parasite induced factors involved in protection and long-term immunity of vaccines against VL.


Subject(s)
Leishmania donovani , Leishmaniasis Vaccines , Leishmaniasis, Visceral , Parasites , Animals , Mice , CD8-Positive T-Lymphocytes , Leishmaniasis, Visceral/parasitology , Leishmania donovani/genetics , CD4-Positive T-Lymphocytes , Mice, Inbred BALB C
2.
Virol J ; 19(1): 31, 2022 02 22.
Article in English | MEDLINE | ID: mdl-35193667

ABSTRACT

BACKGROUND: The worldwide epidemics of diseases as dengue and Zika have triggered an intense effort to repurpose drugs and search for novel antivirals to treat patients as no approved drugs for these diseases are currently available. Our aim was to screen plant-derived extracts to identify and isolate compounds with antiviral properties against dengue virus (DENV) and Zika virus (ZIKV). METHODS: Seven thousand plant extracts were screened in vitro for their antiviral properties against DENV-2 and ZIKV by their viral cytopathic effect reduction followed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, previously validated for this purpose. Selected extracts were submitted to bioactivity-guided fractionation using high- and ultrahigh-pressure liquid chromatography. In parallel, high-resolution mass spectrometric data (MSn) were collected from each fraction, allowing compounds into the active fractions to be tracked in subsequent fractionation procedures. The virucidal activity of extracts and compounds was assessed by using the plaque reduction assay. EC50 and CC50 were determined by dose response experiments, and the ratio (EC50/CC50) was used as a selectivity index (SI) to measure the antiviral vs. cytotoxic activity. Purified compounds were used in nuclear magnetic resonance spectroscopy to identify their chemical structures. Two compounds were associated in different proportions and submitted to bioassays against both viruses to investigate possible synergy. In silico prediction of the pharmacokinetic and toxicity (ADMET) properties of the antiviral compounds were calculated using the pkCSM platform. RESULTS: We detected antiviral activity against DENV-2 and ZIKV in 21 extracts obtained from 15 plant species. Hippeastrum (Amaryllidaceae) was the most represented genus, affording seven active extracts. Bioactivity-guided fractionation of several extracts led to the purification of lycorine, pretazettine, narciclasine, and narciclasine-4-O-ß-D-xylopyranoside (NXP). Another 16 compounds were identified in active fractions. Association of lycorine and pretazettine did not improve their antiviral activity against DENV-2 and neither to ZIKV. ADMET prediction suggested that these four compounds may have a good metabolism and no mutagenic toxicity. Predicted oral absorption, distribution, and excretion parameters of lycorine and pretazettine indicate them as candidates to be tested in animal models. CONCLUSIONS: Our results showed that plant extracts, especially those from the Hippeastrum genus, can be a valuable source of antiviral compounds against ZIKV and DENV-2. The majority of compounds identified have never been previously described for their activity against ZIKV and other viruses.


Subject(s)
Dengue Virus , Dengue , Zika Virus Infection , Zika Virus , Animals , Antiviral Agents/chemistry , Chlorocebus aethiops , Dengue/drug therapy , Humans , Vero Cells
3.
Nanomedicine (Lond) ; 16(29): 2633-2650, 2021 12.
Article in English | MEDLINE | ID: mdl-34854309

ABSTRACT

Cancer immunotherapy is the most promising trend in oncology, focusing on helping or activating the patient's immune system to identify and fight against cancer. In the last decade, interest in metabolic reprogramming of tumor-associated macrophages from M2-like phenotype (promoting tumor progression) to M1-like phenotypes (suppressing tumor growth) as a therapeutic strategy against cancer has increased considerably. Iron metabolism has been standing out as a target for the reprogramming of tumor-associated macrophages to M1-like phenotype with therapeutic purposes against cancer. Due to the importance of the iron levels in macrophage polarization states, iron oxide nanoparticles can be used to change the activation state of tumor-associated macrophages for a tumor suppressor phenotype and as an anti-tumor strategy.


Subject(s)
Nanoparticles , Neoplasms , Humans , Immunotherapy , Macrophages , Magnetic Iron Oxide Nanoparticles , Neoplasms/drug therapy , Tumor-Associated Macrophages
4.
PLoS Negl Trop Dis ; 14(8): e0008635, 2020 08.
Article in English | MEDLINE | ID: mdl-32853206

