No description available.

Orientador: Silvio Luis de Oliveira / Banca: Marcelo De Franco / Banca: Angela Maria Victoriano de Campos Soares / Resumo: Camundongos selecionados para a máxima (AIRmax) ou mínima (AIRmin) reação inflamatória aguda apresentam desvio de freqüência do gene Slc11a1. Este gene está envolvido no transporte de íons divalentes no compartimento endossomal/lisossomal de macrófagos e neutrófilos, interferindo na sua ativação e suscetibilidade a infecções. Neste estudo, nós investigamos a interação dos alelos Slc11a1 R (Slc11a1rGly169) e S (expressão nula da proteína Slc11a1, Slc11a1sAsp169) com os loci de características quantitativas (QTL) moduladores da inflamação, durante a paracoccidioidomicose (PCM) em linhagens AIRmaxRR, AIRmaxSS, AIRminRR and AIRminSS homozigotas para o gene Slc11a1, produzidas por acasalamentos assistidos por genotipagem. Nós verificamos que o alelo R em homozigose foi responsável por um maior influxo neutrofílico em camundongos com background AIRmax. Observamos ainda, que as linhagens AIRmaxRR e AIRmaxSS foram mais resistentes enquanto a linhagem AIRmin portadora do alelo R foi implicada em uma maior recuperação de UFC de P. brasiliensis. Desta forma, apesar de não observarmos diferença na recuperação de UFC entre as sublinhagens AIRmax, um aumento no influxo de neutrófilos para o pulmão dos animais AIRmaxRR pode ter compensado a influência do alelo Slc11a1 R na multiplicação do fungo. Nós também mostramos que o número de UFC nos pulmões foi relacionado a síntese de IL-4 e IL-10 neste órgão, mas a produção de óxido nítrico foi semelhante em ambas as linhagens mostrando que este metabólito não foi o fator determinante de resistência/suscetibilidade nas linhagens analisadas. Quanto a análise de diferentes citocinas em sobrenadante de cultura de células do baço e no pulmão das linhagens utilizadas, mostramos que o gene modula a síntese de várias citocinas, porém... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Mice selected for the maximum (AIRmax) or minimum (AIRmin) acute inflammatory reaction show disequilibrium of the Slc11a1 gene. This gene is involved in the transport of divalent ions at the endosomal/lysosomal compartment within macrophages and neutrophils, interfering in their activation and susceptibility to infections. In this study, we investigated the interaction of the Slc11a1 R (Slc11a1rGly169) and S (null Slc11a1 protein expression, Slc11a1sAsp169) alleles with the Quantitative Trait Loci (QTL) modulated-inflammation during paracoccidioidomycosis in homozygous AIRmaxRR, AIRmaxSS, AIRminRR and AIRminSS lines produced by genotype-assisted breedings. It could be verified that R allele in homozygosis is associated with a more intense neutrophil influx in AIRmax background. The AIRmax lines showed to be more resistant wile AIRmin bearing allele R implicated in a higher recovered P. brasiliensis CFU. Although, the increase of neutrophil influx to the lungs in AIRmaxRR mice can be compensating the influence of Slc11a1 R allele in P. brasilinsis multiplication. We have also observed that the number of CFU in lungs was not related to NO production but instead to modulation of IL-4 and IL-10 synthesis in the lungs. Moreover, we present the effect of Slc11a1 modulating the release of differents cytokines in both supernatant of spleen cells and lungs, but this effect was time-dependent and change in accordance of host genetic background and microenviroment produced by immune response during P. brasiliensis infection. In conclusion, these findings suggest that the lower PMN leukocyte infiltration to the lungs and Slc11a1 R genotype seemed to be a decisive factor in determining the susceptibility profiles in P.brasiliensis infection. / Mestre

Made available in DSpace on 2014-06-11T19:24:16Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-05-18Bitstream added on 2014-06-13T20:31:23Z : No. of bitstreams: 1 trindade_bc_me_botfm.pdf: 386096 bytes, checksum: 6ac59f53d4ce6464ee8a4aac318a9483 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Universidade Estadual Paulista (UNESP) / Camundongos selecionados para a máxima (AIRmax) ou mínima (AIRmin) reação inflamatória aguda apresentam desvio de freqüência do gene Slc11a1. Este gene está envolvido no transporte de íons divalentes no compartimento endossomal/lisossomal de macrófagos e neutrófilos, interferindo na sua ativação e suscetibilidade a infecções. Neste estudo, nós investigamos a interação dos alelos Slc11a1 R (Slc11a1rGly169) e S (expressão nula da proteína Slc11a1, Slc11a1sAsp169) com os loci de características quantitativas (QTL) moduladores da inflamação, durante a paracoccidioidomicose (PCM) em linhagens AIRmaxRR, AIRmaxSS, AIRminRR and AIRminSS homozigotas para o gene Slc11a1, produzidas por acasalamentos assistidos por genotipagem. Nós verificamos que o alelo R em homozigose foi responsável por um maior influxo neutrofílico em camundongos com background AIRmax. Observamos ainda, que as linhagens AIRmaxRR e AIRmaxSS foram mais resistentes enquanto a linhagem AIRmin portadora do alelo R foi implicada em uma maior recuperação de UFC de P. brasiliensis. Desta forma, apesar de não observarmos diferença na recuperação de UFC entre as sublinhagens AIRmax, um aumento no influxo de neutrófilos para o pulmão dos animais AIRmaxRR pode ter compensado a influência do alelo Slc11a1 R na multiplicação do fungo. Nós também mostramos que o número de UFC nos pulmões foi relacionado a síntese de IL-4 e IL-10 neste órgão, mas a produção de óxido nítrico foi semelhante em ambas as linhagens mostrando que este metabólito não foi o fator determinante de resistência/suscetibilidade nas linhagens analisadas. Quanto a análise de diferentes citocinas em sobrenadante de cultura de células do baço e no pulmão das linhagens utilizadas, mostramos que o gene modula a síntese de várias citocinas, porém... / Mice selected for the maximum (AIRmax) or minimum (AIRmin) acute inflammatory reaction show disequilibrium of the Slc11a1 gene. This gene is involved in the transport of divalent ions at the endosomal/lysosomal compartment within macrophages and neutrophils, interfering in their activation and susceptibility to infections. In this study, we investigated the interaction of the Slc11a1 R (Slc11a1rGly169) and S (null Slc11a1 protein expression, Slc11a1sAsp169) alleles with the Quantitative Trait Loci (QTL) modulated-inflammation during paracoccidioidomycosis in homozygous AIRmaxRR, AIRmaxSS, AIRminRR and AIRminSS lines produced by genotype-assisted breedings. It could be verified that R allele in homozygosis is associated with a more intense neutrophil influx in AIRmax background. The AIRmax lines showed to be more resistant wile AIRmin bearing allele R implicated in a higher recovered P. brasiliensis CFU. Although, the increase of neutrophil influx to the lungs in AIRmaxRR mice can be compensating the influence of Slc11a1 R allele in P. brasilinsis multiplication. We have also observed that the number of CFU in lungs was not related to NO production but instead to modulation of IL-4 and IL-10 synthesis in the lungs. Moreover, we present the effect of Slc11a1 modulating the release of differents cytokines in both supernatant of spleen cells and lungs, but this effect was time-dependent and change in accordance of host genetic background and microenviroment produced by immune response during P. brasiliensis infection. In conclusion, these findings suggest that the lower PMN leukocyte infiltration to the lungs and Slc11a1 R genotype seemed to be a decisive factor in determining the susceptibility profiles in P.brasiliensis infection.