Rozprawy doktorskie: „Leishmaniasis-Disease”

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Yakovich, Adam J. "Old targets and new beginnings a multifaceted approach to combating Leishmaniasis, a neglected tropical disease /". Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1193247442.

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MARITATI, MARTINA. "LEISHMANIASIS: A RE-EMERGING NEGLECTED DISEASE. BIOMOLECULAR AND METABOLOMIC STUDIES AIMED AT IMPLANTING ITS CONTROL IN EMILIA-ROMAGNA". Doctoral thesis, Università degli studi di Ferrara, 2021. http://hdl.handle.net/11392/2487987.

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Background. Leishmaniases (VL) represents a major health problem. The first part of the thesis evaluates by molecular techniques and cytokine analysis the prevalence of asymptomatic Leishmania infections in autoimmune rheumatic patients treated with biological drugs and living in Leishmania endemic foci in Italy. In the second part, the effect of the niacin analogue, 6-AN on Leishmania parasite growth and metabolism using the metabolomics technology was investigated. The pentose phosphate pathway (PPP), has been reported as a target of 6-AN, thus PPP might represent a good target. Methods. VL qualitative and real-time PCR were performed on DNA extracted from PBMCs from 50 autoimmune rheumatic patients treated with immunosuppressive biologic drugs for at least 5 years. Plasma cytokine concentrations were also measured in plasma from Leishmania DNA-positive and -negative rheumatic patients as well as from the healthy control group. In the 6-AN study, L. mexicana M379 and L. infantum PCM5 promastigotes were treated with 7.8 mM 6-AN and 2.17% DMSO for 24 hours. After vitality, infectivity of 6-AN-treated promastigotes to mouse macrophages, and 6-AN interactions with oxidizing compounds were also studied. Small metabolites were extracted and analysed by pHILIC-LC-MS in polarity switching mode and data were analysed with IDEOMv19 and MetaboAnalyst 3.0. Results.Eighteen out the 50 (36%) autoimmune rheumatic patients were positive for Leishmania DNA by conventional and/or quantitative PCR with a detection of high parasite burdens (1 to 136 parasite/ml in 4 patients, 1.000 to 40.000 in 11 patients and over 1.000.000 in 3 patients). Patients that were taking a steroid in association with the biological drug showed a higher positivity for circulating L. infantum kDNA than those given the biological drug only (p<0.05). Pro-inflammatory IL-1, IL-6, IL-12(p70), IL-7, IL-15, IFN-γ and TNF-α; anti-inflammatory IL-4, IL-13; and regulatory IL-10 cytokines were markedly elevated in all autoimmune rheumatic patients with additional increases in inflammatory mediators in autoimmune rheumatic patients positive for Leishmania DNA. In both L. mexicana and L. infantum, 6-AN caused significant depletion of phosphoribosylpyrophosphate (PRPP) and nicotinate (Na) and as a result purine and pyrimidine nucleotides were reduced and their nucleobases accumulated. Glutathione, ribose-5-phosphate, 6-phosphogluconate levels and downstream PPP intermediates were similar to controls. For L. infantum, it was possible to analyse NAD+ and NADPH, which were found decreased together with the PPP intermediate D-sedoheptulose 7-phosphate. Moreover, 6-AN treatment caused a marked elongation in parasite body. 6-AN in combination with the oxidizing compounds has additive effects against Leishmania and did not affect the infectivity of the treated promastigotes to mouse macrophages. Conclusions.VL molecular screening and cytokine analysis should be taken into account before treating autoimmune rheumatic patients with biologic drugs, especially in rural areas. In mammals 6-AN is converted to abnormal 6-ANAD/P by NAD+ glycohydrolase, however, in Leishmania its toxicity is only seen in millimolar range, in which 6-AN is responsible for the depletion of cellular phosphoribosyl pyrophosphate (PRPP) content probably in the Preiss-Handler NAD+ salvage pathway, resulting in depletion of nucleotides required for nucleic acid biosynthesis. The marked elongation in the 6-AN-treated parasite bodies confirms nucleotide starvation. Leishmania NAD+ glycohydrolase might decompose NAD+ but might not catalyze exchange reactions, as found in other microrganisms, however, combined 13C-glucose labeling and flux analysis might be useful to ascertain the fate and action mechanism of 6-AN in Leishmania. In addition, PRPP synthetase should also be a good target for new potential drugs against leishmaniasis pointing to the growth-inhibitory effect of PRPP depletion.
Background. Leishmaniases (VL) represents a major health problem. The first part of the thesis evaluates by molecular techniques and cytokine analysis the prevalence of asymptomatic Leishmania infections in autoimmune rheumatic patients treated with biological drugs and living in Leishmania endemic foci in Italy. In the second part, the effect of the niacin analogue, 6-AN on Leishmania parasite growth and metabolism using the metabolomics technology was investigated. The pentose phosphate pathway (PPP), has been reported as a target of 6-AN, thus PPP might represent a good target. Methods. VL qualitative and real-time PCR were performed on DNA extracted from PBMCs from 50 autoimmune rheumatic patients treated with immunosuppressive biologic drugs for at least 5 years. Plasma cytokine concentrations were also measured in plasma from Leishmania DNA-positive and -negative rheumatic patients as well as from the healthy control group. In the 6-AN study, L. mexicana M379 and L. infantum PCM5 promastigotes were treated with 7.8 mM 6-AN and 2.17% DMSO for 24 hours. After vitality, infectivity of 6-AN-treated promastigotes to mouse macrophages, and 6-AN interactions with oxidizing compounds were also studied. Small metabolites were extracted and analysed by pHILIC-LC-MS in polarity switching mode and data were analysed with IDEOMv19 and MetaboAnalyst 3.0. Results.Eighteen out the 50 (36%) autoimmune rheumatic patients were positive for Leishmania DNA by conventional and/or quantitative PCR with a detection of high parasite burdens (1 to 136 parasite/ml in 4 patients, 1.000 to 40.000 in 11 patients and over 1.000.000 in 3 patients). Patients that were taking a steroid in association with the biological drug showed a higher positivity for circulating L. infantum kDNA than those given the biological drug only (p<0.05). Pro-inflammatory IL-1, IL-6, IL-12(p70), IL-7, IL-15, IFN-γ and TNF-α; anti-inflammatory IL-4, IL-13; and regulatory IL-10 cytokines were markedly elevated in all autoimmune rheumatic patients with additional increases in inflammatory mediators in autoimmune rheumatic patients positive for Leishmania DNA. In both L. mexicana and L. infantum, 6-AN caused significant depletion of phosphoribosylpyrophosphate (PRPP) and nicotinate (Na) and as a result purine and pyrimidine nucleotides were reduced and their nucleobases accumulated. Glutathione, ribose-5-phosphate, 6-phosphogluconate levels and downstream PPP intermediates were similar to controls. For L. infantum, it was possible to analyse NAD+ and NADPH, which were found decreased together with the PPP intermediate D-sedoheptulose 7-phosphate. Moreover, 6-AN treatment caused a marked elongation in parasite body. 6-AN in combination with the oxidizing compounds has additive effects against Leishmania and did not affect the infectivity of the treated promastigotes to mouse macrophages. Conclusions.VL molecular screening and cytokine analysis should be taken into account before treating autoimmune rheumatic patients with biologic drugs, especially in rural areas. In mammals 6-AN is converted to abnormal 6-ANAD/P by NAD+ glycohydrolase, however, in Leishmania its toxicity is only seen in millimolar range, in which 6-AN is responsible for the depletion of cellular phosphoribosyl pyrophosphate (PRPP) content probably in the Preiss-Handler NAD+ salvage pathway, resulting in depletion of nucleotides required for nucleic acid biosynthesis. The marked elongation in the 6-AN-treated parasite bodies confirms nucleotide starvation. Leishmania NAD+ glycohydrolase might decompose NAD+ but might not catalyze exchange reactions, as found in other microrganisms, however, combined 13C-glucose labeling and flux analysis might be useful to ascertain the fate and action mechanism of 6-AN in Leishmania. In addition, PRPP synthetase should also be a good target for new potential drugs against leishmaniasis pointing to the growth-inhibitory effect of PRPP depletion.

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Boraschi, Cláudia Souza e. Silva [UNESP]. "Inquérito sobre o conhecimento da população da cidade de Três Lagoas – MS sobre leishmaniose visceral". Universidade Estadual Paulista (UNESP), 2007. http://hdl.handle.net/11449/94685.

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A leishmaniose visceral (LV) é um importante problema de saúde pública e as medidas de prevenção preconizadas nem sempre são conhecidas pela população. Esta pesquisa avaliou, por meio da aplicação de um questionário, o conhecimento que a população de Três Lagoas, MS tem sobre esta zoonose. Dos 384 entrevistados, 100% afirmaram que já tinham conhecimento prévio da LV, 64,5% sabiam que é transmitida através do inseto vetor e 65,4% sabiam que a prevenção se dá evitando o criadouro deste. Observaram-se 93,5% de respostas para manutenção do quintal limpo como medida preventiva conhecida. Pelo menos um método de prevenção era utilizado no animal por 50,5% dos entrevistados e observou-se associação estatisticamente significante entre o grupo de proprietários cujos cães nunca apresentaram leishmaniose visceral canina e o grupo que fazia uso de alguma prevenção no animal (p=0,0006).
Visceral Leishmaniasis (VL) is an important public health problem and the measures to prevent it are not always known by the population. This research evaluated the knowledge that the population of Três Lagoas, MS, Brazil has about this zoonosis. One hundred percent of the interviewed (384) had previous knowledge of the disease, 64.5% knew that a vector transmits it and 65.4% knew that the prevention is achieved by preventing vector’s breeding sites. Maintenance of the backyard clean was informed by 93,5% as a known preventive measure. At least one preventive method was used in the animal by 51% of the interviewed ones and statically significant association between the group of owners whose dogs had never presented canine visceral leishmaniasis and owners that used some preventive method in the animal (p=0.0006) was observed.

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Sánchez, Fabio. "Genetic factors influencing susceptibility to intracellular infections /". Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-225-6.

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Collar, Catharine Jane. "Rational Drug Design for Neglected Diseases: Implementation of Computational Methods to Construct Predictive Devices and Examine Mechanisms". Digital Archive @ GSU, 2010. http://digitalarchive.gsu.edu/chemistry_diss/48.

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Over a billion individuals worldwide suffer from neglected diseases. This equates to approximately one-sixth of the human population. These infections are often endemic in remote tropical regions of impoverished populations where vectors can flourish and infected individuals cannot be effectively treated due to a lack of hospitals, medical equipment, drugs, and trained personnel. The few drugs that have been approved for the treatments of such illnesses are not widely used because they are riddled with inadequate implications of cost, safety, drug availability, administration, and resistance. Hence, there exists an eminent need for the design and development of improved new therapeutics. Influential world-renowned scientists in the Consortium for Parasitic Drug Development (CPDD) have preformed extensive biological testing for compounds active against parasites that cause neglected diseases. These data were acquired through several collaborations and found applicable to computational studies that examine quantitative structure-activity relationships through the development of predictive models and explore structural relationships through docking. Both of these in silico tools can contribute to an understanding of compound structural importance for specific targets. The compilation of manuscripts presented in this dissertation focus on three neglected diseases: trypanosomiasis, Chagas disease, and leishmaniasis. These diseases are caused by kinetoplastid parasites Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp., respectively. Statistically significant predictive devices were developed for the inhibition of the: (1) T. brucei P2 nucleoside transporter, (2) T. cruzi parasite at two temperatures, and (3) two species of Leishmania. From these studies compound structural importance was assessed for the targeting of each parasitic system. Since these three parasites are all from the Order Kinetoplastida and the kinetoplast DNA has been determined a viable target, compound interactions with DNA were explored to gain insight into binding modes of known and novel compounds.

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Bhattacharyya, T. "Parasite diversity and innovative serology : development of Trypanosoma cruzi lineage-specific diagnosis of Chagas disease and of prognostic assays for visceral leishmaniasis". Thesis, London School of Hygiene and Tropical Medicine (University of London), 2015. http://researchonline.lshtm.ac.uk/2173663/.

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Trypanosoma cruzi and the Leishmania donovani complex are parasitic protozoa that, respectively, cause Chagas disease in the Americas, and visceral leishmaniasis, predominantly in South Asia, East Africa, and Brazil. T. cruzi is divided into the lineages TcI-TcVI. The relationship between infecting lineage(s) and spectrum of clinical presentations remains poorly understood. This project developed lineage-specific serology to identify an individual’s history of lineage infection. A high level of polymorphism in the surface mucin TSSA was identified, and lineage-specific synthetic peptides based on this diversity were applied here in ELISA with chagasic sera from endemic countries. Peptide TSSApep-II/V/VI, based on a sequence common to those lineages, was widely recognised by sera from Southern Cone countries, and also unexpectedly by four samples from Ecuador; TSSApep-V/VI, which differs by a single amino acid from TSSApep-II/V/VI, was also recognised in these regions. A single TSSApep-IV reaction was seen in both Colombia and Venezuela. However, TSSApep-I was rarely and weakly recognised among the serum panel. Among the Brazilian patients, a much higher proportion of TSSApep-II/V/VI responders had ECG abnormailities than non-responders (38% vs. 17%, p<0.0001). Rapid diagnostic tests for L. donovani complex infection based on rK39 antigen have lower sensitivity in East Africa compared to South Asia. The homologous sequences of rK39, and of another proposed diagnostic antigen HASPB, were amplified from a panel of East African L. donovani strains, and compared to published sequences, revealing significant diversity from rK39 and South Asian sequences, and non-canonical combinations of HASPB repeats. Cohorts of Indian and Sudanese VL patients were assayed by ELISA for anti- Leishmania IgG levels. There was an overall 46.8 – 61.7 fold lower response in the Sudanese cohort, as calculated by mean reciprocal log10t50 titres, regardless of antigen source, patient gender or age. An investigation into the association of IgG subclass reactivity with VL clinical status revealed significantly elevated IgG1 levels in patients with active (pre-treatment) VL and those with post-therapy relapse compared to those deemed to be cured. A novel prototype rapid immunochromatographic test to detect IgG1 gave > 80% of relapsed VL patients as IgG1 positive, and 80% of cured patients as IgG1 negative.