ABSTRACT

BACKGROUND: In view of the potential immunosuppressive and regenerative properties of mesenchymal stem cells (MSC), we investigated whether transplantation of adipose tissue-derived stem cells (ASC) could be used to control the granulomatous reaction in the liver of mice infected with Schistosoma mansoni after Praziquantel (PZQ) treatment. METHODOLOGY/PRINICPAL FINDINGS: C57BL/6 mice infected with S. mansoni were treated with PZQ and transplanted intravenously with ASC from uninfected mice. Liver morpho-physiological and immunological analyses were performed. The combined PZQ/ASC therapy significantly reduced the volume of hepatic granulomas, as well as liver damage as measured by ALT levels. We also observed that ASC accelerated the progression of the granulomatous inflammation to the advanced/curative phase. The faster healing interfered with the expression of CD28 and CTLA-4 molecules in CD4+ T lymphocytes, and the levels of IL-10 and IL-17 cytokines, mainly in the livers of PZQ/ASC-treated mice. CONCLUSIONS: Our results show that ASC therapy after PZQ treatment results in smaller granulomas with little tissue damage, suggesting the potential of ASC for the development of novel therapeutic approaches to minimize hepatic lesions as well as a granulomatous reaction following S. mansoni infection. Further studies using the chronic model of schistosomiasis are required to corroborate the therapeutic use of ASC for schistosomiasis.


Subject(s)
Adipose Tissue/physiology , Cell- and Tissue-Based Therapy/methods , Liver Diseases/therapy , Liver/parasitology , Praziquantel/therapeutic use , Schistosomiasis/drug therapy , Animals , Cytokines/metabolism , Disease Models, Animal , Granuloma , Liver/metabolism , Liver/pathology , Liver Diseases/pathology , Male , Mice , Mice, Inbred C57BL , Schistosoma mansoni , Schistosomiasis/pathology , Schistosomiasis mansoni
5.
Int J Dent ; 2020: 8636795, 2020.
Article in English | MEDLINE | ID: mdl-32148505

ABSTRACT

BACKGROUND: Several studies have focused on the association between periodontitis and systemic implications; however, the biological mechanisms of the immune responses before and after periodontal therapy involved in this relationship, such as phagocytic functions, remain unclear. OBJECTIVES: This study aimed to investigate whether periodontal treatment improves the phagocytic function of blood monocytes in patients with severe periodontitis. Materials and Methods. A nonrandomized sample of 55 participants was enrolled in the study. Two groups were studied: control (n = 27, healthy subjects without periodontal disease) and patients (n = 27, healthy subjects without periodontal disease) and patients (. RESULTS: Periodontitis induced impaired phagocytosis by monocytes. Phagocytosis at baseline was significantly lower in periodontitis patients [median, 13.2 (range of 7.1 to 20.8) and 60.7 (40.6 to 88.6)] than in controls [27.4 (15.5 to 40.5)] and 98 (68.2 to 122.9)] for nonsensitized or sensitized samples, respectively. After supportive therapy, patients showed a significant enhancement of phagocytic functions [33.7 (14.6 to 53.2) and 108.5 (99.6 to 159.5)] for nonsensitized and sensitized samples, respectively. Periodontal treatment increased the phagocytic capacity to a level similar to that observed in the control group and improved the capacity of phagocytes to produce superoxide anion. CONCLUSIONS: The results suggest that periodontal therapy in patients with severe periodontitis provides a state of homeostasis due to the reestablishment of phagocytic function and increased production of NBT (Regional Registry No. RBR-24T799; Universal Registry No. U1111-1133-5512).

6.
Vaccine ; 38(8): 2005-2015, 2020 02 18.
Article in English | MEDLINE | ID: mdl-31982262

ABSTRACT

Dengue virus (DENV) is a Flavivirus estimated to cause 390 million infections/year. Currently, there is no anti-viral specific treatment for dengue, and efficient DENV vector control is still unfeasible. Here, we designed and produced chimeric proteins containing potential immunogenic epitopes from the four DENV serotypes in an attempt to further compose safer, balanced tetravalent dengue vaccines. For this, South American DENV isolate sequences were downloaded from the NCBI/Virus Variation/Dengue virus databases and intraserotype-aligned to generate four consensuses. Four homologous DENV sequences were retrieved using BLAST and then interserotype-aligned. In parallel, sequences were subjected to linear B epitope prediction analysis. Regions of the envelope and NS1 proteins that are highly homologous among the four DENV serotypes, non-conserved antigenic regions and the most antigenic epitopes found in the C, prM, E and NS1 DENV proteins were used to construct 11 chimeric peptides. Genes encoding the chimeric proteins were commercially synthesized, and proteins were expressed, purified by affinity chromatography and further subjected to ELISA assays using sera from individuals infected with DENVs 1, 2, 3 or 4. As a proof-of-concept, the chimeric EnvEpII protein was selected to immunize BALB/c and C57BL/6 mice strains. The immunization with EnvEpII protein associated with aluminum induced an increased number of T CD4+ and CD8+ cells, high production of IgG1 and IgG2 antibodies, and increased levels of IL-2 and IL-17 cytokines, in both mouse strains. Because the EnvEpII protein associated with aluminum induced an efficient cellular response by stimulating the production of IL-2, IL-4, IL-17 and induced a robust humoral response in mice, we conclude that it resembles an efficient specific response against DENV infection. Although further experiments are required, our results indicate that epitope selection by bioinformatic tools is efficient to create recombinant proteins that can be used as candidates for the development of vaccines against infectious diseases.


