Submitted by Setor de Tratamento da Informa??o - BC/PUCRS (tede2@pucrs.br) on 2016-06-22T19:27:40Z No. of bitstreams: 1 TES_TALITA_CARNEIRO_BRANDAO_PEREIRA_COMPLETO.pdf: 639031 bytes, checksum: 5fa4cd79fd277a716b47890fcca5b580 (MD5) / Made available in DSpace on 2016-06-22T19:27:40Z (GMT). No. of bitstreams: 1 TES_TALITA_CARNEIRO_BRANDAO_PEREIRA_COMPLETO.pdf: 639031 bytes, checksum: 5fa4cd79fd277a716b47890fcca5b580 (MD5) Previous issue date: 2016-02-29 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / First identified in Saccharomyces ceresvisie, the sirtuins (SIRTs) are a diverse family of histones deacilases that act as deacetilases, ADP-ribosil transferases, desuccinilases and demalonilases; using nicotinamide adenine dinucleotide (NAD+) as co-substrate. Their regulatory involvement targeting histones, structural proteins and transcription factors implicate them in a broad range of biological processes and raised promising roles as therapeutic targets in apoptosis, oxidative stress and inflammation, among many others. These processes in turn, can be easily modeled in zebrafish (Danio rerio), a model organism with great developmental, genetic and economical advantages. Despite growing interest in this fresh water teleost as model organism and the regulatory and therapeutical potential of sirtuins in inflammation and associated processes, next to nothing is known about sirtuins in zebrafish. In order to contribute to this scenario and accelerate zebrafish potential as screening platform for sirtuins modulators, this work aimed to characterize sirtuins roles in a copper-induced inflammation model in zebrafish larvae. Alterations in locomotor behavior, sirtuin-related genes expression pattern and gene expression of inflammation, oxidative stress and apoptosis markers were observed after copper exposure. In order to further evaluate SIRT1 contribution to this scenario, a SIRT1 knockout line was developed using CRISPR-Cas9 technology, which showed an exarcebated inflammatory response after copper exposures. Additional studies will help to elucidate sirtuin roles in inflammation and associated processes, taking advantage of zebrafish?s translational potential. / Inicialmente identificadas em Saccharomyces cerevisie como reguladores de silenciamento de informa??o, as sirtu?nas (SIRTs) s?o uma diversa fam?lia de histonas desacilases da classe III (HDACs) que atuam como desacetilases, mono-ADP-ribosil transferases, desuccinilases e demalonilases; todas dependentes de nicotinamida adenina dinucleot?deo (NAD+). Presentes em todos os dom?nios de vida e tamb?m em v?rus, as sirtu?nas se tornaram promissores alvos terap?uticos devido seu envolvimento em diversos processos biol?gicos, incluindo apoptose, estresse oxidativo e inflama??o. Estes por sua vez s?o considerados denominadores comuns de diversas patologias e podem ser facilmente estudados utilizando os transl?cidos embri?es e larvas do zebrafish (Danio rerio) como organismo modelo. Apesar do crescente uso deste pequeno tele?steo de ?gua doce em diversas ?reas de estudo, e das sirtu?nas terem um promissor, mas pouco esclarecido, papel em eventos de inflama??o, apoptose e estresse oxidativo, pouco se sabe sobre as sirtu?nas no zebrafish - retardando seu uso como ferramenta de screening de drogas potencialmente moduladoras das SIRTs. Sob este cen?rio, o objetivo deste trabalho foi caracterizar o papel das sirtu?nas em modelo de inflama??o induzido por sulfato de cobre em larva de zebrafish. Altera??es em comportamento explorat?rio da larva, express?o de genes associados a sirtu?nas, bem como em marcadores de inflama??o, estresse oxidativo e apostose foram observados ap?s a exposi??o ao cobre. Para investigar o papel do mais conhecido e abrangente membro das sirtu?nas, desenvolvemos uma linhagem nocaute para SIRT1 utilizando a tecnologia CRISPR/Cas9, a qual apresentou reposta inflamat?ria exarcebada quando exposta ao cobre. Estudos adicionais neste modelo podem contribuir com descobertas sobre a biologia e modula??o das SIRTs ao usufruir do potencial translacional do zebrafish.

Submitted by Setor de Tratamento da Informa??o - BC/PUCRS (tede2@pucrs.br) on 2016-08-25T16:23:46Z No. of bitstreams: 1 DIS_LUIZA_REALI_NAZARIO_PARCIAL.pdf: 804114 bytes, checksum: d4d4d3525f9a5a4a62c1c8080197776f (MD5) / Made available in DSpace on 2016-08-25T16:23:46Z (GMT). No. of bitstreams: 1 DIS_LUIZA_REALI_NAZARIO_PARCIAL.pdf: 804114 bytes, checksum: d4d4d3525f9a5a4a62c1c8080197776f (MD5) Previous issue date: 2016-03-21 / 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 and treated animals. To keep the animals in ?PET/CT was performed anesthetic concentration curve (tricaine - 0.1, 0.12, 0.15 g/L) and standardized an apparatus to keep the fish in the presence of water, but yet still. A curve of time after injection of 18F-FDG was performed to obtain images in ?PET/CT (0, 10, 20 and 30 min) for standardizing the radiation quantitation in a gamma counter (15, 30, 60 90 and 120 min). Exposure to the LPS was able to increase the tnf-? expression in nearly all tissues studied (heart, kidney and intestine) and cox-2 in the kidney. The number of active peripheral blood white cells was also increased, confirming the induction of the inflammatory response. Hydrolysis of AMP in animals injected with LPS was increased in the heart in 24 hpi [72% compared to control] with no change in gene expression of ecto-5'-nucleotidase. The gene expression of ecto-5'-nucleotidase was adjusted temporarily in the kidney and intestine without altering the enzyme activity. After patterning images with ?PET/ CT and quantitation radiation by gamma counter for each organ examined, 30 minutes was defined as the best