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  • Artigo IPEN-doc 29882
    Scavenger receptors mediate increased uptake of irradiated T.gondii extracts by J774 macrophages
    2023 - COSTA, ANDREA da; CARVALHO, CAMILA A. de; NASCIMENTO, NANCI do; ANDRADE JUNIOR, HEITOR F. de
    Purpose Protein extracts developed increased immunogenicity without the aid of adjuvants after gamma irradiation. Gamma irradiation of snake venom increased antivenin production by detoxification and enhanced immunity, probably due preferential uptake of irradiated venoms by macrophage scavenger receptors. We studied this uptake of irradiated soluble Toxoplasma gondii extract (STag) by the J774 macrophage cell line similar to antigen presenting cells. Material And Methods We labeled STag by biosynthesis in living tachyzoites with radioactive amino acids before purification and irradiation or by adding labels as biotin or fluorescein in stored STag, for quantitative studies or subcellular distribution visualization. Results There was enhanced binding and uptake of irradiated STag into the cells compared to non-irradiated STag. Using fluorescein labeled antigens and morphological assays, we confirmed that cells avidly ingested both native and irradiated proteins but native STag were digested after ingestion while irradiated proteins remained in the cell, suggesting diverse intracytoplasmic pathways. Native or irradiated STag present the same in vitro sensitivity to three types of peptidases. Inhibitors of scavenger receptors (SRs) such as Dextran sulfate (SR-A1 blocker) or Probucol (SR-B blocker) affect the specific uptake of irradiated antigens, suggesting its association with enhanced immunity. Conclusions Our data suggests that cell SRs recognize irradiated proteins, mainly SRs for oxidized proteins, leading to antigen uptake by an intracytoplasmic pathway with fewer peptidases that prolongs presentation to nascent major histocompatibility complex I or II and enhances immunity by better antigen presentation.
  • Artigo IPEN-doc 27471
    Radiation effects on Toxoplasma antigens
    2020 - COSTA, ANDREA da; NASCIMENTO, NANCI do; GALISTEO JUNIOR, ANDRES J.; PASSOS, ALINE B.D. dos; ANDRADE JUNIOR, HEITOR F. de
    Purpose: Purpose: Protein irradiation causes aggregation, chain breakage, and oxidation, enhancing its uptake by antigen-presenting cells. To evaluate if irradiated proteins participate on the protection, we studied the immune response induced in mice immunized with irradiated soluble extracts of T. gondii tachyzoites (STag) or irradiated intact T. gondii RH tachyzoites (RH0.25 kGy). Material and Methods: Soluble extracts of Toxoplasma gondii tachyzoites (STag) were irradiated at different dose by Cobalt-60 source. By polyacrylamide gel electrophoresis (SDS-Page) we evaluated the effects on primary structures of protein STags induced by irradiation. By Enzyme-linked Immunosorbent Assay (ELISA) we evaluated the difference between humoral immune response induced by irradiated STag or RH tachyzoites in immunized mice from the detection of specific immunoglobulin G (IgG) antibodies in the serum of immunized mice. From challenge with viable RH strain of T. gondii we evaluated the protection induced in the immunized animals. By cytometry we performed the phenotyping of T and B lymphocytes in the peripheral blood of the immunized animals. Results: Irradiation dose of 1.5 kGy induced minimal changes in most proteins, without affecting their antigenicity or immunogenicity. Immunization showed saturation at the dose of 10 µg/mice, with worst response at higher doses. STag irradiated at 1.5  kGy (STag1.5 kGy) induced higher survival and protection similar to T. gondii RH strain irradiated at 0.25 kGy (RH0.25 kGy), with higher serum levels of high affinity IgG compared to STag native. Blood immune memory cells of mice immunized with STag1.5 kGy had higher proportions of CD19+ (cluster of differentiation 19) and CD4+ (cluster of differentiation 14) cells, whereas mice RH0.25 kGy had high proportion of memory CD8+ (cluster of differentiation 8) cells. Conclusions: Our data suggest that major histocompatibility complex type I (MHCI) pathway, appears seem to be used by RH0.25 kGy to generate cytotoxic cells while STag1.5 kGy uses a major histocompatibility complex type II (MHCII) pathway for B-cell memory, but both induce sufficient immune response for protection in mice without any adjuvant. Irradiation of soluble protein extracts enhances their immune response, allowing similar protection against T. gondii in mice as compared to irradiated intact parasites.