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Furini, Júnior. "Estratégias terapêuticas usando o ácido ursólico sobre infecções determinadas por tripanosomatideos". Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/60/60135/tde-12122016-154937/.

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Doença de Chagas e Leishmaniose, são doenças causadas por protozoários da família Trypanosomatidae (Trypanosoma cruzi e Leishmania sp., respectivamente) e estão, ambas, no grupo das doenças consideradas tropicais negligenciadas (DTNs). Juntas, elas afetam cerca de 30 milhões de pessoas em 98 países no mundo. Embora tão epidemiologicamente importantes, essas doenças ainda carecem de um tratamento quimioterápico robusto e seguro, pois os medicamentos disponíveis apresentam, além de baixa eficácia terapêutica, baixas taxas de adesão, devido aos sérios efeitos colaterais gerados por serem extremamente tóxicos e acabando, por isso, sendo geradores de resistência. Nas últimas décadas, tem sido intenso o esforço dos grupos de pesquisa em desenvolver alternativas para o tratamento dessas doenças, especialmente explorando produtos de origem natural e através do emprego de tecnologia farmacêutica, gerando formulações mais viáveis clinicamente devido ao provimento de propriedades físico-químicas favoráveis à absorção e permeabilidade celular, com consequente maior biodisponibilidade e potencialização do efeito biológico. Em nosso presente trabalho, objetivamos propor novas estratégias de tratamento dessas doenças, utilizando como candidato, o ácido ursólico (AU), um triterpenoide de origem natural. Foram testados o AU isolado e associado com fármacos estabelecidos, assim como uma dispersão sólida contendo 10% do princípio ativo (DSAU). Em ensaios in vitro contra as várias formas evolutivas intra e extracelulares de Trypanosoma cruzi e Leishmania braziliensis, obtivemos muito bons resultados, como 99,8% de lise em 128 ?M sobre as formas tripomastigotas, com IC50 de 14,1 ?M para o AU. Em experimentos in vivo sobre doença de Chagas experimental, observamos uma redução de parasitemia de 60,2% e 61,6% em animais tratados com doses de 20 mg/Kg de AU e DSAU, respectivamente. Embora não tenham causado diminuição na carga parasitária nos tecidos analisados (coração e fígado) em relação ao controle negativo, a sobrevida dos animais tratados com AU e DSAU foi semelhante a dos animais tratados com benzonidazol na mesma dose. Sobre leishmaniose muco-cutânea experimental, observamos a diminuição do diâmetro médio das lesões em animais tratados com dose de 20 mg/Kg de nossos compostos avaliados. Esses resultados demonstram que o ácido ursólico é um potente candidato a quimioterápico para o tratamento de tripanosomíases. Além disso, a associação a fármacos existentes, e a utilização de tecnologia farmacêutica podem ser boas estratégias para o tratamento dessas doenças.
Chagas disease and Leishmaniasis are diseases caused by protozoa of the family Trypanosomatidae (Trypanosoma cruzi and Leishmania sp., Respectively) and both are in the group of diseases considered neglected tropical (NTDs). All together, they affect about 30 million people in 98 countries worldwide. Although so very epidemiologically important, these diseases still lack a safe and robust chemotherapeutic treatment seeing that the available drugs present besides low therapeutic efficacy, low compliance rates, since they are extremely toxic and cause serious side effects ending up, therefore, being resistance generators. In recent decades, there have been intense efforts of research groups to develop alternatives for treating these diseases, especially exploring natural products and by applying pharmaceutical technology, generating more clinically viable formulations due to providing favorable physicochemical properties to the cell absorption and permeability, thus resulting in increased bioavailability and enhancement of biological effect. In our present study, we aimed to propose new treatment strategies for these diseases by using as a candidate, the ursolic acid (UA), a naturally occurring triterpenoid. Isolated UA and associated with established drugs have been tested, as well as a solid dispersion containing 10% of the active ingredient (SDUA). In the in vitro tests against several extracellular and intracellular evolving forms of Trypanosoma cruzi and Leishmania braziliensis, we have obtained very good results, such as 99.8 of lysis at 128 ?M on trypomastigotes, with IC50 of 14.1 ?M for the UA. In the in vivo experiments about experimental Chagas disease, a decrease of parasitaemi of 60.2% and 61.6% has been observed in animals treated with doses of 20 mg / kg of UA and SDUA respectively. Although not having caused a decrease in the parasite load in the tissues analyzed (heart and liver) compared to the negative control, the PFS of animals treated with UA and SDUA was similar to that of the animals treated with the same dose of benznidazole. About the experimental skin mucus leishmaniasis, we have observed a decrease of the average diameter of lesions in animals treated with 20 mg / kg of our evaluated compounds. These results demonstrate that the ursolic acid is a potent candidate for chemotherapy for the treatment of trypanosomiasis. Furthermore, the association of existing drugs, and the use of pharmaceutical technology can be good strategies to treat these diseases

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Boraschi, Cláudia Souza e. Silva. "Inquérito sobre o conhecimento da população da cidade de Três Lagoas - MS sobre leishmaniose visceral /". Araçatuba : [s.n.], 2007. http://hdl.handle.net/11449/94685.

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Orientador: Cáris Maroni Nunes
Banca: Mary Marcondes
Banca: Sonia Regina Pinheiro
Resumo: A leishmaniose visceral (LV) é um importante problema de saúde pública e as medidas de prevenção preconizadas nem sempre são conhecidas pela população. Esta pesquisa avaliou, por meio da aplicação de um questionário, o conhecimento que a população de Três Lagoas, MS tem sobre esta zoonose. Dos 384 entrevistados, 100% afirmaram que já tinham conhecimento prévio da LV, 64,5% sabiam que é transmitida através do inseto vetor e 65,4% sabiam que a prevenção se dá evitando o criadouro deste. Observaram-se 93,5% de respostas para manutenção do quintal limpo como medida preventiva conhecida. Pelo menos um método de prevenção era utilizado no animal por 50,5% dos entrevistados e observou-se associação estatisticamente significante entre o grupo de proprietários cujos cães nunca apresentaram leishmaniose visceral canina e o grupo que fazia uso de alguma prevenção no animal (p=0,0006).
Abstract: Visceral Leishmaniasis (VL) is an important public health problem and the measures to prevent it are not always known by the population. This research evaluated the knowledge that the population of Três Lagoas, MS, Brazil has about this zoonosis. One hundred percent of the interviewed (384) had previous knowledge of the disease, 64.5% knew that a vector transmits it and 65.4% knew that the prevention is achieved by preventing vector's breeding sites. Maintenance of the backyard clean was informed by 93,5% as a known preventive measure. At least one preventive method was used in the animal by 51% of the interviewed ones and statically significant association between the group of owners whose dogs had never presented canine visceral leishmaniasis and owners that used some preventive method in the animal (p=0.0006) was observed.
Mestre

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Zuque, Maria Angelina da Silva. "Participação de gambás e cães domiciliados como reservatórios de Leishmania infantum e Trypanosoma cruzi georreferenciados nos municípios da Regional de Saúde de Três Lagoas - MS". Botucatu, 2016. http://hdl.handle.net/11449/136267.

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Orientador: Simone Baldini Lucheis
Resumo: A Leishmaniose Visceral e a Doença de Chagas são importantes zoonoses negligenciadas do ponto de vista de saúde pública. Animais domésticos, como o cão, e animais silvestres, como os gambás, fazem parte do ciclo destas zoonoses como fontes de infecção para os vetores. O estudo foi realizado em cinco municípios da Regional de Saúde de Três Lagoas, Mato Grosso do Sul, em 2013 e 2014, com objetivo de identificar a ocorrência da infecção natural por Leishmania spp e Trypanosoma cruzi em gambás (Didelphis albiventris) e cães domiciliados, descrever aspectos epidemiológicos dessas doenças na população canina e humana, seus vetores, e a distribuição espacial da Leishmaniose Visceral Canina usando técnicas do georrefenciamento. Amostras de sangue dos cães foram submetidas a análises sorológicas e moleculares, e a dos gambás somente as análises moleculares. Em relação à pesquisa de anticorpos contra a Leishmania spp., as provas sorológicas de 683 amostras dos cães, revelaram reagentes 320 amostras ao Dual Path Platform, 300 amostras ao Enzyme Linked Immunosorbent Assay e 116 a Reação de Imunofluorescência Indireta. Para Trypanosoma cruzi, pela Reação de Imunofluorescência Indireta, quatro amostras do município de Três Lagoas foram reagentes. Das 683 amostras de sangue total, dos cães submetidas à Reação em Cadeia pela Polimerase, todas foram negativas para Trypanosoma cruzi e obteve-se êxito na amplificação de Leishmania spp em 17 amostras. As 39 amostras de sangue total dos gambás fo... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Visceral Leishmaniasis (VL ) and Chagas disease (CD ) are important neglected zoonoses in accordance with public health. Domestic animals such as dogs and wildlife such as possums , are part of these zoonoses cycles as reservoirs and sources of infection for vectors. The study was conducted in five Regional Health of the municipalities of Três Lagoas , Mato Grosso do Sul in 2013 and 2014 , in order to verify the occurrence of natural infection with Leishmania infantum and Trypanosoma cruzi in opossums (Didelphis albiventris) and the pet dogs, and describe the characteristics of diseases in human and canine population , vectors , and the spatial distribution of canine Visceral Leishmaniasis using techniques georrefenciamento. In dog´s blood there were performed serological analysis and molecular tests ande the samples of the opossums were performed molecular tests. Regarding the research for Leishmania antibodies the techniques serological to 683 dog samples, showed reagent 320 samples to Dual Path Platform, 300 samples to Enzyme Linked Immunosorbent Assay and 116 to Immunofluorescence Antibody Test. For Trypanosoma cruzi, the test Immunofluorescence Antibody Test (IFAT) four samples of Três Lagoas municipality were reactive. Of the samples from dogs 683 submitted to the Polymerase Chain Reaction were all negative by Trypanosoma cruzi gave successful amplification Leishmania spp in 17 of them. The 39 samples of the opossums were all negative by PCR to Leishmania spp. and Trypa... (Complete abstract click electronic access below)
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Barbosa, Sofia Diniz de Nazaré. "A leishmaniose canina e os condicionalismos determinados pelas respectivas alterações renais". Bachelor's thesis, Universidade Técnica de Lisboa. Faculdade de Medicina Veterinária, 2011. http://hdl.handle.net/10400.5/3548.