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-07-28T14:51:26Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) DISSERTAÇÃO - FICHA CATALOGRÁFICA - Tamires Meira Menezes - IMPRESSAO definitivo 20 de maio def.pdf: 2274072 bytes, checksum: e16a0eba082be492ae84d83288410672 (MD5) / Made available in DSpace on 2016-07-28T14:51:26Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) DISSERTAÇÃO - FICHA CATALOGRÁFICA - Tamires Meira Menezes - IMPRESSAO definitivo 20 de maio def.pdf: 2274072 bytes, checksum: e16a0eba082be492ae84d83288410672 (MD5) Previous issue date: 2016-02-25 / CAPEs / Estudos epidemiológicos evidenciam que a obesidade durante a gestação prejudica o desenvolvimento fetal e predispõe a prole a maior incidência de doenças crônicas não transmissíveis (DCNT) frequentemente coexistentes com processos inflamatórios. Dessa forma, este estudo tem como objetivo avaliar a fase aguda da resposta inflamatória e a eficácia farmacológica da nimesulida na prole adulta de ratos Wistar alimentados com uma Dieta Ocidentalizada durante a gestação e lactação. A partir do 1º dia de gestação, as matrizes foram divididas aleatoriamente em dois grupos: 1) DPgl – que permaneceram recebendo a DP de biotério (Presence ®) durante a gestação e lactação e 2) DOgl que passaram a receber DO durante a gestação e lactação. Em seguida, segundo a manipulação nutricional, as proles foram divididas em quatro grupos: i) DPgl-DP - prole das matrizes que receberam a DP durante a gestação e lactação e permaneceram com a mesma no pós-desmame até o 60º dia de vida; ii) DOgl-DO - prole de matrizes que receberam a DO durante a gestação e lactação e permaneceram com a mesma no pós-desmame até o 60º dia de vida; DPgl-DO - prole de matrizes que receberam DP durante a gestação e lactação, mas que passaram a consumir DO no pós-desmame até o 60º dia de vida e iv) DOgl-DP - prole das matrizes que receberam DO durante a gestação e lactação, mas que passaram a receber DP no pós-desmame até o 60º dia de vida. Nesse experimento os animais receberam Carragenina (0,1 mL, 1% w/v) na região subplantar da pata esquerda traseira para avaliar a resposta inflamatória aguda da prole e o efeito anti-inflamatório da nimesulida. No modelo de inflamação aguda nos intervalos de 120, 180 e 240 min, respectivamente, o grupo DOgl–DO (1,66 ± 0,61*; 2,06 ± 0,62* e 2,10 ± 0,67*) e o grupo DOgl–DP (1,62 ± 0,16*; 1,92 ± 0,36* e 1,51 ± 0,37*) exibiram aumento significativo (p<0,05) em relação ao DPgl–DP (0,93 ± 0,20; 1,11 ± 0,26 e 1,07±0,14). Enquanto o DPgl–DO (1,35 ± 0,16* e 1,55 ± 0,23*) só apresentou diferença (p<0,05) comparada ao DPgl–DP nos intervalos de 120 e 180 min, respectivamente. A atividade anti-edematogênica da nimesulida no grupo DPgl-DPn, foi observada nos intervalos de 120, 180 e 240 min; enquanto no grupo DOgl-DOn esse efeito foi observado apenas no intervalo de 120 min após a injeção subplantar da carragenina. Quando comparados a seus respectivos grupos controle tratados com carboximetilcelulose (DOgl-DOc versus DOgl-DOn ou DPgl-DPc versus DPgl-DPn), o efeito anti-edematogênico da nimesulida, expresso em percentual de inibição do edema, medido nos intervalos de 180 (33,98%) e 240 minutos (33,80%), após a injeção do agente edematogênico, foi significativamente (p<0,05) menor em relação ao grupo DPgl-DPn (38,73% e 38,31%, respectivamente). A partir dos dados concluímos que, a dieta ocidentalizada acentuou a intensidade da resposta inflamatória aguda e reduziu o efeito da nimesulida sobre o edema de pata induzido por carragenina em ratos Wistar. / Epidemiological studies show that obesity during pregnancy affect fetal development and predispose the offspring to higher incidence of chronic noncommunicable diseases (NCDs) often coexisting with inflammatory processes. Thus, this study aims to evaluate the acute phase of the inflammatory response and the pharmacological efficacy of nimesulide in the adult offspring of Wistar rats fed a Westernized diet during pregnancy and lactation. From the 1st day of pregnancy, the mothers were randomly divided into two groups: 1) SDgl - that were fed the SD vivarium (Presence ®) during pregnancy and lactation and 2) WDgl that have received WD during pregnancy and lactation. Then, according to nutritional manipulation, the proles were divided into four groups: i) SDgl-SD - offspring of mothers who received SD during pregnancy and lactation and kept the same post-weaning until 60 days of life; ii) WDgl-WD - offspring of mothers who received the WD during pregnancy and lactation and kept the same post-weaning until 60 days of life; SDgl-WD - offspring of mothers who received SD during pregnancy and lactation, but that began to consume WD post-weaning until the 60th day of life and iv) WDgl-SD - offspring of mothers who received WD during pregnancy and lactation but have received SD post-weaning until the 60th day of life. In this experiment the animals received carrageenan (0.1ml of 1% w / v) in the subplantar region of the left hind paw to assess acute inflammatory response of offspring and anti-inflammatory effect of nimesulide. In the model of acute inflammation in the intervals 120, 180 and 240 min, respectively, WDgl-WD group (1.66 ± 0.61 *; 2.06 * ± 0.62 and 2.10 ± 0.67 *) and WDgl-SD group (1.62 ± 0.16 *; 1.92 * ± 0.36 and 1.51 ± 0.37 *) showed a significant increase (p <0.05) compared to SDgl-SD (0.93 ± 0.20, 1.11 ± 0.26 and 1.07 ± 0.14). While SDgl-WD (1.35 ± 0.16 and 1.55 ± 0.23 * *), the only difference (p <0.05) compared to SDgl-SD in the intervals 120 and 180 min, respectively. The anti-edema activity of nimesulide in SDgl-SDn group was observed at intervals of 120, 180 and 240 min; while in WDgl-WDn group this effect was only observed in the range of 120 min after subplantar injection of carrageenan. When compared to their respective control groups treated with carboxymethylcellulose (WDgl-WD vs. WDgl-WDn or SDgl-SD versus SDgl-SDn), anti-oedematogenic effect of nimesulide expressed as percentage inhibition of edema measured at the intervals of 180 ( 33.98%) and 240 minutes (33.80%), after injection of oedematogenic agent, was significantly (p <0.05) lower in relation to SDgl-SDn group (38.73% and 38.31%, respectively). From the data we conclude that the westernized diet accentuated the intensity of the acute inflammatory response and reduce the effect of nimesulide on the paw edema induced by carrageenan in rats.

