Conselho Nacional de Desenvolvimento Científico e Tecnológico / The intensive use and/or inadequate management of pesticides have led to contamination of the aquatic ecosystem, reaching the biota living there, including the fish. Pesticides can affect toxicological parameters these animals, harming their survival. In this way, the aim this study has to evaluate biochemistry changes in carps (Cyprinus carpio) after exposure to a commercial formulation of the fungicide tebuconazole (Folicur®). At first, we performed a test of acute toxicity to determine the LC50 (96h) of tebuconazole for C. carpio. The animals were exposed to concentrations 1.0, 1.5, 2.0, 2.5 and 3.0 mg/L for 96 hours. After this period, were anesthetized and euthanized. Using the whole-body method, we investigated the levels of TBARS, protein carbonyls, activities of enzymes GST, CAT, SOD and AChE, levels of non-enzymatic antioxidants GSH and AsA and metabolic parameters, among which, lactate, glycogen, glucose, ammonia, amino acids and protein. Secondly, fish were exposed to the fungicide during seven days, both in field conditions (rice paddy field) as a laboratory. The concentrations used in the laboratory (33.5 and 36.2 mg/L) were close to the concentration used for rice farming (31.9 mg/L). After the experimental periods, we sampled brain, liver and muscle of fish. The biochemical parameters analyzed were as follows: TBARS levels in brain, liver and muscle, protein carbonyl in liver, enzyme activities CAT and GST in liver and AChE in brain and muscle. In the first experiment was obtained as LC50 (96h) of tebuconazole for C. carpio concentration 2.37 mg/L. The body levels of TBARS showed to be high at all concentrations tested. In contrast, the enzymes GST, CAT and SOD showed reduction in their activities. The levels of GSH and AsA were also decreased after the same period. Regarding the activity of AChE and the levels of protein carbonyls, there were no statistically significant changes. Among the metabolic parameters, there was an increase in the levels of glycogen and glucose concentration 1.5 mg/L, whereas protein levels were reduced at concentrations 2.0 and 2.5 mg/L. In the second experiment, we observed increased levels of TBARS in brain only in the field condition, while in liver and muscle this increase was observed both in field and laboratory. Likewise, the levels of protein carbonyls increased in both experimental conditions. The activity of AChE in brain was increased only in the field condition, whereas in the laboratory no significant change was observed. The activities of CAT, GST and AChE in muscle showed no significant change in both experimental conditions. The results of this research, considering the two experiments show that this fungicide causes disorders in antioxidants and metabolic parameters in fish exposed, indicating the occurrence of oxidative stress, which can compromise their survival in the wild. The evaluation of TBARS levels and protein carbonyl in the liver of carp can be used as a biomarker of exposure to tebuconazole. / O intenso uso e/ou manejo inadequado de pesticidas têm levado à contaminação do ecossistema aquático, atingindo a biota ali existente, incluindo os peixes. Pesticidas podem afetar parâmetros toxicológicos desses animais, prejudicando sua sobrevivência. Neste sentido, o objetivo deste trabalho foi avaliar alterações bioquímicas em carpas (Cyprinus carpio) após exposição a uma formulação comercial do fungicida tebuconazole (Folicur®). Num primeiro momento, foi realizado um teste de toxicidade aguda a fim de determinar a CL50 (96h) do tebuconazole para C. carpio. Os animais foram expostos às concentrações 1,0, 1,5, 2,0, 2,5 e 3,0 mg/L, durante 96 horas. Após esse período, foram anestesiados e eutanasiados. Utilizando o método whole-body, foram investigados os níveis de TBARS, proteína carbonil, atividades das enzimas GST, CAT, SOD e AChE, níveis dos antioxidantes não enzimáticos GSH e AsA e parâmetros metabólicos, dentre os quais, lactato, glicogênio, glicose, amônia, aminoácidos e proteína. Num segundo momento, os peixes foram expostos ao fungicida durante sete dias, tanto em condição de campo (lavoura de arroz irrigado) como de laboratório. As concentrações utilizadas em laboratório (33,5 e 36,2 μg/L) foram próximas à concentração utilizada na lavoura de arroz (31,9 μg/L). Decorridos os períodos experimentais, foram amostrados cérebro, fígado e músculo dos peixes. Os parâmetros bioquímicos analisados foram os seguintes: níveis de TBARS em cérebro, fígado e músculo; proteína carbonil em fígado; atividades das enzimas CAT e GST em fígado e da AChE em cérebro e músculo. No primeiro experimento obteve-se como CL50 (96h) do tebuconazole para C. carpio a concentração 2,37 mg/L. Os níveis corporais de TBARS mostraram-se elevados em todas as concentrações testadas. Ao contrário, as enzimas GST, CAT e SOD mostraram redução em suas atividades. Os níveis de GSH e AsA também se mostraram diminuídos após o mesmo período. Em relação à atividade da AChE e aos níveis de proteína carbonil, não foram observadas alterações estatisticamente significativas. Dentre os parâmetros metabólicos, houve aumento nos níveis de glicogênio e glicose na concentração 1,5 mg/L, enquanto que os níveis de proteína foram reduzidos nas concentrações 2,0 e 2,5 mg/L. No segundo experimento, observou-se aumento nos níveis de TBARS em cérebro somente na condição de campo, enquanto que em fígado e músculo esse aumento foi verificado tanto em campo quanto em laboratório. Da mesma forma, os níveis de proteína carbonil aumentaram em ambas as condições experimentais. A atividade da AChE em cérebro se mostrou aumentada somente em condição de campo, enquanto que em laboratório nenhuma alteração significativa foi observada. As atividades da CAT, GST e AChE em músculo não apresentaram mudanças significativas em ambas as condições experimentais. Os resultados da presente investigação, considerando os dois experimentos realizados, mostram que esse fungicida provoca desordens em parâmetros antioxidantes e metabólicos nos peixes expostos, indicando a ocorrência de estresse oxidativo, o que pode comprometer sua sobrevivência no meio natural. A avaliação dos níveis de TBARS e de proteína carbonil em fígado de carpas pode ser utilizada como biomarcador de exposição ao tebuconazole.