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Dissertação de Mestrado Integrado em Medicina Veterinária
A Leishmaniose é uma doença zoonótica causada pelo protozoário da espécie Leishmania infantum, que existe predominantemente na Bacia do Mediterrâneo. O ciclo de vida deste parasita requer a existência de um vector, um insecto do género Phlebotomus, que é responsável pela transmissão das formas infectantes, os promastigotas metacíclicos, aos hospedeiros vertebrados, nomeadamente os canídeos. Em Portugal, apenas as espécies P. ariasi e P. perniciosus são vectores comprovados de L. infantum. As características clínicas da Leishmaniose canina variam amplamente como consequência dos numerosos mecanismos patogénicos do protozoário, da diversidade de respostas imunológicas desenvolvidas nos hospedeiros e dos diferentes órgãos afectados. A doença renal pode ser a única manifestação clínica nos animais infectados, podendo progredir de proteinúria assintomática até síndrome nefrótico ou Insuficiência Renal Crónica, que é responsável pela degradação do estado geral e a principal causa de morte nos cães com Leishmaniose. A aplicação do tratamento adequado requer, previamente, um diagnóstico precoce da doença e a avaliação do estado sanitário e imunitário do animal, através do exame clínico e de exames complementares, que devem ser repetidos a cada 6 meses. A presença de Insuficiência Renal Crónica impõe algumas limitações no tratamento da Leishmaniose canina, sendo fundamental seleccionar cautelosamente os fármacos e respectivas doses a administrar a cada paciente. Neste estudo retrospectivo foram observados 19 canídeos com Leishmaniose, sendo a sua sintomatologia muito variável, da qual se destaca a linfadenopatia, o emagrecimento e as lesões dermatológicas. As alterações laboratoriais mais frequentes foram a anemia não-regenerativa, a trombocitopénia, a hiperproteinémia com hiperglobulinémia e a proteinúria. O diagnóstico etiológico foi realizado com base nas técnicas de imunocromatografia rápida e de imunofluorescência indirecta. Foi também diagnosticada Insuficiência Renal Crónica em 4 canídeos da amostra. Diferentes fármacos foram utilizados no tratamento etiológico e sintomático, porém foi mais frequente a administração de alopurinol em monoterapia ou em associação com o antimoniato de glucamina.
ABSTRACT - CANINE LEISHMANIASIS AND CONSTRAINTS DETERMINED BY THEIR RENAL CHANGES - Leishmaniasis is a zoonotic disease caused by the protozoan Leishmania infantum, which is the most common species of Leishmania in the Mediterranean basin. The life cycle of this parasite requires the existence of a vector, the insect of the genus Phlebotomus, which is responsible for the transmission of infectious form, the metacyclic promastigotes, to the vertebrate host, namely the dog. In Portugal, only the species P. ariasi and P. perniciosus are proven vectors of L. infantum. The clinical features of canine Leishmaniasis are highly variable as a consequence of the numerous pathogenic mechanisms, the diversity of immune responses of individual hosts and the different organs affected. Renal disease may be the only clinical manifestation in infected dogs and may progress from asymptomatic proteinuria to nephrotic syndrome or to Chronic Kidney Disease, which is responsible for the deterioration of general condition and leading cause of death in dogs with Leishmaniasis. The application of suitable treatment requires, previously, an early diagnosis and assessment of dog’s health and immunity status, by clinical examination and several routine diagnostic tests, which must be repeated every six months. The presence of Chronic Kidney Disease imposes some limitations in the treatment of canine Leishmaniasis and is necessary to select carefully the drugs and doses to be administered in each patient. In this retrospective study, 19 dogs with Leishmaniasis were observed and many clinical signs were found, mainly lymphadenopathy, weight loss and dermatologic lesions. The most frequent laboratory abnormalities were non-regenerative anemia, thrombocytopenia, hyperproteinemia with hyperglobulinemia and proteinuria. The definitive diagnosis was made by a rapid immunomigration test and indirect fluorescent antibody technique. Chronic Kidney Disease was also diagnosed in 4 dogs of sample. Different drugs were used in the etiological and symptomatic treatment, but the administration of alopurinol alone or in combination with glucamine antimoniate were the most frequent.

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Santos, Anderson Pacheco dos. "Sorologia de leishmaniose tegumentar americana em areas de avaliação de infecção chagasica no estado de São Paulo, Brasil". [s.n.], 2008. http://repositorio.unicamp.br/jspui/handle/REPOSIP/315103.

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Orientador: Maria Esther de Carvalho
Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
Made available in DSpace on 2018-08-11T09:30:13Z (GMT). No. of bitstreams: 1 Santos_AndersonPachecodos_M.pdf: 3380754 bytes, checksum: 9736aa6f219de1691e4d55d474a7d293 (MD5) Previous issue date: 2008
Resumo: As zonas endêmicas de leishmanioses e doença de Chagas, duas grandes endemias causadas por cinetoplastídeos, sobrepõe-se na América do Sul, especialmente na região Sudeste do Brasil, o que pode gerar casos de co-infecção entre Leishmania spp. e Trypanosoma cruzi. Ocorrem reações cruzadas, mesmo com baixos títulos, em inquéritos sorológicos de pacientes infectados com os parasitas, o que leva a falsas estimativas de prevalência de ambas as infecções. Este trabalho tem o objetivo de observar o efeito de um diluente de amostra proposto para reduzir a ocorrência de reações cruzadas em testes sorológicos para doenças causadas por cinetoplastídeos e outros parasitas. Foram selecionadas 585 amostras de sangue provenientes de quatro regiões do Estado de São Paulo, entre litoral e planalto, colhidas no período compreendido entre 1996 a 2003, durante atividades do Programa de Controle da Doença de Chagas. As análises das amostras foram feitas através das Reações de Imunofluorescência (RIFI) e do ensaio imunoenzimático (ELISA). Com as amostras reagentes (onze no total), para doença de Chagas e leishmaniose em ambas as técnicas, foi realizado o teste ELISA alta avidez, que utiliza um diluente com caotrópico, que demonstrou redução nos títulos da reação positiva falsa, restando apenas uma amostra sem redução significativa do seu título, que sugeriu ser um caso de co-infecção de doença de Chagas e leishmaniose, epidemiologicamente factível dada a existência de ambas as infecções na área estudada. O uso deste diluente em estudos clínicos e epidemiológicos pode aprimorar o diagnóstico para a identificação de soropositivos em regiões de sobreposição de endemias causadas por cinetoplastídeos
Abstract: Leishmaniases and Chagas disease are endemic in extensive areas of the American Continent. These parasitic diseases can occur together in South America, particularly in southwestern regions of Brazil, which poses a serious epidemiological problem due to the observed serological cross-reactivity between Leishmania spp. and Trypanosoma cruzi, even at low titers. As false prevalence estimates of these agents are critically misleading, we designed an experiment aiming at analyzing the effect of a diluent intended to reduce the chances of false positive tests resulting from serological cross-reactivity between these kinetoplastids and other parasites. As a part of the activities of the Program for the Control of Chagas disease, we selected 585 blood samples collected, during the period from 1996 to 2003, from residents in four regions situated between the seacoast and the plateau of the State of São Paulo. The serological tests used (IFAT and ELISA) produced a total of eleven positive reactions. Lower false positive titers resulted from the use of high avidity ELISA plus a chaotropic diluent. The only serological result in which titers corresponding to both infections were not significantly reduced was suggestive of mixed infection, on the basis of the fact that it was connected to a patient evidently exposed to both agents. This experiment suggests that the use of a chaotropic diluent can be a useful tool to reduce the proportion of such false parasitic mixed infection results as those investigated by us
Mestrado
Mestre em Parasitologia

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Frade, Amanda Farage. "Identificação de polimorfismos genéticos com impacto no desenvolvimento e progressão da leishmaniose visceral em indivíduos de áreas endêmicas do Maranhão e Piauí". Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/5/5146/tde-27082010-165613/.

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A leishmaniose visceral constitui grave doença infecciosa causada por um protozoário parasita intracelular obrigatório. Alguns fatores podem alterar a gravidade das manifestações clínicas, sendo um deles a predisposição genética. Este estudo investigou polimorfismos dos genes TGFB1, IL8 e IL6, que são citocinas relacionadas com o desencadeamento e a gravidade da doença, visando identificar fatores de susceptibilidade. Os polimorfismos TGFB1 -509 C/T e TGFB1 +869 T/C, IL8 -251A/T e IL6 -174G/C foram analisados por PCR-RFLP, em 198 pacientes com leishmaniose visceral (LV), 98 indivíduos com infecção assintomática (teste de hipersensibilidade tardia - DTH+) e 100 indivíduos sem evidências de infecção (DTH-). O alelo T na posição -509 do gene TGFB1 conferiu risco duas vezes maior de desenvolver LV ou ser positivo para o teste DTH (p = 0,007, OR = 1,9 [1,19-3,02]), em comparação com indivíduos DTH-. Os resultados sugerem uma associação do polimorfismo TGFB1 -509C/T com a susceptibilidade à LV, podendo contribuir para o desencadeamento da doença clínica.
Visceral leishmaniasis is a serious protozoan infectious disease caused by an obligate intracellular parasite. Some factors can affect the severity of the clinical manifestations; one of which is genetic susceptibility. This study investigated polymorphisms in the TGFB1, IL8 and IL6 genes, which are cytokines related with the onset and severity of the disease, to look for genetic susceptibility factors. Polymorphisms at TGFB1 -509C/T and +869T/C, and IL8 - 251A/T and IL6 -174G/C were analyzed by a PCR-RFLP technique, in 198 patients with Visceral Leishmaniasis (VL), 98 individuals with asymptomatic infection (positive delayed-type hypersensitivity, DTH+) and 100 individuals with no evidence of infection (DTH-). The T allele of the TGFB1 polymorphism in position -509C/T conferred a two risk fold to develop LV or to be DTH+ (p=0.007; OR=1.9 [1.19 - 3.02]) when compared with DTH- individuals. We suggest the TGFB1 -509C/T polymorphism is associated with susceptibility to LV and may contribute to development of the clinical disease.

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Kinkead, James Robert H. "Study of the molecular regulation of trypanosomatid phosphofructokinases as drug targets". Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31144.

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The trypanosomatid parasites T. brucei, T. cruzi and Leishmania spp. are responsible for the ‘neglected diseases’ Human African Trypanosomiasis, Chagas disease and Leishmaniasis respectively. In their human infective form in the bloodstream all three trypanosomatid parasites rely heavily on glycolysis for ATP production. Phosphofructokinase (PFK) catalyses the third step of the glycolytic pathway in all organisms using aerobic respiration. It facilitates the phospho transfer from ATP to fructose 6-phosphate (F6P) to make the products fructose 1,6- bisphosphate (F16BP) and ADP. RNAi knockout of T. brucei PFK has shown the enzyme is essential for survival of the bloodstream form parasites. Trypanosomatid PFKs have a unique set of structural and regulatory differences compared to the mammalian host enzyme. These differences, coupled with the availability of trypanosomatid PFK crystal structures present an opportunity for the structure-based design of specific inhibitors against the enzyme. Here we present an enzymatic characterisation of recombinant PFKs from T. brucei, T. cruzi and Leishmania infantum trypanosomatids, their regulation by the allosteric activator AMP, and their inhibition by drug-like inhibitor compounds. Inhibitor compounds (‘CTCB compounds’) were designed against T. brucei PFK with the aim of developing novel treatments against Human African Trypanosomiasis (HAT). We describe the testing, ranking and biophysical characterisation of these compounds as part of a Wellcome Trust Seeding Drug Discovery program. We found that CTCB inhibitor compounds bound to an allosteric pocket unique to trypanosomatid PFKs. We show that the compounds are specific; neither competing with the natural substrates ATP or F6P nor inhibiting the human PFK enzyme. We describe the development and testing of highly potent and specific low molecular weight PFK inhibitors that translate to both killing of cultured T. b. brucei parasites and a cure of stage I HAT in mice models. We describe the tight, 1:1 binding of these compounds with trypanosomatid PFKs, and the thermodynamic characteristics of binding through various biophysical assays. We also show the unprecedented characterisation of the reverse PFK reaction by trypanosomatid and human forms of the enzymes. We found that PFK can also carry out the reverse enzymatic reaction, under physiologically relevant concentrations of ADP and F16BP to produce F6P and ATP. We show that the reverse reaction is also subject to allosteric regulation by AMP, and can be inhibited by the CTCB compounds with a similar potency to the forward reaction. Finally, we describe the mechanism of allosteric activation by AMP and inhibition by the drug-like compounds against trypanosomatid PFKs.

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Davis, Richard Elliot. "Neutrophil responses to infection with leishmania parasites: MHC class II-expression and parasite life-stage interactions". Diss., University of Iowa, 2016. https://ir.uiowa.edu/etd/2200.

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The vector-borne protozoan Leishmania spp. cause the spectrum of disease known as leishmaniasis in human and animal hosts. The most common manifestations of leishmaniasis are the chronic, ulcerative skin disease cutaneous leishmaniasis (CL), and the more serious visceral leishmaniasis (VL) in which parasites take up residence in internal organs, causing death if not treated. The role of neutrophils (PMNs) in the immune response to CL and VL is unclear. It is s generally thought that PMNs are only a short-lived effector cell, and have been disregarded as playing a role in chronic Leishmania spp. infection. As both CL and VL are diseases characterized by increased inflammatory immune mediators, we hypothesized that PMNs from human or animal models of chronic leishmaniasis would display different properties from PMNs from healthy controls. We found in a subset of CL and VL patients circulating PMNs expressing HLA-DR, the human form of MHC class II, a molecule thought to be restricted primarily to professional antigen cells. When we examined PMNs recruited to CL skin lesions in human patients, or similar lesions in experimental murine model of CL, we found significantly increased MHC class II+ PMNs. Circulating HLA-DR+ PMNs also expressed the co-stimulatory molecules CD80, CD86 and CD40. While this suggested an antigen-presenting cell-like phenotype by these HLA-DR+ PMNs, compared to conventional HLA-DR- PMNs, HLA-DR+ PMNs showed not only a neutrophil-like appearance and function, but in fact increased activation, degranulation, intracellular MPO and phagocytosis of parasites and zymosan particles. Incubation of healthy control whole blood with inflammatory cytokines resulted in increased HLA-DR+ PMNs and the presence of hladrb1 mRNA, suggesting a connection between neutrophil “priming” and upregulation of HLA-DR. In addition to HLA-DR+ PMNs in CL patients, we also identified the presence of so-called “low-density” neutrophils (LD-PMNs). These neutrophils, which are enriched in low-density fractions following centrifugation of blood over a density gradient, are reported in numerous disease states, including cancer, HIV, and systemic lupus erythematosus. In some disease states, LD-PMN are reported to be immunosuppressive toward T cell activation and proliferation. However, LD-PMNs from leishmaniasis patients showed no evidence of immunosuppression. Additionally, we found that LD-PMNs show significantly increased surface expression of MHC class II, suggesting a heretofore unappreciated connection between these atypical neutrophil phenotypes. We also investigated the in vitro interactions with different Leishmania infantum life-stages, both those that cause acute infection (promastigotes) and amastigotes, which are found during chronic stages of the disease. We found that PMNs are readily infected by all L. infantum life-stages, but that amastigotes may have different methods of interacting with PMN surface receptors and are better equipped to avoid PMN anti-microbial responses. These data suggest that circulating PMNs in chronic leishmaniasis may have unique phenotypes and interact differently with the Leishmania spp. life-cycle present during chronic infection. Further investigation of the role of PMNs and atypical PMN phenotypes in chronic disease may help identify new immunomodulatory roles for this cell type.