time for the biodistribution of 18F-FDG. After acquiring inflamed animal ?PET images it was not identified changes in the uptake of 18F-FDG compared to the control. Tissue quantification radiation registered a decrease in bone samples in animals treated with LPS, while other tissues have not changed. These data indicate that zebrafish responds to LPS by altering gene expression of specific markers, especially in kidney, and activation of white blood cells. The inflammation appears to be accompanied by a fine adjustment tissue-specific expression and activity of ecto-5'-nucleotidase in response to the inflammatory process. Although inflammation has been confirmed, the registration images by ?PET and radiation determination in different tissues have not been able to register differences in metabolic activity in animals treated with LPS. However, standardization of these techniques provides an advance in the use of radiopharmaceuticals in small animals, such as zebrafish. / O mecanismo de a??o do LPS ainda n?o ? completamente elucidado em vertebrados como os peixes, e se diferencia dos vertebrados superiores. Em zebrafish, o LPS ? capaz de aumentar o recrutamento de c?lulas imunes e a express?o de genes relacionados com a resposta imune. O sistema purin?rgico tem uma grande rela??o com a regula??o do sistema imune e as respostas inflamat?rias. O ATP ? um nucleot?deo importante na secre??o de citocinas e no recrutamento e diferencia??o de c?lulas imunes, podendo ser sequencialmente desfosforilado gerando adenosina. No contexto da inflama??o, a adenosina atua como uma mol?cula imunomodulat?ria inata. Participam do controle dos n?veis extracelulares da adenosina, os transportadores de nucleos?deos e a ecto-5?-nucleotidase. A ecto-5?-nucleotidase ? uma enzima com papel de marcapasso na produ??o de adenosina e constitui um dos focos do presente estudo. Considerando a contribui??o da abordagem de an?lise de imagens no contexto do estudo da inflama??o, ? sabido que a capta??o do radiof?rmaco 18F-FDG, um an?logo da glicoseest? aumentada em roedores submetidos ? inflama??o, o que gera uma imagem diferenciada. O micro Tom?grafo por Emiss?o de P?sitron/Tomografia Computadorizada (?PET/CT) ? utilizado para pesquisas em animais de pequeno porte e obt?m imagens utilizando um radiof?rmaco. O uso da ?PET/CT contribui com informa??es a n?vel molecular, funcional e estrutural em tempo real e permite acompanhar o efeito de f?rmacos em situa??es fisiol?gicas/patol?gicas na escala de um animal diminuto como o zebrafish. A tecnologia do ?PET/CT ? relativamente nova e at? o momento n?o existem estudos cient?ficos publicados aplicando radiof?rmacos em zebrafish. Neste contexto, o objetivo do projeto foi estudar o envolvimento da enzima ecto-5?-nucleotidase no desenvolvimento de inflama??o induzida por LPS utilizando-se de par?metros citol?gicos, bioqu?micos, moleculares e de imagem por ?PET em diferentes tecidos de zebrafish adulto (Danio rerio). Para induzir inflama??o no zebrafish, os animais foram injetados com uma solu??o de LPS (10 ?g/g de peso corporal; i.p) ap?s terem sido submetidos ? anestesia (trica?na 0.1 g/L). Os animais permaneceram por 2 h ou 24 h neste tratamento. Para confirma??o da inflama??o foram analisadas a express?o g?nica de marcadores espec?ficos (tnf-? e cox-2) em enc?falo, cora??o, rim e intestino e contagem diferencial de c?lulas do sistema imune. A atividade e express?o da enzima ecto-5?-nucleotidase foi analisada no enc?falo, cora??o, rim e intestino dos animais controle e tratados. Para manter os animais no ?PET/CT foi realizada uma curva de concentra??o de anest?sico MS-222 (0.1, 0. 12, 0.15 g/L) e determinado um aparato para manter o peixe na presen?a de ?gua mas, ainda im?vel. Uma curva de tempo ap?s a inje??o de 18F-FDG foi realizada para a obten??o de imagens em ?PET/CT (0, 10, 20 e 30 min) e para a padroniza??o da quantifica??o de radia??o em um Gamma counter (15, 30, 60, 90 e 120 min). A exposi??o ao LPS foi capaz de aumentar a express?o de tnf-? em quase todos os tecidos estudados (cora??o, rim e intestino) e de cox-2 no rim. O n?mero de c?lulas brancas ativas do sangue perif?rico tamb?m foi aumentado, confirmando a indu??o da resposta inflamat?ria. A hidr?lise de AMP em animais injetados com LPS foi aumentada no cora??o em 24 hpi [72% em rela??o ao controle] com nenhuma altera??o na express?o g?nica da ecto-5?-nucleotidase. A express?o g?nica do ecto-5?-nucleotidase foi ajustada temporalmente no rim e intestino sem altera??o da atividade enzim?tica. Ap?s a padroniza??o de imagens com ?PET/CT e da quantifica??o de radia??o por Gamma counter para cada ?rg?o analisado, definiu-se 30 min como o melhor tempo para a biodistribui??o do 18F-FDG. Ap?s a aquisi??o de imagens em ?PET de animais inflamados n?o se identificou altera??es na capta??o do 18F-FDG comparado com o controle. A quantifica??o tecidual de radia??o registrou uma queda nas amostras de ossos nos animais tratados com LPS, embora os demais tecidos n?o tenham sido alterados. Estes dados indicam que o zebrafish responde ao LPS alterando express?o g?nica de marcadores espec?ficos, especialmente no rim e ativando c?lulas brancas do sangue. A inflama??o induzida parece estar acompanhada por um t?nue ajuste tecido-espec?fico da atividade e express?o da ecto-5?-nucleotidase em resposta ao processo inflamat?rio. Ainda que a inflama??o tenha sido confirmada, o registro de imagens por ?PET e a determina??o de radia??o nos diferentes tecidos n?o foram capazes de registrar diferen?as na atividade metab?lica em animais tratados com LPS. Entretanto, a padroniza??o destas t?cnicas oferece um avan?o no uso de radiof?rmacos em animais de pequeno porte, como o zebrafish.