Made available in DSpace on 2014-06-11T19:31:10Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-05-07Bitstream added on 2014-06-13T20:01:49Z : No. of bitstreams: 1 monteiro_eas_dr_jabo.pdf: 1292087 bytes, checksum: afe60a582e1c90873b89d65e31b1723d (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A Ipomoea asarifolia é uma planta tóxica, conhecida como salsa, batata salsa e salsa brava da família convolvulaceae, presente as margens de rios, lagoas e praias marítimas em todo o Brasil, sendo responsável pela intoxicação natural em ruminantes, principalmente no Nordeste brasileiro, causando excitabilidade e alterações no hemograma e perfil bioquímico desses animais, além de pequenas lesões macroscópicas e microscópicas nos órgãos internos (encéfalo, fígado e rins). Pela falta de trabalhos científicos que relatem a sua interferência sobre o desenvolvimento cerebral nas espécies animais o nosso objetivo foi avaliar o potencial tóxico dessa planta, em ratos, um modelo experimental confiável e de fácil repetibilidade, as possíveis alterações hematológicas, bioquímicas e o comportamento perinatal neste modelo. Os resultados obtidos no perfil bioquímico, hemograma e no exame histopatológico dos ratos intoxicados com extrato aquoso e hidroalcoólico nos permitiu constatar alterações significantes no perfil bioquímico para as variáveis glicose, proteína, alanina aminotransferase e bilirrubina direta na intoxicação aguda com os extratos aquoso e hidroalcoólico. Na intoxicação subaguda observamos alterações para as proteínas e creatinina nos dois extratos. Quanto ao hemograma, tanto na intoxicação aguda como na subaguda constatamos alterações para as variáveis plaquetas e monócitos entre o grupo controle e o grupo tratado. No histopatológico foi observado no encéfalo edema intersticial e degeneração hidrópica no fígado e rins dos ratos intoxicados o que caracteriza um quadro de intoxicação. Quanto à avaliação perinatal podemos observar que houve diferenças entre os filhotes de ratas controles daquelas que se alimentaram com ração de salsa durante toda a gestação, no desenvolvimento físico da prole (Esquiva ao Abismo) e na avaliação... / Ipomoea asarifolia is a toxic plant from Convolvulaceae family, known as “parsley” or “salsa”, present on banks of rivers and lakes and seasides throughout Brazil and is responsible for natural poisoning of ruminants, mainly in brazilian northeast, causing excitability and changes in blood count and biochemical profile of these animals, besides macro and microscopic lesions in internal organs (encephalon, liver and kidneys). From the lack of scientific papers that report its interference on animal species brain development, our aim was to evaluate the toxic potential of this plant in rats, an experimental model reliable and easily repeatable, and possible changes in hematological, biochemical and perinatal behavior in this model. Achieved results in biochemical profile, complete blood count and histopathological exams of rats intoxicated with aqueous and hydroalcoholic extracts, allowed us to observe significant changes in biochemical profile for variables as glucose, protein, alanine aminotransferase and direct bilirubin in acute intoxication with aqueous and hydroalcoholic extracts. In subacute intoxication changes were observed for protein and creatinine on both extracts. According to blood count, changes were found for platelet and monocyte variables between treated and control group, both in acute and in subacute intoxication. In histopathological exam, interstitial edema was observed in encephalon, as hydropic degeneration in liver and kidneys of intoxicated rats, which characterize intoxication. As for perinatal evaluation, is possible to observe differences between the offspring of animals from control group and those fed with salsa diet throughout pregnancy, in offspring physical development (elude the abyss) and neurobehavioral evaluation (Morris Water Maze), wich can indicate lesion on descendants brain development

Made available in DSpace on 2014-06-11T19:32:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-12-14Bitstream added on 2014-06-13T19:42:31Z : No. of bitstreams: 1 vizioli_eo_dr_arafcf.pdf: 7064778 bytes, checksum: e872f0937bcd407f465d83cdf5ba7ec6 (MD5) / Universidade Estadual Paulista (UNESP) / A inflamação é uma reação de defesa e reparo fisiológico, importante em resposta a agressões físicas, químicas ou biológicas ao organismo, que geram o aparecimento dos quatro sinais cardinais dor, edema, calor, rubor, incluindo, muitas vezes a perda de função do tecido ou órgão. O processo inflamatório agudo é imediato e inespecífico contra o agente agressor, podendo evoluir para crônico, caso haja a permanência do agente agressivo e é caracterizado pelo aumento de celularidade e outros elementos teciduais. Várias substâncias estão envolvidas no processo inflamatório, como a prostaglandinas, histamina, serotonina e citocinas pró-inflamatórias como IL-1b, 1L-6, IL-8, TNF-a, NF-kB. Estima-se que exista na terapêutica, mais de 50 antiinflamatórios não esteróides (AINEs) diferentes, mas nenhum deles totalmente destituído de efeitos tóxicos, como a gastrotoxicidade, mesmo os compostos mais novos, seletivos para receptores COX2, como o celecoxibe. Por este