Chronic low-grade endotoxemia is an important player in obesity and insulin resistance associated to a high-fat diet (HFD). On the other hand, although it is known that intense endotoxemia and infection reduce appetite and induce intense catabolism, leading to weight loss during the acute inflammatory phase, the late effects of an intense endotoxemia were previously unexplored. Here we report that, besides the concurrent effects, multiple and intense endotoxemia causes long lasting biochemical alterations in the adipose tissue that intensify the harmful effects of a HFD. Mice submitted to multiple and severe endotoxemia had increased the adipose tissue expression of TLR-4, CD14 and SAA3, remaining altered after one week in recovery. When associated to a HFD, mice previously submitted to acute endotoxemia showed a more severe weight gain and impaired insulin sensitivity. Adopting the HFD as an obesogenic stimulus, we evaluated the participation of the protein serum amyloid A (SAA) in obesity development. Using a SAA-targeted antisense oligonucleotide, we observed that the depletion of SAA prevented metabolic alterations, endotoxin elevation, weight gain and insulin resistance in a diet-induced obesity protocol. Inadequate sleep is another important factor to be considered in the obesity epidemic. We found that sleep restriction (SR) causes biochemical and morphological alterations in mice adipose tissue. The levels of serum resistin and the adipose tissue mRNA expression of resistin, TNF-&#945; and IL-6 were increased after SR. When associated to a HFD, mice previously submitted to SR gained more weight with increased macrophage infiltration in the epididymal adipose tissue, and insulin resistance. SAA is also part of the initial biochemical alterations caused by SR. It was observed that the expression of SAA in liver and adipose tissue is upregulated, with return to baseline when sleep is restored. Furthermore, 48 hours of total sleep restriction in healthy human volunteers also caused a serum elevation in SAA concentrations. Considering that SAA induces cell proliferation, we suggest that situations with an increase in SAA production and the consecutive preadipocyte proliferation would prime the adipose tissue to further adipocyte differentiation and hypertrophy. Furthermore, we suggest that SAA alter LPS signaling, possibly inhibiting its clearance. The mechanism associating inflammation and obesity is complex and encompass a diversity of factors; the inflammatory protein SAA may be one of them. In conclusion, our data describes the relationship between SAA, acute inflammation, sleep restriction and obesity. / Endotoxemia crônica de baixo grau tem um importante papel na obesidade e resistência à insulina associada a uma ração hiperlipídica. Por outro lado, embora se saiba que a endotoxemia intensa e infecção reduzam o apetite e induzam a um intenso catabolismo, conduzindo a perda de peso durante a fase aguda da inflamação, os efeitos tardios da endotoxemia intensa nunca foram explorados. Aqui mostramos que, além dos efeitos correntes, a endotoxemia aguda provoca alterações bioquímicas prolongadas no tecido adiposo que intensificam os efeitos deletérios de uma ração hiperlipídica. Camundongos submetidos à endotoxemia aguda apresentaram aumento na expressão de TLR-4, CD14 e SAA3 no tecido adiposo, permanecendo alteradas após uma semana em recuperação. Quando associado a uma ração hiperlipídica, os camundongos previamente submetidos à endotoxemia aguda mostraram um ganho de peso mais pronunciado e uma maior resistência à insulina. Adotando a ração hiperlipídica como um estímulo obesogênico, foi avaliada a participação da proteína amilóide sérica A (SAA) no desenvolvimento da obesidade. Usando um oligonucleotídeo antisense anti-SAA, observamos que a depleção da SAA previne as alterações metabólicas, elevação de endotoxina, ganho de peso e resistência à insulina associadas a ração rica em gordura. O sono inadequado é outro fator importante a ser considerado na epidemia de obesidade. Descobrimos que a restrição do sono (SR) provoca alterações bioquímicas e morfológicas no tecido adiposo de camundongos. A concentração de resistina no soro e a expressão de mRNA no tecido adiposo de resistina, TNF-&#945; e IL- 6 foram aumentadas após SR. Quando associado a uma ração hiperlipídica, os camundongos submetidos previamente à SR ganharam mais massa com aumento da infiltração de macrófagos no tecido adiposo epididimal, e resistência à insulina. SAA também faz parte das alterações bioquímicas iniciais provocadas pelo SR. Observou-se que a expressão de SAA no fígado e tecido adiposo é regulada positivamente, com retorno ao basal quando o sono é restaurado. Além disso, 48 horas de restrição de sono total em voluntários humanos saudáveis também causou uma elevação nas concentrações séricas de SAA. Considerando que SAA induz proliferação, sugerimos que situações onde ocorra aumento na produção de SAA e a consecutiva proliferação celular, o tecido adiposo se tornaria predisposto a futura diferenciação e hipertrofia. Além disso, sugerimos que SAA altera a sinalização de LPS, possivelmente inibindo sua depuração. O mecanismo de associação entre a inflamação e a obesidade é complexo e inclui uma diversidade de fatores; a proteína inflamatória SAA pode ser um deles. Em conclusão, nossos dados descrevem a relação entre SAA, inflamação aguda, restrição do sono e obesidade.

