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In recent years, increased focus has been placed on the role of intrauterine infection and inflammation in the pathogenesis of fetal brain injury leading to neurodevelopmental disorders such as cerebral palsy. At present, the mechanisms by which inflammatory processes during pregnancy cause this effect on the fetus are poorly understood. Our previous work has indicated an association between experimentally-induced intrauterine infection, increased proinflammatory cytokines, and increased white matter injury in the guinea pig fetus. In order to further elucidate the pathways by which inflammation in the maternal system or the fetal membranes leads to fetal impairment, a number of studies investigating aspects of the disease process have been performed. These studies represent a body of work encompassing novel research and results in a number of human and animal studies. Using a guinea pig model of inflammation, increased amniotic fluid proinflammatory cytokines and fetal brain injury were found after a maternal inflammatory response was initiated using endotoxin. In order to more closely monitor the fetal response to chorioamnionitis, a model using the chronically catheterized fetal ovine was carried out. This study demonstrated the adverse effects on fetal white matter after intrauterine exposure to bacterial inoculation, though the physiological parameters of the fetus were relatively stable throughout the experimental protocol, even when challenged with intermittent hypoxic episodes. The placenta is an important mediator between mother and fetus during gestation, though its role in the inflammatory process is largely undefined. Studies on the placental role in the inflammatory process were undertaken, and the limited ability of proinflammatory cytokines and endotoxin to cross the placenta are detailed herein. Neurodevelopmental disorders can be monitored in animal models in order to determine effective disease models for characterization of injury and use in therapeutic strategies. Our characterizations of postnatal behaviour in the guinea pig model using motility monitoring and spatial memory testing have shown small but significant differences in pups exposed to inflammatory processes in utero. The data presented herein contributes a breadth of knowledge to the ongoing elucidation of the pathways by which fetal brain injury occurs. Determining the pathway of damage will lead to discovery of diagnostic criteria, while determining the vulnerabilities of the developing fetus is essential in formulating therapeutic options. / Thesis (Ph.D, Anatomy & Cell Biology) -- Queen's University, 2008-03-06 20:24:03.417

yes / Purpose.: The aim of this work was to develop an in vitro cornea model to study the effect of proinflammatory cytokines on wound healing. Methods.: Initial studies investigated how to maintain the ex vivo models for up to 4 weeks without loss of epithelium. To study the effect of cytokines, corneas were cultured with the interleukins IL-17A, IL-22, or a combination of IL-17A and IL-22, or lipopolysaccharide (LPS). The effect of IL-17A on wound healing was then examined. Results.: With static culture conditions, organ cultures deteriorated within 2 weeks. With gentle rocking of media over the corneas and carbon dioxide perfusion, the ex vivo models survived for up to 4 weeks without loss of epithelium. The cytokine that caused the most damage to the cornea was IL-17A. Under static conditions, wound healing of the central corneal epithelium occurred within 9 days, but only a single-layered epithelium formed whether the cornea was exposed to IL-17A or not. With rocking of media gently over the corneas, a multilayered epithelium was achieved 9 days after wounding. In the presence of IL-17A, however, there was no wound healing evident. Characterization of the cells showed that wherever epithelium was present, both differentiated cells and highly proliferative cells were present. Conclusions.: We propose that introducing rocking to extend the effective working life of this model and the introduction of IL-17A to this model to induce aspects of inflammation extend its usefulness to study the effects of agents that influence corneal regeneration under normal and inflamed conditions.