motivo nenhum AINEs é recomendado para utilização em processos inflamatórios crônicos. Neste sentido, Vizioli (2006) e Castro (2008), planejaram pró-fármacos taurínicos e híbridos ftalimídicos, respectivamente, obtendo resultados promissores como antiinflamatórios potenciais destituídos de gastrotoxicidade. O presente trabalho visa realizar os testes pré-clinicos de atividade antiinflamatória aguda e crônica. Os resultados demostraram que que todos os derivados testados não apresentam gastrotoxicidade em relação ao padrão AINE testado, sem alteração significativa da resposta inflamatória aguda, com exceção do derivado de ibuprofeno N-(1,3-dioxo-1,3-diidro-2H-isoindol-2-il)-2-(4-isobutilfenil) propanamida, que demonstrou atividade inferior. Em estudo de atividade inflamatória crônica... / Inflammation is a defense and repair physiologic reaction important in response to an physical, chemical or biological aggression of the body, providing the appearance of the four cardinal signs of pain, swelling, heat, redness, including often the loss of function of the tissue or organs. The acute inflammatory process is immediate and nonspecific against the aggressive agent and it is characterized by increased cellular and other tissue elements. Series of substances are involved in the inflammatory process such as prostaglandins, histamine, serotonin and pro-inflammatory cytokines such as 1L-6, IL-8, a-TNF, NF- kB. It is estimated that exists more than 50 different non steroidal anti-inflammatory drugs (NSAIDs) drugs in the market, but none of them are wholly without side effects such as gastro toxicity, even the newer compounds, selective to COX2 receptors, as the celecoxib. For this reason none of NSAIDs is recommended for use in chronic inflammatory diseases. In this sense, Vizioli (2006) and Castro (2008), planned new taurine prodrugs and phtalimide hybride NSAIDs, respectively, showing promising results as anti-inflammatory without toxicity. This work aims to accomplish pre-clinical assay by acute and chronic models of inflammation. The results showed that all derivatives tested have no gastro toxicity when compared with the NSAIDs standard. No significant inflammatory response was observed with the exception toibuprofen derivative N-(1,3-dioxo-1,3-diidro-2H-isoindol-2-il)-2-(4-isobutilfenil) propanamide, which showed less activity. In the chronic inflammatory study activity all compounds phthalimide and taurine showed increase of activity compared to standard NSAIDs with decrease of the mortality and exclusion of the clinical signals such as bleeding, weight loss, and increased defecation rate... (Complete abstract click electronic access below)

Acetaminophen, known as paracetamol in the UK and Tylenol in the United States, is a widespread and commonly used painkiller all over the world. Taken in large enough doses, however, it can cause fatal liver damage. In the U.S., 56000 people are admitted to hospital each year due to acetaminophen overdose and its related effects, at great cost to healthcare services. In this thesis we present a number of different models of acetaminophen metabolism and toxicity. Previously, models of acetaminophen toxicity have been complex and due to this complexity, do not lend themselves well to more advanced mathematical analysis such as the perturbation analysis presented later in this thesis. We begin with a simple model of acetaminophen metabolism, studying a single liver cell and performing numerical and sensitivity analysis to further understand the most important mechanisms and pathways of the model. Through this we identify key parameters that affect the total toxicity in our model. We then proceed to perform singular perturbation analysis, studying the behaviour of the model over different timescales, finding a number of key timescales for the depletion and subsequent recovery of various cofactors as well as critical dose above which we see toxicity occurring. Later in the thesis, this model is used to model metabolism in a spheroid cell culture, examining the difference spatial effects have on metabolism across a 3D cell culture. We then present a more complex model, examining the difference the addition of an adaptive response to acetaminophen overdose from the Nrf2 signalling pathway, has on our results. We aim to reproduce an unexplained result in the experimental data of our colleagues, and so analyse the steady states of our model when subjected to an infused dose, rather than a bolus one. We identify another critical dose which leads to GSH depletion in the infused dose case and find that Nrf2 adaptation decreases toxicity and model sensitivity. This model is then used as part of a whole-body PBPK model, exploring the effects that the distribution of the drug across the bloodstream and different organs has. We explore the affects of that a delay in up-regulation from the Nrf2 pathway has on the model, and find that with rescaled parameters we can qualitatively reproduce the results of our collaborators. Finally, we present the results of in vitro work that we have undertaken, the aim of which was to find new parameters for the model in human hepatocytes, rather than from rodent models, and find a new value for a parameter in our model from human cell lines.