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Bispo, Ana Jovina Barreto. "Avaliação de alterações pulmonares na leishmaniose visceral humana". Universidade Federal de Sergipe, 2015. https://ri.ufs.br/handle/riufs/3882.

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Visceral leishmaniasis (VL) is a serious zoonosis large incidence worldwide. It is characterized by systemic involvement and high potential lethality. The lung, as well as any other body, may be involved in its pathogenesis. Cough is a symptom described frequently in symptomatic forms of LV, but little studied. The main pulmonary alterations described are histological and immunological characterized by a inflammatory response predominantly interstitial and Th2 immune pattern. There is a gap involving lung function in patients of this disease This study has a cross-sectional design, aimed to describe the symptoms and pulmonary radiology, and also determine the frequency of spirometric alterations in patients with LV, through the realization of clinical evaluation, physical examination, chest radiography and spirometry in patients with diagnosis of VL during hospitalization. The study included 33 patients admitted to the University Hospital of the Universidade Federal de Sergipe in the period July 2013 to July 2014. The sample was characterized as follows: half of the patients had age up to 14 years; were predominantly male (72.7%); most of the patients were residents of the state capital (42.2%); 87.9% of subjects had nutritional diagnosis of normal weight; the median time between symptom onset and hospitalization was 30 days. Respiratory symptoms was cough observed in 13 patients (39.4%), tachypnea in four (12.1%), hemoptysis in two (6%). Chest radiography was considered abnormal in four (12%) patients. Spirometry showed 56.3% frequency of spirometric alterations and average FEV1, FVC, FEV1 / FVC, FEF 25-75% below the expected values. The predominant lung disease was the restrictive (37.5%), followed by mixed disorder (12.5%) and obstructive disorder (6.3%). The frequency of respiratory symptoms shows pulmonary involvement in LV. The average of the measured values of FVC and FEV1 significantly lower compared to the average of the predicted values and the high percentage of spirometric alterations demonstrate the presence of functional disorders in the respiratory system. The prevalence of restrictive lung disease may be related to the main pulmonary abnormality described in LV, the interstitial lung disease.
A leishmaniose visceral (LV) é uma zoonose grave de ampla incidência mundial. Caracteriza-se pelo envolvimento sistêmico e alto potencial de letalidade. O pulmão, assim como qualquer outro órgão, pode estar envolvido na sua patogênese. A tosse é um sintoma descrito com frequência nas formas sintomáticas da LV, porém, pouco estudada. As principais alterações pulmonares descritas são histológicas e imunológicas, caracterizadas por uma resposta inflamatória predominantemente intersticial e padrão imunológico do tipo Th2. Existe, no entanto, uma lacuna envolvendo as características funcionais pulmonares. Este estudo, de delineamento transversal, objetivou descrever a sintomatologia e a radiologia pulmonar, e, também, determinar a frequência de alterações funcionais em pacientes portadores de LV, através da realização de avaliação clínica, exame físico, radiografia de tórax e espirometria em pacientes com diagnóstico de LV durante sua internação. Participaram do estudo 33 pacientes internados no Hospital Universitário da Universidade Federal de Sergipe, no período de julho de 2013 a julho de 2014. A amostra ficou assim caracterizada: metade dos pacientes possuía idade até 14 anos; houve predominância do sexo masculino (72,7%); a maior parte dos pacientes foi procedente da capital do Estado (42,2%); 87,9% dos indivíduos tiveram diagnóstico nutricional de eutrofia; a mediana de tempo decorrido entre o início dos sintomas e o internamento foi de 30 dias. Sintomas respiratórios estiveram presentes em 14 pacientes (42,4%). A radiografia de tórax foi considerada anormal em quatro (12%). A espirometria mostrou 56,3% de frequência de alterações funcionais e média dos valores VEF1, CVF, VEF1/CVF, FEF25-75% abaixo dos valores previstos. O distúrbio ventilatório predominante foi o restritivo (37,5%), seguido do distúrbio misto (12,5%) e do distúrbio obstrutivo (6,3%). A frequência de sintomas respiratórios evidencia envolvimento pulmonar na LV. A média dos valores medidos de CVF e do VEF1 significativamente menor em comparação à média dos valores previstos e o elevado percentual de alterações espirométricas demonstram a presença de distúrbios funcionais no sistema respiratório. A predominância do distúrbio ventilatório restritivo pode estar relacionada com a principal alteração pulmonar descrita na LV, a doença pulmonar intersticial.

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Santos, Priscilla Vargas Walsh Gonçalves dos. "Relação imunogenética dos pênfigos com a leishmaniose tegumentar". Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/17/17138/tde-20072016-144443/.

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Pênfigo é uma dermatose bolhosa autoimune, endêmica em algumas áreas, como no nordeste do estado de São Paulo, Brasil, caracterizada pela produção de autoanticorpos contra desmogleínas (Dsg) - proteínas de adesão dos queratinócitos. O pênfigo vulgar (PV) acomete mucosas e pele, pela produção de anti-Dsg 3 e 1, respectivamente. O pênfigo foliáceo (PF) apresenta lesões exclusivamente na pele, pela produção de anti-Dgs1. Esta região também é endêmica para a Leishmaniose Tegumentar Americana (LTA), cujo principal fator etiológico é Leishmania (Viannia) braziliensis. Objetivos: Relacionar fatores imunogenéticos dos pênfigos com aqueles da LTA, investigando, em pacientes com pênfigos, LTA e em controles: a resposta humoral às Dsg 1 e 3 e contra Chagas; a resposta humoral e celular aos antígenos de leishmania; e a associação dos alelos HLA de classe II -DR e -DQ no grupo LTA com aqueles de suscetibilidade e de resistência descritos nos pênfigos. Métodos: A resposta humoral foi investigada por: (i) ELISA para determinação dos anticorpos anti-Dsg 1 e 3, anti-L. V. braziliensis e contra T. cruzi; (ii) imunoblotting (IB) com extrato proteico de epiderme e com extrato proteico de L. (V.) braziliensis; (iii) imunofluorescência indireta (IFI) com substrato de pele humana e soro de pacientes com LTA. A resposta celular foi realizada por teste intradérmico de Montenegro (TIM). A tipificação dos alelos HLA -DR e -DQ foi realizada por PCR-SSOP. Resultados: A resposta humoral às Dsg confirmou o esperado - anti-Dsg1: 84,6% no grupo PF e 54,8% no grupo PV; e antiDsg3: 83,9% no PV; não havendo diferença significativa entre os grupos LTA e controles - anti-Dsg1: 16% nos familiares de PF (FPF); 5,2% no grupo LTA; 4,2% no grupo FPV; e 2,7% nos controles vizinhos; e anti-Dsg3: 12% no grupo FPF; 6,4% no grupo PF e 5,2% no grupo LTA. Houve reconhecimento dos peptídeos de 130kDa (corresponde ao PM da Dsg3), 145kDa, 150kDa (Dsg2), 160kDa (Dsg1), 230kDa (BP230), 250kDa, 290kDa, 350kDa, 410kDa, 425kDa e 460kDa da epiderme humana por soro de pacientes com LTA. A IFI resultou positiva para anti-IgG em 2/6 pacientes com LTA. Em um deles, houve reconhecimento de peptídeos intercelulares da epiderme, guardando semelhança aos pênfigos; e, no outro, de antígenos da zona da membrana basal, guardando semelhança ao penfigoide bolhoso. A resposta humoral a L. (V.) braziliensis resultou mais elevada no grupo LTA (73% para LTAc e 62% para LTAm) em relação aos demais grupos, sem diferença significativa entre os grupos pênfigos (1,3% no grupo PF e 1,6% no PV) e os controles (10,8% nos controles vizinhos e 4% no grupo FPF, FPV e controles Banco de Sangue). Pacientes com pênfigos apresentaram títulos sorológicos para T. cruzi semelhantes aos controles. Houve reconhecimento de peptídeos de L. (V.) braziliensis pelo soro dos pacientes com pênfigo (45kDa, 95kDa, 100kDa, 120kDa, 125kDa, 145kDa, 150kDa, 305kDa, 330kDa, 410kDa e >500kDa). O TIM foi negativo nos 6 pacientes com PF ou PV avaliados. Os alelos DRB1*01:02 e DQA1*01 mostraram associação de resistência para LTA e suscetibilidade para PF; o alelo DRB1*04:02 de resistência para LTA e suscetibilidade para PV; os alelos DRB1*07:01 e *11:01 de suscetibilidade para LTA e resistência para PF; e o DQA1*01:02 mostrou associação de suscetibilidade a ambos LTA e PF. Conclusões: os pacientes com LTA têm resposta humoral às Dsg 1 e 3, e os pacientes com pênfigo, aos antígenos de L. (V.) braziliensis e de T. cruzi semelhante aos controles. Os soros de pacientes com pênfigos reconhecem peptídeos da epiderme e da zona da membrana basal por IB e IFI. Os demais peptídeos reconhecidos pelos pacientes com LTA ao extrato epidérmico, assim como dos pacientes com pênfigos ao extrato de L. (V.) braziliensis necessitam sequenciamento. As associações de suscetibilidade ou resistência dos alelos HLA de classe II -DR e -DQ são opostas para LTA e pênfigo. Os resultados confirmam a não participação do parasito L. (V.) braziliensis na patogênese dos pênfigos, assim como corroboram a observação clínica da ausência da associação de ambas as doenças na região do estudo
Pemphigus is an autoimmune bullous dermatosis, endemic in some areas, such as in the northeastern of São Paulo state, characterized by the production of autoantibodies against desmoglein (Dsg) - keratinocytes adhesion proteins. Pemphigus vulgaris (PV) affects mucous membranes and skin, by the production of anti-Dsg 3 and 1, respectively. Pemphigus foliaceus (PF) affects only the skin, by the production of anti-Dsg 1. This region is also endemic for American Cutaneous Leishmaniasis (ACL), whose main etiological factor is Leishmania (V.) braziliensis. Objectives: To relate immunogenetic factors of pemphigus with those of ACL, investigating, in patients with pemphigus, ACL and controls: the humoral response to Dsg 1 and 3; the humoral and cellular responses to Leishmania antigens; and the association of class II -DR and -DQ HLA alleles in ACL group with those of susceptibility and resistance described in pemphigus. Methods: The humoral response was investigated by (i) ELISA for determination of anti-Dsg1 and anti-Dsg3 antibodies and anti-antibodies from T. cruzi and L. braziliensis; (ii) immunoblotting (IB) with protein extract of the epidermis and protein extract of L. braziliensis; (iii) indirect immunofluorescence (IIF) with human skin substrate and serum of ACL patients. The cellular response was carried out by intradermal test Montenegro (ITM). The typing of HLA-DQ and -DR alleles was performed by PCR-SSOP. Results: The humoral response to Dsg confirmed expected in groups of PV and PF (anti-Dsg1: 84.6% in the PF group and 54.8% in the PV group, and anti-Dsg3: 83.9% in PV), with no significant difference between the ACL and control groups [anti-Dsg1: 16% in relatives of PF (RPF), 5.2% in the ACL, 4.2% in relatives of PV (RPV) and 2.7% of controls neighbors; anti-Dsg3: 12% in RPF, 6.4% in the PF group and 5.2% in ACL)]. There has been recognition of peptides 130kDa, 145 kDa, 150kDa, 160kDa, 230 kDa, 250 kDa, 290 kDa, 350 kDa, 410 kDa, 425 kDa and 460 kDa of human epidermis by serum of ACL patients. The IFI was positive in 1/6 ACL patients evaluated. The humoral response to L. braziliensis resulted higher in ACL group (73% to ACLc and 62% to ACLm) compared to the other groups, with no significant difference between pemphigus groups (1.3% in the PF group and 1.6% the group PV) and controls (10.8% in neighboring controls and 4% in FPF, in FPV and BS controls). Patients with pemphigus have serological titers to T. cruzi similar to controls. There was L. braziliensis recognition of peptides by the patients with pemphigus (45 kDa, 95 kDa, 100 kDa, 120 kDa, 125 kDa, 145 kDa, 150 kDa, 305 kDa, 330 kDa, 410 kDa and> 500 kDa). The ITM was negative in 06 patients with PF or PV evaluated. The DRB1*01:02 and DQA1*01 showed resistance association for LTA and susceptibility to PF; allele DRB1*04:02 resistance to ACL and susceptibility to PV; the DRB1*07: 01 and *11:01 susceptibility to ACL and resistance to PF; and DQA1*01:02 showed susceptibility association with both ACL and PF. Conclusions: Patients with ACL have humoral response to Dsg 1 and 3, and pemphigus patients to L. braziliensis and T. cruzi antigens similar to controls. The peptides recognized by patients with pemphigus to L. braziliensis extract require sequencing. The susceptibility or resistance associations of class II -DR and -DQ HLA alleles are opposed to ACL and pemphigus. The results confirm the non-participation of the parasite L. (V.) braziliensis in the pathogenesis of pemphigus, as well as support the clinical observation of the absence of both diseases association

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Pinto, Erika Gracielle. "Isolamento, caracterização e atividade anti-leishmania chagasi e anti-trypanosoma cruzi de compostos bioativos de venenos de anfíbios brasileiros". Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/99/99131/tde-31012014-154317/.