Subject(s)
Dengue Vaccines , Dengue , Recombinant Fusion Proteins/immunology , Viral Proteins/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Cytokines/immunology , Dengue/prevention & control , Dengue Vaccines/genetics , Dengue Virus/genetics , Dengue Virus/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Recombinant Fusion Proteins/genetics , T-Lymphocytes/immunology , Vaccines, Combined/genetics , Viral Proteins/genetics
7.
Int Immunopharmacol ; 60: 179-188, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29747123

ABSTRACT

HIV aspartyl protease inhibitors are able to modulate multiple defense mechanisms. However, their influence on the immune response against Leishmania has rarely been investigated. The aim of our study was to investigate whether in vivo treatment with HIV aspartyl protease inhibitors is able to modulate the immune response during Leishmania infection. Using Leishmania (L.) amazonensis-infected mice, we analyzed the disease evolution and parasite load, immunophenotypic profiles of splenic T and B lymphocytes, numbers of lymphoid aggregates in the spleen, percentages of circulating atypical lymphocytes and reactive monocytes, and serum levels of cytokines and nitric oxide (NO) after 30 days of oral treatment with lopinavir/ritonavir (LPV/RTV) or atazanavir (ATV). We observed that LPV/RTV and ATV did not modify the disease evolution or parasite load. However, the antiretroviral treatment induced an increase in activated lymphocytes in the spleen and blood, as well as a decrease in CD69 expression in T and B lymphocytes in the spleen. The treatment also resulted in an increase in activated monocytes in the blood. In addition, antiretrovirals decreased levels of IL-17A and increased levels of NO in sera from Leishmania-infected mice. Thus, our results demonstrate for the first time that in vivo treatment with HIV aspartyl protease inhibitors modifies innate and adaptative immune responses during Leishmania infection and suggest that these drugs could change the clinical course of leishmaniasis in HIV infected-individuals.


Subject(s)
HIV Protease Inhibitors/pharmacology , HIV Protease Inhibitors/therapeutic use , Leishmaniasis/drug therapy , Animals , Atazanavir Sulfate/pharmacology , Atazanavir Sulfate/therapeutic use , Cytokines/blood , Female , Leishmaniasis/blood , Leishmaniasis/parasitology , Leukocyte Count , Leukocytes/drug effects , Lopinavir/pharmacology , Lopinavir/therapeutic use , Mice, Inbred BALB C , Nitric Oxide/blood , Ritonavir/pharmacology , Ritonavir/therapeutic use , Skin/drug effects , Skin/parasitology , Spleen/drug effects , Spleen/immunology , Spleen/parasitology
8.
J Gastroenterol Hepatol ; 32(7): 1318-1327, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28005266

ABSTRACT

BACKGROUND AND AIM: Eosinophils are markers of the eosinophilic esophagitis (EoE) disease, and this work aimed to assess whether activation of eosinophils could be a noninvasive test to contribute for EoE diagnosis. METHODS: The activation state of peripheral blood eosinophils in EoE patients and control subjects was assessed based on the morphological aspects of the eosinophil after adherence to slide. Cyclooxygenase-2 and 5-lipoxygenase expressions were evaluated by means of immunofluorescence microscopy to verify if and which eicosanoid pathway is triggered in eosinophils in blood in EoE. RESULTS: The eosinophils of patients with EoE were significantly more activated than those of control individuals. The lowest percentage of normal eosinophils for control subjects was 40%, while the highest percentage of eosinophils of normal aspect for patients with EoE was 32%. Considering 36% as a cutoff for normal eosinophils, this value differentiated all individuals with EoE from individuals without the disease with a sensitivity of 100%, considering the diagnosis of EoE as currently defined. Eosinophils of EoE patients showed higher expression of cyclooxygenase-2 than those of control subjects. CONCLUSIONS: The quantification of morphological changes in eosinophils is a feasible, easy, and reliable manner to identify EoE patients. Therefore, patients with symptoms of esophageal dysfunction showing higher than 36% activated eosinophils in peripheral blood could be a useful way to help definition and diagnostic criterion for EoE.