  • Artigo IPEN-doc 27224
    Paratrygon aiereba irradiated anti-mucus serum reduce edematogenic activity induced in experimental model
    2020 - THOMAZI, GABRIELA O.C.; COSTA, ANDREA da; RODRIGUES, JAQUELINE P.; ALVES, GLAUCIE J.; PREZOTTO NETO, JOSE P.; TURIBIO, THOMPSON de O.; ROCHA, ANDRE M.; AIRES, RAQUEL da S.; SEIBERT, CARLA S.; SPENCER, PATRICK J.; GALISTEO JUNIOR, ANDRES J.; ANDRADE JUNIOR, HEITOR F. de; NASCIMENTO, NANCI do
    Accidents by freshwater stingrays are common in northern Brazil, there is no specific therapy for high morbidity and local tissue destruction. The irradiation of venoms and toxins by ionizing radiation has been used to produce appropriate immunogens for the production of antisera. We planned to study the efficacy of stinging mucus irradiation in the production of antisera, with serum neutralization assays of edematogenic activity and quantification of cytokines performed in animal models of immunization with native and irradiated mucus of Paratrygon aiereba, a large freshwater stingray. Antiserum potency and its cross-reactivity with mucus from other freshwater stingrays were detected by ELISA. Immunization models demonstrated the ability to stimulate a strong humoral response with elevated levels of serum IgG detectable by ELISA, and both native and irradiated mucus were immunogenic and capable of recognizing mucus proteins from other freshwater neotropical stingrays. Mucus P. aiereba causes cellular and humoral adaptive immune responses in cells of immunized mice producing antibodies and cytokines such as TNF-α, IL-6 and IL-17. Rabbit antisera immunized with mucus from P. aiereba irradiated at 2 kGy showed a significant reduction of mucus-induced edematogenic activity in mice. Our data suggest that the use of antisera against freshwater stingray mucus show the possibility of specific therapy for these accidents.
  • Resumo IPEN-doc 26937
    Gamma irradiated soluble extracts of Toxoplasma gondii tachyzoites induced better humoral and cellular immune response due to preferential uptake by APCs scavenger receptors
    2017 - COSTA, ANDREA da; ZORGI, NAHIARA E.; NASCIMENTO, NANCI do; GALISTEO JUNIOR, ANDRES J.; ANDRADE JUNIOR, HEITOR F. de
    Toxoplasmosis occurs in one-third of the adult world population, without adequate vaccines and causing disease in fetus or specific groups. Aside to sterilizing effect, gamma radiation acts on antigens inducing enhanced antisera production against snake venoms or cell and humoral response to recombinant leprosy proteins. Gamma radiation affects proteins directly or indirectly in water by action of oxidant radicals from water radiolysis. Early reports showed gamma irradiated crotoxin had enhanced uptake by macrophages, limited by scavenger receptors competitors, as probucol. Irradiated tachyzoites induced adequate immune response with protection, attributed to mitotic death and DNA damage. Irradiated proteins could take a part in this process and we study the immune response induced by gamma irradiated soluble extracts of Toxoplasma gondii tachyzoites, using mice immunized with native proteins as controls. Mice immunized with irradiated extracts without adjuvants showed significant protection after challenge with ME-49 (p<0.05) and RH (p<0.0001) strains compared to controls. There are increased specific and high avidity IgG production (p<0.05) when compare d to controls group. By flow cytometry and in vitro culture, spleens of mice immunized irradiated extract presented increased proliferation of CD4+, CD8+ and B cells and IFN-γ production as compared to controls. J774 cells had increased uptake of biotinylated irradiated extracts as compared to the uptake of native extract (p<0.05), due to longer and continuous uptake. All these data points to an alternative and effective uptake and immune processing of irradiated T. gondii extracts, probably due to specific receptor of oxidized proteins as scavenger receptors, resulting in enhanced immunity. This data also implies that irradiated proteins could be involved in the protection induced by irradiated parasites. Use of antigen gamma radiation can be a simple process to enhance vaccine efficiency, avoiding the use of adjuvants.
