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Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES

Well-defined estimates of mutation rates in highly polymorphic tetra-nucleotide short tandem repeats (STR) loci are a prerequisite for human identification (paternity) in the routines of civil and criminal investigations. Studding 15 autosomal STR loci of forensic interest (CSF1PO, D13S317, D16S539, D18S51, D19S433, D21S11, D2S1338, D3S1358, D5S818, D7S820, D8S1179, FGA, TH01, TPOX and vWA) we detected 193 slippage mutations (189 one-step and 4 two-step mutations) in 148,875 parent?child allelic transfers from 5,171 paternity cases with true biological relationship (15,096 individuals; 4,754 trios and 417 duos; 9,925 meioses). The overall mutation rate was 1.3x10-3. The highest rates were observed in vWA (2.8x10-3), FGA and D18S51 (2.7x10-3 for both) loci, while TH01 and TPOX loci presented no mutations in this populational sample. Mean slippage mutation rate of paternal origin (1.8x10-3) was six times higher than that observed from maternal origin (0.3x10-3), except for locus D21S11.

Estimativas bem definidas de taxas de muta??o em l?cus polim?rficos tetra-nuclet?deos do tipo STR (short tandem repeats) s?o um pr?-requisito para exames de investiga??o gen?tica de paternidade nas rotinas de investiga??es c?veis e criminais. Estudando 15 l?cus STR autoss?micos de interesse forense, n?s identificamos 193 muta??es do tipo slippage (189 one-step e 4 two-steps) em 148.875 transfer?ncias al?licas entre duas gera??es a partir de 5.171 casos de paternidade, nos quais havia rela??o biol?gica confirmada entre os indiv?dos (15.096 indiv?duos; 4.754 trios e 417 duos; 9.925 meioses). A taxa global de muta??o foi 1,3x10-3. As taxas mais elevadas foram observadas nos l?cus vWA (2,8x10-3), FGA e D18S51 (2,7x10-3 para ambos), enquanto nos l?cus TH01 e TPOX n?o foram observadas muta??es nessa amostra populacional. A taxa de muta??o decorrente de meiose paterna (1,8x10-3) foi seis vezes superior ? taxa decorrente da origem materna (0,3x10-3), exceto para o l?cus D21S11.

Advisors/Committee Members: Alho, Clarice Sampaio.

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This work aims to discuss, from the analysis of the Rcl 4374/PE, the use of the constitutional complaint as a instrument processual able to promote the update of the jurisprudence of the Supreme Court, which are firmed under abstract judicial review of the standards. It assumes that the Court???s decisions remain open to a constant process of reinterpretation, by itself, and the constitutional complaint can be the locus for assessment of those changes. It understands that the Constitution of a State, under the guise of being stable, can???t stifle in a way that fails to meet the interests of its people, leading to an institutional breakdown. At the same time, it cannot be subject to a process of deformation through constant changes in its text, destabilizing the legal relations. The question which arises, therefore, is the idea that the Constitution must be interpreted in a temporal context in which required the solution of a given case. Similarly, the judicial decisions which care about the relationship between the standards, whereas continuing legal relationship, aren???t precluded from being modified when there is a material change of context. So, when considering the occurrence of substantial changes in the factual relationships or general legal concept, this reinterpretative process can lead to an evolution in the jurisprudence set in an abstract control of the standards and result in an unconstitutionality, when it was considered constitutional before. Thus, it is proposed the understanding that the legal standards suffer a permanent process of updating of their meaning, which is why the study of the phenomenon of constitutional mutation and interpretation arises as being of great relevance for this update take place. The constitutional mutation is recognized as one of the most important contemporary discussions in Law, by providing a radical change in the interpretation of the Constitution, allowing its renewal, at the light of the social evolution, and offering meanings in line with the current reality

O presente trabalho discute, com base na an??lise da Rcl 4374/PE, o uso da reclama????o constitucional como um instrumento processual apto a promover a atualiza????o da jurisprud??ncia do Supremo Tribunal Federal firmada em sede controle abstrato de constitucionalidade das normas. Parte-se da premissa de que as decis??es da Corte permanecem abertas a um constante processo de reinterpreta????o pelo pr??prio Tribunal, e que a reclama????o constitucional pode ser o locus de aprecia????o dessas mudan??as. A Constitui????o de um Estado, sob o pretexto de ser est??vel, n??o pode se engessar de tal forma que deixe de…

Advisors/Committee Members: Correia Neto, Celso de Barros.

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INTRODU????O: A doen??a de Fabry (DF) ?? um erro inato do metabolismo dos glicoesfingol??pidos devido ?? defici??ncia da atividade da enzima ??-galactosidase A; ?? ligada ao cromossomo X e pacientes do sexo masculino geralmente apresentam sintomas cl??ssicos. N??o h?? muta????es comuns para este gene; mais de 600 muta????es j?? foram descritas no Human Gene Mutation Database. OBJETIVO: O objetivo deste estudo ?? relatar todas as muta????es e altera????es polim??rficas observadas nos membros de cinco fam??lias com a doen??a de Fabry do estado da Bahia-Brasil. MATERIAL E M??TODOS: Um total de 48 pacientes com suspeita de DF foi encaminhado para avalia????o no Servi??o de Gen??tica M??dica do Hospital Universit??rio Professor Edgard Santos durante o per??odo de janeiro de 2009 a dezembro de 2011. Os 14 pacientes (06 homens/08 mulheres) com diagn??stico de Doen??a de Fabry envolvidos neste trabalho s??o acompanhados no Ambulat??rio de Erros Inatos do Metabolismo do Hospital Professor Edgard Santos - Universidade Federal da Bahia. Eles pertencem a cinco fam??lias (I, II, III, IV e V) n??o relacionadas. O gene GLA foi analisado atrav??s da amplifica????o por PCR (rea????o em cadeia da polimerase) e sequenciamento de ambas as cadeias de DNA de toda a regi??o codificadora e de regi??es nas jun????es entre ??xons e ??ntrons. Para todos os pacientes do sexo masculino e alguns do sexo feminino foi realizada a medida da atividade da enzima ??-galactosidase em gota de sangue seca atrav??s da espectrometria de massa em tandem. RESULTADOS: Quatro diferentes muta????es causadoras de DF foram encontradas e todas elas j?? foram relatadas previamente. Duas das cinco fam??lias compartilham a mesma muta????o (p.A156D). Nas fam??lias I e V (ambas com muta????o p.A156D) foi encontrado o mesmo polimorfismo (c.1000-22C> T), mas uma outra diferente varia????o foi encontrada apenas na Fam??lia I. DISCUSS??O: Apesar do pequeno n??mero de pacientes envolvidos neste estudo, este trabalho ?? o mais completo em an??lise de polimorfismos do gene GLA, incluindo todos os pacientes diagnosticados com a doen??a de Fabry do estado da Bahia-Brasil. A an??lise de altera????es polim??rficas sugere que duas das cinco fam??lias t??m uma mesma origem ancestral. Mais estudos para avaliar esta hip??tese est??o ocorrendo neste momento, atrav??s da an??lise de hapl??tipos.

Advisors/Committee Members: Toralles, Maria Bet??nia Pereira, Alves, Cr??sio de Arag??o Dantas, Melo, Maria Ermec??lia Almeida, Pond??, Milena Pereira, Adan, Lu??s Fernando Fernandes.

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Submitted by ROBERTO PAULO CORREIA DE ARA??JO ([email protected]) on 2015-07-17T19:51:36Z No. of bitstreams: 1 PEREIRA, Danielle Pess??a.pdf: 2273847 bytes, checksum: 9fd911d989bc9942943233a4ba36bf38 (MD5)

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Este trabalho foi financiado pela Funda????o de Amparo ?? Pesquisa no Estado da Bahia (FAPESB)

Introdu????o: A oncog??nese tireoidiana frequentemente envolve a ativa????o constitutiva da via RAS-RAF-MEK-ERK. A muta????o BRAFV600E contribui para a sua ativa????o e tem sido considerada o evento oncog??nico mais frequente do carcinoma papil??fero de tireoide (CPT). Estudos cl??nicos e experimentais t??m predominantemente demonstrado associa????o positiva entre a presen??a da muta????o BRAFV600E e mau progn??stico do CPT. No entanto, alguns estudos n??o constataram esta associa????o, indicando que ainda h?? discrep??ncias e variabilidade nos resultados obtidos. Objetivos: Determinar a preval??ncia da muta????o BRAFV600E em casos consecutivos de CPT em pacientes diagnosticados e tratados no Hospital S??o Rafael, SalvadorBahia-Brasil e associar a presen??a da muta????o com aspectos clinicopatol??gicos conhecidos do CPT e risco de recorr??ncia segundo protocolos do Consenso Brasileiro e a American Thyroid Association. Metodologia: Estudo retrospectivo de 135 casos consecutivos de CPT. Extra????o de DNA de tecido tumoral parafinado. Rea????o em cadeia da polimerase e sequenciamento direto do exon 15 do gene BRAF. Dados cl??nicos e patol??gicos foram obtidos atrav??s da revis??o de prontu??rios f??sicos e eletr??nicos. A positividade da muta????o BRAFV600E foi confrontada com os aspectos clinicopatol??gicos dos pacientes utilizando Teste de Qui-Quadrado e an??lise multivariada de regress??o log??stica. Resultados: A preval??ncia da muta????o BRAFV600E foi de 65,1% (28/43). A muta????o BRAFV600E esteve positivamente associada com idade avan??ada (40,96 ?? 13,69 vs 29,73 ?? 10,18; P = 0,008) e negativamente com presen??a de tireoidite de Hashimoto (TH) (25% vs 66,7%; P = 0,008). Contudo, o efeito independente foi somente observado para TH (OR: 0,14; P = 0,024). Neste estudo, n??o foram observadas associa????es com o sexo do paciente, hist??ria familiar, subtipo histol??gico, tamanho tumoral, multifocalidade, invas??o vascular, met??stases linfonodais e ?? dist??ncia, est??dio cl??nico avan??ado (TNM/AJCC) e risco de recorr??ncia tumoral. Conclus??o: A preval??ncia da muta????o BRAFV600E foi semelhante ?? apresentada em estudos pr??vios. A muta????o BRAFV600E n??o esteve associada com a maioria dos aspectos clinicopatol??gicos investigados. Tireoidite de Hashimoto esteve negativamente associado com a muta????o BRAFV600E .