Made available in DSpace on 2015-04-14T14:51:26Z (GMT). No. of bitstreams: 1 449167.pdf: 7073688 bytes, checksum: 13ee832fb2876ff096e89bb359eef9f8 (MD5) Previous issue date: 2013-03-22 / 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 na reatividade/responsividade ao estresse na vida adulta. Diversos estudos v?m demonstrando altera??es neuroimunoend?crinas importantes na patofisiologia dos transtornos de humor. Estudos pr?vios do nosso grupo e outros t?m observado um perfil pr?‐inflamat?rio perif?rico e uma maior ativa??o linfocit?ria em pacientes com transtorno bipolar (TB). Os objetivos da tese s?o: 1) analisar os efeitos do estresse no desenvolvimento atrav?s do protocolo de separa??o materna em modelo animal; 2) analisar par?metros neuroimunoend?crinos em resposta ao estresse em pacientes com TB tipo 1 eut?micos, utilizando‐se um protocolo de estresse laboratorial, o Trier Social Stress Test (TSST). Dados do presente trabalho demonstram que a exposi??o ao estresse na inf?ncia (em modelo animal) resulta em ativa??o imune, caracterizada por aumento nos n?veis plasm?ticos de citocinas pr?‐inflamat?rias (interleucina 1‐β) perifericamente. Uma poss?vel consequ?ncia dessa ativa??o imune ? a perda de neur?nios contendo parvalbumina, importantes para o desenvolvimento de comunica??o serotonin?rgica. A inflama??o perif?rica serviu como marcador para os danos neuronais observados, pois quando houve a administra??o de interleucina‐10 (IL‐10, principal citocina anti‐inflamat?ria) foi poss?vel reverter os danos neuronais e a inflama??o perif?rica. Neste trabalho, os pacientes com TB apresentaram respostas simp?ticas e neuroend?crinas (cortisol) muito reduzidas ap?s o estresse agudo quando comparados aos controles saud?veis. Ao n?vel basal, os pacientes com TB apresentaram uma redu??o na porcentagem de c?lulas T regulat?rias (Treg), aumento na porcentagem das c?lulas T ativadas (CD4+CD25+) e aumento na sinaliza??o celular atrav?s de uma maior fosforila??o de ERK1/2 e NF‐κB corroborando para um estado de ativa??o celular. Al?m disso, observamos uma incapacidade em reduzir a ativa??o imune em resposta ao estresse, caracterizada pelo aumento ainda maior na porcentagem de c?lulas T ativadas e concomitante redu??o nas c?lulas Treg em pacientes TB. Tal incapacidade em controlar a resposta imune ao estresse pode ser explicada n?o apenas pelos baixos n?veis de cortisol secretado, mas tamb?m a uma maior insensibilidade aos glicocorticoides no TB. Conclu?mos que os indiv?duos com TB possuem altera??es no eixo HPA que resultam em reduzida reatividade end?crina ao estresse assim como incapacidade de modular corretamente as respostas imunes.

Made available in DSpace on 2014-12-17T14:03:31Z (GMT). No. of bitstreams: 1 AdrianeTML.pdf: 2113007 bytes, checksum: bca6e876ace0dbfe30a0861199114512 (MD5) Previous issue date: 2009-12-17 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / Polymers of mushroom cellular wall are recognized for presenting a lot of biological activities such as anti-inflammatory, antioxidant and anti-tumoral action. Polysaccharides from mushrooms of different molecular mass obtained mushrooms can activate leucocytes, stimulate fagocitic, citotoxic and antimicrobial activity including oxygen reactive species production. In this study were investigated chemical characteristics, in vitro antioxidant activity and anti-inflammatory action in an acute inflammation model of the polysaccharides extracted from Tylopilus ballouii. Results showed that were mainly extracted polysaccharides and that it primarily consisted of mannose and galactose with variable amounts of xylose and fucose. Infrared analysis showed a possible interation between this polysaccharides and proteins. In addition, molecular mass was about 140KDa. Antioxidant activity was tested by superoxide and hydroxyl radical scavenging assay, total antioxidant activity and lipid peroxidation assay. For superoxide and hydroxyl radical generation inhibition, polysaccharides have an IC50 of 2.36 and 0.36 mg/mL, respectively. Lipid peroxidation assay results showed that polysaccharides from Tylopilus ballouii present an IC50 of 3.42 mg/mL. Futhermore, anti-inflammatory assay showed that polysaccharides cause an paw edema decreasing in 32.8, 42 and 56% in 30, 50 and 70 mg/Kg dose, respectively. Thus, these results can indicate a possible use for these polysaccharides from Tylopilus ballouii as an anti-inflammatory and antioxidant. / Pol?meros da parede celular de fungos s?o conhecidos por possu?rem muitas atividades biol?gicas como suas a??es antiinflamat?rias, antioxidante e antitumoral. Polissacar?deos de diferentes pesos moleculares obtidos de cogumelos podem ativar os leuc?citos, estimular a atividade fagoc?tica, citot?xica e antimicrobiana, incluindo a produ??o de esp?cies reativas de oxig?nio. No presente estudo, foi investigada a caracter?stica qu?mica dos polissacar?deos extra?dos de Tylopilus ballouii sua atividade antioxidante in vitro e a sua atividade antiinflamat?ria no modelo de inflama??o aguda. Os resultados mostraram que foram extra?dos predominantemente polissacar?deos e esses consistiram primariamente de manose e galactose e possui quantidades vari?veis de xilose e fucose. As an?lises de infravermelho mostraram a poss?vel intera??o entre estes polissacar?deos e prote?nas. Al?m disso, seu peso molecular ? de cerca de 140 kDa. A atividade antioxidante foi testada com rela??o ao seq?estro sobre os radicais super?xido e hidroxila, atividade antioxidante total e peroxida??o lip?dica. Com rela??o ? inibi??o da forma??o dos radicais super?xido e hidroxila, os polissacar?deos atingiram um IC50 de 1,64 e 1,25 mg/ml, respectivamente. Os resultados do ensaio de peroxida??o lip?dica mostraram que os polissacar?deos de Tylopilus ballouii apresentam um IC50 de 1,65 mg/ml. Al?m disso, a atividade antiinflamat?ria mostrou que eles agem reduzindo o edema em 32,8, 42 e 56% nas doses de 30, 50 e 70 mg/kg, respectivamente. Assim, estes resultados podem indicar o poss?vel uso dos polissacar?deos de Tylopilus ballouii como antiinflamat?rio e antioxidante.