Background: Psychiatric diseases such as bipolar disorder, major depressive disorder (MDD)and schizophrenia are chronic ailments that severely affect daily function and quality of life. A relationship between elevated levels of proinflammatory cytokines and these disorders hasbeen suggested in several studies. Lithium is used as a treatment in bipolar disorder, and as anadjunctive treatment in MDD and schizophrenia. Despite the extensive use of lithium, it’smechanism of action is not fully understood. One of the proposed hypotheses of lithium’smechanism of action is reduction in the levels of proinflammatory cytokines. Aim: The aim of this systematic literature review is to describe the effects of lithium onproinflammatory cytokines (IL-1, IL-6, INF- γ, TNF) in bipolar disorder, MDD andschizophrenia. Methods: The study was conducted through a search in the electronic database PubMed.Using the PICOS format, inclusion and exclusion criteria were specified. Search words andfilters were combined using both Medical Subject Headings (MeSH) terms and free textsearch words. The search initially resulted in 105 articles and through inclusion and exclusioncriteria full-text articles were estimated for eligibility. Risk of bias was estimated using theCochrane Handbook. Results: A total of 10 eligible articlets were included in this study. Nine out of 10 articlesinvestigated bipolar patients, and one article investigated patients with MDD. No article investigated patients with schizophrenia. Four out of 9 articles regarding bipolar patientsreported a significant decrease in some proinflammatory cytokines after lithiumtreatment, 4 articles reported a significant increase, and one article reported no change in theproinflammatory cytokines. In two well conducted studies where bipolar disorder wasinvestigated, lithium had differential effects, namely decreasing proinflammatory cytokines inlithium responders compared to lithium non-responders. No significant change inproinflammatory cytokine levels after lithium treatment were found in the article studyingMDD patients. Conclusions: The results indicated that lithium may have different effects depending onwhich specific cytokine was studied and on the specific characteristics of the studiedpopulation. Therefore, the outcomes of our review cannot unequivocally answer whetherlithium acts by increasing or decreasing proinflammatory cytokines, or both depending on theexperimental conditions. Further research is needed to fully elucidate the relationship betweenlithium and proinflammatory cytokines in bipolar disorder, MDD and schizophrenia.

! BACKGROUND: Exposure to Environmental Tobacco Smoke (ETS) is elevating blood levels of inflammatory mediators and chemoattractants which seem to play an important role in the development of several diseases (e.g. Chronic Obstructive Pulmonary Disease). First evidences showed that men and women might differ in their proneness for these diseases. The aim of this study was to investigate whether there are effects of ETS during pregnancy on inflammatory cytokines in cord blood and in mother’s blood and if there are any differences between male and female newborns. METHODS: Within the LiNA (Lifestyle and environmental factors and their influence on Newborn Allergy Risk) study, whole blood samples of 460 mother-child pairs were analyzed for the concentrations of IL-6, IL-8, IL-10, IL-12, IL-4, IL-5, INF-gamma, TNF-alpha and MCP-1 using cytrometic bead asseys. The association between ETS exposure and cytokines was calculated using the Mann-Whitney-U-test and adjusted with a multiple regression model for parental atopy, parental education status and cat ownership. The exposure assessment is based on questionnaire data on smoking behaviour of the parents and measurement of indoor benzene concentration. RESULTS: Female newborn, being exposed in utero to 10 cigarettes a day or more, had significantly higher blood concentrations of IL-8, IL-6 and MCP-1 whereas there have been no elevations in male newborn being exposed to the same amount of