Background: Thyroid oncogenesis often involves constitutive activation of the RAS-RAFMEK-ERK pathway. BRAFV600E mutation contributes to this activation and has been considered the most frequent oncogenic event in papillary…

Advisors/Committee Members: Ramos, Helton Estrela.

▼ A serpente Lachesis muta rhombeata (Viperidae), popularmente conhecida como surucucu pico-de-jaca, é uma subespécie de Lachesis muta endêmica na Mata Atlântica brasileira, podendo ser encontrada do Ceará até o Rio de Janeiro. O gênero Lachesis apresenta uma peçonha complexa que engloba diferentes proteínas que possuem uma ampla variedade de atividades biológicas, como por exemplo, aquelas que afetam os fatores da coagulação sanguínea, agem na fibrinólise, provocam uma ação inflamatória no local da picada, e induzem um choque hipotensivo. Com o auxílio de técnicas proteômicas e de Bioinformática, este projeto teve como objetivo principal analisar o proteoma da peçonha de L. m. rhombeata, identificando as principais famílias proteicas presentes. Para isso, 200μg da peçonha desta serpente foram aplicados em géis bidimensionais-2D. As proteínas obtidas foram extraídas dos géis, tratadas, e posteriormente identificadas e analisadas por meio de espectrometria de massas (MALDI-TOF/TOF). Os arquivos brutos provenientes dessas análises foram aplicados no programa MASCOT utilizando para a identificação proteica o banco de dados SwissProt e como especificação taxonômica o banco de dados SNAKES contido no site do NCBI. Foram identificadas 11 famílias proteicas: PLA2s (37,93%), inibidores de proteases (22,41%), proteínas de sinalização intracelular (13,79%), NGFs (5,17%), metaloproteases (3,45%), fatores associados à DDB1 e CUL4 (3,45%), oxidorredutases (3,45%), proteínas de transdução de sinal (1,72%), componentes do complemento (1,72%), proteínas NipSnap (1,72%) e proteínas lin-7 (1,72%), das quais a grande maioria é de função metabólica e ajuda na difusão/entrada dos componentes tóxicos no organismo da vítima/presa. Cerca de 1-5mg da mesma peçonha também foram analisados por meio de FPLC e sequenciamento proteico e as proteínas obtidas foram identificadas por meio de busca no banco de dados nr (nonredundant protein sequences) do NCBI utilizando a ferramenta blast-p. As seguintes famílias proteicas foram encontradas: serinoproteases (30,03%), metaloproteases (24,17%), BPPs (19,64%), PLA2s (14,95%), lectinas tipo C (1,94%), LAAOs (1,40%) e metaloendopeptidases (0,73%), ressaltando a toxicidade da peçonha. Os dois resultados obtidos foram comparados com proteomas de outras serpentes do gênero Lachesis encontrados na literatura. Observou-se que há uma grande similaridade entre os proteomas das peçonhas deste gênero, mas que alguns componentes proteicos são diferenciais e assim, podem ajudar na taxonomia destas serpentes, mantendo-as em suas respectivas espécies e subespécies. Além disso, a peçonha também foi analisada por eletroforese unidimensional (SDS-PAGE) para avaliar se o espécime em estudo era um neonato, um juvenil ou um adulto. A presença de uma proteína similar à mutalisina II (metaloprotease) confirmou que a L. m. rhombeata utilizada neste estudo era uma adulta. O conhecimento do proteoma da peçonha de L. m. rhombeata auxiliará (1) os estudos envolvendo a Sistemática do gênero e (2) a produção de novos fármacos que… Advisors/Committee Members: Heloísa Sobreiro Selistre de Araujo.

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Universidade Federal de Sao Carlos

A serpente Lachesis muta rhombeata (Viperidae), popularmente conhecida como surucucu pico-de-jaca, é uma subespécie de Lachesis muta endêmica na Mata Atlântica brasileira, podendo ser encontrada do Ceará até o Rio de Janeiro. O gênero Lachesis apresenta uma peçonha complexa que engloba diferentes proteínas que possuem uma ampla variedade de atividades biológicas, como por exemplo, aquelas que afetam os fatores da coagulação sanguínea, agem na fibrinólise, provocam uma ação inflamatória no local da picada, e induzem um choque hipotensivo. Com o auxílio de técnicas proteômicas e de Bioinformática, este projeto teve como objetivo principal analisar o proteoma da peçonha de L. m. rhombeata, identificando as principais famílias proteicas presentes. Para isso, 200μg da peçonha desta serpente foram aplicados em géis bidimensionais-2D. As proteínas obtidas foram extraídas dos géis, tratadas, e posteriormente identificadas e analisadas por meio de espectrometria de massas (MALDI-TOF/TOF). Os arquivos brutos provenientes dessas análises foram aplicados no programa MASCOT utilizando para a identificação proteica o banco de dados SwissProt e como especificação taxonômica o banco de dados SNAKES contido no site do NCBI. Foram identificadas 11 famílias proteicas: PLA2s (37,93%), inibidores de proteases (22,41%), proteínas de sinalização intracelular (13,79%), NGFs (5,17%), metaloproteases (3,45%), fatores associados à DDB1 e CUL4 (3,45%), oxidorredutases (3,45%), proteínas de transdução de sinal (1,72%), componentes do complemento (1,72%), proteínas NipSnap (1,72%) e proteínas lin-7 (1,72%), das quais a grande maioria é de função metabólica e ajuda na difusão/entrada dos componentes tóxicos no organismo da vítima/presa. Cerca de 1-5mg da mesma peçonha também foram analisados por meio de FPLC e sequenciamento proteico e as proteínas obtidas foram identificadas por meio de busca no banco de dados nr (nonredundant protein sequences) do NCBI utilizando a ferramenta blast-p. As seguintes famílias proteicas foram encontradas: serinoproteases (30,03%), metaloproteases (24,17%), BPPs (19,64%), PLA2s (14,95%), lectinas tipo C (1,94%), LAAOs (1,40%) e metaloendopeptidases (0,73%), ressaltando a toxicidade da peçonha. Os dois resultados obtidos foram comparados com proteomas de outras serpentes do gênero Lachesis encontrados na literatura. Observou-se que há uma grande similaridade entre os proteomas das peçonhas deste gênero, mas que alguns componentes proteicos são diferenciais e assim, podem ajudar na taxonomia destas serpentes, mantendo-as em suas respectivas espécies e subespécies. Além disso, a peçonha também foi analisada por eletroforese unidimensional (SDS-PAGE) para avaliar se o espécime em estudo era um neonato, um juvenil ou um adulto. A presença de uma proteína similar à mutalisina II (metaloprotease) confirmou que a L. m. rhombeata utilizada neste estudo era uma adulta. O conhecimento do proteoma da peçonha de L. m. rhombeata auxiliará (1) os estudos envolvendo a Sistemática do gênero…

Advisors/Committee Members: Araújo, Heloísa Sobreiro Selistre de.

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Submitted by Ricardo Cedraz Duque Moliterno ([email protected]) on 2017-10-05T21:58:20Z No. of bitstreams: 1 TESE- MARIA MAIANY DE OLIVEIRA.pdf: 1486275 bytes, checksum: 077fcda867394bf1737e7758d79af6a2 (MD5)

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Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES

Banana (Musa spp.) is considered one of the most important fruits in world trade due to its nutritional and economic potential.But although there is a large number varieties on the market, the banana is still affected by many diseases.The application of the method of crosses in this species is very difficult because the majority of cultivated varieties is triploid presenting low fertility. In this case, it is necessary to use biotechnology and its tools applied to non-conventional genetic improvement to develop new varieties that have resistance to their different types of pathogens.This work was carried out with the objective of adapting the technique of obtaining embryogeniccallus of banana by means of the Scalp method in cultivars Brazilian Ma?? and Pacovan, adjusting the processes of induction of meristematic structures and multiplication of shoots and induce increased genetic variability by in vitro mutagenesis using the chemical agent ethylmethanesulfonate and, of the genetic transformation by the bombardment of microparticles. Was evaluated the callus formation, the effect of mutagenic in the in vitro cultivation of shoots and the effects of genetic transformation on shoot resistance in selection medium containing the herbicide Imazapyr. The results showed that the merystematic structures obtained have the capacity to origin callus with only one month of cultivation, and both cultivars developed friable callus with average values above 90%.The efficiency of this method was evidenced by the high capacity of induction of friable callus in the two evaluated cultivars but also by the rapidity in the process of obtaining calluses, being the first study of adaptation of the methodology for Brazilian banana cultivars.On the other hand, the evaluation of the mutation induction allowed to conclude that the survival and the capacity of bud formation decreased as a function of the increase of the concentration and the immersion time in the ethylmethanesulfonate.The surviving plants underwent a sorting with the fusaric acid selective agent in which it was possible to regenerate in vitro plants of the cultivars submitted to treatment with the mutagen and to select possible mutants with fusaric acid resistance for cultivarsMa?? and Pacovan.And the genetic transformation method proved efficient in the regeneration of shoots resulting in high values of survival and multiplication, where possible transgenic plants of banana cv. Ma?? were obtained after selection of resistance to the herbicide.Therefore, it is concluded that all…

Advisors/Committee Members: Melo, Natoniel Franklin de.