Dietary antioxidants are believed to play an important role in the prevention and treatment of a variety of diseases associated with oxidative stress. Although there is a wide range of dietary antioxidants, the bulk of the research to date has been focused on the nutrient antioxidants vitamin C, E, and carotenoids. Certain relatively uncommon antioxidants such as lipoic acid (LA), and phenolic compounds such as (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and (-)-epigallocatechin gallate (EGCG), have not been extensively investigated although they may exert greater antioxidant potency than that of carotenoids and vitamins. Extracts from selected plants and plant byproducts may represent rich sources for one or more of such antioxidants and therefore exhibit higher effects than a single antioxidant due to the synergistic effects produced between such antioxidants. However, in the last decade a number of epidemiological, animal and in vitro studies have suggested a protective and therapeutic potency of these antioxidants in a broad range of diseases such as cancer, diabetes, atherosclerosis, cataract and acute and chronic neurological disorders. Inflammation, the response of the host toward any infection or injury, plays a central role in the development of many chronic diseases. Several evidences demonstrated the rise of different types of cancer from sites of inflammation. This suggests that active oxygen species and some cytokines generated in the inflamed tissues can cause injury to DNA and ultimately lead to carcinogenesis. Diethylnitrosamine (DEN) is one of the most important environmental carcinogens, present in a variety of foods, alcoholic beverages, tobacco smoke and it can be synthesized endogenously. In addition to the liver it can induce carcinogenesis in other organs like kidney, trachea, lung, esophagus, fore stomach, and nasal cavity. Several epidemiological and laboratory studies indicate that nitroso compounds including DEN may induce hyperplasia and chronic inflammation which is closely associated with the development of hepatocellular carcinoma. Despite increasing evidence on the potential of antioxidants in modulating the etiology of chronic diseases, little is known about their role in inflammation and acute phase response (APR). Therefore the aim of the present work was to study the protective effect of water and solvent extracts of eight plant and plant byproducts including green tea, artichoke, spinach, broccoli, onion and eggplant, orange and potato peels as well as eight antioxidants agents including EC, EGC, ECG, EGCG, ascorbic acid (AA), acetylcysteine (NAC), α-LA, and alpha-tocopherol (α-TOC) toward acute inflammation induced by interleukin-6 (IL-6) and hepatotoxicity induced by DEN in vitro. The negative acute phase proteins (APP), transthyretin (TTR) and retinol-binding protein (RBP) were used as inflammatory biomarkers analyzed by ELISA, whereas neutral red assay was used for evaluating the cytotoxicity. All experiments were performed in vitro using human hepatocarcinoma cell line (HepG2). Additionally the antioxidant activity was measured by TEAC and FRAP assays, phenolic content was measured by Folin–Ciocalteu and characterized by HPLC. Moreover, the microheterogeneity of TTR was detected using immunoprecipitation assay combined with SELDI-TOF MS. Results of present study showed that HepG2 cells provide a simple, sensitive in vitro system for studying the regulation of the negative APP, TTR and RBP under free and inflammatory condition. IL-6, a potent proinflammatory cytokine, in a concentration of 25 ng/ml was able to reduce TTR and RBP secretion by approximately 50-60% after 24h of incubation. With exception of broccoli and water extract of onion which showed pro-inflammatory effects in this study, all other plant extracts, at specific concentrations, were able to elevate TTR secretion in normal condition and even under treatment of IL-6 where the effect was quite lower. Green tea followed by artichoke and potato peel exhibited the highest elevation in TTR concentration which reached 1.1 and 2.5 folds of control in presence and absences of IL-6 respectively. In general Plant extracts were ordered according their anti-inflammatory potency as following: in water extracts; green tea > artichoke > potato peel > orange peel > spinach > eggplant peel, where in solvent extracts; green tea > artichoke > potato peel > spinach > eggplant peel > onion > orange peel. The antiinflammatory effect of water extracts of green tea, artichoke and orange peel were significantly higher than their corresponding solvent extracts whereas water extracts of eggplant-, potato peels and spinach showed lower effect than their solvent extracts. On the other hand α-LA followed by EGCG and ECG exhibited the highest elevation in TTR concentration compared to other antioxidants. The relation between the anti-inflammatory potential and antioxidants activity and phenolic content for the investigated substances was generally weak. This may suggest the involvement of other mechanisms than antioxidants properties for the observed effect. TTR secreted by HepG2 cells has a molecular structure quite similar to the purified standard and serum TTR in which all the three main variants are contained including native, S-cystinylated and Sglutathionylated TTR. Interestingly, a variant with molecular mass of 13453.8 + 8.3 Da has been detected only in TTR secreted by HepG2. Among all investigated antioxidants and plant extracts, six substances were able to elevate the native preferable TTR variant. The potency of these substances can be ordered as following α-LA > NAC > onion > AA > EGCG > green tea. A weak correlation between elevation on TTR and shifting to the native form was observed. Similar weak correlation has also been observed between antioxidants activity and elevation in native TTR. Although DEN was able to induce cell death in a concentration dependent manner, it requires considerably higher concentrations for its effects especially after 24h. This may be attributed to a lack in cytochrome P450 enzymes produced by HepG2. At selected concentrations some antioxidants and plant extracts significantly attenuate DEN cytotoxicity as following: spinach > α-LA > artichoke > orange peel > eggplant peel > α-TOC > onion > AA. Contrary all other substances especially green tea, broccoli, potato peel, and ECG stimulate DEN toxicity. In conclusion, this study demonstrated that selected antioxidants and plant extracts may attenuate the inflammatory process, not only by their antioxidants potency but also by other mechanisms which remain unclear. They may also play a vital role on stabilizing the tetramic structure of TTR and thereby prevent amyloidosis diseases. Lipoic acid represents in this study unique function against inflammation and hepatotoxicity. Despite the protective effect demonstrated by investigated substances, attention should also be given to the pro-oxidant and potential cytotoxic effects