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Dentre as doenças parasitárias tropicais, as causadas por protozoários se apresentam como um grande desafio para a saúde pública, sendo representadas pela leishmaniose e doença de Chagas. Afetam grandes populações marginais ao processo econômico globalizado, e desta forma, não são vistas como mercados potenciais. O presente projeto visou o isolamento de novos compostos naturais de venenos animais com atividade anti-Leishmania e anti-T. cruzi. O presente estudo fracionou por diferentes técnicas cromatográficas, os venenos dos anfíbios Siphonops annulatus, Corythomantis greeningi, Aparasphenodon brunoi e Phyllomedusa hypochondrialis, visando o isolamento de peptídeos e metabólitos secundários através de ensaios biomonitorados. Utilizando-se a espectrometria de massas e seqüenciamento por degradação química de Edman, foi possível a caracterização bioquímica de cinco peptídeos ativos da secreção de Phyllomedusa hypochondrialis, sendo estes a bradicinina, as dermaseptinas 1 e 4 e as filoseptinas 7 e 8. Os peptídeos apresentaram uma Concentração Efetiva 50% (CE50) variando entre 0,7 a 20 ?g/mL em L. (L.) infantum chagasi e T. cruzi, com baixa ou nenhuma citotoxicidade para células de mamíferos nas concentrações testadas. Além disso, a separação química da secreção do anfíbio Siphonops annulatus forneceu uma fração altamente ativa em promastigotas de L. (L.) infantum chagasi, com CE50 0,065 ?g/mL, porém com toxicidade bastante elevada para macrófagos peritoneais e nenhuma seletividade nas formas intracelulares. Estudos ultraestruturais de Leishmania demonstraram severos danos mitocondriais, além da formação de grande vacúolos citoplasmáticos, levando o parasita a morte em poucas horas. O presente estudo demonstrou o potencial de peptídeos e metabólitos secundários de venenos de anfíbios, que se adequadamente estudados, poderão contribuir como novos protótipos de fármacos para a doenças negligenciadas.
Among the tropical parasitic diseases, those caused by protozoa present a major challenge to public health, being represented by leishmaniasis and Chagas disease. Affect large populations marginal to the global economic process, and thus are not seen as potential markets. This project aimed the isolation of new natural compounds in animal venoms with anti-Leishmania activity and anti-T. cruzi. The present study fractionated by different chromatographic techniques, the poisons of the amphibians Siphonops annulatus, Corythomantis greeningi, Aparasphenodon brunoi and Phyllomedusa hypochondrialis, aiming the isolation of peptides and secondary metabolites through bioguided assays. By using mass spectrometry and sequencing by Edman degradation, it was possible to do the biochemical characterization of five active peptides from the poison of Phyllomedusa hypochondrialis, as bradykinin, dermaseptins 1 and 4 and phylloseptins 7 and 8. The peptides showed a 50% Effective Concentration (EC50) ranging from 0.7 to 20 ?g/mL in L. (L.) infantum chagasi and T. cruzi, with little or no cytotoxicity to mammalian cells at the tested concentrations. In addition, the chemical separation of the poison of the amphibian Siphonops annulatus provided a highly active fraction against promastigotes of L. (L.) infantum chagasi, with an EC50 of 0.065 ?g/mL, but highly toxicity to peritoneal macrophages and without selectivity against the intracellular forms of Leishmania. Ultrastructural studies of Leishmania showed severe mitochondrial damages and the formation of large cytoplasmic vacuoles, leading to parasite death within few hours. The present study demonstrated the potential of peptides and secondary metabolites of amphibian poisons, and if adequately studied, may contribute as prototypes of new drugs for neglected diseases.

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Turra, Kely Medeiros. "Síntese de nitroderivados potencialmente antichagásicos e leishmanicidas para uso em sistemas ADEPT". Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-08062017-101918/.

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Doenças negligenciadas acometem milhares de pessoas em todo o mundo, principalmente em países subdesenvolvidos. A exemplo destas encontram-se doenças como a leishmaniose e a doença de Chagas que representam relevantes problemas de saúde pública. As terapias disponíveis para estas doenças tropicais, contudo, estão longe de serem satisfatórias e eficazes, considerando-se que os quimioterápicos existentes apresentam reconhecida toxicidade, alto custo e eficácia moderada. Com o propósito de obter alternativas terapêuticas otimizadas, este projeto de pesquisa teve como objetivo a obtenção de pró-fármacos de compostos nitroderivados com comprovada atividade leishmanicida e antichagásica para serem utilizados em sistemas ADEPT visando maior eficácia e menor toxicidade no tratamento destas parasitoses. A princípio, duas frentes de trabalho em paralelo foram adotadas: uma teórica, para determinação do mecanismo catalítico da carboxipeptidase G2 (CPG2) e obtenção de informações relacionadas ao mecanismo de clivagem dos pró-fármacos propostos, e a outra sintética, para obtenção dos compostos propriamente ditos. Estudos teóricos de ancoramento e dinâmica molecular da CPG2 com um de seus reconhecidos substratos, o metotrexato, indicaram que o mecanismo de ação proposto para metaloproteases em geral também pode ser aplicado a esta enzima. Informações relacionadas ao mecanismo de clivagem dos pró-fármacos propostos também foram obtidas. A rota sintética inicialmente proposta para a obtenção dos pró-fármacos partia da ligação dos nitroderivados ao ácido glutâmico por intermédio de um agente espaçante, o ácido succínico. Com base nas informações obtidas nos estudos teóricos, entretanto, o projeto foi reformulado focando-se na síntese dos pró-fármacos sem agente espaçante, pois estes se mostraram mais favoráveis ao reconhecimento pela enzima. Com relação à síntese, a obtenção dos compostos planejados não foi alcançada a despeito dos esforços empreendidos. Estudos teóricos e experimentais de reatividade parecem comprovar a tese de que o grupo nitro desativa as funções nucleofílicas das estruturas dos nitrocompostos que seriam fundamentais para as reações de acoplamento ao transportador ácido glutâmico. Este achado, contudo, constitui um importante problema a ser solucionado, visto que nitroderivados parecem exercer suas atividades principalmente mediante redução do grupo nitro e produção de espécies reativas de oxigênio nas redondezas dos parasitas.
Neglected diseases affect millions of people around the world for the most part in underdeveloped countries. Leishmaniasis and Chagas disease are example of important public health problems spread through Africa, Asia and Latin America. Unfortunately, currently available chemotherapy to treat these diseases remains ineffective, being the most frequently applied drugs toxic, expensive and of moderate potency. By considering this actual picture and envisioning new therapeutic alternatives, the aim of this work was to design and synthesize potential antichagasic and antileishmanial prodrugs of nitroderivatives to be used in Antybody-Directed Enzyme Prodrug Therapy (ADEPT), a drug design approach which results in targeted delivery of the active compounds, increasing their potencies in addition to lowering their toxicity. Theoretical studies to determine the catalytic mechanism of the carboxypeptidase G2 (CPG2) and to obtain information about the cleavage mechanism of proposed prodrugs were performed whereas different synthetic approaches were made to obtain the compounds. Docking and molecular studies of the CPG2 considering theoretical interactions with its known substrate, methotrexate, indicated that the proposed general mechanism for metalloproteases could be indeed applied to this enzyme. Information about the cleavage mechanism of prodrugs was also obtained. Initially prodrugs proposed were composed by nitroderivatives structures attached to glutamic acid, the chosen transporter agent, by a spacer group, the succinic acid. Theoretical studies, however, had showed that prodrugs constructed without a spacer agent could be better recognized by the enzyme. These results re-directed the synthetic approach to new prodrug structure without spacer. Despite all efforts spent, it was impossible to obtain the proposed prodrug structures. Experimental reactivity studies were then accomplished, since it was possible that the nitro group, from nitroderivatives structure, was able to reduce the nucleophilic power of particular functional groups chosen to accomplish the coupling between the active compound and the transporter. The results corroborate this hypothesis and the absence of nitro group facilitates the prodrug synthesis. This, however, constitute an important problem to be solved since the nitroderivative seams to exert their function mainly by nitro group reduction and production of free radical species in the surrounding of the parasites.

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Tezuka, Daiane Yukie. "Triagem de compostos anti-chagásicos com o Trypanosoma cruzi e leishmanicidas com as espécies Leishmania amazonensis e Leishmania chagasi". Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/75/75133/tde-25112015-101003/.

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Infecções causadas por tripanossomatídeos causam milhares de mortes anualmente, além de levarem a redução da capacidade produtiva, com elevada morbidade na população acometida. A eficácia terapêutica é limitada na maioria dos casos, sendo o benzonidazol o único fármaco aprovado para uso do tratamento do Trypanosoma cruzi, sendo ativo somente na fase aguda da Doença de Chagas, com grande efeitos colaterais. No caso das leishmanioses, as substâncias de tratamento existentes causam toxicidade renal e cardíaca, além de induzirem a resistência e apresentarem eficácia insuficiente. Observando todo o contexto torna-se necessário a busca por novas substâncias que sejam mais eficazes e menos tóxicas. Assim, o trabalho representa uma contribuição para a busca de novas moléculas bioativas para o tratamento da doença de Chagas e leishmaniose a partir da padronização e realização de ensaios celulares usando a forma epimastigota da cepa Y do T. cruzi e promastigota para Leishmania chagasi e L. amazonensis. A padronização do método colorimétrico de MTT foi realizada a partir da comparação com o método tradicional de contagem por microscopia usando câmara de Neubauer, seguido do estudo de viabilidade por citometria de fluxo, como método confirmatório e, finalmente a padronização do ensaio de ciclo celular usando os fármacos de referência benzonidazol (T. cruzi) e anfotericina B (Leishmania spp.). Os compostos testados neste estudo são proveniente de classes distintas de inibidores de alvos macromoleculares (cisteíno proteases, DHODH, GAPDH, quinases) e foram planejados e/ou selecionados pelo Grupo de Química Medicinal (NEQUIMED). Dentre todas as substâncias, inibidores de quinases apresentaram maior potencial para estudos subsequentes, sendo o T. cruzi o parasito mais sensível, onde um grande número de substâncias apresentou atividade nos estudos de triagem. Para uma delas (Neq0474) foi realizado o ensaio de dose-resposta, com EC50 = 53 µmol/L. L. chagasi apresentou a maior resistência dentre todos os parasitos estudados neste trabalho, enquanto que L. amazonensis foi sensível para Neq0438. Algumas substâncias estudadas apresentaram potencial para estudos mais aprofundados visando identificar novas alternativas terapêuticas para estas doenças parasitárias.
Infections caused by trypanosomatides lead to thousands of deaths annually, besides the reduction of the quality of life and working capability, with high morbidity to the patients. The therapy efficacy is limited in most cases, being benznidazole the only approved drug in Brazil, which works only in the acute phase of the Chagas Disease with severe collateral effects. For leishmaniasis, the drugs cause renal and cardiac toxicity and trigger resistance. In this context, novel efficacious and secure substantes are necessary to improve the current therapeutic strategies, which was the goal of this project by means of cell-based assays. The first step was the standardization of the MTT colorimetric assay for the epimastigote form of the Y strain of Trypanosoma cruzi and promastigote form of Leishmania chagasi and Leishmania amazonensis. This was achieved by comparing the results with the standard counting using the Neubauer chamber. The use flow cytometry for the determination of cell viability and the perturbation of the cell cycle were also standardized using the reference drugs benznidazole (T. cruzi) and amphotericin B (Leishmania spp.). New compounds tested in this project were designed or selected based on different macromolecular targets (cysteine proteases, DHODH, GAPDH, kinases) by the Medicinal Chemistry Group (NEQUIMED). Among them, many kinase inhibitors promoted the most dramatic results for T. cruzi, reducing the cell viability of this parasite. One of them (Neq0474) was subjected for a follow-up dose-response assay, with EC50 = 53 µmol/L. L. chagasi was the most resistant parasite in this work, whereas L. amazonensis was sensitive to Neq0438. Some of these new compounds are of interest for more in-depth studies to these parasitic diseases.

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Alessi, Claudia Alvares Calvo. "Leishmaniose cutânea americana no Pontal do Paranapanema - SP: avaliação clínica, histopatológica e uso da reação em cadeia da polimerase (PCR) para identificação e caracterização das espécies de Leishmania". Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/5/5144/tde-17022009-115336/.