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We have compared the behaviour and neurochemical effects of synthetic cathinones mephedrone and methedrone in mice, with attempts to evaluate some the mechanisms of action of methedrone, as well as the influence of nightclub-like stimulation on the behaviour. The effects of cathinone derivatives were examined in a series of behavioural tests in mice, and monoamine brain levels were determined by HPLC. Since there is a correlation between club parties and consume of recreational drugs, separated groups were pre-exposed to nightclub-like environment. Cathinone derivatives caused marked hyperlocomotion, allied to motor coordination inability, through 30 min after injection. Moreover, mephedrone caused anxiolytic-like effects, while methedrone induced anxiogenic actions. Both cathinone derivatives increased the latency in the hot-plate test, with a significant reduction of immobility time in tail suspension test. Mephedrone triggered 2- and 3-fold increase of dopamine and serotonin levels, respectively, in the nucleus accumbens, with 1.5-fold elevation of dopamine contents in the frontal cortex. Methedrone caused a 2-fold increase of dopamine in the nucleus accumbens and striatum, and 1.5-fold increase of serotonin levels in the hippocampus and striatum. Part of methedrone effects appear to be dependent on dopamine and serotonin modulation. Noteworthy, nightclub-like stimulation produced a further increase of latency to thermal stimulation, in both mephedrone and methedrone-treated mice. Mephedrone and methedrone induced a series of distinct behavioural changes likely by modulation of dopamine and serotonin systems. Curiously, increased latency to thermal stimulation elicited by cathinones was intensified by nightclub-like environment.

O presente estudo comparou os efeitos das catinonas sint?ticas metiladas, mefedrona e metedrona, sobre diversos par?metros comportamentais e bioqu?micos em camundongos, al?m de avaliar alguns dos poss?veis mecanismos relacionados com os efeitos in vivo da metedrona. Al?m disso, tamb?m foram analisados os efeitos da estimula??o semelhante a nightclubs sobre os efeitos comportamentais das duas subst?ncias de abuso. Os efeitos das catinonas, mefedrona e metedrona, foram avaliados em diversos paradigmas comportamentais e, ainda, sobre os n?veis cerebrais de monoaminas em camundongos, atrav?s de HPLC. Considerando a correla??o entre nightclubs e o consumo de drogas recreacionais, alguns grupos experimentais foram pr?-expostos a um ambiente com temperatura elevada, m?sica eletr?nica e luzes estrobosc?picas, durante sete dias antes da administra??o das subst?ncias-teste, a fim de reproduzir o local de consumo das catinonas. Os derivados das catinonas, mefedrona e metedrona, causaram hiperlocomo??o, associada com sinais de redu??o da coordena??o motora, durante 30 min ap?s os tratamentos. Al?m disso, a…

Advisors/Committee Members: Campos, Maria Martha.

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Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES

Conselho Nacional de Pesquisa e Desenvolvimento Cient?fico e Tecnol?gico - CNPq

Funda??o de Amparo ? Pesquisa do Estado do Rio Grande do Sul - FAPERGS

Neonatal exposure to lipopolysaccharides (LPS) generates a stressful stimulus capable of affecting the development of important systems, which causes lasting behavioral and neuroendocrine alterations. The aim of this study is to evaluate the response to an inflammatory stimulus in Balb/c mice exposed to LPS-induced neonatal stress at different ages and genders. Mice underwent intraperitonial injections on postnatal days 3 and 10 with either LPS (100ug/Kg) or saline solution. After 21 or 60 days of age, either saline solution was injected or an inflammatory stimulus was induced by the injection of 1% carrageenan. Inflammatory cytokines, reactive oxygen species and NETs production were measured in the peritoneal lavage. Our findings indicate that LPS-induced neonatal stress can reduce inflammatory cytokines in young animals, males and females. In adults, however, only females showed the same response pattern. In nLPS group, an increase in NETs production was observed in animals that were 60-days-old when compared to 21-days-old in both genders, which indicates an effect of neonatal stress on the ontogeny of NETs formation. The production of ROS was not affected by neonatal stress, even though an increased production was found among adults regardless of neonatal intervention. The results shown here indicate that LPS-induced neonatal stress can alter cytokine production in response to inflammatory stimuli at different ages, in a gender dependent way. Moreover, it seems like the formation of NETs throughout life is also influenced by alterations undergone during the neonatal period.

A exposi??o neonatal ao lipopolissacar?deo (LPS) gera um estimulo estressor capaz de afetar o desenvolvimento de importantes sistemas, dando origem a altera??es comportamentais e neuroend?crinas duradoras. O objetivo desta disserta??o ? avaliar a resposta a um est?mulo inflamat?rio em camundongos Balb/c submetidos ? estresse neonatal por LPS em diferentes idades e sexos. Os camundongos receberam, no 3? e 10? dias de vida, inje??o i.p. de LPS (100?g /Kg) ou solu??o salina. Ap?s 21 ou 60 dias de vida, os mesmos foram submetidos ? inje??o de solu??o salina ou a um est?mulo inflamat?rio atrav?s da inje??o de carragenina 1%. Foram mensurados no lavado peritoneal citocinas inflamat?rias, esp?cies reativas de oxig?nio e produ??o de Redes Extracelulares de Neutr?filos (NETs). Os resultados encontrados…

Advisors/Committee Members: Donadio, M?rcio Vin?cius Fagundes, Oliveira, Jarbas Rodrigues de.

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DNA obtained from body fluids recovered from crime scenes can be used to identify the donor of the biological material but it cannot reveal the tissue source or the possible age of the donor. DNA methylation is an epigenetic modification involved in transcriptional regulation. It is known that methylation is important in cell differentiation and genomic loci are differentially methylated between tissues. Because of this, different methylation patterns between tissues and cells can provide the basis of an assay for body fluid identification. We also know that the ability to determine the age of the sample donor based on DNA would be a powerful tool for forensic investigation. Human aging is associated with epigenetic modifications such as DNA methylation. Several studies have investigated biomarkers for aging which can be used to track donor age, presenting practical implications in forensic analysis. Two genes previously found to be DNA methylation age-associated, NPTX2 and GRIA2, were tested for prediction of age in saliva and blood samples. Both age markers were hypermethylated with the increase of age. The epigenetic predicted age was calculated for both markers, with an average difference of 6.9 years between estimated and observed ages for GRIA2 marker, and an average difference of 9.2 years for NPTX2 marker. Other studies investigated biomarkers for identification of bodyfluids. The most common body fluids found at crime scenes are blood, semen and saliva. A set of epigenetic markers, cg-06379435, ZC3H12D and BCAS4, which produce unique and specific patterns of DNA methylation, can be used to identify these body fluid types. However, to ensure the efficiency of these epigenetic markers, developmental validation studies need to be performed to determine the conditions and limitations of this new tool for forensic analysis. When testing the markers for body fluid identification using different organisms, we did obtain positive results for certain primate samples, however all other tested species were negative. The lowest concentration consistently detected varied from 0.1 to 10ng, depending on the locus. The method also proved to be effective when inhibitors were present in the samples or when samples were degraded by heat. In the case of mixtures, the overall methylation values varied in a consistent and predictable manner when multiple cell types were present in the same sample. Overall, the search of age markers candidates can be an important key in tracking suspects/victims in forensic investigations, and the ability to identify the biological sample using DNA would be a powerful tool.…

Advisors/Committee Members: Alho, Clarice Sampaio.

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The raw glycerol derived from the biodiesel production is considered an industrial waste that has raised great concerns in the biofuels industry, mainly due to its low commercial value, its reduced assimilation after purification as well as to the high costs associated with its disposal. In this context, the use of microorganisms on biodegradation processes and bioconversion of raw glycerol to molecules with high added-values tends to enhance the biodiesel production chain, and minimize environmental impacts associated with its disposal, often done improperly. Thus, the goal of this work was to investigate and identify, in different environmental samples, the presence of yeasts capable of using raw glycerol as sole carbon source, and investigate in a preliminary manner their eventual metabolic products. Fifty-seven yeasts derived from the regional biodiversity were evaluated and five of them were selected as metabolically able for raw glycerol consumption. The selected isolates were cultured under different conditions of temperature, glycerol concentration and oxygenation in order to establish the best growing conditions. In order to investigate eventual products generated from the raw glycerol assimilation, high-performance liquid chromatography (HPLC) analyses and emulsification assays were performed. As results, this work presents the first report of raw glycerol consumption by Zygowilliopsis californica, Pichia fermentans, Candida melibiosica and by a probable new yeast species of Candida genus (Candida sp.) isolated in this work. Still, this is the first report of this metabolic feature for a species of Zygowilliopsis genus. Moreover, Z. californica and Candida sp. presented some evidence to bear the metabolic potential to produce molecules of industrial interest from raw glycerol. These data may contribute for future strategies that aim the value increase of the biodiesel production chain.

O glicerol bruto derivado da produ??o do biodiesel ? considerado um rejeito industrial que tem despertado grande preocupa??o na ind?stria de biocombust?veis, dentre outros fatores, devido ao seu baixo valor comercial, sua reduzida assimila??o ap?s processo de purifica??o e aos altos custos associados ao seu descarte. Nesse contexto, a aplica??o de microrganismos em processos de biodegrada??o ou bioconvers?o do glicerol bruto em mol?culas de maior valor agregado tende a valorizar a cadeia produtiva do biodiesel, e a minimizar impactos ambientais associados ao seu descarte, muitas vezes feito de forma inadequada. Deste modo, o objetivo desde trabalho foi investigar e identificar, em diferentes amostras ambientais, a presen?a de leveduras capazes de utilizar, como ?nica fonte de carbono, o glicerol bruto, bem como investigar de maneira preliminar eventuais produtos metab?licos. Cinquenta e sete leveduras oriundas da biodiversidade local…

Advisors/Committee Members: Oliveira, Silvia Dias de.