produced at higher concentrations. / Substanzen und Lebensmittelinhaltstoffe mit antioxidativer Wirkung spielen eine entscheidende Rolle in Prävention und Behandlung zahlreicher Erkrankungen, die mit oxidativen Stress assoziiert sind. Dabei stehen v. a. die Lebensmittelinhaltsstoffen Vitamin C (Ascorbinsäure, AA), Vitamin E und die Carotinoide im Zentrum der Forschung. Da einige bislang relativ ungebräuchliche Antioxidantien wie Liponsäure (LA) und phenolische Substanzen wie (-)-Epicatechin (EC), (-)-Epigallocatechin(EGC), (-)-Epicatechingallat (ECG), und (-)-Epigallocatechingallat (EGCG) ein größeres antioxidatives Potential als Carotinoide und die Vitamine C und E aufweisen, geraten diese in zunehmendem Maße in den Fokus der Forschung und wecken auch immer mehr das Interesse gesundheitsbewusster Verbraucher. Einige ausgewählte Pflanzenextrakte und Extrake pflanzlicher Nebenprodukte stellen ergiebige Quellen der oben erwähnten Substanzen dar und zeichnen sich daher durch eine höhere Wirksamkeit aus, die teilweise auch auf synergetische Effekte zwischen diesen Antioxidantien zurückzuführen ist. Eine Vielzahl epidemiologischer Studien sowie zahlreiche Tier- und in-vitro-Experimente deuten daher darauf hin, daß die oben erwähnten Antioxidantien bei einer Vielzahl von Erkrankugen, wie Krebs, Diabetes, Arteriosklerose, Katarakt, akute bzw. chronische neurologische Störungen, ein schützendes und therapeutisches Potential entfalten. Entzündungen, als Antwort eines Individuums auf Infektion oder Verletzungen, spielen eine zentrale Rolle bei der Entwicklung vieler chronischer Erkrankungen. So konnten mehrere Studien den Zusammenhang zwischen der Entstehung verschiedener Krebsarten und zugrundeliegender Infektionen belegen. Dies deutet darauf hin, dass reaktive Sauerstoffspezies und einige Zytokinen, die im entzündeten Geweben generiert werden und DNA-Schäden verursachen können, letztendlich auch eine Karzinogenese auslösen können. Diethylnitrosamin (DEN) ist eines der bekanntesten Umweltkarzinogene, daß neben Hepatokarzinomen auch Krebs in Nieren, Trachea, Lunge, Speiseröhre, Magen und Nasenhöhle hervorrufen kann und in vielen Lebensmitteln, alkoholischen Getränke sowie Tabakrauch enthalten ist und darüber hinaus endogen synthetisiert wird. Dabei geht man auf Grundlage mehrere epidemiologischer und Forschungsstudien davon aus, dass durch Nitroso-Verbindungen, u.a. auch DEN, induzierte Hyperplasien und chronische Entzündungen die Entwicklung hepatozellulärer Karzinome begünstigt. Trotz zunehmender Beweise bezüglich des Potentials von Antioxidantien die Ätiologie chronischer Erkrankungen zu modulieren, ist bislang nur sehr wenig über ihre Rolle im Entzündungsprozess und der Akutphasereaktion (APR) bekannt. Deshalb war das Ziel der vorliegenden Arbeit die schützende Wirkung von Extrakten verschiedener Pflanzen und Pflanzennebenprodukten sowie isolierten Antikoxidantien bei akuten Entzündungssituationen zu testen. Dazu wurden wässrige und Lösungsmittelextratke aus acht Pflanzen bzw. deren Nebenprodukten (Grüntee, Artischocke, Spinat, Brokkoli, Zwiebel, Aubergine-, Orangen- und Kartoffelschalen) hergestellt und ihre Wirkung sowie die acht weiterer reiner Antioxidantien (EC, EGC, ECG, EGCG, Ascorbinsäure (AA), Acetylcystein (NAC), LA, und -Tocopherol (TOC) in in-vitro-Modellen der akuten Entzündung, induziert durch interleukin-6 (IL-6), bzw. der Hepatoxizität, induziert durch DEN, getestet.. Transthyretin (TTR) und Retinol-Bindungsprotein (RBP), zwei negative Akutphasenproteine (APP) wurden als Entzündungsbiomarker (Analyse per ELISA) und Neutral-Red-Assay als ein Maß für die Cytotoxizität herangezogen. Alle Experimente wurden in-vitro in einer immortalisierten humanen Hepatokarzinom-Zelllinie (HepG2) durchgeführt. Die antioxidativen Kapazität wurde mittels TEAC und FRAP-Methoden evaluiert und der Gesamtphenolgehalt durch die Folin–Ciocalteu-Methode erfasst, wobei die qualitative Charakterisierung über die HPLC erfolgte. Die Mikroheterogenität des TTR wurde durch Immunopräzipitation in Kombination mit SELDI-TOF-MS Technik analysiert. Die Ergebnisse dieser Studie zeigen, dass HepG2-Zellen ein einfaches und empfindliches in-vitro System zur Regulierung von negativen Akutphasenproteinen, TTR und RBP, unter physiologischen und infllammatorischen Bedingungen darstellen. IL-6, ein potentes Pro-Entzündungszytokine, war bei einer 24stündigen Inkubation mit einer Konzentration von 25 ng/ ml in der Lage die Sekretion von TTR und RBP um ca. 50-60% zu reduzieren. Mit Ausnahme von Broccoli und Wasser Extrakt der Zwiebel, die zeigten, proinflammatorischen Effekt Wirkungen in dieser Studie, die alle anderen Pflanzenextrakten, in bestimmten Konzentrationen, waren in der Lage zu erheben TTR Sekretion im normalen, aber auch bei der Behandlung von IL-6 bei denen die Wirkung war niedriger. Grüntee, gefolgt von Artischocken und Kartoffelschälen zeigte die höchste Erhebung in der TTRKonzentration, die erreicht, 1,1 und 2,5 Falten der Kontrolle in Behandlung und ohne Behandlung von IL-6 bzw. Die wässrigen Pflanzenextrakte lassen sich in der folgenden Reihenfolge des anti-Entzündungspotentials einordnen: Grüntee > Artischocke > Kartoffelschalen > Orangenschalen > Spinat > Aubergineschalen, wogegen bei Lösungsmittelextrakte folgende Reihenfolge ermittelt wurde: Grüntee > Artischocke > Kartoffelnschalen > Spinat > Aubergineschalen > Zwiebel > Orangenschalen. Die schützende Wirkung der wässrigen Extrakte von Grüntee, Artischocke und Orangenschalen war signifikant höher als die der entsprechenden Lösungsmittelextrakte. Wohingegen wässrige Extrakte aus Aubergineschalen, Kartoffelschalen, Spinat und Zwiebel weniger effektiv waren. Auf der anderen Seite, LA gefolgt von EGCG und ECG zeigte die höchste Erhebung in der TTRKonzentration im Vergleich zu anderen Antioxidantien. Somit konnte ein schwacher aber Zusammenhang zwischen antinflammatorischem Potential, antioxidativer Aktivität und Phenolgehalt nachgewiesen werden. Daher ist anzunehmen, dass den beobachteten Effekten anderen Mechanismen zu Grunde liegen. Das durch HepG2-Zellen sezernierte TTR erwies eine molekulare Struktur ähnlich der des verwendeten Standards bzw. des TTR aus humanem Serum auf. Es enthielt alle drei Hauptvarianten, einschließlich der nativen, S-cystinylierten und S-glutathionylierten TTR-Formen. Darüber hinaus wurde nur im in-vitro sezerniertem TTR (TTR aus HepG2-Zellen) eine Variante mit einer molekularen Masse von 13453.8 + 8.3 Da nachgewiesen. Von den untersuchten Substanzen wiesen nur sechs Verbindungen die Fähigkeit auf den Anteil der günstigen nativen TTR-Form zu erhöhen aus. Dabei konnte folgende Wirksamkeitsreihenfolge zugeordnet werden : LA > NAC > Zwiebel > AA > EGCG > Grüntee. Eine schwache Korrelation zwischen der Erhöhung der TTRKonzentration und der Verschiebung zu der nativen Form hin wurde festgestellt. Ein ähnlicher Zusammenhang zwischen der antioxidativen Aktivität und dieser Erhöhung wurde auch beobachtet. Obwohl DEN in der Lage war konzentrationsabhängig