Subject(s)
Eosinophilic Esophagitis/diagnosis , Eosinophils/immunology , Adult , Arachidonate 5-Lipoxygenase/blood , Biomarkers/blood , Cross-Sectional Studies , Cyclooxygenase 2/blood , Eosinophilic Esophagitis/immunology , Eosinophils/enzymology , Eosinophils/pathology , Female , Humans , Male , Young Adult
9.
Int Immunopharmacol ; 24(2): 314-324, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25545854

ABSTRACT

This study evaluated the influence of HIV protease inhibitors lopinavir/ritonavir (LPV/RTV) and atazanavir (ATV) on macrophage functions during their first interaction with Leishmania. Macrophages from BALB/c mice treated for 10days with LPV/RTV and ATV, infected or not in vitro with L. (L.) amazonensis, were used to investigate the effects of these drugs on infection index, leishmanicidal capacity, cytokine production and PPAR-γ and RelB expression. LPV/RTV and ATV treatments significantly increased the infection index and the percentage of Leishmania-infected macrophages compared to untreated infected macrophages. There was no correlated increase in the production of NO and H2O2 leishmanicidal molecules. Promastigotes derived from Leishmania-infected macrophages from LPV/RTV and ATV-treated BALB/c mice had an in vitro growth 45.1% and 56.4% higher in groups treated with LPV/RTV and ATV than with PBS in culture. ATV treatment reduced IL-12p70 and IL-10 secretion in Leishmania-infected macrophages, but had no effect on IL-23 and TNF production. LPV reduced IL-10 and had no effect on IL-12p70, TNF and IL-23 secretion. ATV treatment decreased PPAR-γ expression in Leishmania-infected macrophages compared to untreated infected macrophages. In addition, LPV/RTV, but not ATV, reduced RelB cytoplasm-to-nucleus translocation in Leishmania-infected macrophages. Results showed that LPV/RTV and ATV HIV protease inhibitors were able to modulate innate defense mechanisms against Leishmania via different intracellular pathways. Although HIV protease inhibitors are highly efficient to control the Human Immunodeficiency Virus, these drugs might also influence the course of leishmaniasis in HIV-Leishmania-co-infected individuals.


Subject(s)
Anti-HIV Agents/pharmacology , Leishmania/drug effects , Leishmaniasis/immunology , Macrophages, Peritoneal/drug effects , NF-kappa B/immunology , PPAR gamma/immunology , Animals , Atazanavir Sulfate/pharmacology , Cells, Cultured , Cytokines/immunology , Female , Hydrogen Peroxide/metabolism , Immunity, Innate/drug effects , Leishmania/growth & development , Leishmania/pathogenicity , Leishmaniasis/parasitology , Lopinavir/pharmacology , Macrophages, Peritoneal/immunology , Macrophages, Peritoneal/parasitology , Mice, Inbred BALB C , Nitrites/immunology , Ritonavir/pharmacology
10.
Int Immunopharmacol ; 13(1): 114-9, 2012 May.
Article in English | MEDLINE | ID: mdl-22465961

ABSTRACT

Miltefosine is an anticancer drug currently used to treat visceral and cutaneous leishmaniasis, also presents a broad-spectrum of fungicidal and antiamoebae activities. It acts on the metabolism of phospholipids and glycoproteins of the membrane of parasites. Our study aimed to evaluate the effects of miltefosine (0.4 to 50.0 µg/mL) on the phagocytosis and nitric oxide production by macrophages of C57BL/6 mice to clarify the immunomodulatory effects of the drug on macrophages of C57BL/6, strain mice that is biased to Th1 response. Peritoneal macrophages were in vitro treated with miltefosine and phagocytosis of sensitized or nonsensitized Saccharomyces cerevisiae was assessed. NO production was evaluated by Griess reaction. In the concentration of 1.6 µg/mL and 50.0 µg/mL, miltefosine increased phagocytosis of non-opsonized S. cerevisiae in 59.7% and 214.3%, respectively. For phagocytosis through opsonin receptors, miltefosine (50.0 µg/mL) increased the phagocytic index in 208.6% (p=0.04, paired t test). Miltefosine (50.0 µg/mL) decreased in 39.3% NO production by macrophages. However, treatment with miltefosine (50.0 µg/mL) after infection of macrophages with Leishmania amazonensis increased NO production in 73.4% (p=0.01, Wilcoxon test). Our data showed that, besides the antimicrobial effect of miltefosine, the drug showed immunomodulatory effects on macrophages of C57BL/6 mice, improving phagocytosis and decreasing NO production, but was able to increase NO production when macrophages were previously infected with L. amazonensis. These results suggest that miltefosine may favor the better evolution of infectious diseases by improving the innate immune response of macrophages.


Subject(s)
Immunologic Factors/pharmacology , Macrophages, Peritoneal/drug effects , Nitric Oxide/biosynthesis , Phagocytosis/drug effects , Phosphorylcholine/analogs & derivatives , Animals , Cells, Cultured , Dose-Response Relationship, Drug , Female , Leishmania/immunology , Macrophages, Peritoneal/immunology , Macrophages, Peritoneal/microbiology , Macrophages, Peritoneal/parasitology , Mice , Mice, Inbred C57BL , Phagocytosis/immunology , Phosphorylcholine/pharmacology , Saccharomyces cerevisiae/immunology
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