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Submitted by Setor de Tratamento da Informa??o - BC/PUCRS ([email protected]) on 2016-08-03T18:12:49Z No. of bitstreams: 1 DIS_MANOEL_OSORIO_ALBUQUERQUE_FILHO_COMPLETO.pdf: 1445518 bytes, checksum: 398ccd6bab55b53f888f953ea35d9bb4 (MD5)

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Exposure to stressful events early in life may have permanent deleterious consequences on nervous system function and increase the susceptibility to cognitive impairment later in life. Maternal deprivation, commonly used as a source of early life stress, impairs memory in adult rats and reduces hippocampal brain-derived neurotrophic factor (BDNF) levels in a very heterogeneous way among individuals. The aim of the present study was to investigate the possible epigenetic modulation underlying recognition memory impairment and reduced BDNF levels in the hippocampus of adult maternal deprived rats. We also evaluated the potential ameliorating properties of the histone deacetylase (HDAC) inhibitor, sodium butyrate, on memory deficits and BDNF changes associated with maternal deprivation. For this study, maternal deprived animals were categorized as ?inferior learners? and ?superior learners? according to their performance in novel object recognition memory task. Results indicated that HDAC activity was higher in individuals submitted to maternal deprivation with the worst cognitive performance (inferior learners). Acute administration of sodium butyrate increased histone H3 acetylation and BDNF levels, and restored recognition memory in maternally deprived animals with the worst cognitive performance. Moreover, we also showed that there is a positive correlation between BDNF levels and memory performance. Taken together, the results indicated that HDAC inhibitors could be considered as a possible therapeutic agent to improve cognitive performance in inferior learners individuals. Further studies need to be conducted for a better understanding of the mechanisms associated with persistent alterations observed in adult life induced by early stressful events and those leading to resilience.

Estudos recentes t?m mostrado que o estresse no per?odo de desenvolvimento do SNC pode ter consequ?ncias vari?veis sobre a cogni??o, alterando a forma como o indiv?duo responde frente a situa??es semelhantes a que ? exposto na vida adulta, aumentando a susceptibilidade ou resili?ncia de uma forma dependente tanto do background gen?tico do indiv?duo como da forma como ele ? exposto ao estressor na inf?ncia e na vida adulta. A t?cnica da priva??o materna, que busca mimetizar a exposi??o ao estresse na inf?ncia por meio da separa??o da m?e de sua prole no per?odo considerado chave para o desenvolvimento do SNC, foi utilizada neste estudo com a finalidade de se investigar a variabilidade de resposta ao estresse na vida adulta em animais separados da m?e, bem como para se investigar…

Advisors/Committee Members: Schr?der, Nadja.

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Although Parkinson s Disease (PD) is predominantly a movement disorder, the presence of cognitive problems related to frontal function, even in the earliest stages has been observed. These problems include attentional, executive and memory deficits. A study using an experimental paradigm developed to investigate the effects of different encoding instructions on contextual memory showed that, unlike healthy controls, PD patients could not reverse their contextual memory deficits and take any advantage of encoding instructions. However, it is unclear whether they have a memory deficit or executive dysfunction would be accountable for results. Attentional and executive deficits observed in PD patients have important implications for daily activities, mainly when patient perform concomitant cognitive and motor activities that are attention demanding. Catechol- O-methyltransferase (COMT) is an enzyme that degrades cortical dopamine. Some studies have examined the relationship between the COMT val158met polymorphism and executive function in PD patients and have found low enzyme activity, associated to met/met polymorphism- implying higher prefrontal dopamine levels- is related to worse performance. However, a recent study did not demonstrate a direct effect of COMT genotype on the executive performance. The present study aimed to characterize different cognitive parameters of patients with PD and to assess their relationship with the COMT polymorphism. In this study participated 18 patients with early disease stage PD and 18 healthy adults matched for age, gender and education. Patients were selected from a data bank of patients genotyped for COMT polymorphism. All participants completed the Wisconsin Card Sorting Test (WCST), the Stroop Color and Word Test, and dual tasking paradigm. In addition, patients completed a contextual memory paradigm. No effect of COMT val158met genotype on frontal function in patients with PD (executive function and contextual memory) was observed. A decrease in cognitive task performance under dual-tasking was observed in PD patients, by contrast to healthy controls. Relative dual-task cognitive cost was significantly greater for PD patients compared to controls in the arithmetic-walking condition. In conclusion, difficulties in performing a cognitive task while walking can be influenced by the executive/attentional load of the task.

Embora a Doen?a de Parkinson (DP) seja predominantemente um dist?rbio do movimento, a presen?a de altera??es cognitivas relacionadas ? fun??o frontal tem sido observada mesmo nos est?gios iniciais da doen?a. Estas altera??es incluem d?ficits atencionais, executivos e de mem?ria. Um estudo usando um paradigma experimental desenvolvido para investigar os efeitos de diferentes instru??es codificadoras na mem?ria contextual mostrou que, ao contr?rio dos idosos, pacientes com DP…

Advisors/Committee Members: Bromberg, Elke.

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According to data from the World Health Organization (WHO), stress affects more than 90% of the world's population and is considered a global epidemy. Stress has become an integral part of human life and organisms are constantly subjected to stressful stimuli that change various physiological processes, representing a risk factor for many diseases, such as cancer, cardiovascular, metabolic, infectious and gastrointestinal deseases and depression. The zebrafish (Danio rerio) has many similarities with mammalian in terms of overall organization and the functioning of their stress regulatory systems. The zebrafish hypothalamic-pituitary-interrenal (HPI), analogous to the mammalian hypothalamic-pituitary-adrenal (HPA), has been found in zebrafish and the activation of this pathway is essential for the maintenance of vital functions in response to stressful events. Despite extensive knowledge regarding stress responses in mammals, data on the relationship between chronic unpredictable stress and its effects on purinergic signaling is limited. Purinergic signaling is mediated by ATP and adenosine receptor activation through P2 and P1, respectively. The catabolism of extracellular ATP to adenosine is promoted by the ectonucleotidases, such as Ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) and ecto-5 '-nucleotidases (E-5?NT). Adenosine is deaminated by adenosine deaminase (ADA) producing inosine. Thus, these enzymes control the levels of extracellular nucleotides and nucleosides, exerting an influence on purinergic signaling. Considering some models of stress can affect the signalling systems, the objective of this study was to verify whether the unpredictable chronic stress changes ectonucleotidases and adenosine deaminase activities in zebrafish brain. In addition, we analyzed the metabolism of ATP as well as the expression of genes related to ADA, ada1, ada2.1, ada2.2, adaL, adaasi and the effects of agonists and antagonists of adenosine receptors in an unpredictable chronic stress model in zebrafish. Our results demonstrated that there are no changes on ATP (P = 0.1499), ADP (P = 0.3615) and AMP (P = 0.8987) hydrolysis in zebrafish brain membranes submitted to unpredictable chronic stress. In contrast, ecto-ADA activity significantly decreased (26.8%; 8,164 ? 0.78 NH3 min − 1 mg− 1 of protein; p 0.05; n = 5 <) in brain membranes of animals exposed to the unpredictable chronic stress when compared to the control group (11.15 ? 2.16 NH3 min − 1 mg − 1 of protein; p 0.05; n = 5). However, the activity of cytosolic ADA was not changed after the unpredictable chronic stress. Quantitative analysis by RT-qPCR did not show significant changes after chronic unpredictable stress exposure on gene expression in the genes ada1, ada2.1, ada2.2, adaL, adaasi. ATP metabolism in brain membrane preparations of…

Advisors/Committee Members: Bonan, Carla Denise.

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This study investigated whether the spinal or systemic treatment with the lipid resolution mediators resolvin D1 (RvD1), aspirin-triggered resolvin D1 (AT-RvD1) and resolvin D2 (RvD2) might interfere with behavioral and neurochemical changes in the mouse fibromyalgia-like model induced by reserpine. Acute administration of AT-RvD1 and RvD2 produced a significant inhibition of mechanical allodynia and thermal sensitization in reserpine-treated mice, whereas RvD1 was devoid of effects. A similar antinociceptive effect was obtained by acutely treating animals with the reference drug pregabalin. Noteworthy, the repeated administration of AT-RvD1 and RvD2 also prevented the depressive-like behavior in reserpine-treated animals, according to assessment of immobility time, although the chronic administration of pregabalin failed to affect this parameter. The induction of fibromyalgia by reserpine triggered a marked decrease of dopamine and serotonin (5-HT) levels, as examined in total brain, spinal cord, cortex and thalamus. Reserpine also elicited a reduction of glutamate levels in total brain, and a significant increase in the spinal cord and thalamus. Chronic treatment with RvD2 prevented 5-HT reduction in total brain, and reversed the glutamate increases in total brain and spinal cord. Otherwise, AT-RvD1 led to a recovery of dopamine levels in cortex, and 5-HT in thalamus, whilst it diminished brain glutamate contents. Concerning pregabalin, this drug prevented dopamine reduction in total brain, and inhibited glutamate increase in brain and spinal cord of reserpine-treated animals. Our data provide novel evidence, showing the ability of D-series resolvins AT-RvD1, and mainly RvD2, in reducing painful and depressive symptoms allied to fibromyalgia in mice.