den Zelltod zu induzieren, war eine wesentlich höhere Konzentration notwendig, um die volle Wirksamkeit während 24stündiger Inkubation zu gewährleisten. Dies mag auf die mangelnde Ausstattung mit Cytochrom-P450-Enzymen, die in den HepG2 Zellen produziert werden, zurück zu führen sein. Ausgewählte Konzentrationen einiger eingesetzter Substanzen führten zu einer signifikanten Schwächung der DEN-induzierten Zytotoxizität mit folgender Wirksamkeit: Spinat > LA > Artischocke > Orangen- > Aubergineschalen > TOC > Zwiebel > AA. Im Gegensatz dazu, stimulierten alle anderen Substanzen, insbesondere Grüntee, Brokkoli, Kartoffelschalen und ECG, die DEN –induzierten Toxizität. Diese Arbeit zeigt somit, dass ausgewählte Antioxidantien und Pflanzenextrakten in der Lage sind, den antinflammatorischen Prozess sowohl durch ihre antioxidative Wirkung als auch durch bislang nicht aufgeklärten Mechanismen grundlegend zu beeinflussen. Sie könnten daher eine entscheidende Rolle bei der Stabilisierung von Proteinstrukturen übernehmen (gezeigt am Beispiel vom TTR) und in diesem Zusammenhang möglicherweise auch zur Prävention von Krankheiten wie Amyloidosen beitragen. Liponsäure überzeugte in dieser Arbeit durch seine einzigartigen Funktion gegenüber Entzündungssituationen und Hepatoxizität. Wie oft beobachtet und durch diese Studie bestätigt, weisen die verwendeten Subsatzen neben der schützenden anti- auch pro-oxidativen Wirkungen auf, wodurch die Notwendigkeit weiterer Untersuchungen zur Erfassung der Zytotoxizität beim Einsatz höherer Konzentration verdeutlicht wird.

Chronic low-grade endotoxemia is an important player in obesity and insulin resistance associated to a high-fat diet (HFD). On the other hand, although it is known that intense endotoxemia and infection reduce appetite and induce intense catabolism, leading to weight loss during the acute inflammatory phase, the late effects of an intense endotoxemia were previously unexplored. Here we report that, besides the concurrent effects, multiple and intense endotoxemia causes long lasting biochemical alterations in the adipose tissue that intensify the harmful effects of a HFD. Mice submitted to multiple and severe endotoxemia had increased the adipose tissue expression of TLR-4, CD14 and SAA3, remaining altered after one week in recovery. When associated to a HFD, mice previously submitted to acute endotoxemia showed a more severe weight gain and impaired insulin sensitivity. Adopting the HFD as an obesogenic stimulus, we evaluated the participation of the protein serum amyloid A (SAA) in obesity development. Using a SAA-targeted antisense oligonucleotide, we observed that the depletion of SAA prevented metabolic alterations, endotoxin elevation, weight gain and insulin resistance in a diet-induced obesity protocol. Inadequate sleep is another important factor to be considered in the obesity epidemic. We found that sleep restriction (SR) causes biochemical and morphological alterations in mice adipose tissue. The levels of serum resistin and the adipose tissue mRNA expression of resistin, TNF-&#945; and IL-6 were increased after SR. When associated to a HFD, mice previously submitted to SR gained more weight with increased macrophage infiltration in the epididymal adipose tissue, and insulin resistance. SAA is also part of the initial biochemical alterations caused by SR. It was observed that the expression of SAA in liver and adipose tissue is upregulated, with return to baseline when sleep is restored. Furthermore, 48 hours of total sleep restriction in healthy human volunteers also caused a serum elevation in SAA concentrations. Considering that SAA induces cell proliferation, we suggest that situations with an increase in SAA production and the consecutive preadipocyte proliferation would prime the adipose tissue to further adipocyte differentiation and hypertrophy. Furthermore, we suggest that SAA alter LPS signaling, possibly inhibiting its clearance. The mechanism associating inflammation and obesity is complex and encompass a diversity of factors; the inflammatory protein SAA may be one of them. In conclusion, our data describes the relationship between SAA, acute inflammation, sleep restriction and obesity. / Endotoxemia crônica de baixo grau tem um importante papel na obesidade e resistência à insulina associada a uma ração hiperlipídica. Por outro lado, embora se saiba que a endotoxemia intensa e infecção reduzam o apetite e induzam a um intenso catabolismo, conduzindo a perda de peso durante a fase aguda da inflamação, os efeitos tardios da endotoxemia intensa nunca foram explorados. Aqui mostramos que, além dos efeitos correntes, a endotoxemia aguda provoca alterações bioquímicas prolongadas no tecido adiposo que intensificam os efeitos deletérios de uma ração hiperlipídica. Camundongos submetidos à endotoxemia aguda apresentaram aumento na expressão de TLR-4, CD14 e SAA3 no tecido adiposo, permanecendo alteradas após uma semana em recuperação. Quando associado a uma ração hiperlipídica, os camundongos previamente submetidos à endotoxemia aguda mostraram um ganho de peso mais pronunciado e uma maior resistência à insulina. Adotando a ração hiperlipídica como um estímulo obesogênico, foi avaliada a participação da proteína amilóide sérica A (SAA) no desenvolvimento da obesidade. Usando um oligonucleotídeo antisense anti-SAA, observamos que a depleção da SAA previne as alterações metabólicas, elevação de endotoxina, ganho de peso e resistência à insulina associadas a ração rica em gordura. O sono inadequado é outro fator importante a ser considerado na epidemia de obesidade. Descobrimos que a restrição do sono (SR) provoca alterações bioquímicas e morfológicas no tecido adiposo de camundongos. A concentração de resistina no soro e a expressão de mRNA no tecido adiposo de resistina, TNF-&#945; e IL- 6 foram aumentadas após SR. Quando associado a uma ração hiperlipídica, os camundongos submetidos previamente à SR ganharam mais massa com aumento da infiltração de macrófagos no tecido adiposo epididimal, e resistência à insulina. SAA também faz parte das alterações bioquímicas iniciais provocadas pelo SR. Observou-se que a expressão de SAA no fígado e tecido adiposo é regulada positivamente, com retorno ao basal quando o sono é restaurado. Além disso, 48 horas de restrição de sono total em voluntários humanos saudáveis também causou uma elevação nas concentrações séricas de SAA. Considerando que SAA induz proliferação, sugerimos que situações onde ocorra aumento na produção de SAA e a consecutiva proliferação celular, o tecido adiposo se tornaria predisposto a futura diferenciação e hipertrofia. Além disso, sugerimos que SAA altera a sinalização de LPS, possivelmente inibindo sua depuração. O mecanismo de associação entre a inflamação e a obesidade é complexo e inclui uma diversidade de fatores; a proteína inflamatória SAA pode ser um deles. Em conclusão, nossos dados descrevem a relação entre SAA, inflamação aguda, restrição do sono e obesidade.