Diabetes mellitus (DM) é um grupo de anomalias metabólicas caracterizadas principalmente pela hiperglicemia. Componentes macro- e microvasculares, além de neuropáticos inter-relacionados com a elevação da glicemia são fatores freqüentemente envolvidos em acidentes cérebro-vasculares, infartos miocárdicos, doença vascular periférica, retinopatia e nefropatia diabética. Na literatura científica atual pode-se obter um grande número de trabalhos onde o uso de plantas medicinais, extratos ou substâncias vegetais isoladas é positivamente relacionado ao tratamento do DM e/ou seus efeitos diretos e indiretos. Bauhinia microstachya (RADDI) MACBR. (Caesalpinaceae) é uma planta que ocorre naturalmente na região sul do Brasil onde é conhecida popularmente como “escada-de-macaco”. Algumas populações fazem uso de preparações das folhas no tratamento do DM e suas complicações. Neste trabalho propomos que os extratos aquoso e hidro-etanólico, obtidos das folhas de B. microstachya possuem ação antioxidante in vitro e que o extrato hidro-etanólico apresenta poder antioxidante in vivo, além de efeito hipoglicemiante, apesar de ser potencialmente hepatotóxico. / Diabetes mellitus (DM) is a heterogeneous group of metabolic disorders characterized by chronic hyperglycemia. Both DM types share aspects that are related to uncontrolled hyperglycaemia: alterations in the carbohydrate, fat, and protein metabolism. In addition, increased cardiovascular disease risk, retinopathy, nephropathy, and neuropathy are vascular complications associated to diabetes. In scientific literature there are several reports where the use of folk medicine is positively related to DM treatment and/or their direct and indirect effects. Bauhinia microstachya (RADDI) MACBR. (Caesalpinaceae) is a creeper plant that occurs naturally in southern Brazil where is popularly known as “escada-de-macaco” (monkey’s ladder) and often used as herbal antidiabetic medicine. In the present work, we propose that the extracts obtained from B. microstachya leaves have in vitro and in vivo antioxidant action, hypoglycemic effect, despite their hepatotoxic potential.