O presente estudo investigou o poss?vel efeito do tratamento central ou sist?mico com os mediadores lip?dicos de resolu??o da inflama??o, Resolvina D1 (RvD1), RvD1 ativada pela aspirina (AT-RvD1) e Resolvina D2 (RvD2) sobre mudan?as comportamentais e neuroqu?micas em um model de fibromialgia induzido por reserpina em camundongos. A administra??o aguda de AT-RvD1 e RvD2 produziu um efeito inibit?rio significativo sobre a alod?nia mec?nica e a hipersensibiliza??o t?rmica nos animais tratados com reserpina, sendo que nenhum efeito foi observado quando os animais foram tratados com RvD1. A administra??o aguda de pregabalina, f?rmaco de refer?ncia para o tratamento da fibromialgia, apresentou um efeito antinociceptivo similar ?quele observado para AT-RvD1 e RvD2. Interessante, a administra??o repetida e sist?mica de AT-RvD1 e RvD2 tamb?m preveniu o comportamento depressivo nos animais que receberam reserpina, de acordo com a avalia??o do tempo de imobilidade, enquanto que a administra??o cr?nica de pregabalina n?o apresentou efeito sobre esse par?metro. A indu??o de fibromialgia pela…

Advisors/Committee Members: Campos, Maria Martha.

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Disturbances in glutamatergic signaling have been proposed as the cause of many diseases of the nervous system. The zebrafish has been considered as an efficient model in the investigation of the neurochemical basis of various disorders, such as schizophrenia and epilepsy. Several neurotransmitter systems have been characterized in zebrafish, including the glutamatergic system. Moreover, a vast repertoire of behavioral responses to drugs has been characterized in particular in adults. However, little information is available about the ability to generate response to classic drugs of glutamatergic action in the early stages of development in zebrafish. Throughout development, ionotropic glutamate receptors have an orderly variability between the subunits that compose them, giving them different pharmacokinetic properties and degree of affinity for their ligands. In this way, we analyzed the locomotor/behavioral profile of zebrafish in response to the glutamate receptor antagonist, MK-801, in different doses in 30, 60, 120 days post-fertilization (dpf) and 2 years post-fertilization animals, as well the effect of caffeine pre-exposure on MK-801 action. Additionally, we analyzed the expression profile of subunits that comprise the NMDA receptor in whole brain of zebrafish during development. Locomotor/behavioral response to kainic acid (KA) was evaluated in different doses at ages 7, 15 and 30 dpf. Also, the pre-exposure to kainic acid in 24 hours post-fertilization (hpf) and 7 and 15 dpf animals was challenged by a second exposure to kainic acid at 2 months post-fertilization The results demonstrated that zebrafish has an age-dependent response to MK-801 and kainic acid, at least on the locomotor/behavior aspects. The peak of locomotor response to MK-801 occurred at 60-120 days post-fertilization, which was partially prevented by caffeine and able to alter the time on upper zone of aquarium as a measure of anxiety. Analysis of gene expression of NMDA receptor subunits in zebrafish brain demonstrated that NR2C and NR2D subunits have later expression in comparison to subunits NR1, NR2A and NR2B. The animals that were exposed to KA showed alterations in locomotor activity without displaying classic convulsive characteristics. However, pre- exposure to 7dpf KA was able to partially prevent the seizure events in response to KA injection (6 mg / K) at 2 months post- fertilization.

Dist?rbios na sinaliza??o glutamat?rgica s?o propostos como a causa de in?meras patologias do sistema nervoso. O peixe-zebra tem sido considerado um eficiente modelo na investiga??o das bases neuroqu?micas de diversos transtornos, tais como a esquizofrenia e a epilepsia. Diversos sistemas de neurotransmiss?o j? foram caracterizados em peixe-zebra, incluindo o sistema glutamat?rgico. Al?m disto, um vasto repert?rio de respostas comportamentais a f?rmacos j?…

Advisors/Committee Members: Silva, Rosane Souza da.

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The ethanol exposure during early embryonic development can cause morphological and behavioral changes even when ingested in low doses. Growth retardation, microcephaly and mental retardation are some of the features observed in children with FAS (fetal alcohol syndrome) whose mothers ingested ethanol during pregnancy. The mechanisms by which ethanol affects embryonic development and cause such changes have not been fully elucidated. The increase in the extracellular adenosine levels after chronic and acute exposure to ethanol indicates that the purinergic system has an important role in this situation. Adenosine is a neuromodulator that acts through the activation of metabotropic receptors type P1 (A1, A2A, A2B and A3) and can act as an endogenous neuroprotector. In the extracellular space, adenosine can be produced by sequential hydrolysis of adenosine triphosphate (ATP) held by ectonucleotidases, a cascade of a family of enzymes located on the cell surface, which the key process to hydrolyze to adenosine is performed by ecto-5'-nucleotidase. The use of zebrafish in toxicology studies and development offers a number of advantages. Its size and breeding allow the maintenance of a large quantity of fish in a relatively small space. The production of a large number of eggs and the development occurs rapidly, and progresses through well-defined steps. Recent studies have employed the zebrafish as a model for fetal alcohol syndrome and demonstrated that embryonic exposure to ethanol results in phenotypes comparable to those observed in other vertebrate models. The objective of this study was to evaluate the role of adenosine metabolism in the morphological and locomotor parameters of zebrafish larvae exposed to ethanol. The results showed that in addition to morphological damage already known, there is a change in the enzymatic activity of ecto-5'-nucleotidase in larvae of seven days, in both treatments, acute and chronic, independent of gene expression form, which in time was not changed. Pre-treatment with AOPCP, an inhibitor of ecto-5'- nucleotidase, was unable to prevent the morphological damage in a relevant way, although statistically there was a slight prevention. Pre-treatment with dipyridamole, an adenosine transport blocker further worsened the effects caused by ethanol. Considering the changes that occur in extracellular levels of adenosine after exposure to ethanol and the involvement of the purinergic system in early stages of development, our results suggest that there is a combined action of the enzyme ecto-5'-nucleotidase and nucleoside transporters in this rising of extracellular…

Advisors/Committee Members: Silva, Rosane Souza da.

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Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES

The major depressive disorder (MDD) is a psychiatric condition which profoundly alters with the brain metabolism and neurochemistry characterized by a state of deep, chronic sadness, accompanied by anhedonia, sensation of worthlessness and lack of motivation, often leading the patient to suicide. The ventral tegmental area (VTA) is an important dopaminergic region intimately associated with the pathophysiology of MDD. Ketamine is a drug that antagonizes the glutamatergic NMDA receptors which has been shown to exert an immediate antidepressant effect and the treatment with ketamine is a promising new alternative for MDD therapeutic. Furthermore, the small animal positron emission tomography (microPET) is a technique which allows the assessment of the temporal-spatial distribution of radiolabelled molecules in vivo, and the utilization of 18F-Fluorodeoxyglucose (18F-FDG) as a radiotracer for this analysis still needs standardization in our University. In this sense, this thesis has been divided into two stages. Firstly, we standardized the brain metabolic assessment technique using 18F-FDG associated with microPET in Wistar rats, and with it, we rendered a neurometabolic atlas of the distribution of 18F-FDG in 56 brain regions. We compared our neurometabolic data with data from five other scientific articles which assessed the biochemical and immunohistochemical activity of cytochrome c oxidase (COX), these techniques are traditionally used for assessment of ex vivo brain metabolism. Thus, we ranked the regions analyzed in our study and the regions from the selected COX studies, and correlated the rankings with the Spearman test for non-parametric ranked data correlation. In this study we detailed the distribution of 18F-FDG in the brain of Wistar rats. On four of the selected studies we did not find a correlation, only on Shumake at al.?s study we found a moderate correlation (r=0.56, p=0.023). In the second stage, we analyzed the influence of acute ketamine treatment on the depressive-like behavior, the glucose metabolism and tyrosine hydroxylase activity (TH) (a rate-limiting dopamine synthesis enzyme) in the VTA of animals exposed to the chronic unpredictable stress (CUS). In this study, 48 Wistar rats were divided into four groups: 1-Control, 2-Ketamine, 3-CUS, 4-CUS+Ketamine. The animals undergone the CUS protocol were expose to several stressors, twice-daily, for 28 consecutive days. The treatment consisted of a single intraperitoneal injection of 10mg/kg of ketamine. For the behavioral analysis the sucrose preference test,…

Advisors/Committee Members: Xavier, L?der Leal.

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Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES

Funda??o de Amparo ? Pesquisa do Estado do Rio Grande do Sul - FAPERGS

The LPS mechanism of action is still not completely elucidated on vertebrates like fish, and indeed differs from higher vertebrates. In zebrafish, LPS is capable of increasing the recruitment of immune cells and the expression of genes related to the immune response. The purinergic system has a great relation to the regulation of the immune system and inflammatory responses. The nucleotide ATP is able to induce cytokine secretion, recruitment and differentiation of immune cells. ATP can be dephosphorylated sequentially generating adenosine. In the context of inflammation adenosine serves as an innate immunomodulatory molecule. The control of adenosine extracellular levels is performed by nucleoside transporters and ecto-5'-nucleotidase. The ecto-5'-nucelotidase is an ectonucleotidase with pacemaker role in the production of adenosine and is one of the focuses of this study. Considering the analysis of the input images approach to the study of inflammation context, it is known that in rodents the uptake of 18F-FDG, an analogue of glucose, is increased under inflammation, which generates a differential image. The micro Positron Emission Tomography/ Computed Tomography (?PET /CT) is used for research in small animals and take images using a radiopharmaceutical. The use of ?PET/CT contributes with information at the molecular, structural and functional level and allows too monitor the effect of drugs in physiological / pathological situations in the range of a small animal as the zebrafish. The technology ?PET/CT is relatively new and so far there are no published scientific studies applying radiopharmaceuticals in zebrafish. In this context, the aim of the project was to study the involvement of the enzyme ecto-5'-nucleotidase in the development of inflammation induced by LPS using the cytological, biochemical, molecular and image (?PET) in different tissues of adult zebrafish (Danio rerio). To induce inflammation in zebrafish, the animals were injected with a solution of LPS (10 ug/g body weight, i.p) after being subjected to anesthesia (tricaine 0.1 g/L). The animals were kept for 2 hours or 24 hours in this treatment. For confirmation of inflammation were analyzed the gene expression of specific markers (tnf-? and cox-2) in encephalon, heart, kidney and intestine and differential counts of cells of the immune system. The activity and expression of ecto-5'-nucleotidase enzyme was analyzed in the encephalon, heart, kidney and intestine of control…

Advisors/Committee Members: Silva, Rosane Souza da, Jeckel, Cristina Maria Moriguchi.