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As leishmanioses são doenças parasitárias causadas por protozoários do gênero Leishmania e são importante problema de saúde pública. A leishmaniose cutânea americana é considerada doença autóctone do continente americano e se apresenta com diversas formas clínicas, que dependem da espécie que causa a infecção e de outros fatores como virulência e capacidade de evasão do sistema immune. São reconhecidas seis espécies de Leishmania que causam casos humanos de LCA no Brasil, destas, cinco pertencem ao subgênero Viannia e uma ao subgênero Leishmania. Elas são: Leishmania (Viannia) braziliensis, Leishmania (Viannia) guyanensis, Leishmania (Viannia) lainsoni, Leishmania (Viannia) shawi, Leishmania (Viannia) naiffi e a Leishmania (Leishmania) amazonensis. A transmissão da leishmaniose cutânea se mantém na região do Pontal da Paranapanema, com 20 casos notificados em 2006. A Leishmania (V.) braziliensis é a única espécie considerada como agente da doença na região, com identificação dos vetores envolvidos e de possíveis reservatórios silvestres. O objetivo do trabalho é o estudo dos aspectos epidemiológicos, clínicos e histopatológicos da leishmaniose cutânea no Pontal do Paranapanema e a identificação, por métodos moleculares, PCR, do agente etiológico e a caracterização do gênero, subgênero e a espécie de Leishmania presentes na região. A doença foi encontrada em ambos os sexos, predominando no sexo masculino (67,9%), em todas as faixas etárias, mas 70,5% estavam na faixa de 20 a 49 anos de idade. A forma clínica mais encontrada foi a cutânea, com 92,3% dos casos. A pesquisa de parasita na lesão em 78 pacientes que realizaram biópsias foi positiva em 40 amostras (51.3%), em lâminas coradas pela HE; quando se utilizou a IH foi 66,7%. O índice de concordância entre as técnicas da HE e IH foi de 58,97%. Entretanto, 10 casos negativos na IH foram positivos na HE, e de 38 casos negativos na HE, 22 foram positivos na IH. Isto mostra que há necessidade de associação dos dois métodos. A positividade na PCR foi de 53,8%. Avaliando-se os resultados obtidos nesse estudo, podemos verificar que dos 40 casos positivos pela HE, 24 também foram positivos pela PCR; porém, 16 destes, foram negativos pela PCR. Em contrapartida, das 38 amostras negativas na HE, 18 delas foram positivas pela PCR. Pela imunohistoquímica, do total de 26 amostras negativas, apenas 12 permaneceram negativas e 14 foram positivas na PCR; enquanto que, das 52 amostras positivas pela IH, 28 foram positivas e 24 negativas pela PCR. Os níveis de concordância da PCR com HE foram de 56,41% e da PCR com IH de 51,28%. Esses resultados reforçam a idéia da necessidade de se associar os três métodos para o diagnóstico da LC. As características das lesões histopatológicas foram: reação granulomatosa (RG) encontradas em 71,85%, reação granulomatosa com células gigantes (RGCG) em 12,8%, reação granulomatosa com necrose (RGN) em 10,3% e reação granulomatosa com necrose e células gigantes (RGNCG) em 5,1% dos casos. Utilizando-se os primers SSU rDNA S17/S18, foi possível caracterizar, através do seqüenciamento, 27 (34,6%) amostras como sendo do subgênero Viannia e 06 amostras como L. (L.) amazonensis. Este estudo identificou o primeiro caso de L. (L.) amazonensis na região
Leishmaniasis are parasitic diseases caused by protozoans of the Leishmania genus and are important public health problems. American cutaneous leishmaniasis (ACL) is considered an autochthonous disease of the American continent and presents several clinical forms which depend on the causative species of the infection and other factors such as virulence and ability to evade the immune system. Six Leishmania species are recognized to cause human ACL cases in Brazil of which five belong to the Viannia and one to the Leishmania subspecies. They are: Leishmania (Viannia) braziliensis, Leishmania (Viannia) guyanensis, Leishmania (Viannia) lainsoni, Leishmania (Viannia) shawi, Leishmania (Viannia) naiffi and Leishmania (Leishmania) amazonensis. Cutaneous leishmaniasis transmission is maintained in the Pontal do Paranapanema region, with 20 notified cases in 2006. Leishmania (V.) braziliensis is the only species considered to be the disease agent in the region with identification of the involved vectors and possible wild reservoirs. The aim of this research is the studies of the epidemiological, clinical and histopathological aspects of cutaneous leishmaniasis in the Pontal do Paranapanema and the identification by molecular methods, PCR, of the etiologic agent and characterization of the Leishmania genus, subgenus and species present in the region. The disease was found in both genders, with predominance of males (67.9%), in all age ranges, but 70.5% were in the range of 20 to 49 years. The cutaneous was the mostly found clinical form with 92.3% of the cases. Search for the parasite in the lesion of 78 patients who underwent biopsies was positive in 40 samples (51.5%), in HE stained slides; when IH was used, 66.7% were positive. Agreement index between the HE and IH techniques were 58.97%. However, 10 negative cases using IH were positive with HE, and of 38 HE negative cases 22 were positive using IH. This shows that association of the two methods is needed. Using PCR, there was a positivity of 53.8%. Evaluating the results obtained in this study, we may observe that of the 40 HE positive cases 24 were also positive on PCR; but 16 of these were PCR negative. Contrariwise, of the 38 HE negative samples 18 were positive PCR. Using immunohistochemistry, of the total of 38 HE negative samples, 18 were positive with PCR; while of the 52 IH positive samples, 28 were positive and 24 negative on PCR. Agreement levels of PCR with HE were 56.41%, and of PCR with IH 51.28%. These results reinforce the idea of the need for association of the three methods for CL diagnosis. Histopathological lesion characteristics were: granulomatous reaction (GR) found in 71.85%, granulomatous reaction with giant cells (GRGC) in 12.8T, granulomatous reaction with necrosis (GRN) in 10.3% and granuloma with necrosis and giant cells (GRNGC) in 5.1% of the cases. Using SSU rDNAS 17/S18 primers it was possible to characterize through sequencing 27 (34.6%) samples as being of the Viannia subgenus and 06 samples of the L. (L.).amazonensis This study identified the first L. (L.) amazonensis case in the region

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Abbehusen, Melissa Moura Costa. "Imunização de cães com produtos oriundos de Lutzomyia Longipalpis em duas diferentes abordagens: Canarypoxvirus sp. expressando o gene que codifica para a proteína salivar LJM17 e/ou LJL143, e a proteína do intestino médio luloper1 como vacina a proteína salivar LJM17 e/ou LJL143, e a proteína do intestino médio luloper1 como vacina bloqueadora de transmissão". reponame:Repositório Institucional da FIOCRUZ, 2015. https://www.arca.fiocruz.br/handle/icict/12697.

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Fundação Oswaldo Cruz, Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
As interações entre flebótomo, parasita e hospedeiro desempenham um papel importante na transmissão da leishmaniose. As moléculas provenientes do vetor são relevantes para estas interações e incluem as proteínas da saliva e do intestino médio. Nos flebótomos, as Leishmanias passam por um ciclo de desenvolvimento complexo dentro do intestino médio sob a proteção da matriz peritrófica, necessário para a geração de formas metacíclicas infectantes. As Leishmanias são transmitidas pelos flebótomos que co-injetam parasitas juntamente com a saliva, na derme do hospedeiro. Estudos anteriores demonstraram que a imunização de cães com duas proteínas salivares (LJM17 ou LJL143) de L. longipalpis, resultaram em uma imunidade mediada por células Th1 sistêmica e local afetando a sobrevivência do parasita in vitro. Assim, o objetivo deste trabalho foi avaliar a imunidade conferida pela imunização de cães com DNA e rCanarypoxvirus expressando o gene que codifica para as proteínas salivares de L. longipalpis (LJM17 e/ou LJL143). A imunização com ambas LJL143 e/ou LJM17 induziu uma forte resposta imune humoral. A produção específica do IFN-γ foi observada apenas nas CMSP dos grupos imunizados estimuladas com a proteína. Trinta dias após a última imunização, os cães foram desafiados por via intradérmica com 107 de L. infantum na presença de saliva de L. longipalpis, e a infecção foi detectada no segundo mês após o desafio em todos os grupos. Os cães imunizados com a LJM17 apresentaram maior produção de IFN-γ, IL-2, IL-6, IL-7, IL-15, IL-18, TNF-α, IP-10 e GM-CSF durante a infecção quando comparados com os controles, indicando que o efeito da imunização induzida por LJM17 persistiu mesmo após o desafio. Adicionalmente, diversos estudos realizados no controle da malária, têm demonstrado o uso de antígenos provenientes do vetor para o desenvolvimento de vacinas bloqueadoras de transmissão. Esta estratégia altruísta de imunização visa criar anticorpos que interfiram no desenvolvimento do parasita no interior do vetor. Assim, na segunda etapa do nosso trabalho, foi testada em cães uma estratégia de imunização utilizando uma proteína extraída do intestino médio do L. longipalpis (Luloper1) para induzir a produção de anticorpos em cães saudáveis e infectados e a interrupção da transmissão no flebótomo. Dessa forma, a imunização de cães saudáveis não infectados ou infectados assintomáticos induziu uma potente produção de anticorpos, porém nenhum efeito de bloqueio de transmissão foi detectado em flebótomos alimentados com o sangue desses animais contendo promastigotas de L. infantum.
Sand fly, parasite, host interactions play an important role in the transmission of leishmaniasis. Vector molecules are relevant for such interactions and include midgut and salivary proteins. In vector sand fly species, Leishmania parasites undergo a complex developmental cycle within the midgut, protected by the peritrophic matrix that is necessary for generation of infectious metacyclics. Leishmania parasites are transmitted by sand flies that co-inject parasites and saliva, in the host’s skin. Previous studies showed immunization of dogs with two proteins (LJM17 or LJL143) from Lutzomyia longipalpis, resulted in a systemic and local Th1 cell-mediated immunity affecting parasite survival in vitro. In this work we evaluated the immunity conferredbyimmunization of dogs with DNA and recombinant Canarypoxvírusexpressing the gene encoding the salivary ofL.longipalpis (LJM17and/orLJL143). Immunization with both LJL143 and LJM17 induced a strong specific humoral response. Specific production of IFN-γ was observed only in protein stimulated PBMC immunized groups. Thirty days after last immunization, dogs were challenged intradermally with 107L. infantum in the presence of L. longipalpis saliva and infection was detected in the second month after challenge in all the groups. It was observed that dogs immunized with LJM17 presented higher IFN-γ, IL-2, IL-6, IL-7, IL-15, IL-18, TNF-α, IP-10 and GM-CSF production during infection when compared with controls, indicating that the effect of immunization induced by LJM17 persisted even after challenge. Adittionally, previous studies, mostly with malaria control, have shown the use of several vector antigens for the development of transmission blocking vaccines. This altruist strategy of immunization aims to raise antibodies that could affect the development of the parasite inside the vector. Thus, in the second stage of our work we tested in dogs an immunization using a protein extracted from L. longipalpis midgut (Luloper1) to evaluate antibodies production in healthy and infected dogs and the interruption of transmission in the sand fly. Immunization of either healthy non infected or asymptomatic infected dogs induced a potent antibodies production, but no blocking transmission effect was detect in sand flies fed with blood of these animals containing L. infantum promastigotes

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Perez, J. Enrique. "Studies on Lutzomyia spp. vectors of leishmaniasis in Peru". Thesis, University of Liverpool, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261907.

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Cotterell, Sarah Elizabeth Jane. "The production and recruitment of leukocytes during murine visceral leishmaniasis". Thesis, London School of Hygiene and Tropical Medicine (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321966.

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Ribeiro, Jean Francisco Rosa. "Inibidores de Cisteíno Proteases como Candidatos Terapêuticos para o Tratamento de Doenças Parasitárias". Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/75/75133/tde-10102018-160410/.

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A necessidade urgente de descoberta de terapias mais seguras e eficazes para o tratamento da doença de Chagas e leishmanioses tem motivado a pesquisa por novos inibidores das enzimas cruzaína e CPB, as principais cisteíno proteases do T. cruzie e Leishmania spp., respectivamente. Uma série de 52 compostos nitrílicos que atuam como inibidores covalente-reversíveis de cisteíno proteases foi sintetizada no grupo NEQUIMED/IQSC/USP e avaliada quanto a sua atividade inibitória contra as enzimas cruzaína, CPB de Leishmania mexicana e catepsina L de humanos. Utilizando planejamento molecular baseado em hipótese, mapeamos as relações estrutura-atividade (SARs) desses inibidores através de variações nas posições P1, P2, P3 e P1\' do esqueleto dipeptidil nitrílico. A substituição do grupo eletrofílico (warhead) aminonitrila em P1 pelo grupo azanitrila melhorou a afinidade em duas ordens de magnitude para todos os alvos avaliados. Um dos mais potentes inibidores, o análogo azanitrila Neq0690 mostrou uma cinética de ligação lenta com valores de pKi de 8,8, 9,3 e 9,7 para cruzaína, catepsina L e LmCPB, respectivamente. A substituição bioisostérica da ligação amida entre as posições P2-P3 pelo grupo trifluoroetilamina resultou na síntese do Neq0659, um potente inibidor com um perfil de ação seletivo para as proteases de parasitos. A substituição do grupo metileno em P1 pelo ciclopropano aumentou a afinidade para todas as enzimas. Contudo, uma inibição seletiva da cruzaína e LmCPB foi associada à presença do grupo (R)-benzila como substituinte da posição P1 dos derivados CF3 substituídos. Embora os compostos substituídos com leucina, tirosina, triptofano e 3-cloro fenilalanina como substituintes da posição P2 foram relativamente bem tolerados pela cruzaína e catepsina L, uma restrita especificidade foi verificada para LmCPB com pequenos ganhos de afinidade para os inibidores que possuíam os grupos leucina e metil benzoato como substituintes dessa posição. Com relação à posição P3, a inserção do grupo 3-terc-butilpirazol e 3-bromo piridina aumentou a afinidade para todos os alvos avaliados enquanto que um ganho seletivo para a LmCPB foi observado para os compostos que possuíam o grupo bifenila nessa posição. Além disso, duas novas estruturas cristalográficas da LmCPB complexada com o Neq0690 e metil metanotiossulfonato (MMTS) foram determinadas com resoluções de 1,3 Å e 1,5 Å, respectivamente. As estruturas dos co-complexos revelaram os modos de interação (MoB) desses ligantes, bem como as principais características do processo de reconhecimento bimolecular. Isso permitirá o uso de estratégias de planejamento baseado na estrutura do alvo com translação natural para a pesquisa por novos inibidores de cisteíno proteases, com amplo espectro de ação na quimioterapia de doenças a elas relacionadas.