O fitoterápico Xarope de Agrião Composto Cibecol® é uma associação de extratos de Roripa nasturtium Rusby (Agrião), Musa spp. (Bananeira), Ficus carica Linné (Figueira), Tagetes minuta Linné (Chinchilia) e mel de abelhas. Avaliou-se a segurança deste fitoterápico através de estudos de toxicidade aguda e subcrônica, tendo como base a resolução Nº 90, de 16 de março de 2004 da ANVISA. Para o teste de toxicidade aguda, ratos Wistar de ambos os sexos foram tratados por via oral com uma única dose de 26 ml/kg, correspondendo a 20 vezes a dose terapêutica indicada pelo fabricante para seres humanos adultos. Os resultados revelaram não haver sinais de toxicidade sistêmica, não causando interferência no desenvolvimento ponderal dos animais, nos consumos de água e ração, nas produções de urina e fezes, bem como alterações macroscópicas nos órgãos dos animais. Avaliou-se também a exposição a doses repetidas do fitoterápico. Constituíram-se em quatro grupos experimentais (10 animais/sexo/dose), onde administrou-se por via oral a ratos Wistar, durante 30 dias, doses diárias de 1,3 ml/kg, 6,5 ml/kg e 13 ml/kg, respectivamente a dose terapêutica indicada pelo fabricante para seres humanos adultos, 5 vezes, e 10 vezes a dose terapêutica, além de um grupo controle, onde foi administrado o veículo do fitoterápico. Os resultados revelaram ausência de toxicidade sistêmica, fundamentados na ausência de alterações hematológicas e bioquímicas sangüíneas, bem como no peso e análises histopatológicas dos órgãos, nos diferentes grupos. Concluiu-se que, a utilização do fitoterápico nas doses e períodos referidos, pode ser considerada segura. / The phytotherapic Xarope de Agrião Composto Cibecol® is an association of extracts of Roripa nasturtium Rusby (water-cress), Musa spp. (banana tree), Ficus carica Linné (fig tree), Tagetes minuta Linné (Chinchilia) and honey. The safety of the phytotherapic was evaluated through studies of acute and sub-chronic toxicity, being based in the resolution Nº 90, March 16th, 2004 from ANVISA. For the test of acute toxicity Wistar rats of both sexes were treated orally with a single dose of 26 ml/kg, which corresponds to 20 times the therapeutic dose indicated by the producer for adult humans. The results revealed that there are no signals of systemic toxicity, no interference in the development of weight gain in the animals, in water and feed consume, in the production of urine and feces, neither macroscopic alterations in the animals’ organs. It was also evaluated the exposition of repeated doses of the phytotherapic (sub-chronic toxicity). Four experimental groups (10 animals/sex/dose) were orally treated during 30 days with daily doses of 1.3 ml/kg, 6.5 ml/kg and 13 ml/kg, respectively the therapeutic dose indicated to humans, 5 times, and 10 times the therapeutic dose, and a control group, receiving the phytotherapic vehicle. The results revealed the absence of systemic toxicity, based in the absence of hematological and blood biochemical alterations, as well as weigh and histopatological analysis of organs, in the different groups. It was concluded that the utilization of the referred phytotherapic in the mentioned doses and periods might be considered secure.

O ferro é um elemento essencial para o crescimento e desenvolvimento das plantas, envolvido em processos metabólicos essenciais, como fotossíntese e respiração. Entretanto, quando livre e em excesso, pode gerar estresse oxidativo. A toxidez por excesso de ferro trata-se do maior problema nutricional em arroz alagado, sendo responsável por perdas na produtividade. Diversas estratégias para minimizar os efeitos tóxicos do ferro vêm sendo desenvolvidas, e entre elas, o uso de cultivares tolerantes é considerada a mais efetiva. Porém, poucos dados com relação à interação entre diferentes genótipos de arroz e o ambiente encontram-se disponíveis. Utilizando-se de abordagens bioquímicas e moleculares, foram analisadas as respostas de diferentes cultivares de arroz expostas a altos níveis de ferro, crescidas em campo ou em laboratório. A toxidez por excesso de ferro teve um claro efeito foto-oxidativo, levando a quedas nos teores de clorofila, bem como a danos oxidativos. Excessivos níveis de ferro levaram a um aumento na atividade de enzimas antioxidantes, bem como a alterações no estado oxidativo da célula, modificando as concentrações das formas oxidadas e reduzidas de ascorbato e glutationa. A concentração de ferro apresentou-se variável nas cultivares tolerantes testadas. Os dados obtidos indicam que possíveis mecanismos de tolerância ao excesso de ferro podem envolver a capacidade de acumular ferro em frações superiores a 3kDa, maior atividade de SOD (através da expressão diferencial de três isoformas), bem como a limitação da captura do metal, possivelmente envolvendo a lignificação e remodelamento da parede celular das células da raiz. Altos níveis de ferro levaram ao acúmulo de transcritos dos genes de ferritina, em especial de OsFER2, dependente de um passo oxidativo, bem como à expressão de outros genes relacionados a homeostase de ferro. Cinco genes pertencentes às famílias gênicas ZIP (OsZIP1, OsZIP7 e OsZIP8) e NRAMP (OsNRAMP4 e OsNRAMP5) tiveram sua expressão induzida em plantas expostas a altos níveis de ferro, sugerindo seu possível envolvimento em respostas