Made available in DSpace on 2014-12-17T14:03:34Z (GMT). No. of bitstreams: 1 CelinaMPGD.pdf: 1314503 bytes, checksum: 36d544c2b00794858e90a0efed0d11ea (MD5) Previous issue date: 2006-05-04 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Fungal polysaccharides have received a great deal of attention due to itsbecause of their potential use in a wide rangegreat variety fromof industries. Some studies have demonstrated that polysaccharides extracted offrom basidiomycetes they have presented significant properties as anti-inflammatory, antimicrobial, antioxidant and anti-tumoral properties. In spite of thisDespite these potential properties, these mushrooms have not been insufficiently investigated, and the great number of antibiotics number produced forby these organisms suggests that they canmay be a new source of bioactives composites source. In tThe present work, reports onlated the chemical composition, potential antioxidant, antiinflammatory and citotoxycity of extracted polymers extracted offrom the fruits bodies of the fungiius Geastrum saccatum and Polyporus dermoporus, native mushrooms of the Atlantic forest inof the state of the Rio Grande do Norte, Brazil. The Cchemical analyses had revealed ademonstrated text of total sugar rates of 65% and 49%, and proteins of 7.0% for in extracts of G. saccatum and P. dermoporus extracts, respectively. The analyses ofNMR spectroscopy of RMN had demonstrated that these extracts are composites forof a complex involving β- glucans and- proteins complex. The inhibition of the formation of superoxide radicals formation was of 88.4% in G. saccatum and 83.3% in P. dermoporus, and 75 and 100% for inhibition of hydroxyls radicals inhibition. TopicalThe topic application of extracts the 10, 30 and 50 mg/kg extract in BALBc mice with cutaneous inflammation induced byfor croton oil demonstrated to inhibitedion of ear edema of ear and cells polimorfonuclears cells atin the inflamed siteplace, being this reply more effective in lower concentrations being more effective. The evaluation of the glucans of G. saccatum and P. dermoporus glucans under induced pleurisy for carrageenan-induced pleurisya of showed the antiinflammatory action of these composites., being analyzed tThe frame number in the pleural exudates and thedosage of nitric oxide dosage was also analyzed. The cytotoxic action of these polymers was analyzed throughthrough the mitochondrial function (MTT). The incubation of the glucans with mononuclear cells of the peripheral blood demonstrated that the extracted glucans extracted fromof G. saccatum havepossess a moderate cytotoxic action. These results suggest that these mushrooms possess polymers formed byfor a complex glucana-protein complex, with antiinflammatory and antioxidant actions / Polissacar?deos de fungos t?m recebido grande aten??o devido ao seu uso potencial numa grande variedade de ind?strias. V?rios estudos t?m demonstrado que polissacar?deos extra?dos de basidiomicetos t?m apresentado propriedades significantes como anti-inflamat?rio, antimicrobial , antioxidante e anti-tumoral. Apesar dessas propriedades potenciais, esses cogumelos t?m sido insuficientemente investigados, e o grande n?mero de antibi?ticos produzidos por esses organismos sugere que eles podem ser uma fonte de novos compostos bioativos. No presente trabalho, relatamos a composi??o qu?mica, potencial antioxidante, antiinflamat?rio e citotoxico de pol?meros extra?dos dos corpos de frutifica??o dos fungos Geastrum saccatum e Polyporus dermoporus, cogumelos nativos da mata atl?ntica do estado do Rio Grande do Norte. As an?lises qu?micas demonstraram teor de a??cares totais de 65% e 49%, prote?nas a 7,0% nos extratos de G. saccatum e P. dermoporus, respectivamente. As an?lises de espectroscopia de RMN demonstraram que esses extratos s?o compostos por um complexo envolvendo b - glucanas e por??es prot?icas. A inibi??o da forma??o de radicais super?xido foi de 88,4% G. saccatum e 83,3% em P. dermoporus, e 75 e 100% para inibi??o de radicais hidroxilas. A aplica??o dos extratos a 10, 30 e 50 mg/kg em camundongos BALBc com inflama??o cut?nea induzida por ?leo de cr?ton demonstrou inibi??o de edema de orelha e de c?lulas polimorfonucleares no local inflamado, sendo esta resposta mais efetiva em concentra??es mais baixas. A avalia??o das glucanas de G. saccatum e P. dermoporus sob pleurisia induzida por carragenana de montrou a??o antiinflamat?ria desses compostos, sendo analisado o n?mero de c?lulas no exudato pleural e dosagem de ?xido n?trico. A a??o citot?xica desses pol?meros foi analisada atrav?s da fun??o mitocondrial (MTT). A incuba??o das glucanas com c?lulas mononucleares do sangue perif?rico demonstrou que as glucanas extra?das de G. saccatum possuem um a??o citot?xica moderada. Estes resultados sugerem que esses cogumelos possuem pol?meros formados por um complexo glucana-prote?na, ativos como antiinflamat?rio e antioxidante