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Liver fibrosis is the wound healing response to repeated injury of the liver. It is characterized by disruption of the liver architecture associated with increased expression of extracellular matrix components. Hepatic stellate cells (HSCs) play a key role in the process of fibrogenesis. In normal liver, HSCs are quiescent and its main function is to store vitamin A. During liver injury, these cells undergo activation, become myofibroblasts and acquire fibrogenic properties. Capsaicin, the active ingredient of red pepper has been extensively studied in recent years for possessing a wide range of pharmacological properties, including analgesic, anti-inflammatory, antiproliferative and anticarcinogenic in a variety of cell types. Therefore, the aim of this study was to investigate the in vitro effects of capsaicin on deactivation, differentiation and proliferation of HSCs, besides studying the possible mechanisms involved. The results showed that capsaicin is capable of inducing the quiescent phenotype in HSCs via PPARγ activation and blockage of TGF-β signaling. Increased levels of antifibrotic cytokines (IFN-γ and IL-10) and the reduction of pro-inflammatory and pro-fibrotic mediators (COX-2, MCP-1, type I collagen) showed that capsaicin inhibits the activation and migration of these cells. Furthermore, the mechanism used by capsaicin to inhibit cell proliferation is via cell cycle arrest. These findings demonstrate that capsaicin has the potential to be a novel therapeutic agent in the treatment of liver fibrosis due to its antifibrogenic and antiproliferative actions.

A fibrose hep?tica ? a resposta cicatricial do f?gado a les?es repetidas, caracterizada pelo rompimento da arquitetura hep?tica associada ao aumento da express?o dos componentes da matriz extracelular. As c?lulas estreladas hep?ticas (HSCs) desempenham um papel-chave no processo de fibrog?nese. No f?gado normal, as HSCs encontram-se em sua forma quiescente de dep?sito de vitamina A. Durante a les?o hep?tica, essas c?lulas passam por uma ativa??o fenot?pica, tornam-se miofibroblastos e adquirem propriedades fibrog?nicas. A capsaicina, princ?pio ativo da pimenta vermelha, tem sido muito estudada nos ?ltimos anos por possuir uma extensa gama de propriedades farmacol?gicas, que incluem efeitos analg?sicos, anti-inflamat?rios, antiproliferativos e anticarcinog?nicos em uma variedade de tipos celulares. Por essa raz?o, o objetivo deste estudo foi investigar os efeitos in vitro da capsaicina na inativa??o, diferencia??o e prolifera??o das HSCs, al?m de estudar os poss?veis mecanismos envolvidos. Os resultados obtidos mostraram que a capsaicina ? capaz de induzir o fen?tipo quiescente nas HSCs via ativa??o de PPARγ e bloqueio da sinaliza??o de TGF-β. O aumento nos n?veis de citocinas antifibr?ticas (IFN-γ e IL-10) e a diminui??o de…

Advisors/Committee Members: Oliveira, Jarbas Rodrigues de.

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Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES

Several psychiatric and neurological diseases are characterized by impairments in social function, such as autism spectrum disorders (ASD) and schizophrenia (SCZ). In this study, we conducted a behavioral screening at different times of zebrafish development at 6, 30, 70 and 120 dpf (postfertilization days) to establish a social interaction deficit model induced by valproic acid (VPA) at 48 ?M concentration to investigate social behavior, locomotion, aggression and anxiety. To analyze the social behavior of each fish was placed in an experimental tank. On one side of the experimental tank, an empty fish tank was placed; on the other side, a tank of identical size held 15 zebrafish, which were designed the ?stimulus fish?. We quantify the time of the experimental fish from the side of the tank "fish stimulus" in relation to empty tank. The locomotion of the animals was assessed by evaluating the following parameters: distance traveled, average speed, number of crossings and the time spent in each tank position (bottom vs. upper levels) was considered an index of anxiety. To analyze the aggression the animals were individually placed in an experimental tank. A mirror was placed at the side of the tank at an angle of 22.5? to the backwall of the tank so that the left vertical edge of the mirror touched the side of the tank and the right edge was further away.Thus, when the experimental fish swam to the left side of the tank, their mirror image appeared closer to them. indicating preference for the opponent.Our results showed that exposure to VPA induced changes on locomotor activity and anxiety in different periods of development in zebrafish. In addition, VPA-treated animals presented a deficit in social interaction to 70 dpf and 120 dpf. Exposure to VPA did not affect aggression in the adult stage after 70 dpf and 120 dpf. This study also investigated the purinergic signaling in a model of embryonic exposure to VPA, which induced deficit in social interaction in adult zebrafish. This study demonstrates the first evidence that exposure to VPA in embryonic zebrafish in 120 dpf can modulate the hydrolysis of nucleotide and nucleoside and adenosine deamination in zebrafish brain membranes. In addition, we analyzed the effects of oxytocin, the oxytocin receptor agonist (carbetocin) and oxytocin receptor antagonist (L-368,899) on the reversal of behavioral effects induced by MK-801 in zebrafish regarding behavior social, such as, changes in social interaction and aggression. These results support the…

Advisors/Committee Members: Bonan, Carla Denise.

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Esta tese trata de uma investiga????o, de natureza qualitativa, sobre a incid??ncia de muta????es culturais no brincar contempor??neo da crian??a de quatro a cinco anos e suas implica????es na aprendizagem. Para alcan??ar esse objetivo, a autora realiza, primeiramente, uma pesquisa bibliogr??fica, contemplando refer??ncias da Antropologia, Sociologia, Filosofia e Psican??lise, al??m de outras da ??rea da Educa????o Infantil, as quais lhe permitem discutir alguns conceitos fundamentais ao desenvolvimento do estudo: muta????es culturais, inf??ncia, brincar infantil e rela????o com o objeto de conhecimento; posteriormente, desenvolve pesquisa de campo, na cidade de Salvador do estado da Bahia, organizada em dois momentos: sem e com intencionalidade pedag??gica. No primeiro momento, foram feitas observa????es numa livraria, em quatro pra??as p??blicas e numa loja de brinquedos, sendo tamb??m percorrida uma avenida com camel??s e visitadas uma exposi????o de brinquedos e uma feira de troca de brinquedos; no segundo momento, o estudo tem lugar em duas turmas de grupo 4 da Educa????o Infantil, numa escola da rede municipal de ensino. Os dados coletados, a partir das observa????es e entrevistas com crian??as, pais, professores, donos de com??rcio e de loja de brinquedos, assim como os desenhos das crian??as sobre seus brinquedos e brincadeiras preferidos foram analisados e interpretados, sob a refer??ncia de indicadores (velocidade, consumismo, virtualidade e uso descart??vel do objeto) da Matriz de An??lise constru??da para esse fim. A pesquisa revelou a pertin??ncia dos pressupostos formulados, sendo poss??vel dizer que o brincar ?? inerente ?? crian??a, cumprindo fun????o espec??fica, apesar de influenciado pelas muta????es culturais. Ainda que haja novas formas de brincar na contemporaneidade, permanece a condi????o como produ????o imagin??ria. Em rela????o ?? aprendizagem, a pesquisa revelou que a rela????o da crian??a com o objeto, na contemporaneidade, apresenta uma din??mica na qual o objeto de conhecimento se mostra presentificado. Enfim, o estudo oferece contribui????es para os profissionais da ??rea da Educa????o, principalmente os da Educa????o Infantil.

ABSTRACT This thesis is an investigation, of a qualitative nature, about the incidence of cultural mutations in contemporary play of children from four to five years old and its implications on learning. To achieve this goal, the author holds,…

Advisors/Committee Members: Muniz, Din??a Maria Sobral, Almeida, Ord??lia Alves de, Silva, Cleverson Suzart, Beltr??o, L??cia Maria Freire, Ornellas, Maria de Lourdes.

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CAPES

J?? se sabe que o excesso de conte??dos conceituais nos curr??culos de biologia do ensino m??dio ?? um obst??culo para uma aprendizagem bem sucedida. A grande quantidade de mat??ria nos curr??culos afeta a qualidade do ensino: afeta tamb??m a aprendizagem de conte??dos relacionados a pr??ticas t??cnicas e m??todos, assim como daqueles relacionados a valores, normas e atitudes. Mas mesmo que a necessidade de reduzir a quantidade de conte??dos conceituais tenha sido reconhecida h?? j?? mais de um s??culo, h?? uma car??ncia de discuss??es sobre crit??rios claros para a sele????o do que deve ser mantido ou inclu??do nos curr??culos. Este trabalho se prop??e a contribuir para esta quest??o identificando quatro crit??rios para a sele????o de conte??do conceitual. O primeiro ?? oferecer uma hierarquia de conceitos. Os conceitos abordados no ensino m??dio devem permitir ao estudante compreender a estrutura conceitual da biologia, incluindo os pontos de integra????o entre suas sub??reas. Portanto, os conceitos que devemos priorizar no ensino devem preferencialmente possuir um papel estruturante na biologia. O segundo crit??rio ?? que, para identificar estes conceitos, adotemos a moldura conceitual da biologia proposta por Scheiner. O terceiro ?? buscar um equil??brio entre o n??mero de conceitos relevantes para a biologia funcional e aqueles relevantes para a biologia evolutiva. Por fim, o quarto ?? manter um equil??brio entre conceitos relativos aos componentes, conceitos relativos a processos e conceitos que descrevem propriedades e padr??es encontrados nos sistemas biol??gicos e em classifica????es que criamos com base nestes sistemas. Se aplicados, estes crit??rios n??o apenas permitiriam que os estudantes compreendessem a estrutura conceitual da biologia, mas tamb??m lhes daria a capacidade de aprofundar seus conhecimentos desta ci??ncia mesmo ap??s conclu??rem o ensino m??dio. Com este artigo, pretendemos iniciar uma discuss??o sobre a sele????o de conte??dos conceituais para os curr??culos de biologia do ensino m??dio, assim como fornecer subs??dios para formadores de pol??ticas educacionais, especificamente aqueles encarregados de estabelecer objetivos curriculares.