ao excesso de ferro. Os genes OsIRT1 e OsIRT2, OsNRAMP1 e OsYS7, cuja expressão relativa foi aumentada em condições de deficiência de ferro, tiveram sua expressão reduzida em excesso de ferro. Esses genes codificam transportadores de alta afinidade por ferro, sugerindo a ocorrência de uma resposta coordenada, dependente da concentração de ferro. Plantas de cultivares de arroz distintas apresentaram diferentes mecanismos de tolerância ao excesso de ferro. / Iron is an essential nutrient for growth and development of plants, involved in important plant biological processes, such as photosynthesis and respiration. However, when free and in excessive levels inside the cell, iron can act as a pro-oxidant, leading to oxidative stress. Iron toxicity is considered the major nutritional disorder in waterlogged and lowland rice, being responsible for losses on rice production. Several management strategies have been developed to overcome iron toxicity, and the most cost-effective approach is the use of tolerant rice cultivars. Despite this, few data concerning the relation between different rice cultivars and its environment are available. Through the use of molecular and biochemical approaches, we analyzed the responses of distinct rice genotypes exposed to iron excess, cultivated in the field or in the laboratory. Iron toxicity had a clear photo oxidative damage, leading to decreases in chlorophyll levels and generating oxidative damage. Iron excess also induced the activity of antioxidant enzymes, as well as an alteration in the redox status of the cell, besides concentration varied between the studied cultivars. Mechanisms involved in the tolerance to iron toxicity may involve the capacity to accumulate iron at molecular mass fractions, a higher SOD activity (probably through the differential induction of SOD isoforms), and also the limitation of iron uptake in nutrient solution. This limitation may rely in the root cell wall remodeling and lignifications. Iron lead to an up-regulation of ferritin genes, especially OsFER2, with this induction being dependent on an oxidative step. Iron excess also lead to an induction on the relative gene expression of iron homeostasis-related genes. Five genes belonging to two distinct gene families, ZIP (OsZIP1, OsZIP7 and OsZIP8) and NRAMP (OsNRAMP4 e OsNRAMP5), were up-regulated in plants exposed to iron excess, suggesting their possible role in response to excessive amounts of iron. Interestingly, five genes (OsIRT1 and OsIRT2, OsNRAMP1 and OsYS7) up-regulated by iron deficiency, were regulated in an opposite way by iron excess. All the five genes encode proteins involved in the uptake and transport of iron, suggesting a coordinated response, depending on the iron concentration. Taken together, our results indicated that different rice cultivars can use distinct tolerance mechanisms.

Despite of its known toxicity and potential to cause cancer, arsenic has been proven to be a very important tool for the treatment of various refractory neoplasms. One of the promising arsenic-containing chemotherapeutic agents in clinical trials is Darinaparsin (dimethylarsinous glutathione, DMAIII(GS)). In order to understand its toxicity and therapeutic efficacy, the metabolism of Darinaparsin in human cancer cells was evaluated. With the aim of detecting all potential intermediates and final products of the biotransformation of Darinaparsin and other arsenicals, an analytical method employing high performance liquid chromatography inductively coupled mass spectrometry (HPLC-ICP-MS) was developed. This method was shown to be capable of separating and detecting fourteen human arsenic metabolites in one chromatographic run. The developed analytical technique was used to evaluate the metabolism of Darinaparsin in human cancer cells. The major metabolites of Darinaparsin were identified as dimethylarsinic acid (DMAV), DMAIII(GS), and dimethylarsinothioyl glutathione (DMMTAV(GS)). Moreover, the method was employed to study the conditions and mechanisms of formation of thiol-containing arsenic metabolites from DMAIII(GS) and DMAV as the mechanisms of formation of these important As species were unknown. The arsenic sulfur compounds studied included but were not limited to the newly discovered human arsenic metabolite DMMTAV(GS) and the unusually highly toxic dimethylmonothioarsinic acid (DMMTAV). It was found that these species may form from hydrogen sulfide produced in enzymatic reactions or by utilizing the sulfur present in protein persulfides. Possible pathways of thiolated arsenical formation were proposed and supporting data for their existence provided. In addition to known mechanism of arsenic toxicity such as protein-binding and reactive oxygen formation, it was proposed that the utilization of thiols from protein persulfides during the formation of thiolated arsenicals may be an additional mechanism of toxicity. The toxicities of DMAV(GS), DMMTAV, and DMMTAV(GS) were evaluated in cancer cells, and the ability of these cells to take the compounds up were compared. When assessing the toxicity by exposing multiple myeloma cells to arsenicals externally, DMMTAV(GS) was much less toxic than DMAIII(GS) and DMMTAV, probably as a result of its very limited uptake (less than 10% and 16% of DMAIII(GS) and DMMTAV respectively).