Made available in DSpace on 2014-12-17T14:03:38Z (GMT). No. of bitstreams: 1 DayseSA_DISSERT.pdf: 846190 bytes, checksum: eef38ab14de25ca6c9fac44eeac25ae1 (MD5) Previous issue date: 2011-08-05 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / In the last years, heparin has become target of many studies related to inflammation due its ability of biding to proteins involved on immune response. Recently, it was demonstrated, at our laboratory, using a thIoglycollate-induced peritonitis model, heparin s capacity of reduce cellular influx into the peritoneal cavity, 3 hours after the inflammatory stimulus. Once neutrophilic infiltration is highest around 8 hours after the inflammatory stimulus, at the present work, using the same peritonitis model, it was assessed heparin s ability of keeping the interference on leukocyte infiltration, 8 hours after inflammation induction. Moreover, using cellular differential count, it was evaluated how the cellular populations involved in the inflammatory process would be affected by the treatment. Eight hours after the inflammatory stimulus, only heparin dosage of 1 &#956;g/Kg was able to reduce the cellular influx to peritoneum, 62.8% of reduction when compared to positive control (p < 0.001). Furthermore, heparin dosage of 15 &#956;g/Kg presented a pro-inflammatory effect in whole blood verified by the increase of 60.9% (p < 0.001) and 117.8% (p < 0.001) on neutrophils and monocytes proportion, respectively, when compared to positive control. In addition, this dosage also presented a neutrophilic proportion on peritoneal fluid 27.3% higher than positive control (p < 0.05). This duality between anti- and pro-inflammatory effects at different times corroborates studies that attribute a pleiotropic immunomodulator role to heparin. / Nos ?ltimos anos, a heparina vem sendo alvo de v?rios estudos relacionados ? inflama??o, devido sua capacidade de se ligar a diversas prote?nas envolvidas com a resposta imune. Recentemente, em nosso laborat?rio, foi demonstrada, em modelo de peritonite induzida por tioglicolato, a capacidade da heparina em reduzir o influxo celular ? cavidade peritoneal, 3 horas ap?s o est?mulo inflamat?rio. No presente trabalho, utilizando o mesmo modelo, foi avaliada a capacidade da heparina em interferir na infiltra??o leucocit?ria ap?s 8 horas da indu??o da inflama??o, momento em que a infiltra??o neutrof?lica ? m?xima. Utilizando contagem diferencial celular, avaliou-se a influ?ncia da heparina sobre as popula??es celulares envolvidas na inflama??o. Oito horas ap?s o est?mulo inflamat?rio, apenas a dosagem de heparina de 1 &#956;g/Kg, manteve a capacidade de interferir na migra??o leucocit?ria, apresentando 62,8% de diminui??o (p < 0,001) no influxo celular, quando comparada ao controle positivo. Enquanto para a dosagem de heparina de 15 &#956;g/Kg foi observado efeito pr?-inflamat?rio no sangue total verificado pelos aumentos de 60,9% (p < 0,001) e 117,8% (p < 0,001) na propor??o de neutr?filos e mon?citos, respectivamente, em compara??o ao controle positivo. Al?m disso, essa dosagem tamb?m apresentou propor??o neutrof?lica no l?quido peritoneal 27,3% maior que o controle positivo (p < 0,05). Essa dualidade entre efeitos anti- e pr?-inflamat?rio nos diferentes tempos e doses analisados corroboram dados da literatura que atribuem ? heparina um papel como imunomodulador pleiotr?pico.

Made available in DSpace on 2014-12-17T14:03:43Z (GMT). No. of bitstreams: 1 FernandoRFS2.pdf: 536272 bytes, checksum: 3a3c1cb63097447c30d5446bdc4b166a (MD5) Previous issue date: 2005-07-19 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / The Iota, Kappa and Lambda commercial carrageenans are rarely pure and normally contain varying amounts of the other types of carrageenans. The exact amount of impurity depends on the seaweed source and extraction procedure. Then, different analysis methods have been applied for determination of the main constituents of carrageenans because these three carrageenans are extensively used in food, cosmetic and pharmaceutical industry. The electrophoresis of these compounds proved that the carrageenans are constituted by sulfated polysaccharides. These compounds were characterized by colorimetric methods and was observed that the Lambda carrageenan shown the greater value (33.38%) of sulfate. These polymers were examined by means of 13C NMR spectroscopy and infrared spectra. The polysaccharides consisted mainly of units alternating of sulfated galactoses and anhydrogalactoses. The aim of the study was also to test the inflammatory action of these different polysaccharides. A suitable model of inflammation is acute sterile inflammation of the rat hind limb induced by carrageenan. Paw edema was induced by injecting carrageenans (&#x3ba;, &#953; and &#955;) in saline into the hind paw of a male Wistar rats (175&#8211;200 g). The pathway to acute inflammation by carrageenan (kappa, iota and lambda) were expressed as time-edema dependence and measured by paw edema volume. For this purpose, was used an apparatus (pakymeter), which makes it possible to measure the inflammation (swelling of the rat foot) with sufficient accuracy. The results showed that &#954;-carrageenan (1%) have an edema of 3.7 mm and the paw edema increase was time and dose dependent; the &#953;-carrageenan (0.2%) caused an edema of 4 mm and the &#955;-carrageenan (1%) caused an edema of 3.6 mm. Other model was used in this study based in the inflammation of pleura for comparatives studies. Injection of carrageenans into the pleural cavity of rat induced an acute inflammatory response characterized by fluid accumulation in the pleural cavity, a large number of neutrophils and raised NO production. The levels of NO were measured by Griess reactive. The &#953;-carrageenan caused the greater inflammation, because it has high concentration of nitrite/nitrate (63.478 nmoles/rat), exudato volume (1.52 ml) and PMNs (4902 x 103 cells). Quantitative evaluation of inflammations of rats is a useful and important parameter for the evaluation of the efficacy of anti-inflammatory drugs / As carragenanas comerciais Iota, Kappa e Lambda s?o raramente puras e, normalmente, apresentam v?rios outros tipos de pol?meros. A quantidade exata de impurezas depende do m?todo de extra??o e da alga utilizada. Logo, diferentes m?todos t?m sido utilizados para a determina??o do conte?do das carragenanas, tento em vista que elas s?o extensivamente usadas nas ind?strias aliment?cia, de cosm?ticos e farmac?utica. A eletroforese desses