cigarettes. Furthermore a significantly decreased amount of INF-gamma was found in cord blood of male newborns but not in female newborns. General increasing levels of TNF-alpha in cord blood where found for daily smoke exposure without relating it to the exact number of cigarettes. CONCLUSION: The data of this study refer to gender-specific differences in the susceptibility to ETS exposure. The induction of inflammatory signals in cord blood in response to cigarette smoke exposure is stronger in female than in male newborn. / Die vorliegende Arbeit ist Teil einer umweltepidemiologischen Kohortenstudie (LiNA), in der der Einfluss von Umwelt- und Lebensbedingungen auf die Entwicklung von Immunsystem und Allergien bei Neugeborenen unter Einbezug der vorgeburtlichen Zeit untersucht wird. In welchem Maße sich eine Rauchbelastung während der Schwangerschaft auf die Zytokinmuster der Neugeborenen im Nabelschnurblut auswirkt und inwiefern dies mit dem Zytokinmuster der Mutter korreliert, sollte das Ziel dieser Dissertation sein. Dafür wurden Daten von insgesamt 629 Mutter-Kind-Paaren erhoben, Zytokin- und Chemokinbestimmungen, sowie die des Gesamt-IgE aus den Blutproben der 34. SSW und denen der Nabelschnur vorgenommen. Interessanterweise konnten geschlechterspezifische Unterschiede im Zytokinspektrum der Neugeborenen gefunden werden. Bei den weiblichen Neugeborenen zeigte sich eine deutliche Erhöhung proinflammatorischer Marker, wenn deren Mütter dem Rauch von mehr als 10 Zigaretten pro Tag ausgesetzt waren. Dieser Anstieg war weder im Blut der männlichen Neugeborenen noch im Blut der Schwangeren in der 34. SSW zu beobachten. Zusätzlich konnte beobachtet werden, dass auch einzig die männlichen Neugeborenen stark negativ mit ihrer IFN-gamma-Produktion auf die passive Rauchbelastung reagieren. Die mit dieser Arbeit ermittelten Daten, dass das Immunsystem beim Neugeborenen geschlechterspezifisch unterschiedlich auf Tabakrauch zu reagieren scheint, sind erstmals in der Literatur zu finden. Die Erforschung des Immunsystems und dessen Beteiligung an zahlreichen Erkrankungen, besonders den chronisch Inflammatorischen, ist durchaus relevant im medizinischen Alltag. Diese Arbeit trägt einen weiteren Baustein dazu bei und gibt Anstoß für weitere Studien.

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No. of bitstreams: 1 carneiro_lc_dr_jabo.pdf: 2347194 bytes, checksum: 385e788cab291232de3fc02da72024b3 (MD5) Previous issue date: 2016-02-03 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / De modo geral, o objetivo deste estudo foi determinar se as células endometriais bovinas responderam a análogos virais de padrões moleculares associados a patógenos (PAMPs) mediante a produção de citocinas pró-inflamatórias após ativadas pelos receptores “Toll-Like” (TLRs) no endossoma celular e no citoplasma celular pelo genes indutores de ácido retinóico tipo I (RIG-I). No primeiro experimento, amostras uterinas de vacas de corte mestiças pós-púberes foram dissectadas para obtenção de células endometriais epiteliais e estromais. Um controle negativo e quatro PAMPs: LPS, ssRNA, Poly I:C (LMW), Poly (I:C) HMW foram utilizados. Dois grupos de tratamentos (transfectados e não transfectados) foram analisados durante 24 horas. Em outro experimento, células endometriais foram tratadas apenas com o PAMP Poly (I:C) LMW e um grupo Controle Negativo. Neste, os grupos foram incubados às 0, 2, 6, 12, 24, 36, 48 e 72 horas. Sobrenadantes foram colhidos para desenvolver o teste de ELISA para IL-6 e IL-8. Células epiteliais produziram IL-6 em resposta ao Poly I:C (HMW) quando comparadas com o Controle (Grupo DOTAP positivo; P< 0.05), enquanto que o LPS induziu produção de IL-6 e IL-8 em células estromais (P< 0.05). O uso de um reagente de transfecção entre as células e tratamentos demonstrou efeito (P> 0.05). Ainda, células estromais tratadas por Poly I:C (LMW) demonstraram uma maior produção de IL-6 às 48 e 72 horas (P< 0.05), e para o IL-8 às 6, 12, 24, 36, 48 e72 horas quando comparadas com o grupo Controle (P< 0.05). No segundo