  • Resumo IPEN-doc 26933
    Redução da atividade edematogênica promovida pelo muco da raia de água doce Paratrygon aiereba utilizando soro produzido contra o muco irradiado com raios gama de 60Co
    2016 - THOMAZI, G.O.C.; PREZOTTO NETO, J.P.; ALVES, G.J.; TURIBIO, T.O.; AIRES, R.S.; ROCHA, A.M.; SEIBERT, C.S.; SPENCER, P.J.; NASCIMENTO, N.
    Introdução: As raias são peixes peçonhentos com ampla distribuição geográfica nos principais rios brasileiros e merecem destaque por estarem frequentemente associadas a acidentes em seres humanos. Estes agravos são frequentes na região Norte do país e favorecidos pelo hábito desses peixes de permanecerem em repouso no fundo arenoso ou lamacento de águas rasas e pela frequente utilização humana dos rios, seja por lazer ou atividades ocupacionais. Os ferimentos provocados pelos ferrões das raias são dolorosos, de difícil cicatrização, causam necroses extensas e fenômenos sistêmicos. O muco que recobre toda a extensão do corpo desses peixes pode aumentar a gravidade desses ferimentos. A escassez de estudos voltados para o tratamento específico das lesões oriundas dos agravos por esses peixes, a ausência de estudos com outros gêneros de raias dulcícolas e a possibilidade de produção de soro contra o veneno de raias estimularam o desenvolvimento deste estudo utilizando a radiação ionizante que tem se mostrado vantajosa na atenuação de toxinas animais, resultando na obtenção de melhores imunógenos para a produção de soros. Objetivo: Avaliar e comparar o potencial neutralizante dos soros anti-mucoda raia Paratrygonaierebanativo ou irradiado (2 kGy-60Co) contra a ação edematogênicado muco nativo. Método: Mediante aprovação da CEUA/IPEN/SP n°126/2013 e do ICMBion.º 45407-1/2014 foi desenvolvido este trabalho. O muco (50μg/mL) de P. aierebafoi incubado em banho-maria com os soros anti-muconativo ou soro anti-mucoirradiado diluídos de 1:100 ou 1:1.000 (soros de coelhos imunizados contra o muco nativo ou irradiado por 60Co de P. aiereba). Após a incubação, as amostras foram injetadas (30μL) no coxim plantar da pata posterior de camundongos Swissmachos, 18 a 20g, (n=30). A interferência na atividade edematogênicafoi verificada nos tempos de 1h, 2h, 4h e 24h após a inoculação. Em todos os animais foi verificado o volume inicial individual de cada pata antes da injeção das amostras. Os volumes foram mensurados em pletismômetroe os resultados expressos como a variação do volume em relação ao volume basal em μL por período (ExpBioMed. 239:601, 2014). A avaliação estatística foi realizada pela análise de variância com auxílio do softwareGraphPadPrism5.0. Resultados: O muco de P. aierebafoi capaz de induzir edema de 1h a 4h após a inoculação, com declínio de 4 a 24h (p<0,01 em relação aos controles). O soro anti-muconativo não foi capaz de inibir a formação do edema nas diluições testadas, sem diferença estatística com o edema induzido pelo muco (p>0,05). O soro anti-mucoirradiado diluído 1:100 apresentou interferência significativa na atividade edematogênicanas primeiras quatro horas (p<0,01). O soro anti-mucoirradiado 1:1000 foi capaz de diminuir a formação de edema nas 1ª e 4ª horas (p<0,01). O edema foi reduzido pelo soro anti-mucoirradiado pré-incubado com o muco não irradiado (nativo). Conclusão: Esse resultado mostra que além do muco irradiado ser capaz de estimular a proliferação de células de memória, ou seja, a produção de anticorpos IgGespecíficos, estas imunoglobulinas são capazes de reconhecer a fração responsável pela atividade edematogênica. Estes resultados nos permite concluir que o processo de irradiação tornou o muco da raia P. aierebamais antigênico.