compostos provou que eles s?o constitu?dos de polissacar?deos sulfatados. Estes compostos foram caracterizados por m?todos colorim?tricos e foi observado que a carragenana Lambda possui o maior teor de sulfato (33,38%). Esses pol?meros foram analisados por espectroscopias de IV e 13C RNM. Estes polissacar?deos consistem principalmente de unidades alternadas de galactose e anidrogalactose sulfatadas. Foi poss?vel avaliar a a??o inflamat?ria desses diferentes compostos atrav?s de um modelo cl?ssico de inflama??o, que ? o de inflama??o aguda, na pata de ratos, induzida por carragenanas. O edema plantar foi induzido pela inje??o das carragenanas (&#x3ba;, &#953; e &#955;) na pata direita de ratos machos da ra?a Wistar (175-200g). A inflama??o aguda induzida por carragenanas foi expressa pela rela??o tempo-edema e medida pelo volume do edema plantar. Para isto, foi utilizado um paqu?metro, que confere mais precis?o a mensura??o da inflama??o (incha?o na pata do rato). Os resultados mostraram que a carragenana Kappa (1%) induz um edema de 3,7mm e o aumento de volume do edema ? tempo e dose-dependente; a Iota (0,2%) provoca um edema de 4mm; e a Lambda (1%) um edema de 3,6mm. O outro modelo usado neste estudo comparativo ? baseado na inflama??o da pleura (pleurisia). A inje??o de carragenanas na cavidade pleural dos ratos induz uma resposta inflamat?ria aguda caracterizada pelo acumulo de l?quido na cavidade pleural, um grande n?mero de neutr?filos e aumento na produ??o de NO. A carragenana Iota provocou a inflama??o intensa, o que pode ser comprovado pela verifica??o do volume do exudato (1,52 ml), o teor de nitrato/nitrito (63,478 nmol/rato) e a contagem de leuc?citos polimorfonucleares - PMN (4902 x 103 c?lulas). A avalia??o quantitativa da inflama??o em ratos ? um par?metro importante para a avalia??o da efic?cia de drogas antiinflamat?rias

Made available in DSpace on 2014-12-17T14:10:28Z (GMT). No. of bitstreams: 1 HylarinaMDS_DISSERT.pdf: 1971584 bytes, checksum: 9428714bda1598d765036d4f0b211af1 (MD5) Previous issue date: 2013-03-15 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / Ulcerative colitis comprising an inflammatory bowel disease, whose most severe consequence is the development of intestinal neoplasia. The drugs currently used to treat the disease trigger a variety of serious adverse effects and are not effective in many cases. Recent studies demonstrated the effectiveness of natural products for the treatment of inflammatory processes. Seaweed extracts and their purified products have shown protective effects in models of inflammation and the association of traditional therapies with probiotics has significantly improved the clinical symptoms of ulcerative colitis. Therefore, the aims of this study include evaluating the potential effects of the use of probiotic strain Enterococcus faecium 32 (Ef32), the methanolic extract of the green seaweed Caulerpa mexicana (M.E.) and their concomitant administration in a murine model of colitis induced by dextran sodium sulfate (DSS). Accordingly, C57BL /6 mice were pretreated orally with Ef32 (109 CFU/ml) for seven days. In the seven days following, the colitis was induced by administration of 3% DSS (w/v) diluted in the animals drinking water. During this period, animals were treated daily with Ef32 and the M.E. (2.0 mg/kg) every other day by intravenous route. The development of colitis was monitored by the disease activity index (DAI), which takes into account the loss of body weight, consistency and presence of blood in stools. After euthanasia, the colon was removed, its length measured and tissue samples were destined for histological analysis and culture for cytokine quantification. The levels of cytokines in the culture supernatant of the colon were measured by ELISA. The treatments with the probiotic Ef32 or the M.E. alone or the combination of these two substances provoked significant improvement as to weight loss and DAI, and prevented the shortening of the colon in response to DSS. The isolated treatments triggered a slight improvement in intestinal mucosal tissue damage. However, their combination was able to completely repair the injury triggered by DSS. The association was also able to reduce the levels of all the cytokines analyzed (IFN-&#947;, IL-4, IL-6, IL-12, IL-17A and TNF-&#945;). On the other hand, the treatment with Ef32 did not interfere with the levels of TNF-&#945;, whereas treatment with M.E. did not alter the levels of IL-6. Moreover, the treatment with Ef32 not interferes in TNF-&#945; levels, whereas treatment with M.E. did not alter the levels of IL-6. Therefore, the potential probiotic Ef32 and M.E. and especially when these samples were associated proved promising alternatives in the treatment of ulcerative colitis as demonstrated in an experimental model because of its beneficial effects on morphological and clinical parameters, and by reducing the production of proinflammatory cytokines of Th1, Th2 and Th17 / A colite ulcerativa compreende uma doen?a inflamat?ria intestinal, cuja consequ?ncia mais severa ? o desenvolvimento de neoplasia intestinal. Os medicamentos atualmente utilizados para o tratamento da doen?a desencadeiam uma variedade de efeitos adversos s?rios e n?o s?o eficazes em muitos casos. Estudos recentes apontaram para a efic?cia de produtos naturais no tratamento de processos inflamat?rios. Extratos de algas marinhas e seus produtos purificados t?m mostrado efeito protetor em modelos de inflama??o e a associa??o de terapias tradicionais com probi?ticos tem melhorado significativamente o quadro cl?nico da colite ulcerativa. Sendo assim, os objetivos do presente estudo inclu?ram avaliar os efeitos do uso da potencial cepa probi?tica Enterococcus faecium 32 (Ef32), do extrato metan?lico da alga marinha verde Caulerpa mexicana (E.M.) e da administra??o conjunta no modelo murino de colite induzida por dextrana sulfato de s?dio (DSS). Nesse sentido, camundongos C57BL/6 machos foram pr?