experimento, outras amostras uterinas de vacas de corte pós-púberes foram utilizadas. A obtenção de células endometriais estromais e epiteliais foram isoladas pelo mesmo protocolo do primeiro experimento. O PAMP Poly (I:C) LMW e um controle negativo foram utilizados. Proteínas para o RIG-I e p65 foram colhidas após 12, 24, 48 e 72 horas de tratamento. Em resposta a Poly (I:C) LMW, células estromais ativaram o RIG-I às 48 hours (P< 0.05) quando comparadas com o grupo controle. Enquanto que, as células epiteliais não foram suficientemente estimuladas pelo Poly (I:C) LMW na ativação do RIG-I em nenhum momento testado (P> 0.05). A proteína p65 depois de estimulada pela Poly (I:C) LMW foi ativada às 12 horas pelas células estromais (P< 0.05) e às 24 horas pelas células epiteliais (P< 0.05). Conclui-se que, células endometriais bovinas foram essenciais na ativação das vias exercidas tanto pelos TLR como RIG-I com função de iniciar uma defesa imunológica contra infecções virais. / In general, the objective of this study was to determine if bovine endometrial cells replied to virus analogs of pathogen associated molecular pattern (PAMPs) by production of proinflammatory cytokines after Toll-Like Receptor (TLR) activation in the cell endosome and after retinoic acid inducible gene – I (RIG-I) stimulation in the cell cytoplasm. In the first experiment, uterine samples from post pubertal cross-breed beef cows were dissected using a protocol to obtain epithelial and stromal cells. A negative control and four different PAMPs: LPS, ssRNA, Poly I:C (LMW), Poly (I:C) HMW were used. Two treatments (transfected and non-transfected) groups were investigated during 24 hours. In the other experiment, endometrial cells were treated with only Poly (I:C) LMW and a negative Control group. All incubated at 0, 2, 6, 12, 24, 36, 48 and 72 hours. Supernatants were collected to develop Elisa for IL-6 and IL-8. Epithelial cells produced IL-6 in response do Poly I:C (HMW) compared to Control (P< 0.05), otherwise, LPS induced IL-6 and IL-8 in stromal (P< 0.05). The transfection Reagent differ between cells and treatments (P> 0.05). Still, in stromal cells treated by Poly I:C (LMW) the production of IL-6 was higher at 48 and 72 hours (P< 0.05), and for IL-8 at 6, 12, 24, 36, 48 and 72 hours when compared to the Control (P< 0.05). In the second experiment, uterine samples from others post pubertal mixed-breed beef cows were used. To obtain stromal and epithelial cells, uterine samples were dissected with the same protocol as the first experiment. The PAMP Poly (I:C) LMW and a negative control were used. Proteins for RIG-I and p65 were collected after 12, 24, 48 and 72 hours. In response to Poly (I:C) LMW induction, stromal cells activated RIG-I at 48 hours (P< 0.05) were compared to the Control group. On the other hand, epithelial cells were not sufficient stimulated Poly (I:C) LMW to activate RIG-I at any time point evaluated (P> 0.05). The protein p65 after stimulated by Poly (I:C) LMW was activated at 12 hours by stromal (P< 0.05) and at 24 hours by epithelial cells (P< 0.05). In conclusion, bovine endometrial cells were elemental factors in the activation of both TLR and RIG-I pathway in order to start an immune defense against viral infection. / CNPq: 140625/2013-5

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Made available in DSpace on 2014-06-11T19:32:41Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-11-26Bitstream added on 2014-06-13T18:43:57Z : No. of bitstreams: 1 lopes_fcm_dr_arafcf.pdf: 1909059 bytes, checksum: 974b3ea32c4f5b47c9236b3e9490981c (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Universidade Estadual Paulista (UNESP) / Produtos naturais têm contribuído intensamente para o desenvolvimento da terapêutica moderna. As plantas produzem um vasto número de substâncias, que em estado natural ou após sofrerem transformações químicas, possuem diversas atividades farmacológicas. Fungos endofíticos, organismos que vivem no interior das plantas, também podem representar novas fontes de produtos