abstract: Solar photovoltaic (PV) deployment has grown at unprecedented rates since the early 2000s. As the global PV market increases, so will the volume of decommissioned PV panels. Growing PV panel waste presents a new environmental challenge, but also unprecedented opportunities to create value and pursue new economic avenues. Currently, in the United States, there are no regulations for governing the recycling of solar panels and the recycling process varies by the manufacturer. To bring in PV specific recycling regulations, whether the PV panels are toxic to the landfills, is to be determined. Per existing EPA regulations, PV panels are categorized as general waste and are subjected to a toxicity characterization leaching procedure (TCLP) to determine if it contains any toxic metals that can possibly leach into the landfill. In this thesis, a standardized procedure is developed for extracting samples from an end of life PV module. A literature review of the existing regulations in Europe and other countries is done. The sample extraction procedure is tested on a crystalline Si module to validate the method. The extracted samples are sent to an independent TCLP testing lab and the results are obtained. Image processing technique developed at ASU PRL is used to detect the particle size in a broken module and the size of samples sent is confirmed to follow the regulation. / Dissertation/Thesis / Masters Thesis Engineering 2017

Submitted by Simone Souza (simonecgsouza@hotmail.com) on 2017-09-20T13:55:03Z No. of bitstreams: 1 DISS_2014_Morenna Alana Giordani.pdf: 1859265 bytes, checksum: b5d9642bcb74a3b47527bc37b687bab3 (MD5) / Approved for entry into archive by Jordan (jordanbiblio@gmail.com) on 2017-09-26T12:41:05Z (GMT) No. of bitstreams: 1 DISS_2014_Morenna Alana Giordani.pdf: 1859265 bytes, checksum: b5d9642bcb74a3b47527bc37b687bab3 (MD5) / Made available in DSpace on 2017-09-26T12:41:05Z (GMT). No. of bitstreams: 1 DISS_2014_Morenna Alana Giordani.pdf: 1859265 bytes, checksum: b5d9642bcb74a3b47527bc37b687bab3 (MD5) Previous issue date: 2014-08-25 / CNPq / A Cedrela odorata L. (cedro-rosa) foi selecionada para a avaliação antidiabética in vivo, com base nos resultados obtidos em triagem in vitro, realizada com várias plantas citadas em levantamento etnofarmacológico na região do Vale do Juruena – Mato Grosso. Nesta triagem foram avaliadas a inibição da alfa-glicosidase e a capacidade antioxidante pelo sequestro do radical DPPH dos extratos hidroetanólicos. O extrato hidroetanólico da entrecasca de C. odorata L. (EHeCo) apresentou CI50 e CD50 na avaliação inibidora da alfa-glicosidase e antioxidante de 84,6 e 3,7 μg/mL respectivamente, muito abaixo do controles positivos acarbose e vitamina C (5115,5 e 7,9 μg/mL) respectivamente. O fingerprint do EHeCo mostrou a presença de ácido gálico, (-)-galocatequina e (+)-catequinas. Os testes de toxicidade aguda (10 a 5000 mg/kg) e de toxicidade subcrônica (500 mg/kg), mostraram que o extrato apresentou baixa toxicidade nas doses avaliadas. Nos testes de avaliação antidiabética subcrônica, foram utilizados animais diabéticos induzidos com estreptozotocina (40 mg/kg em tampão citrato 0,01 M pH 4,5 iv) e não diabéticos. Os animais diabéticos foram tratados com 250 e 500 mg/kg de EHeCo (DT250 e DT500) por 21 dias e os resultados comparados com o grupo diabético tratados com veículo – DMSO 2% (DC) e com o grupo controle positivo (metformina 500 mg/kg - DMet). Não foram observadas alterações no peso corporal, consumo de ração e água, volume urinário de 24h, glicemia, glicosúria e ureia urinária. O nível de triglicérides plasmáticos foi reduzido nas duas doses avaliadas (N = 132 ± 15; DC = 123 ± 15; DT250 = 73 ± 10#; DT500 = 78 ± 8#; DMet = 142 ± 10 mg/dL, #p<0,05). Após 21 dias de tratamento com EHeCo houve redução na concentração de malonaldeído no sangue (N = 1,9 ± 0,3; DC = 5,6 ± 0,5; DT250 = 3,3 ± 0,3; DT500 = 2,9 ± 0,5#; DMet = 3,9 ± 1,0 μmol/L, #p<0,05) e aumento da atividade das enzimas superóxido dismutase (N = 42,3 ± 0,3; DC = 40,9 ± 0,7; DT250 = 60,7 ± 1,8#; DT500 = 60,8 ± 1,1#; DMet = 42,0 ± 0,4 U/L, #p<0,05) e glutationa peroxidase (N = 16,2 ± 0,5; DC = 11,4 ± 0,7*; DT250 = 15,6 ± 0,5#; DT500 = 14,8 ± 0,3#; DMet = 12,2 ± 0,5 103 U/L, *p<0,05 vs N, #p<0,05 vs DC). O efeito do EHeCo sobre a tolerância à glicose, foi avaliada após uma sobrecarga de glicose, amido e sacarose, sendo o extrato administrado nas