  • Artigo IPEN-doc 25811
    Pharmacokinetics of neutron-irradiated meglumine antimoniate in Leishmania amazonensis-infected BALB/c mice
    2019 - BORBOREMA, SAMANTA E.T.; OSSO JUNIOR, JOAO A.; ANDRADE JUNIOR, HEITOR F. de; NASCIMENTO, NANCI do
    Background: Cutaneous leishmaniasis (CL) is a parasitic disease caused by the protozoan Leishmania spp. Pentavalent antimonial agents have been used as an effective therapy, despite their side effects and resistant cases. Their pharmacokinetics remain largely unexplored. This study aimed to investigate the pharmacokinetic profile of meglumine antimoniate in a murine model of cutaneous leishmaniasis using a radiotracer approach. Methods: Meglumine antimoniate was neutron-irradiated inside a nuclear reactor and was administered once intraperitoneally to uninfected and L. amazonensis-infected BALB/c mice. Different organs and tissues were collected and the total antimony was measured. Results: Higher antimony levels were found in infected than uninfected footpad (0.29% IA vs. 0.14% IA, p = 0.0057) and maintained the concentration. The animals accumulated and retained antimony in the liver, which cleared slowly. The kidney and intestinal uptake data support the hypothesis that antimony has two elimination pathways, first through renal excretion, followed by biliary excretion. Both processes demonstrated a biphasic elimination profile classified as fast and slow. In the blood, antimony followed a biexponential open model. Infected mice showed a lower maximum concentration (6.2% IA/mL vs. 11.8% IA/mL, p = 0.0001), a 2.5-fold smaller area under the curve, a 2.7-fold reduction in the mean residence time, and a 2.5-fold higher clearance rate when compared to the uninfected mice. Conclusions: neutron-irradiated meglumine antimoniate concentrates in infected footpad, while the infection affects antimony pharmacokinetics.
  • Artigo IPEN-doc 25082
    Gamma irradiation of Toxoplasma gondii protein extract improve immune response and protection in mice models
    2018 - COSTA, ANDREA da; ZORGI, NAHIARA E.; NASCIMENTO, NANCI do; GALISTEO JUNIOR, ANDRES J.; ANDRADE JUNIOR, HEITOR F. de
    Gamma radiation induces protein changes that enhance immunogenicity for venoms, used in antivenin production. Coccidian parasites exposed to gamma radiation elicit immune response with protection in mice and man, but without studies on the effect of gamma radiation in soluble acellular extracts or isolated proteins. Toxoplasmosis is a highly prevalent coccidian disease with only one vaccine for veterinary use but with remaining tissue cysts. Total parasite extracts or recombinant proteins used as immunogen induce usually low protection. Here, we study gamma radiation effect on T. gondii extracts proteins (STAG) and its induced immunity in experimental mice models. By SDS-PAGE, protein degradation is seen at high radiation doses, but at ideal dose (1500 Gy), there are preservation of the antigenicity and immunogenicity, detected by specific antibody recognition or production after mice immunization. Immunization with STAG irradiated at 1500 Gy induced significant protection in mice immunized and challenged with distinct T. gondii strains. In their blood, higher levels of specific CD19+, CD3+CD4+ and CD3+CD8+ activated cells were found when compared to mice immunized with STAG. Irradiated T. gondii tachyzoites extracts induce immune response and protection in mice in addition, could be a feasible alternative for Toxoplasma vaccine.