It is by now well-established that the excess of conceptual contents in high school biology curricula is an obstacle to successful learning. The sheer quantity of materials in curricula affects the quality of the…

Advisors/Committee Members: Nunes Neto, Nei de Freitas, El-Hani, Charbel Ni??o, Barzano, Marco Antonio Leandro, Caponi, Gustavo Andr??s, Scarpa, Daniela Lopes.

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Neste estudo, a fra??o heterocrom?tica do cromossomo W de Apareiodon sp. foi isolado por microdissec??o com posterior amplifica??o por DOP-PCR. As seq??ncias obtidas foram utilizadas no procedimento de hibrida??o in situ fluorescente em cromossomos de esp?cies de Parodontidae. Esta sonda foi denominada WAp. Assim, de posse deste marcador e de outros j? dispon?veis o trabalho apresentou uma an?lise de citogen?tica molecular em exemplares da fam?lia presentes em diferentes bacias hidrogr?ficas brasileiras. Foram analisadas as esp?cies: Apareiodon sp., A. ibitiensis, A. vladii, A. piracicabae, A. vittatus, A. affinis, P. hilarii, P. moreirai, P. nasus e P. pongoensis. Os resultados evidenciaram a proximidade da localiza??o do marcador do rDNA 18S encontrado em esp?cies de Parodon em compara??o ao grupo irm?o Anostomidae. Ainda, foi visualizado um alta identidade do par cromoss?mico portador dos s?tios de rDNA 5S em todos Parodontidae estudados. Com o mapeamento dos DNAs repetitivos WAp e pPh2004 por hibrida??o in situ fluorescente nos cromossomos de algumas esp?cies de Parodontidae foram lan?adas hip?teses de origem e diferencia??o do sistema de cromossomos sexuais ZZ/ZW a partir de uma invers?o alocando s?tios WAp em regi?o proximal de um par cromoss?mico metac?ntrico. Esses resultados permitiram inferir tamb?m que o sistema de cromossomos sexuais m?ltiplos ZZ/ZW1W2 de A. affinis pode ter origem de um sistema ZW similar ao encontrado em popula??es ancestrais da esp?cie P. hilarii. Assim, este trabalho contribui para o entendimento da evolu??o e diversifica??o do genoma de algumas esp?cies de Parodontidae, principalmente para o esclarecimento da origem e diferencia??o dos cromossomos sexuais.

In this study, the fraction of the heterochromatin of the Apareiodon sp. chromosome W was isolated by microdissection with subsequent amplification by DOP-PCR. The sequences obtained were used in the procedure of the fluorescence in situ hybridization in Parodontidae species chromosomes. This probe was named WAp. Then, with this marker and others available, the study presented a molecular cytogenetic analysis in Parodontidae species present in different Brazilian hydrographic basin. The species analyzed were: Apareiodon sp., A. ibitiensis, A. vladii, A. piracicabae, A. vittatus, A. affinis, P. hilarii, P. moreirai, P. nasus and P. pongoensis. The results reveal closeness of the location of 18S rDNA marker found in Parodon species compared to the sister group Anostomidae. Still, it has been viewed a high identity chromosome pair bearing the rDNA 5S sites in all Parodontidae studied. Mapping of repetitive DNAs WAp and pPh2004 by fluorescence in situ hybridization in chromosomes of some species of Parodontidae permitted deduce the origin and differentiation of sex chromosome system ZZ/ZW from a inversion allocating proximal region WAp sites of a chromosome metacentric pair. These results allowed inferring that the sex chromosome system multiple ZZ/ZW1W2 of A. affinis can originate from one system ZW similar to that found in ancient…

Advisors/Committee Members: Marcelo Ricardo Vicari, Marta Margarete Cestari, Rafael Bueno Noleto, Mara Cristina de Almeida.

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This research develops from the initial consideration of the promotion of innovative educational proposals they can engage students in an integral and active in their own learning process, and to sensitize the students emotionally involving, are potentially decisive factors in building knowledge. With this, the study evaluated the influence of emotional-affective classes in Natural Environments developed in the discipline of biology, with high school students from a private school in Porto Alegre. This research has a bibliographical character, based primarily contemporary literature on the subject, and analysis of data obtained from responses given by students to a questionnaire specially designed for this purpose, as well as the observation and recording of students' attitudes, and count also the researcher's experience as a professor of biology. The results showed that the classes in the natural environment have led students to become more interested and, consequently, better establish personal relationships with each other and with the teacher, encouraging learning.

A presente pesquisa se desenvolveu a partir da considera??o inicial de que a promo??o de propostas educativas inovadoras que consigam envolver o aluno de forma integral e ativa no pr?prio processo de aprendizagem, e que sensibilizem o aluno o envolvendo afetivamente, s?o fatores potencialmente decisivos na constru??o do conhecimento. Com isso, o trabalho avaliou a influ?ncia desse envolvimento emocional-afetivo em aulas em ambientes naturais desenvolvidas na disciplina de Biologia com alunos do ensino m?dio de uma escola particular de Porto Alegre. Essa pesquisa tem um car?ter bibliogr?fico, tomando como base principalmente a literatura contempor?nea sobre o assunto, e a an?lise de dados obtidos de respostas dadas pelos alunos a um question?rio elaborado especialmente para este fim, bem como a observa??o e registro das atitudes dos alunos, al?m de contar tamb?m com a experi?ncia profissional do pesquisador como professor de Biologia. Os resultados obtidos evidenciaram que as aulas em ambiente natural levaram os alunos a se interessarem mais e, por consequ?ncia, estabelecerem melhores rela??es afetivas entre si, com o professor e com o conte?do, favorecendo a aprendizagem.

Advisors/Committee Members: Rocha Filho, Jo?o Bernardes da.

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The clinical depression treatment faces serious obstacles as the disease mechanism is not fully elucidated. In addition, there are no effective means to predict and prevent depression as well as any biological method of diagnosis. The use of antidepressants is still the basis of the treatments for depression. Lithium has been used clinically as effective drug to treat all phases of bipolar disorder, including major depression. The Selective serotonin re-uptake inhibitors (SSRIs), such as fluoxetine and citalopram, and Tricyclic antidepressant (TCA) as clomipramine are drugs constantly used for depression treatment. Recent evidence has shown an involvement of adenosine and its receptors in the pathophysiology of depression. ATP can be stored and co-released with other neurotransmitters like serotonin and can be hydrolyzed by a cell-surface enzyme family known as ectonucleotidases. Among these members, we highlight the nucleoside triphosphate diphosphohtdrolases (NTPDases) and ecto-5'-nucleotidase. They are able to control the availability of ligands such as ATP and adenosine to its specific receptors. Adenosine deaminase (ADA) can promote the hydrolytic deamination of adenosine to inosine, modulating the extracellulr levels of this neuromodulator. In cholinergic signaling, after its release, acetylcholine (ACh) promotes the activation of specific muscarinic or nicotinic receptors and thus, it promotes diverse cellular responses. ACh is hydrolyzed by acetylcholinesterase (AChE) in acetate and choline in synaptic cleft. The zebrafish has been used in research behavioral neuroscience and is also a choice model for elucidating the development and function of neuronal circuitry. Considering the cholinergic and purinergic signaling are important participation in the CNS and these neurotransmitter pathways have been identified and characterized in zebrafish, the objective of this study was to evaluate the effect of antidepressants on ectonucleotidases, ADA and ACh activities, which are essential enzymes in the modulation of these signaling pathways in the zebrafish brain. We evaluated the ex vivo effects of fluoxetine (1-10 ?M), clomipramine (1-10 ?M), citalopram (70-300 ?M) on ectonucleotidases and ADA activities. It has been also analyzed the in vitro (1 to 1000 ?M) and ex vivo (1 to 10mg/L) effect of lithium on ectonucleotidases and AChE activities and gene expression. There was a significant inhibition of ADP hydrolysis after ex vivo exposure to lithium at 5 and 10 mg/L, whereas an inhibitory effect was observed for AMP hydrolysis only at 10 mg/L. The same treatment decreased the AChE activity in a concentration of 10mg/L. Lithium did not induce significant changes in the analysis of gene expression patterns in the concentrations tested. In vivo treatment, there were no significant changes inectonucleotidases and AChE activities.…

Advisors/Committee Members: Bonan, Carla Denise.

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Sepsis, a medical condition that affects 18 million people per year worldwide, is characterized by a generalized inflammatory state caused by infection. The widespread activation of coagulation pathways and inflammation progresses to multiple organ failure, the collapse of the circulatory system (septic shock) and death. Despite decades of research and numerous clinical trials, little progress has been made in developing new treatments and mortality rates are virtually the same in the last 20 to 30 years. As such, sepsis remains a difficult opponent for surgeons and their patients, so the search for new therapeutic alternatives becomes strictly essential. Recently stem cells have emerged as a promising therapy for a variety of diseases, including cardiovascular diseases, neurodegenerative disorders, peripheral vascular disease, renal disease, and several others. Its beneficial effects are due mainly to their ability to connect to injury and inflammation, to attenuate the inflammatory response, and accelerate tissue healing and neoangiogenesis due to noxious stimuli. Considering this therapeutic potential, this study aimed to evaluate whether these cells could lead to immune response back into balance, reducing the pathophysiology of sepsis and thereby increase the survival time in mice using an experimental model of sepsis. Our results demonstrated that treatment with mesenchymal stem cells was able to increase survival time of the animals that were tested. This effect is due to the ability of these cells to modulate the immune response providing a smaller reduction in tissue injury and apoptotic cells. These findings demonstrate that mesenchymal stem cells have therapeutic potential and can function as a possible future treatment for sepsis.