mesmas doses dos experimentos subcrônicos, 30 minutos antes da sobrecarga de carboidratos. Foram utilizadas floridzina (DF) como controle positivo para o teste em que a sobrecarga foi glicose, e a acarbose (DA), quando a sobrecarga foi de sacarose ou amido. O extrato, nas duas doses reduziu o pico glicêmico e também a área sobre a curva (glicemia x tempo de avaliação) quando a sobrecarga foi de glicose (N = 16253 ± 318; DC = 37666 ± 2347*; DT250 = 32353 ± 1467; DT500 = 27666 ± 1423#; DF = 25033 ± 1241# mg/dL x 120 minutos, *p<0,05 vs N, #p<0,05 vs DC). Quando a sobrecarga foi de sacarose, o extrato na dose de 500 mg/kg reduziu o pico glicêmico após 30 minutos (N = 138 ± 3; DC = 437 ± 39*; DT250 = 294 ± 38; DT500 = 243 ± 69#; DA = 253 ± 22# mg/dL, *p<0,05 vs N, #p<0,05 vs DC) sem redução da área sobre a curva. O EHeCo não teve efeito sobre a glicemia dos animais que receberam amido. O EHeCo apresentou efeitos anti-hiperglicemiante, hipolipidêmico e antioxidante, mostrando o potencial terapêutico da entrecasca de C. odorata no tratamento do diabetes e das complicações relacionadas à doença. / Cedrela odorata L. (cedro-rosa) was selected for the antidiabetic in vivo evaluation, based on the results obtained from an in vitro screening performed with various plants mentioned in an ethnopharmacological survey in the region of Vale do Juruena - Mato Grosso, Brazil. This screening aimed to evaluate the inhibition of alpha-glucosidase and the antioxidant capacity by DPPH radical sequestering of hydroethanolic extracts. The hydroethanolic extract of the inner stem bark of Cedrela odorata L. (HeECo) showed IC50 and DC50 in the evaluation of inhibition of alpha-glucosidase and an antioxidant capacity of 84.7 e 3.7 μg/mL, respectively, well below the positive control acarbose and vitamin C (5115.5 e 7.9 μg/mL), respectively. The fingerprint of EHeCo showed the presence of gallic acid, (-)- gallocatechin and (+)- catechins. Tests for acute and sub-chronic toxicity showed that the extract presented low toxicity at the evaluated doses. In the sub-chronic antidiabetic evaluation tests, streptozotocin-induced diabetic rats (40 mg/kg in 0.01 M citrate buffer pH 4.5 iv) and non-diabetic rats were used. Diabetic animals were treated with 250 and 500 mg/kg HeECo for 21 days and the results were compared with the vehicle-treated diabetic group - 2% DMSO (DC) and the positive control group (metformin - DMet). No changes were observed in body weight, food and water intake, urine volume, blood glucose, glucosuria and urinary urea. The triglyceride level was reduced at the two doses (N = 132 ± 15; DC = 123 ± 15; DT250 = 73 ± 10#; DT500 = 78 ± 8#; DMet = 142 ± 10 mg/dL, #p<0,05). After 21 days of treatment with HeECo, the concentration of malondialdehyde in the blood was reduced (N = 1.9 ± 0.3; DC = 5.6 ± 0.5; DT250 = 3.3 ± 0.3; DT500 = 2.9 ± 0.5#; DMet = 3.9 ± 1.0 μmol/L, #p<0.05) and the activity of superoxide dismutase (N = 42.3 ± 0.3; DC = 40.9 ± 0.7; DT250 = 60.7 ± 1.8#; DT500 = 60.8 ± 1.1#; DMet = 42.0 ± 0,4 U/L, #p<0.05) and glutathione peroxidase increased (N = 16.2 ± 0.5; DC = 11.4 ± 0.7*; DT250 = 15.6 ± 0.5#; DT500 = 14.8 ± 0.3#; DMet = 12.2 ± 0.5 103 U/L, *p<0.05 vs N, #p<0.05 vs DC). The HeECo effect on glucose tolerance was assessed after a glucose, starch and sucrose overload, the extract being administered at the same dose as in the sub-chronic experiment, 30 minutes before the carbohydrate overload. Phloridzin (DF) was used as positive control for the test in which the overload consisted of glucose, and acarbose (DA), when the overload was sucrose or starch. The extract, at both doses reduced the glycemic peak and also the area under the curve (N = 16253 ± 318; DC = 37666 ± 2347*; DT250 = 32353 ± 1467; DT500 = 27666 ± 1423#; DF = 25033 ± 1241# mg/dL x 120 minutes, *p<0.05 vs N, #p<0.05 vs DC) when the overload was glucose. When the loading was sucrose, the extract at a dose of 500 mg/kg, reduced the peak blood glucose after 30 minutes without reduction in the area under the curve (N = 138 ± 3; DC = 437 ± 39*; DT250 = 294 ± 38; DT500 = 243 ± 69#; DA = 253 ± 22# mg/dL, *p<0.05 vs N, #p<0.05 vs DC). The HeECo had no effect on blood glucose levels of the animals receiving starch. The HeECo showed antihyperglycaemic, hypolipidemic and antioxidant, showing the therapeutic potential of the inner stem bark of C. odorata in the treatment of diabetes and disease-related complications.