In Acute Myocardial Infarction (AMI), inflammation is a prerequisite for healing but it can paradoxically extend tissue injury; hence it needs to be modulated. Here, we investigated the role of the pro resolving GPCR FPR2/ALX and its agonist Annexin A1 (AnxA1) in AMI using mice lacking of the Fpr2/3 genes and with an in-frame GFP gene ‘knocked-in’. We developed protocols aimed to determine GFP expression as an indication of Fpr2 gene activity. Also, the Left Anterior Descending Coronary Artery of male Fpr2/3 KO and littermate controls (WT) was occluded for 30min and re-opened for 90min. At the end tissue injury and inflammatory response were studied. A significant proportion of Fpr2/3 KO perished during the procedure. The rest survived up to 90 min and exhibited a larger infarct size, with higher troponin I and inflammation markers (KC, TNFα) than WT animals. At the end of reperfusion, Fpr2/3 KO displayed an unbalanced production of pro and anti-inflammatory lipids (higher PGE2, PGI2, LTB4 and attenuated PGA1, RvD2, LXA4) and a deregulated activation of the cardioprotective IL-6/JAK/STAT3 signalling. Administration of AnxA1 afforded cardioprotection (reduction of infarct size; Troponin I, Caspase3 activity and TNFα) in WT but not in Fpr2/3 KO. A parallel in vitro investigation on the functional FPR2/ALX domains required by AnxA1 and other agonists was also conducted. HEK-293 cells transfected with FPR1, FPR2/ALX and FPR1/FPR2 chimeric receptor were used and calcium flux, 4 pERK and gene modulation analysed. AnxA1 required the N-terminus and the II and III extracellular loops of FPR2/ALX to evoke canonical responses. SAA interacted/activated the I and the II extracellular loops of FPR2/ALX, whereas the compound 43 suffices the I extracellular loop. In summary, the FPR2/AnxA1 pathway exerts a protective role in AMI. AnxA1 mimetic that activated selective FPR2/ALX domains can be synthetize to prevent tissue damage caused by AMI.

Initiation and perpetuation of inflammatory bowel diseases (IBD) may result from an exaggerated mucosal immune response to the luminal microbiota in a susceptible host. We proposed that this may be caused either 1) by an abnormal microbial composition or 2) by weakening of the protective mucus layer due to excessive mucus degradation, which may lead to an easy access of luminal antigens to the host mucosa triggering inflammation. We tested whether the probiotic Enterococcus faecium NCIMB 10415 (NCIMB) is capable of reducing chronic gut inflammation by changing the existing gut microbiota composition and aimed to identify mechanisms that are involved in possible beneficial effects of the probiotic. To identify health-promoting mechanisms of the strain, we used interleukin (IL)-10 deficient mice that spontaneously develop gut inflammation and fed these mice a diet containing NCIMB (106 cells g-1) for 3, 8 and 24 weeks, respectively. Control mice were fed an identically composed diet but without the probiotic strain. No clear-cut differences between the animals were observed in pro-inflammatory cytokine gene expression and in intestinal microbiota composition after probiotic supplementation. However, we observed a low abundance of the mucin-degrading bacterium Akkermansia muciniphila in the mice that were fed NCIMB for 8 weeks. These low cell numbers were associated with significantly lower interferon gamma (IFN-γ) and IFN-γ-inducible protein (IP-10) mRNA levels as compared to the NCIMB-treated mice that were killed after 3 and 24 weeks of intervention. In conclusion, NCIMB was not capable of reducing gut inflammation in the IL-10-/- mouse model. To further identify the exact role of A. muciniphila and uncover a possible interaction between this bacterium, NCIMB and the host in relation to inflammation, we performed in vitro studies using HT-29 colon cancer cells. The HT-29 cells were treated with bacterial conditioned media obtained by growing either A. muciniphila (AM-CM) or NCIMB (NCIMB-CM) or both together (COMB-CM) in Dulbecco’s Modified Eagle Medium (DMEM) for 2 h at 37 °C followed by bacterial cell removal. HT-29 cells treated with COMB-CM displayed reduced cell viability after 18 h (p<0.01) and no viable cells were detected after 24 h of treatment, in contrast to the other groups or heated COMB-CM. Detection of activated caspase-3 in COMB-CM treated groups indicated that death of the HT-29 cells was brought about by apoptosis. It was concluded that either NCIMB or A. muciniphila produce a soluble and heat-sensitive factor during their concomitant presence that influences cell viability in an in vitro system. We currently hypothesize that this factor is a protein, which has not yet been identified. Based on the potential effect of A. muciniphila on inflammation (in vivo) and cell-viability (in vitro) in the presence of NCIMB, we investigated how the presence of A. muciniphila affects the severity of an intestinal Salmonella enterica Typhimurium (STm)-induced gut inflammation using gnotobiotic C3H mice with a background microbiota of eight bacterial species (SIHUMI, referred to as simplified human intestinal microbiota). Presence of A. muciniphila in STm-infected SIHUMI (SIHUMI-AS) mice caused significantly increased histopathology scores and elevated mRNA levels of IFN-γ, IP-10, tumor necrosis factor alpha (TNF-α), IL-12, IL-17 and IL-6 in cecal and colonic tissue. The number of mucin filled goblet cells was 2- to 3- fold lower in cecal tissue of SIHUMI-AS mice compared to SIHUMI mice associated with STm (SIHUMI-S) or A. muciniphila (SIHUMI-A) or SIHUMI mice. Reduced goblet cell numbers significantly correlated with increased IFN-γ (r2 = -0.86, ***P<0.001) in all infected mice. In addition, loss of cecal mucin sulphation was observed in SIHUMI-AS mice. Concomitant presence of A. muciniphila and STm resulted in a drastic change in microbiota composition of the SIHUMI consortium. The proportion of Bacteroides thetaiotaomicron in SIHUMI, SIHUMI-A and SIHUMI-S mice made up to 80-90% but was completely taken over by STm in SIHUMI-AS mice contributing 94% to total bacteria. These results suggest that A. muciniphila exacerbates STm-induced intestinal inflammation by its ability to disturb host mucus homeostasis. In conclusion, abnormal microbiota composition together with excessive mucus