Sepse, uma condi??o m?dica que afeta 18 milh?es de pessoas por ano no mundo, ? caracterizada por um estado inflamat?rio generalizado causado por uma infec??o. A ativa??o generalizada de vias de coagula??o e inflama??o evolui para disfun??o de m?ltiplos ?rg?os, o colapso do sistema circulat?rio (choque s?ptico) e morte. Apesar de d?cadas de pesquisas e numerosas experimenta??es cl?nicas, pouco progresso tem sido observado no desenvolvimento de novos tratamentos e as taxas de mortalidade s?o praticamente as mesmas nos ?ltimos 20 a 30 anos. Como tal, a sepse continua sendo um dif?cil advers?rio para cirurgi?es e seus pacientes, logo, a busca por novas alternativas terap?uticas torna-se estritamente essencial. Recentemente as c?lulas-tronco t?m emergido como uma terapia promissora para uma variedade de patologias, incluindo doen?as cardiovasculares, neurodegenerativas, doen?a vascular perif?rica, doen?a renal, e v?rias outras. Seus efeitos ben?ficos est?o relacionados principalmente ?s suas capacidades de se conectarem a les?es e inflama??es, para atenuar a resposta inflamat?ria e acelerar a…

Advisors/Committee Members: Oliveira, Jarbas Rodrigues de.

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Made available in DSpace on 2015-04-14T14:51:25Z (GMT). No. of bitstreams: 1 448546.pdf: 1722481 bytes, checksum: a40adfe8bfc8e436fd504a30736f22aa (MD5) Previous issue date: 2013-02-08

Temperament can be regarded as the basis of mood, behavior and personality. It has a strong biological basis, manifested early in the development of the individual, guiding the formation of habits and is relatively stable over time. Although it is known that there are environmental influences, the relationship of temperament with biological markers and social environment is not well defined. Evidence suggests that the temperament and personality traits predict psychiatric disorders and that most of them are recurrent and chronic. Thus, this study aims to investigate the biological and social basis of behavior and in animal models of traits to assess the relationship of temperament with hyperucemia and with self-report of having been bullied in humans. To study the neurobiological basis of this trait, we selected mice with high and low exploration of a central object in an open field. Out of one hundred mice tested, the ten mice with higher (HE) and lower exploratory (LE) activity were evaluated with gene expression (Genechip Mouse Gene 1.0 ST Array Affymetrix) in the striatum and frontal cortex. The results showed 118 and 86 differentially expressed genes (DEGs) in the striatum and frontal cortex, respectively. Through analysis of DEGs biological processes were significantly more enriched in nervous system were development and function and cell-to-cell signaling, particularly in the striatum. These results suggest the involvement of translational and post-translational processes as well as striatal synaptic elements in the trait differences of exploratory behavior. Human studies were conducted with the data collected in a large web-survey on psychological and psychiatric measures (BRAINSTEP). In the study of biological basis of behavior we analyzed temperament in 7.155 males (5.1% hyperuricemic) and 25.225 women (1.8% hyperuricemic). Hyperuricemic subjects scored higher in anger and lower in inhibition and control, but hyperuricemic women also showed a higher emotional sensitivity and a lower degree of volition and coping. Subjects with hyperuricemia present more more externalizing and unstable emotional traits and affective temperaments In the study of the social bases of temperament assessed bullying during childhood and adolescence, through a question on time of exposure to bullying (none, <1 year, 1-3 years and> 3 years). Emotional traits and affective temperaments were evaluated with The Affective and Emotional Composite Temperament Scale (AFECTS). About half of the sample reported exposure to bullying and 10% reported being victimized by peers for longer than 3 years. Longer exposure to bullying was associated with lower Volition, Coping and Control. Bullying victimization was also associated with a much lower proportion of euthymic and hyperthymic types in both genders, which was compensated by an increase mainly in the…

Advisors/Committee Members: Lara, Diogo Rizzato.

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Psychosocial stress has important role in activating endocrine, immune and central nervous systems. Stress exacerbates many chronic inflammatory conditions and is an important risk factor for several mood disorders. Early exposure to stress can be even more detrimental as it may lead to alterations in stress reactivity/responsivity later in life. Several studies have shown important neuroimmune changes associated with the pathophysiology of mood disorders. Previous studies from our group and others reported a pro‐inflammatory profile and increased cellular activation in patients with bipolar disorder (BD). The objectives of the thesis are: 1) to analyze the stress effects on development using animal model of early life stress (maternal separation); 2) to analyze the neuroimmunendocrine responses to acute stress exposure (Trier Social Stress Test) in BD patients. Data presented here suggests that early life stress results in immune activation, characterized by increased pro‐inflammatory serum levels (specifically IL1‐β). As a consequence of this inflammation, a reduction of parvalbumin containing interneurons, substantial for serotonergic branches development, was also observed. Peripheral inflammation is a biological marker of neuronal damage observed, as interleukin‐10 (IL‐10, main anti‐inflammatory cytokine) central administration overturned the neuronal damages as well as peripheral inflammation per se. In the second study, patients with BD showed blunted sympathetic and neuroendocrine (cortisol) stress responses following acute stress compared to healthy controls. Basal data corroborates the presence of increased cellular activation in BD patients as observed by reduced T regulatory (Treg) cells, increased activated T cells (CD4+CD25+) as well as increased intracellular signaling through increased ERK1/2 and NF‐κB phosphorylation. Furthermore, an inability in reducing immune activation in response to stress was observed as increased percentage of activated T cells and concomitantly reduction in regulatory T cells in BD patients. Such inability in controlling immune response after stress exposure may be explained not only by reduced cortisol levels but also by reduced glucocorticoid sensitivity observed in BD patients. Given that, we conclude that BD patients have important HPA axis alterations that may lead to reduced endocrine reactivity to stress as well as inability to duly modulate immune responses.

O estresse psicossocial ? um importante mecanismo de ativa??o dos sistemas nervoso, end?crino e imune muitas vezes levando ? exacerba??o de diversas doen?as inflamat?rias cr?nicas, assim como ? um fator de risco importante para diversos transtornos de humor. A exposi??o ao estresse pode ser mais danosa quando esta ocorre cedo no desenvolvimento e pode resultar em altera??es…

Advisors/Committee Members: Bauer, Mois?s Evandro.

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Introduction : Oxaliplatin is an antineoplastic agent widely used in the treatment of some tumors. It is a third-generation platinum compound developed with the purpose of overcoming the limitations of toxicity, tumor resistance and poor oral bioavailability associated to cisplatin administration. Oxaliplatin-associated neurotoxicity represents the main dose limiting and there is not suitable treatment. Increasing doses of oxaliplatin can leed to the development of mechanical allodynia, cold sensitivity and peripheral sensory neuropathy, with increase of symptoms. Furthermore, despite its usefulness, chemotherapy with oxaliplatin increases the rate of developing hepatic damages together with inflammatory activity. This might be termed chemotherapy-associated steatohepatitis (CASH), a most severe form of non-alcoholic fatty liver disease. Therefore, in the presentstudy, we aimed to compare the effect of antioxidant compounds on simultaneous development of oxaliplatin-induced hepato and neurotoxicity in mice. Methods : The Balb/c mice were treated with doses of oxaliplatin (OXA) for 6 weeks, 10 mg/kg, intraperitoneally (i.p), resulting in mechanical allodynia, and hepatic steatosis. We administered antioxidants compounds such as rutin (RUT) (20 mg/Kg/d), resveratrol (RVS) (100 mg/Kg/d), quercetin (QT) (20 mg/Kg/d) and nanoquerecetin (NQT) (20 mg/Kg/d) daily by gavageto Balb/c. N-acetyl-cysteine was used as control. Euthanasiaoccurred onday 43after treatment. We evaluated mechanical nociceptive threshold, ALT/AST, histopathological analysisand MPOactivity. Statistical analyses were made one way ANOVA, followed by Bonferroni post hoc test. Results : The treatments with RSV, RUT or NQT were able to prevent mechanical allodynia when compared to OXA group. Regarding the effect on steatohepatitis, resveratrol, quercetin and quercetin nanoemulsion almost completely reversed the mean liver weight increase by OXA. In accordance with these previous data, histological evaluation depicted attenuation all features of hepatic steatosis evaluated in resveratrol, rutin, quercetin and quercetin nanoemulsion groups. On the other hand, only quercetin and quercetin nanoemulsion treatments were able to reduce neutrophils migration measured by MPO activity. Conclusion : These results suggest that the use of compounds such as resveratrol, rutin, quercetin and quercetin nanoemulsion can beeffective to avoid oxaliplatin-inducing hepato and neurotoxicity in a rodent model.

Introdu??o : A oxaliplatina ? um agente antineopl?sico e tem sido amplamenteutilizado no tratamento de v?rios tumores. ? um composto derivado da platina de terceira gera??o desenvolvido com o prop?sito de ultrapassar as limita??es da toxicidade, a resist?ncia do tumor e a fraca biodisponibilidade oral associada ? administra??o decisplatina. Sintomas de neurotoxicidade est?o associados ao…

Advisors/Committee Members: Morrone, Fernanda Bueno.