  • Artigo IPEN-doc 25063
    Pharmacokinetic of meglumine antimoniate encapsulated in phosphatidylserine-liposomes in mice model
    2018 - BORBOREMA, SAMANTA E.T.; OSSO JUNIOR, JOAO A.; TEMPONE, ANDRE G.; ANDRADE JUNIOR, HEITOR F. de; NASCIMENTO, NANCI do
    Visceral leishmaniasis (VL) is a fatal parasitic disease caused by the protozoan Leishmania spp. Meglumine antimoniate (MA) is the main treatment and has demonstrated a promising efficacy in a VL-model when encapsulated into negatively charged liposomes. Considering the current concept for the evaluation of pharmacokinetic parameters at early phases of drug discovery, we developed a formulation of MA-encapsulated into phosphatidylserine liposomes (MA-LP) and analyzed the in vitro antileishmanial activity, physicochemical properties, and pharmacokinetic profile in a mice model. The liposomal formulation had an internal mean diameter of 114 nm and a high stability in plasma. MA-LP was 23-fold more in vitro effective against Leishmania infantum-infected macrophages than the free drug, with a selectivity index higher than 220. The pharmacokinetic studies demonstrated that the liposomes increased the uptake of the drug by the liver and spleen and promoted sustained levels. MA-LP was first eliminated through renal excretion, followed by biliary excretion. In the blood, MA-LP followed a biexponential open model. This work emphasizes the importance of liposomes as potential drug delivery systems for visceral leishmaniasis.
  • Artigo IPEN-doc 24364
    Perfil epidemiológico e clínico dos casos de tuberculose em Ipatinga, Minas Gerais
    2018 - MAGALHAES, FLAVIA A.; CUNHA, YAN de O.C.; PIRES, JOSE E.B.; NASCIMENTO, NANCI; SPENCER, PATRICK J.; ANDRADE, DELVONEI A.
    A tuberculose (TB) é uma doença infecciosa de transmissão inalatória causada pelo Mycobacterium tuberculosis. É uma preocupação, dada a alta prevalência, morbidade e mortalidade. Ipatinga é um dos municípios de alta carga da doença no estado de Minas Gerais. O objetivo do estudo foi analisar o perfil epidemiológico e clínico dos pacientes com tuberculose notificados em Ipatinga pelo Programa de Controle da Tuberculose (PCT) no período de 2004 a 2014. Foi realizado estudo epidemiológico transversal, observacional de série temporal. Foram analisados 1.098 casos notificados como TB, sendo perceptível tendência de queda do número de casos ao longo dos anos. Houve predomínio do sexo masculino (66,2%), da faixa etária de 15 a 59 anos (83,9%), da raça branca e parda e do baixo nível de escolaridade. A maioria dos casos era de residentes no município (74,9%), sendo distribuídos irregularmente entre os bairros. Clinicamente predominou casos novos (85,9%), forma pulmonar (80,9%), sendo os agravos associados mais frequentes o alcoolismo (15,3%), Síndrome da Imunodeficiência Adquirida (AIDS) (8,3%) e diabetes (5,7%). Os desfechos clínicos foram: cura em 71,4%, abandono em 8,3% e 0,2% de multidrogarresistência. O perfil dos pacientes notificados encontra-se de acordo com o encontrado na literatura.
  • Artigo IPEN-doc 24387
    Overview of female breast cancer in northern Tocantins – Brazil
    2017 - SULEIMAN, NADER N.; NASCIMENTO, NANCI; BOTELHO, JOAO M.S.; COELHO, RACHEL C.
    Objective: to evaluate the temporal variation of the percentages of female breast cancer in early and late stages and analyze socio-demographic variables associated with these stages. Methods: study of secondary data performed between the years of 2000 and 2015 in the Araguaína Regional Hospital - Araguaína - TO – Brasil. Results: breast cancer in advanced stages were diagnosed in 51.1% of the cases and at an early stage in 48.9%. There was no difference between the percentages of patients with early and late stages over the years. Women of race/black, illiterate and origin of the southeast of Pará presented a higher percentage of late staging at diagnosis. Conclusions: most women was diagnosed with advanced disease; the time evolution of the proportion of cases (advanced/early) did not demonstrate variational changes over the years; association of the disease has been identified in advanced stage in women of race/black, illiterate and from the southeast of Pará state.