biologicamente ativos. Atualmente, a relação causal entre inflamação, imunidade inata e câncer é largamente aceita. O envolvimento de mediadores inflamatórios, como óxido nítrico (NO) e citocinas, gerados por macrófagos ativados, na patogênese das doenças inflamatórias já está bem estabelecido. Além disso, a inibição da angiogênese tem sido reconhecida como uma promissora abordagem terapêutica para o controle do crescimento tumoral, das metástases e das doenças inflamatórias crônicas. Alchornea glandulosa Poepp & Endl. (Euphorbiaceae) é uma planta com conhecida atividade antiinflamatória que está distribuída do sudeste ao sul do Brasil, principalmente na Mata Atlântica e no Cerrado. O potencial antiinflamatório, antitumoral e antiangiogênico dos compostos obtidos a partir da planta (fração acetato de etila e os compostos puros isoquercitrina, afzelina, ácido gálico, pteroginina e pteroginidina) e de fungos endofíticos presentes no interior das suas folhas (extratos acetato de etila ALG-A, ALG-02 e ALG-03) foram estudados por meio de experimentos utilizando-se culturas de macrófagos murinos, linhagens tumorais murinas de câncer de mama (LM2) e pulmão (LP07) e culturas de células endoteliais de veia umbilical humana (HUVEC). Ensaios de determinação de óxido nítrico (reagente de Griess), citocinas pró-inflamatórias TNF-α, IL-1β, IL-6 e IL-12 (ELISA), atividade citotóxica (MTT) e avaliação da taxa de inibição do crescimento de tumores tratados com injeção... / Natural products have contributed enormously to the development of important therapeutic drugs used currently in modern medicine. Plants produce a vast number of compounds that, either directly or after chemical modifications, exert pharmacological activities. Endophytic fungi, organisms which live in plants, are also being recognized as new sources of biological active substances. Nowadays, the relationship among inflammation, innate immunity and cancer are widely accepted. Inflammatory mediators as nitric oxide (NO) and cytokines produced by activated macrophages are involved in the pathogenesis of inflammatory diseases. Besides that, angiogenesis inhibition has been accepted as a promising therapy for the control of tumor growth, metastasis and also chronic inflammatory conditions. Alchornea glandulosa Poepp & Endl. (Euphorbiaceae) is a plant that demonstrates anti-inflammatory activity. It can be found in Brazil, distributed from southeast to south, mainly in the Atlantic Forest and Cerrado. The anti-inflammatory, antitumor and antiangiogenic potential of the compounds obtained from this plant (ethyl acetate fraction and the pure compounds isoquercitrin, afzelin, gallic acid, pterogynine and pterogynidine) and from the endophytic fungi present in its leaves (ALG-A, ALG-02 and ALG-03 ethyl acetate extracts) were studied using macrophage cultures, tumor cell lines (LM2 and LP07) and human umbilical vein endothelial cells (HUVEC). To evaluate anti-inflammatory and antitumor activity, in vitro assays were utilized to determine NO (Griess reagent), TNF-α, IL-1β, IL-6 and IL-12 proinflammatory cytokines (ELISA) and cytotoxicity (MTT). Tumor growth inhibition rate was also studied in vivo. Apoptosis (TUNEL assay), proliferation (bromodeoxiuridine – BrdU), invasion (double-chamber assay), capillary-like structures formation (matrigel) and NFκB activity (ELISA) were realized to study... (Complete abstract click electronic access below)

Made available in DSpace on 2016-12-08T15:59:05Z (GMT). No. of bitstreams: 1 TESE DAIANA BUNDCHEN.pdf: 729468 bytes, checksum: baf7cf5ef2b6e7a70f9f8546f04ecd74 (MD5) Previous issue date: 2013-12-16 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The effects of training on the metabolic pathways in chronic heart failure (CHF), specially the intravascular lipid metabolism are largely unexplored and deserve further investigation. Objectives: To analyze the effects of short-term exercise training on the plasma lipids, on lipid transfer to HDL and cytokine levels in CHF patients.Method: We compared plasma lipids, in vitro