-tratados oralmente com Ef32 (109 UFC/ml) durante sete dias. Nos sete dias seguintes, a colite experimental foi induzida atrav?s da administra??o DSS 3% (p/v) dilu?da na ?gua de beber dos animais. Neste per?odo, os animais foram tratados com Ef32 diariamente e com o E.M. (2,0 mg/kg) em dias alternados pela rota intravenosa. O desenvolvimento de colite foi monitorado atrav?s do ?ndice de atividade da doen?a (IAD), que leva em considera??o a perda de peso corporal, consist?ncia e presen?a de sangue nas fezes. Ap?s eutan?sia dos animais, o c?lon foi removido e mensurado e amostras do tecido foram destinadas ? an?lise histol?gica e cultura para dosagem de citocinas. Os n?veis de citocinas no sobrenadante da cultura do c?lon foram mensurados por ELISA. Os tratamentos com o probi?tico Ef32 ou com o E.M. sozinhos ou com a associa??o dessas duas subst?ncias desencadearam significativa melhora quanto ? perda de peso corporal e IAD, e preveniram o encurtamento do c?lon em resposta ? DSS. Os tratamentos isolados desencadearam uma melhora discreta no dano tecidual da mucosa intestinal. No entanto, a combina??o deles foi capaz de reparar completamente a inj?ria desencadeada pelo DSS. A associa??o foi ainda capaz de reduzir os n?veis de todas as citocinas analisadas (IFN-&#947;, IL-4, IL-6, IL-12, IL-17A e TNF-&#945;). Por outro lado, o tratamento com Ef32 n?o interferiu nos n?veis de TNF-&#945;, enquanto que o tratamento com o E.M n?o alterou os n?veis de IL-6. Portanto, o potencial probi?tico Ef32 e o E.M. e especialmente quando essas subst?ncias foram associadas, mostraram-se alternativas promissoras no tratamento da colite ulcerativa, como demonstrado no modelo experimental em raz?o dos seus efeitos ben?ficos sobre par?metros cl?nicos e morfol?gicos, bem como pela redu??o da produ??o de citocinas pr?-inflamat?rias das respostas Th1, Th2 e Th17

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-02-23T00:15:56Z No. of bitstreams: 1 HugoDeAlmeidaVarela_DISSERT.pdf: 3160219 bytes, checksum: 5e75a6e4f85482a68335030d7da0f1e7 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-02-26T23:37:36Z (GMT) No. of bitstreams: 1 HugoDeAlmeidaVarela_DISSERT.pdf: 3160219 bytes, checksum: 5e75a6e4f85482a68335030d7da0f1e7 (MD5) / Made available in DSpace on 2016-02-26T23:37:36Z (GMT). No. of bitstreams: 1 HugoDeAlmeidaVarela_DISSERT.pdf: 3160219 bytes, checksum: 5e75a6e4f85482a68335030d7da0f1e7 (MD5) Previous issue date: 2015-03-19 / As doen?as periodontais possuem alta preval?ncia na popula??o mundial e manifestam-se, principalmente, em duas entidades distintas, a saber: a gengivite induzida pela placa bacteriana e a periodontite. A periodontite ? uma doen?a inflamat?ria cr?nica caracterizada pela destrui??o em v?rios n?veis do osso alveolar, fibras col?genas e do cemento, ? considerada importante causa de perda dent?ria em adultos. Estudos experimentais recentes demonstram o efeito anti-inflamat?rio e antirreabsortivo dos f?rmacos anti-hipertensivos da classe dos bloqueadores dos receptores de angiotensina II sobre a doen?a periodontal. O objetivo desse estudo foi avaliar os efeitos da azilsartana (AZT) um potente inibidor dos receptores de angiotensina II que apresenta efeitos adversos m?nimos, sobre a perda ?ssea alveolar, inflama??o, express?o das metaloproteinases da matriz (MMP), ligante do receptor do fator nuclear kapa B (RANKL), receptor ativador do fator nuclear kapa B (RANK), osteoprotegerina (OPG), ciclooxigenase-2 (COX-2), Interleucina 10, Interleucina 1?, TNF-?, glutationa (GSH) e catepsina K no modelo de doen?a periodontal induzida por ligadura em ratos. Foram utilizados 100 ratos wistar sendo divididos randomicamente em 5 grupos com 20 ratos cada: (1) n?o foi induzida a doen?a periodontal, ?gua destilada, (2) indu??o da doen?a periodontal, ?gua destilada; (3) indu??o da doen?a periodontal, AZT 1 mg/kg; (4) indu??o da doen?a periodontal, AZT 5 mg/kg; e (5) indu??o da doen?a periodontal, AZT 10 mg/kg. Todos os grupos foram tratados com ?gua destilada ou AZT por 10 dias. Os tecidos periodontais foram submetidos ?s an?lises morfom?trica, histopatol?gica e imunohistoqu?mica para detec??o de MMP-2, MMP-9, RANKL, RANK, OPG e catepsina K. N?veis de IL-1?, IL-10, TNF-? foram determinados por ELISA e n?veis de mieloperoxidase(MPO) e glutationa(GSH) por espectrofotoscopia de UV vis?vel. O tratamento com AZT 5 mg/kg reduziu o MPO (p <0.05) e IL-1? (p <0.05), elevou os n?veis de IL-10 (p <0.05), reduziu a express?o de MMP-2, MMP-9, RANK, RANKL, catepsina K, e elevou a express?o de OPG. Os achados revelam que a AZT na dosagem 5mg/kg apresenta a??o anti-inflamat?ria na doen?a periodontal induzida por ligadura reduzindo a perda ?ssea alveolar, diminuindo os n?veis de citocinas pr?