The urgent need for the discovery of safer and more effective therapies for the treatment of Chagas disease and leishmaniasis has motivated the search for new inhibitors of the enzymes cruzain and CPB, the major T. cruzi and Leishmania spp. cysteine proteases, respectively. A series of 52 nitrile-containing compounds acting as covalent-reversible inhibitors of cysteine proteases was synthesized at the NEQUIMED/IQSC/USP Medicinal Chemistry Group and evaluated for their inhibitory activity against the enzymes cruzain, Leishmania mexicana CPB and cathepsin L from humans. Using hypothesis-driven molecular design, we mapped the structure-activity relationships (SARs) of these inhibitors through variations in the P1, P2, P3 and P1\' positions of the dipeptidyl nitrile scaffold. The substitution of the aminonitrile by the azanitrile group improved the affinity by two orders of magnitude for all the evaluated targets. One of the most potent inhibitors, the azanitrile analogue dubbed Neq0690 showed a slow-binding kinetics with pKi values of 8.8, 9.3 and 9.7 for cruzain, cathepsin L and LmCPB, respectively. Bioisosteric substitution of the amide moiety between the P2-P3 positions by the trifluoroethylamine group resulted in the synthesis of Neq0659, a potent inhibitor with a selective action profile for parasite proteases. Substitution of the methylene group at P1 by cyclopropane increased the affinity for all enzymes. However, selective inhibition of cruzain and LmCPB was associated with the presence of the (R)-benzyl group as substituent of the P1 position of the substituted CF3 derivatives. Although leucine, tyrosine, tryptophan and 3-chloro phenylalanine substituted compounds as substituents of the P2 position were relatively well tolerated by cruzain and cathepsin L, a restricted specificity was verified for LmCPB with small affinity gains for the inhibitors possessing the leucine and methyl benzoate as substituents of that position. Regarding the P3 position, the insertion of the 3-tert-butylpyrazole and 3-bromo pyridine groups increased the affinity for all evaluated targets whereas a selective gain for LmCPB was observed for the compounds having the biphenyl moiety at that position. In addition, it is noteworthy that two new crystallographic structures of LmCPB complexed with Neq0690 and methyl methanethiosulfonate (MMTS) were determined with resolutions of 1.3 Å and 1.5 Å, respectively. The structures of the co-complexes revealed the modes of binding (MoB) of these ligands, as well as the main characteristics of the bimolecular recognition process. This will allow the natural translational target structure strategies for the search for new inhibitors of cysteine proteases with broad spectrum of action in the chemotherapy of related diseases.

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Shimozako, Hélio Junji. "Modelo de otimização para o controle da leishmaniose: análise epidemiológica e econômica". Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/5/5144/tde-22012016-085645/.

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A leishmaniose visceral zoonotica (LVZ) e uma das mais importantes doenc¸as parasitárias emergentes. Em particular, o Brasil é considerado um dos principais centros endêmicos para esta doença. Apesar da publicação de manuais de controle da leishmaniose visceral e dos investimentos aplicados na organizacão de serviços e no desenvolvimento de atividades preventivas e de controle, os vetores e os reservatórios em áreas urbanas são os maiores desafios para os programas de controle. Isto se deve (1) `a necessidade por melhor compreensão do comportamento do vetor no meio urbano; (2) `as dificuldades operacionais para realizar atividades em tempo suficiente para obter resultados de impacto; e (3) ao alto custo envolvido nessas atividades. O principal objetivo deste estudo foi elaborar um modelo de otimização para o controle da leishmaniose, baseado em 5 parâmetros de controle que correspondem `as seguintes estratégias: (I) controle vetorial, (II) eliminação de cães positivos, (III) uso de coleiras impregnadas com inseticida, (IV) vacinação canina e (V) tratamento canino. Este modelo foi construído a partir de um sistema composto por 17 equações diferenciais, sendo que 4 representam a dinâmica da doenc¸a sobre a população humana (humanos suscetíveis (xh), latentes (lh), clinicamente doentes (yh) e recuperados (zh)), 10 para a populacão de cães (cães suscetíveis (xd e xCd ), latentes (ld e lCd ), clinicamente doentes (yd e yCd ), recuperados (zd e zCd ) e vacinados (vd e vCd ), onde o índice C representa as categorias com a aplicação da coleira inseticida) e 3 para a população de vetores (mosquitos não-infectados (s1), infectados (mas não-infectivos) (s2), infectados e infectivos (s3)). Para a an´alise econômica dessas estratégias, foram estimados os custos de cada uma delas por cão (ou, no caso do controle vetorial, por casa tratada). Considerando a simulação sem a introdução das estratégias de controle, as densidades de equilíbrio endêmico para as categorias foram: xh = 0, 394, lh = 0, 0305, yh = 0, 00167, zh = 0, 574, xd = 0, 314, ld = 0, 165, yd = 0, 0163, zd = 0, 505, s1 = 0, 709, s2 = 0, 0858 e s3 = 0, 205. No estado de equilibrio endêmico, o número de reprodutibilidade basal foi estimado em R0 = 4, 50 e o n´umero diário de casos humanos notificados, em R = 3, 58 × 10-6/dia. Considerando a avaliação do impacto das estratégias de controle, o controle vetorial mostrou ser a estrat´egia que causa a diminuição mais rápida sobre o núumero diário de casos humanos notificados e, consequentemente, foi tambem a que mais reduz os custos m´edico-hospitalares. Entretanto, ´e a estratégia que exige o maior investimento. Por outro lado, a estrat´egia de eliminar cães positivos foi considerada a de menor custo. Dado que essas estratégias de controle atuam em pontos distintos na cadeia epidemiológica, o planejamento de um controle envolvendo a ação simultânea delas poderia não apenas apresentar resultados de controle mais interessantes, como tambem poderia otimizar ainda mais os investimentos sobre o controle da leishmaniose visceral
Zoonotic visceral leishmaniasis (ZVL) is one of the most important emerging parasitic diseases. Brazil, in particular, is considered one of the countries in which this disease is most endernic. Despite the publication of visceral leishmaniasis control guidelines and the investment in health services and controljpreventive activities, the vectors and reser- voirs in urban areas are the major challenge for those control programs. This is due to (1) the need for better comprehension regarding the vector behavior in the urban envi- ronment; (2) the operating difficulties in perforrning the activities in time to reach good results; and (3) the high cost of those activities. The main objective of this study was to elaborate an optirnization model for leishmaniasis control. This model is based on 5 con- trol parameters that correspond to the following strategies: (I) vector population control, (11) elirnination of positive dogs, (111) use of insecticide-impregnated dog collars, (IV) dog vaccination and (V) dog treatment. This model was elaborated using an equation system, composed of 17 differential equations, 4 of which represent the disease dynarnic on hu- man population (susceptible (Xh), latent (Ih), clinically ill (Yh) and recovered humans (Zft)), 10 for dog population (susceptible (Xd and xcd), latent (ld and Icd), clinically ill (Yd and Ycd), recovered (Zd and zcd) and vaccinated dogs (Vd and vcd), where C represents the categories using the insecticide-impregnated dog collars) and 3 for vector population (non-infected (SI), infected but not infective (S2), infected and infective sandflies (S3)). For econornic analysis of those control strategies, we estimated the cost of them per dog (in the case of vector control population, it was estimated per treated house). Regarding the nume- rical simulations without the control strategies, the endernic equilibrium densities were: Xh = 0.394, Ih = 0.0305, Yh = 0.00167, Zh = 0.574, Xd = 0.314, Id = 0.165, Yd = 0.0163, Zd = 0.505, SI = 0.709, S2 = 0.0858 and S3 = 0.205. In endernic equilibrium state, the basic reproduction number and the rate of reported human cases per day were estimated as 1%0 = 4.50 and R = 3.58 x 1O-6/day, respectively. Considering the impact evaluation of controI strategies, the vector population control was the strategy that resulted in a fas- ter decrease in the rate of human reported cases per day and, consequently, in the larger reduction of medical and hospital costs too. However, the investment (that is, the cost) of the vector population control was the highest one. On the other hand, the investment in elirninating positive dogs was considered the lowest one. Since those control strategies operate at different points within the epiderniological chain, the planning a control, while taking into account the simultaneous action of these strategies, could not only result in a more interesting control strategy, but could also improve the optirnization of investments on visceralleishmaniasis control

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Scaduto, Ryan. "A Natural Product and High-Throughput Screening Synthetic Approach Towards the Discovery of Antileishmanial Agents". Ohio Dominican University Honors Theses / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=oduhonors1620081955401195.

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Valenta, David Thomas. "The ecology of sandflies (Diptera: Psychodidae), vectors of cutaneous leishmaniasis, in the Andes of Western Venezuela". Thesis, University of London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325477.

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Yadon, Zaida Estela. "Risk factors for American Cutaneous Leishmaniasis in Santiago del Estero, Argentina : a retrospective case-control study". Thesis, London School of Hygiene and Tropical Medicine (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244042.

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Santos, Katia Solange Cardoso Rodrigues dos. "Latenciação de hidroximetilnitrofural com derivados de quitosana, potencialmente ativos em leishmaniose e doença de Chagas". Universidade de São Paulo, 2005. http://www.teses.usp.br/teses/disponiveis/9/9138/tde-05092006-232733/.

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Leishmaniose e doença de Chagas são parasitoses endêmicas causadas, respectivamente, pelos protozoários Leishmania spp. e Trypanosoma cruzi. Ante à escassez de quimioterápicos, à elevada toxicidade dos fármacos disponíveis e à baixa eficácia destes no combate às formas intracelulares, replicantes, dos parasitos há necessidade de buscar novas alternativas quimioterápicas. A atividade tripanomicida do hidroximetilnitrofural, base de Mannich do nitrofural, já era conhecida. O presente trabalho mostra que este derivado também apresenta atividade leishmanicida, quando ensaiado em formas promastigotas de L. amazonensis, L. chagasi e L. baziliensis. Com o objetivo de obter pró-fármacos potencialmente ativos em doença de Chagas e leishmanioses visceral e mucocutânea, planejaram-se e foram sintetizados derivados hidrossolúveis de hidroximetilnitrofural e quitosana, polissacarídeo que apresenta, também, atividade imunomoduladora. Para a aplicação tópica em leishmaniose cutânea sintetizaram-se membranas de quitosana ligada ao hidroximetilnitrofural. Membranas de quitosana copolimerizadas com enxertos de ácido acrílico e metacrilato de hidroxietila foram sintetizadas e avaliadas quanto à biocompatibilidade - trombogenicidade, citotoxicidade e potencial hemolítico. Aquelas com maior teor em metacrilato de hidroxietila não se mostraram citotóxicas, tampouco hemolíticas; aquelas com maior proporção em ácido acrílico, por sua vez, apresentaram excelentes características de intumescimento, mas certo grau de citotoxicidade e hemólise, possivelmente devido à presença de monômeros que não reagiram no material. A ligação do hidroximetilnitrofural à quitosana, por meio de espaçante succínico, produziu prófármaco com propriedades filmogênicas para a aplicação tópica. Os derivados obtidos pró-fármacos e transportadores (quitosanas modificadas) - foram analisados no infravermelho, por ressonância magnética nuclear (RMN 1H e RMN 13C) e por análise térmica - OMTA, TG, OSC. Ensaios de atividade tripanomicida e leishmanicida dos pró-fármacos poliméricos e membranas serão posteriormente efetuados.
Leishmaniasis and Chagas\' disease are endemic parasitosis provoked by the protozoa Leishmania spp and Trypanosoma cruzi, respectively. Due to the scarce chemotherapy, to the high toxicity of the available drugs and to their low effectiveness, mainly in the treatment of intracellular replicant forms of those parasites, the search for new chemotherapeutic alternatives is extremely important. Hydroxymethylnitrofurazone, a nitrofurazone Mannich basis, has proven to be active against trypanomicide before and its activity in cultures of L. amazonensis, L. chagasi and L. braziliensis promastigotes was determined in this work. With the purpose of obtaining prodrugs potentially active in Chagas\' disease and visceral and mucocutaneous leishmaniases, hydrosoluble hydroxymethylnitrofurazone prodrugs have been designed and synthesized using chitosan, a polysaccharide showing immunomudulatory activity, as the carrier. Membranes from chitosan linked with hydroxymethylnitrofurazone have been synthesized for topical administration in cutaneous leishmaniasis. Membranes were obtained by graft copolymerization of hydroxyethy/methacrylate and acrylic acid onto chitosan and their biocompatibility - trombogenicity, citotoxicity and hemolysis potential - was evaluated. Those membranes with higher content of hydroxyethylmethacrylate showed to be neither cytotoxic nor hemolytic; those with higher content of acrylic acid showed good swelling properties, although a certain level of cytotoxicity and haemolysis has been detected, due to the presence of non-reacted monomers. The linkage of hydroxymethylnitrofurazone to chitosan by a succinyl spacer group led to a prodrug with filmogenic properties for topic administration. The derivatives obtained - prodrugs and carriers (modified chitosans) - were analyzed by infrared, nuclear magnetic resonance (1H NMR and 13C NMR) and by thermal analysis - DMTA, TG and DSC. Tests of trypanomicide and leishmanicide activity with polymer prodrugs and membranes will be further developed.