degradation contributes to severe intestinal inflammation in a susceptible host. / Die Initiation and die Manifestation von entzündlichen Darmerkrankungen (inflammatory bowel diseases - IBD) können aus einer übersteigerten mukosalen Immunreaktion auf die luminale Mikrobiota in einem empfänglichen Wirt resultieren. Wir schlagen vor, dass dies entweder durch 1) eine abnormale mikrobielle Zusammensetzung oder 2) die Abschwächung der schützenden Schleimschicht, eingeleitet durch deren fortgeschrittenen Abbau, verursacht werden kann. Diese Entwicklung ermöglicht einen erleichterten Zugang des luminalen Antigens zu der Mukosa des Wirts und somit die Auslösung der Entzündung. Wir haben getestet, ob das probiotische Bakterium Enterococcus faecium NCIMB 10415 (NCIMB) in der Lage ist, der chronischen Darmentzündung durch Veränderung der Zusammensetzung der Darmmikrobiota entgegenzuwirken und strebten an, die zugrunde liegenden Mechanismen der probiotischen Wirkungsweise zu identifizieren. Für die Aufklärung der gesundheitsfördernden Mechanismen dieses Bakterienstammes wurden Interleukin-10 defiziente Mäuse verwendet, die spontan eine Darmentzündung entwickeln. Den Mäusen wurde für 3, 8 und 24 Wochen eine NCIMB enthaltende Diät verabreicht. Nach der Fütterung waren keine eindeutigen Unterschiede zwischen den Gruppen hinsichtlich der Genexpression von pro-inflammatorischen Zytokinen und der Zusammensetzung der Darmmikrobiota zu beobachten, obwohl eine geringere Zellzahl des schleimabbauenden Bakteriums Akkermansia muciniphila in den mit NCIMB gefütterten Mäusen nach 8 Wochen festgestellt wurde. Daraus folgt, dass NCIMB nicht in der Lage ist, dem Verlauf der Darmentzündung im IL-10-/--Mausmodell entgegenzuwirken. In der nachfolgenden Studie wurde untersucht, wie die Anwesenheit von A. muciniphila den Ausprägungsgrad einer intestinalen Salmonella enterica Typhimurium (STm) induzierten Darmentzündung beeinflusst. Dafür wurden gnobiotische C3H-Mäuse mit einem mikrobiellen Hintergrund von acht Bakterienspezies (SIHUMI) verwendet. Die gleichzeitige Anwesenheit von A. muciniphila und STm verursachte eine drastische Veränderung der Mikrobiota-Zusammensetzung des SIHUMI-Konsortiums. Diese Ergebnisse zeigen, dass A. muciniphila durch seine Fähigkeit, die Homöostase/Selbstregulation der Schleimbildung zu stören, die STm-induzierte Darmentzündung verschärft. Es kann geschlußfolgert werden, dass eine abweichende Zusammensetzung der Mikrobiota in Kombination mit einem massiven Abbau des Mucus zur schweren intestinalen Entzündung im empfänglichen Wirt beiträgt.

Made available in DSpace on 2015-04-01T14:16:03Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 2190162 bytes, checksum: 9763593619be7b764f8c70a928a7dba5 (MD5) Previous issue date: 2012-03-28 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Bornyl Salicylate (BS) is a salicylic derivative, obtained by sterification of salicylic acid and monoterpene (-)-borneol, and its topical use in inflammatory diseases has been described in the beginning of 20th century. It is also known that salicylic derivatives have anti-inflammatory activity and borneol have neuroprotective, genoprotective and analgesic activity. The goal of this study was to evaluate activity of BS in experimental models of acute inflammation. The toxicity of BS was analyzed by measuring water and food intake, weight, mortality and weight of major organs. To assess its anti-inflammatory effect, mice pre-treated with BS were subjected to carrageenan, prostaglandin E2, bradikynin or histamine-induced paw edema, zymosan-induced peritonitis and increased vascular permeability induced by acetic acid. NO production was analyzed in peritoneal macrophage cell culture. There were no signs of acute toxicity with the administration of 1000 mg/kg BS in male and female mice. Furthermore, pretreatment with BS was significantly (p<0.05) effective in reducing paw edema induced by carrageenin in early and late times; this effect is related to eicosanoid mediators and bradikynin, and independent of histamine. Neutrophils migration and the release of pro-inflammatory cytokines (TNF-, IL-1 and IL-6) induced by zimosan, and the fluid leakage induced by acetic acid were also reduced in animals treated with BS. In vitro, BS reduced NO release in LPS-stimulated macrophage. These data suggest that BS has anti-inflammatory effects related to different mechanisms of inflammation, and further studies are needed to explore its potential. / O Salicilato de Borneol (SB) é um derivado salicílico, obtido pela esterificação do ácido salicílico e do monoterpeno (-)-borneol, e seu uso tópico em doenças inflamatórias foi descrito no início do século XX. Derivados salicílicos possuem excelente atividade anti-inflamatória e sabe-se que o borneol possui atividade neuroprotetora, genoprotetora e analgésica. Assim, o objetivo deste estudo foi avaliar a atividade do SB em modelos experimentais de inflamação aguda. A toxicidade do SB foi analisada, mensurando-se o consumo de água e ração, peso, letalidade e peso dos principais órgãos. Para avaliar seu efeito anti-inflamatório, camundongos pré-tratados com SB foram submetidos aos protocolos de edema de pata induzido por carragenina, prostaglandina E2, bradicinina ou histamina, peritonite induzida por zimosan e aumento da permeabilidade vascular induzido por ácido acético. A produção de óxido nítrico (NO) foi analisada em cultura de macrófagos peritoneais. Não foram observados sinais de toxicidade aguda com a administração de 1000 mg/kg de SB em camundongos machos e fêmeas. Além disto, o pré-tratamento com SB foi significativamente (p<0,05) eficaz na redução do edema de pata induzido por carragenina em tempos precoces e tardios, pela modulação de eicosanoides e bradicinina, e independente de histamina. A migração de neutrófilos e a liberação de citocinas pró-inflamatórias (TNF-, IL-1 e IL-6) provocadas pelo zimosan, bem como o extravasamento de fluidos mediado pelo ácido acético também foram reduzidos em animais tratados com SB. In vitro, o SB reduziu a liberação de NO em células estimuladas por lipopolissacarídeo de E. coli (LPS). Estes dados sugerem que SB tem efeitos anti-inflamatórios relacionados com diferentes mecanismos da inflamação, e novos estudos são necessários para explorar seu potencial.