transfer of four lipids from a radioactively labeled lipid donor nanoemulsion to HDL and cytokine levels (TNF-&#945; and IL-6) in CHF patients, class II or III (NYHA) with (n=9) or without (n=10) statin treatment before and after 12 weeks of exercise training. The aerobic exercise was performed three times a week, during 40 minutes, with heart rate intensity between L1 and L2 of the cardiopulmonary test. Results: Exercise training reduced the LDL-C in the statin-treated group (-16%; p=0.03) and increased HLD-C (+24%; p=0.05) in without statin group. Exercise training elicited a significant increase the transfer of triglycerides from the donor nanoemulsion to HDL in statin-treated group (p=0.03). The transfers of the three other lipids (unesterified and esterified cholesterol and phospolipids) were unchanged. In the without statin-treatment the transfers of all four lipids were not change by training. For cytokines, in those without statintreatment, the TNF-&#945; reduced 28% (p<0,01), while in the group with statin reduced 12% (p=0,07). The seric concentration of the IL-6 reduced 41% (p<0,001) in the group without simvastatin and 45% (p<0,001) in the statin-treatment group. In both groups no correlation was observed between HDL and proinflammatory cytokines. Conclusion: In CHF patients, the short-term training , increased HLD-C in the statin-treated group, showing no functional change in this lipoprotein particles; reduced the LDL-C and increased significantly the lipis transfer only triglycerides in the statin-treated group. The decrease in cytokine levels for both groups indicated the early benefits of exercise. / Os efeitos do treinamento físico sobre as vias metabólicas na insuficiência cardíaca (IC), especialmente o metabolismo lipídico intravascular e sua associação com as citocinas pró-inflamatórias, são em grande parte inexplorados e merecem uma investigação mais aprofundada. Objetivos: analisar os efeitos de um curto período de treinamento físico nos lipídeos plasmáticos, na transferência de lípides para HDL e nos níveis de citocinas pró-inflamatórias em pacientes com IC. Métodos: antes e após 12 semanas de treinamento físico foram avaliados 19 homens com IC, classe funcional II ou III (NYHA), sendo nove sujeitos em uso de sinvastatina e 10 sem uso de sinvastatina. Foi comparado o perfil lipídico, transferência in vitro dos quatro lípides de uma nanoemulsão doadora de lípides marcada radioativamente para a HDL e níveis de citocinas pró-inflamatórias (TNF-&#945; e IL-6). O exercício aeróbio foi realizado três vezes por semana, durante 40 minutos, com intensidade na frequência cardíaca correspondente a faixa entre o primeiro e segundo ponto dos limiares ventilatórios, determinados pelo teste de esforço cardiopulmonar. Resultados: Foi observada redução do LDL-Colesterol (-16%; p=0,03) no grupo tratado com sinvastatina e aumento de HDL-Colesterol (+24%; p=0,05) no grupo sem sinvastatina. No grupo com sinvastatina ocorreu um aumento significativo da transferência de triglicérides da nanoemulsão doadora de lípides para HDL (p=0,03) enquanto a transferência dos outros três lípides (fosfolípides, colesterol livre e colesterol esterificado) não se modificou. No grupo sem sinvastatina a transferência de todos os quatro lípides não se alterou. No grupo sem uso de sinvastatina o TNF-&#945; reduziu 28% (p<0,01), enquanto no grupo com estatina reduziu 12% (p=0,07). A concentração sérica de IL-6 reduziu 41% (p<0,001) no grupo sem sinvastatina e 45% (p<0,001) no grupo em uso de sinvastatina. Em ambos os grupos não foi observado correlação entre HDL e citocinas pró-inflamatórias. Conclusão: Em pacientes com IC, o curto período de treinamento físico aumentou HDL-Colesterol no grupo sem sinvastatina, não apresentando mudança funcional das partículas desta lipoproteína; reduziu o LDL-Colesterol e aumentou significativamente a transferência apenas dos triglicérides no grupo em tratamento com sinvastatina. A diminuição dos níveis de citocinas para ambos os grupos indicou os benefícios precoces do exercício físico.