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G, Tassone. "Structural studies on human and parasite enzymes related to disease". Doctoral thesis, Università di Siena, 2019. http://hdl.handle.net/11365/1070917.

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Macromolecular X-ray crystallography plays a key role in the drug discovery process, providing essential clues to explain the mechanism of action of protein targets and to elucidate the inhibitor binding mode. The detailed analysis of crystal structures is precious to conceive powerful inhibitors, through a rational structure-based drug discovery approach, that may lead to the development of new drugs. During my PhD, I had the opportunity to face two relevant topics related to human diseases, namely human and parasite Heat shock protein 90 (Hsp90) and human 14-3-3σ, and to study them through X-ray crystallography. In the first chapter, X-ray crystallography was exploited to characterize the role on nucleotide binding of both Arg97 in the N-terminal domain (NTD) of Leishmania braziliensis Hsp90 and of Lys112 in the human counterpart to find new determinants to selectively target the parasite enzyme. In details, we investigated the contribution of parasite Arg97 through the introduction of this residue, by site-directed mutagenesis, in the human protein generating the “leishmanized” variant of human Hsp90-NTD. The alanine variant was also generated to deeply understand the role of this non-conserved residue in human and parasite proteins. A variety of ADP and ATP analogues and cAMP were used to probe the role of these residues. According to our structural results residue Arg97 of Leishmania braziliensis Hsp90-NTD and Lys112 in the human protein are not crucial for substrate binding, making them not exploitable for the development of selective inhibitors targeting parasite Hsp90 over the human counterpart. In the second chapter, an X-ray crystallographic screening was performed on human 14-3- 3σ using small molecular weight compounds to identify new modulators of proteinprotein interactions (PPIs) involving this target. As a matter of fact, human 14-3-3σ protein is crucial for various cellular cascades, making it a target for the development of new anticancer and antileukemia drugs. The crystal structure of h14-3-3σ was solved in complex with pyridoxal phosphate (PLP) and inosine monophosphate (IMP). Notably, our structures revealed the fundamental contribution of the phosphate moiety present in both compounds for h14-3-3σ recognition and binding. The structural informationachieved will guide the rational design of new h14-3-3σ PPIs inhibitors based on these innovative scaffolds.

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Steinkamp, Heidi Marie. "The Role of Macrophages and the Th1 Transcription Factors STAT1 and STAT4 During Visceral Leishmaniasis". The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338335780.

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Jagadesh, Soushieta. "Biogeography of Emerging Infectious Diseases In search for the hotspots of Disease X: A biogeographic approach to mapping the predictive risk of WHO’s Blueprint Priority Diseases Emerging human infectious diseases of aquatic origin: a comparative biogeographic approach using Bayesian spatial modelling Global emergence of Buruli Ulcer Spatial variations between Leishmania species: A biogeographic approach to mapping the distribution of Leishmania species in French Guiana Mapping priority neighborhoods: A novel approach to cluster identification in HIV/AIDS population". Thesis, Guyane, 2020. http://www.theses.fr/2020YANE0007.

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La récente pandémie de Covid19 nous rappelle, si cela était encore nécessaire, que la propagation des maladies infectieuses ignore les frontières géographiques. Les changements combinés de biodiversité locale et l’utilisation des terres, l’augmentation de la connectivité internationale par le transport et le commerce ainsi que la menace imminente du changement climatique a accru le risque d’émergence et de réémergence des maladies infectieuses (EMI). Jusqu’à présent la réponse des politiques de santé publique a été la surveillance passive sans toutefois s’avérer réellement efficace dans la prévention et le contrôle des épidémies. Le choix qui a été fait ici est celui d’une nouvelle approche anticipative, par identification des zones à haut risques d’EMI en se basant sur la détection des facteurs environnementaux les plus favorisant. Parmi ces facteurs on trouve la conversion des terres, la diminution drastique de la biodiversité ou encore le changement climatique. Ainsi la méthode biogéographique a permis d’étudier et d’analyser les EMI à travers différents groupes de taxons de pathogènes comme les bactéries, les virus, les protozoaires et les champignons. L’étude a été portée globalement, ainsi que localement, en Guyane Française, un territoire français d’outre-mer situé en Amérique du Sud. Dans les deux cas, à travers les différents groupes de pathogènes, les risques d’inondation, les récentes conversions de parcelles de forêts en terres agro-minières et l’augmentation du minimum de température due au changement climatique se sont avérés être des facteurs significatifs dans l’émergence globale et locale des maladies infectieuses étudiées. Les principaux résultats de cette thèse sont les suivantes :1. Une approche biogéographique de modélisation de la distribution des EMI en utilisant les bases de données existantes sur les cas cliniques, l’imagerie satellite et un modèle statistique non conventionnel est efficace pour détecter précocement les régions à risque, permettre d’améliorer la prévention, et contrôler leur diffusion.2. Il est possible d’anticiper les EMI en identifiant et en gérant précocement les facteurs favorisant ayant un lien direct avec l’anthropisation de l’environnement
The COVID-19 pandemic highlights that the spread of infectious diseases goes beyond geographical boundaries. Simultaneous changes in local biodiversity and land use, the increasing international connectivity through human transport and trade and the imminent threat of climate change have increased the risk of the emergence and reemergence of infectious diseases. The current public health response to emerging infectious diseases (EID) by passive surveillance has proven largely ineffective in preventing and controlling disease outbreaks. The way toward is to “get ahead of the curve” by identifying potential hotspots of disease emergence and detecting the environmental triggers such as land transformation, biodiversity loss and climate change. I used a biogeographic approach to study and analyze disease emergence across different taxonomic pathogen groups such as bacterial, viral, protozoal and fungal, globally and in French Guiana, a French Overseas territory located in South America. I found that regions at risk of floods, recent conversion of forest to agricultural lands and increasing minimum temperature (i.e. temperature at night) caused by cli mate change were drivers for disease emergence locally and globally across the different pathogen groups. The main findings of the PhD thesis are the following:1. Biogeographic approach to mapping the distribution of EIDs with using existing human cases data, remote sensing imagery and unconventional statistical models is effective to “get ahead of the curve” in the detection of regions at risk and the management of EIDs.2. EIDs are not unprecedented but predictable by identifying and managing the triggers of disease emergence, which have a direct link with the anthropization of the environment

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Singh, Jasdeep. "molecular target based lead identification against leishmaniasis and protein aggregation disorders". Thesis, 2018. http://localhost:8080/xmlui/handle/12345678/7638.

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Iverson, Chad. "Identification of glutathione S-transferase inhibiting natural products from Matricaria chamomilla and biotransformation studies on oxymatrine and harmine". 2010. http://hdl.handle.net/1993/4150.

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This thesis describes the results obtained from the phytochemical analysis of Matricaria chamomilla, and the microbial transformation of oxymatrine (85) and harmine (87), as summarized below. 1. Chemical investigation of the crude methanolic extract of Matricaria chamomilla resulted in the isolation of a new natural product, matriisobenzofuran (72), along with four known compounds: apigenin (73), apigenin-7-O-β-glucopyranoside (74), scopoletin (75), and fraxidin (76). The structures of compounds 72-76 were elucidated with the aid of extensive NMR and mass spectroscopic studies. All of the aforementioned compounds showed moderate to good inhibitory activities against glutathione S-transferase, an enzyme which has been implicated in the resistance of cancer cells to chemotherapeutic agents. These compounds were also evaluated for antioxidant activity and displayed moderate to good free radical scavenging activity. Additionally, compounds 72-76 were screened for anti-leishmanial activity. Compounds 75 and 76 were significantly active in this assay, while the remaining compounds were weakly active. In the antibacterial and antifungal assays, compounds 72-76 were not active. 2. The second part of this thesis deals with the biotransformation studies on oxymatrine (85) and harmine (87). Oxymatrine (85) was metabolized to the deoxy analogue, matrine (84) by Penicillum chrysogeneum (ATCC 9480), Cunninghamella bainieri (ATCC 9244), Cunninghamella blakesleena (ATCC 9245 and 8688A), Curvularia lunata (ATCC 12017), and Fusarium sp. In the time-based analysis of this transformation, the metabolism of oxymatrine (85) could be detected after 48 hours of incubation. Additionally, incubation of harmine (87) with Mucor plumbeus (ATCC 4740) resulted in the isolation of harmine-N-oxide (94). The biotransformed products (84 and 94) were identified using IR, UV, NMR, and mass spectroscopic techniques. Compound 94 was evaluated for its ability to inhibit the enzyme acetylcholinestrase, whose overexpression has been linked to Alzheimer’s disease, and was found to possess weaker activity than harmine (87).

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Mendes, Mafalda Maria Teixeira. "Relatórios de Estágio e Monografia intitulada "Nanotecnologia no Tratamento e Diagnóstico de Doenças Causadas por Tripanossomatídeos"". Master's thesis, 2021. http://hdl.handle.net/10316/99086.

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Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia
O estágio curricular e a realização da dissertação de mestrado representam o culminar dos últimos cinco anos de experiências e aquisição de conhecimentos. Os relatórios elaborados, sob a forma de uma análise SWOT, visam uma avaliação das experiências vividas, competências e conhecimentos adquiridos durante os respetivos estágios em Farmácia Comunitária e Indústria Farmacêutica. Adicionalmente, a dissertação apresentada realizou-se no âmbito do tema “Nanotecnologia no Tratamento e Diagnóstico de Doenças Causadas por Tripanossomatídeos”. Nas últimas décadas, a nanotecnologia tem vindo a mostrar-se vital para o desenvolvimento da indústria farmacêutica, no âmbito das técnicas de tratamento e diagnóstico. A escala nanométrica traz consigo soluções inovadoras, para a incorporação, transporte e entrega dos fármacos e substâncias ativas convencionalmente usados na prática clínica. A melhoria significativa de aspetos como a solubilidade, biodisponibilidade e tempo de retenção dos fármacos, bem como a diminuição da toxicidade de medicação convencional, tornam o uso da nanotecnologia bastante apetecível. Atualmente, encontram-se em estudos in vitro e in vivo uma série de nanomedicamentos, sob diferentes formas, tais como nanopartículas, nanolipossomas e nanoconjugados, existindo já formulações com sucesso comercial. A nanotecnologia no tratamento e diagnóstico de doenças parasitárias tem sido alvo de grande atenção e estudo, uma vez que os regimes terapêuticos disponíveis nesta área são bastante complexos e morosos, tendo associado um elevado risco de toxicidade. Doenças como a leishmaniose, doença de chagas e doença do sono, abordadas nesta monografia, são exemplos claros de infeções que beneficiam das soluções proporcionadas pela nanotecnologia. Estudos de formulação de nanossistemas aplicados ao tratamento destas doenças têm-se mostrado eficazes, demonstrando resultados animadores.
The time of the curricular internship and the writing of the master thesis represent the end of the last five years of learning experiences. The following internship reports aim to evaluate by means of a SWOT analysis the experience, acquired skills and know-how obtained during the internships conducted in community pharmacy and pharmaceutical industry. Additionally, the presented monograph elaborates on the theme “Nanotechnology applied to the Treatment and Diagnostics of Diseases Caused by Trypanosomatids”. In the last decades, nanotechnology has shown to be crucial for the development of the pharmaceutical industry, regarding new treatment and diagnosis techniques. Working at the nanoscale has brought new groundbreaking solutions for drug transport and delivery in regard to the drugs already used in clinic. It significantly improves aspects such as solubility, bioavailability and retention time, whilst decreasing toxicity, which makes the use of nanotechnology very appealing. Currently, there are various nanomedicines going through in vitro and in vivo studies. This medicines are presented in forms such as nanoparticles, nanolipossomes or nanoconjugates, some of which already available in the market. Nanotechnology applied to the treatment of parasitic diseases has been given much attention in the last decades, as the available therapeutic regimens in this area are complex and cumbersome, with high toxicity levels. Parasitic diseases such as leishmaniasis, chagas disease and sleeping sickness are clear examples of infections that will benefit from the incorporation of nanotechnology. Studies on nanosystem formulation have proven nanomedicine to be an effective treatment method and the results have been uplifting.

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