-inflamat?rias e elevando a express?o de agentes anti-inflamat?rios. / Periodontal diseases, highly prevalent disease in worldwide population, manifest primarily in two distinct entities: plaque-induced gingivitis and periodontitis. Periodontitis is a chronic inflammatory disease characterized of different levels of collagen, cementum, and alveolar bone destruction. Recent experimental studies demonstrated anti-inflammatory and antirreabsortive effect of antihypertensive agents of the angiotensin II receptor blockers class on periodontal disease. The aim of this study was to evaluate the effects of azilsartan (AZT), a potent inhibitor of the angiotensin II receptor which has minimal adverse effects on bone loss, inflammation, and the expression of matrix metallo proteinases (MMPs), receptor activator of nuclear factor kB ligand (RANKL), receptor activator of nuclear factor kB (RANK), osteoprotegerin (OPG), cyclooxygenase-2 (COX-2), and cathepsin K in periodontal tissue in a rat model of ligature-induced periodontitis. Male Wistar albino rats were randomly divided into 5 groups of 20 rats each: (1) nonligated, water; (2) ligated, water; (3) ligated, 1 mg/kg AZT; (4) ligated, 5 mg/kg AZT; and (5) ligated, 10 mg/kg AZT. All groups were treated with water or AZT for 10 days. Periodontal tissues were analyzed by morphometric exam, histopathology and immunohistochemical detection of MMP-2, MMP-9, COX-2, RANKL, RANK, OPG, and cathepsin K. Levels of IL-1b, IL-10, TNF-a, myeloperoxidase (MPO), and glutathione (GSH) were determined by ELISA. Treatment with 5 mg/kg AZT resulted in reduced MPO (p?0.05) and IL-1b (p?0.05) levels and increased in Il-10 levels (p?0.05). It was observed a reduced expression of MMP-2, MMP-9, COX-2, RANK, RANKL, cathepsin K, and a increased expression of OPG in the animals subjected to experimental periodontitis and threated with AZT (5 mg/kg). Conclusions: These findings suggest an anti-inflammatory and anti-reabsortive effects of AZT on ligature-induced periodontitis in rats.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-03-29T00:30:04Z No. of bitstreams: 1 MariaPatriciaOliveiraDaSilvaReinaldo_DISSERT.pdf: 1968663 bytes, checksum: 9310ea8c13185d093751709ea668017c (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-03-29T19:38:59Z (GMT) No. of bitstreams: 1 MariaPatriciaOliveiraDaSilvaReinaldo_DISSERT.pdf: 1968663 bytes, checksum: 9310ea8c13185d093751709ea668017c (MD5) / Made available in DSpace on 2016-03-29T19:38:59Z (GMT). No. of bitstreams: 1 MariaPatriciaOliveiraDaSilvaReinaldo_DISSERT.pdf: 1968663 bytes, checksum: 9310ea8c13185d093751709ea668017c (MD5) Previous issue date: 2015-03-19 / A mucosite intestinal ? a inflama??o e/ou ulcera??o da mucosa do trato gastrointestinal causada pelas terapias antic?ncer. Apresenta histologicamente, atrofia das vilosidades, danos nos enter?citos e infiltra??o de c?lulas inflamat?rias. O metotrexato ? um composto que inibe a dihidrofolato redutase, enzima importante na s?ntese de DNA. ? amplamente utilizado no tratamento de leucemia e outras malignidades. O objetivo deste estudo foi avaliar o efeito da Olmesartana (OLM), um antagonista do receptor da angiotensina II, em um modelo de mucosite intestinal (MMI) induzida por MTX em ratos Wistar. MMI foi induzido atrav?s de inje??o intraperitoneal (i.p.) de MTX (7 mg/kg) durante tr?s dias consecutivos. Os animais foram pr?-tratados com OLM oral a 0.5 mg/kg, 1 mg/kg e 5 mg/kg e com solu??o salina, 30 minutos antes da exposi??o ao MTX durante tr?s dias. Fragmentos de intestino delgado (duodeno, jejuno e ?leo) foram homogeneizados para ensaio de pesquisa das citocinas L-1?, IL-10 e TNF-?, atividade do Malonalde?do (MDA) e da Mieloperoxidase (MPO). Al?m disso, an?lises de imunohistoqu?mica da MMP-2, MMP-9, COX-2, RANK / RANKL e SOCS-1 al?m da an?lise da co-localiza??o da express?o de SOCS-1 pela microscopia confocal foram realizadas. O tratamento com MTX+OLM 5 mg/kg resultou numa redu??o da infiltra??o inflamat?ria da mucosa, ulcera??es, vasodilata??o e ?reas hemorr?gicas (p<0,05), bem como as concentra??es reduzidas de MPO (p<0,001) e as citocinas pr?- inflamat?rias IL-1? e TNF-? (p <0,01). Al?m disso, o tratamento combinado reduziu a express?o de MMP-2, MMP-9, COX-2, RANK e RANKL (p<0,05) e aumentou a express?o citoplasm?tica de SOCS-1 (p<0,05). Nossos achados confirmam o envolvimento de OLM na redu??o da resposta inflamat?ria atrav?s do aumento da sinaliza??o imunossupressora em MMI. Sugerimos tamb?m que o efeito ben?fico do tratamento com a Olmesartana ? especificamente exercida durante o dano atrav?s do bloqueio de citocinas inflamat?rias. / Intestinal Mucositis is inflammation and/or ulceration of mucosa of the gastrointestinal tract caused by anticancer therapies. Histologically, villous atrophy, damage to enterocytes and infiltration of inflammatory cells. Methotrexate (MTX) is a compound that depletes dihydrofolate pools and is widely used in the treatment of leukemia and other malignancies. The aim of this study was to evaluate the effect of Olmesartan (OLM), an angiotensin II receptor antagonist, on an Intestinal Mucositis Model (IMM) induced by MTX in Wistar rats. IMM was induced via intraperitoneal (i.p.) administration of MTX (7 mg/kg) for three consecutive days. The animals were pretreated with oral OLM at 0.5, 1 or 5 mg/kg or with vehicle 30 min prior to exposure to MTX, for three days. Small intestinal (duodenum, jejunum and ileum) homogenates were assayed for levels of the IL-1?, IL-10 and TNF-? cytokines, malondialdehyde and myeloperoxidase activity. Additionally, immunohistochemical analyses of MMP-2, MMP-9, COX-2, RANK/RANKL and SOCS-1 and confocal microscopy analysis of SOCS-1 expression were performed. Treatment with MTX+OLM (5 mg/kg) resulted in a reduction of mucosal inflammatory infiltration, ulcerations, vasodilatation and hemorrhagic areas (p<0.05) as well as reduced concentrations of MPO (p<0.001) and the pro-inflammatory cytokines IL-1? and TNF-? (p<0.01), and increase antiinflammatory cytosine IL-10 (p,0.05). Additionally, the combined treatment reduced expression of MMP-2, MMP-9, COX-2, RANK and RANKL (p<0.05) and increased cytoplasmic expression of SOCS-1 (p<0.05). Our findings confirm the involvement of OLM in reducing the inflammatory response through increased immunosuppressive signaling in an IMM. We also suggest that the beneficial effect of Olmesartan treatment is specifically exerted during the damage through blocking inflammatory cytosines.