Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 137-169).

Submitted by Thiago Alves de Souza null (thiagobasouza@hotmail.com) on 2017-12-01T02:38:57Z No. of bitstreams: 1 Dissertação_Thiago_Alves_de_Souza.pdf: 1361479 bytes, checksum: 607ce9719a0123dea1f4b2761a5e36e2 (MD5) / Submitted by Thiago Alves de Souza null (thiagobasouza@hotmail.com) on 2017-12-04T14:43:23Z No. of bitstreams: 1 Dissertação_Thiago_Alves_de_Souza.pdf: 1361479 bytes, checksum: 607ce9719a0123dea1f4b2761a5e36e2 (MD5) / Submitted by Thiago Alves de Souza null (thiagobasouza@hotmail.com) on 2017-12-05T14:11:15Z No. of bitstreams: 1 Dissertação_Thiago_Alves_de_Souza.pdf: 1361479 bytes, checksum: 607ce9719a0123dea1f4b2761a5e36e2 (MD5) / Submitted by Thiago Alves de Souza null (thiagobasouza@hotmail.com) on 2017-12-11T18:47:11Z No. of bitstreams: 1 Dissertação_Thiago_Alves_de_Souza.pdf: 1361479 bytes, checksum: 607ce9719a0123dea1f4b2761a5e36e2 (MD5) / Approved for entry into archive by Alexandra Maria Donadon Lusser Segali null (alexmar@fcav.unesp.br) on 2017-12-13T12:06:42Z (GMT) No. of bitstreams: 1 souza_ta_me_jabo.pdf.pdf: 1361479 bytes, checksum: 607ce9719a0123dea1f4b2761a5e36e2 (MD5) / Made available in DSpace on 2017-12-13T12:06:42Z (GMT). No. of bitstreams: 1 souza_ta_me_jabo.pdf.pdf: 1361479 bytes, checksum: 607ce9719a0123dea1f4b2761a5e36e2 (MD5) Previous issue date: 2017-10-20 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / As neoplasias mamárias constituem os tumores com maior incidência em cadelas. Dentre os fatores que contribuem para o desenvolvimento desta e de outras neoplasias, o microambiente tumoral inflamatório desempenha um papel crucial. Vários estudos relataram papéis importantes para linfócitos, macrófagos, plasmócitos, neutrófilos, eosinófilos e mastócitos neste contexto. No presente estudo, o objetivo foi avaliar a densidade de células inflamatórias e área de fibrose tumoral e sua relação com tumores mamários caninos com diferentes características histológicas e clínicas (tumor misto benigno, carcinoma em tumor misto, carcinoma sólido e carcinoma tubular). A análise de células inflamatórias e área de fibrose tumoral foram realizadas por meio de técnicas histoquímicas, enquanto a identificação de linfócitos Tregs foram realizadas por imuno-histoquímica. A análise estatística das densidades de células inflamatórias e áreas fibrose tumoral e sua relação com os tipos histológicos revelou diferença significativa para as plasmócitos (p = 0,035), neutrófilos (p = 0,0113), macrófagos (p = 0,0047) e fibrose tumoral (p = 0,05). Os dados encontrados sugerem associações entre alto número de neutrófilos e neoplasias mamárias agressivas, entre altas densidades de plasmócitos, macrófagos e células CD8+ e entre menor densidade de células CD4+ e neoplasias menos agressivas. Maiores áreas de fibrose tumoral mostraram relação com neoplasias mamárias caninas mais agressivas. / Mammary neoplasias constitute the tumors with higher incidence in bitches. Among the factors that contribute for the development of this and other neoplasias, the inflammatory tumor microenvironment plays a crucial role. Several studies reported important roles for lymphocytes, macrophages, plasma cells, neutrophils, eosinophils and mast cells in this context. In the present study, the goal was to evaluate density of inflammatory cells and area of tumor fibrosis and their relation with canine mammary tumors with different histologic and clinical presentation (benign mixed tumor, carcinoma in mixed tumor, solid carcinoma and tubular carcinoma) Counting and staining of inflammatory cells and tumor fibrosis were performed through histochemistry, while counting and staining of Tregs were performed through immunohistochemistry. Statistical analysis of the densities of inflammatory cells and tumor fibrosis related to histologic types revealed significant difference for plasma cells (p=0,035), neutrophils (p=0,0113), macrophages (p=0,0047), and tumor fibrosis (p=0,05). The found data suggest associations between high number of neutrophils and agressive mammary neoplasias, between high densities of plasma cells, macrophages and CD8+ cells and between low density of CD4+ cells and less aggressive neoplasias. Higher areas of tumor fibrosis showed relation with more aggressive canine mammary neoplasias.

Elevated levels of pro-inflammatory cytokines are implicated in the pathogenesis of major depression. Human and animal studies have shown that pro-inflammatory cytokines can induce a behavioural repertoire of symptoms collectively referred to as 'sickness behaviours', which include cognitive and mood symptoms, social withdrawal and sleep disturbance. When likened to clinical depression, these symptoms appear to be strikingly similar. Moreover, subsets of depressed patients have raised inflammatory markers, 30-50% of patients receiving cytokine treatment in the form of interferon-α (IFN-α) therapy develop depressive symptoms, and significantly higher rates of depression are associated with chronic inflammatory conditions, such as rheumatoid arthritis (RA). Converging evidence has led to the hypothesis that chronic, low-grade inflammation could lead to more persistent alterations in neuropsychological function that might be instrumental in the pathophysiology of depression. However, the mechanisms for this potential modulation of mood and cognitive function are unclear. The current thesis therefore aimed to enhance understanding of the neuropsychological underpinnings of the link between inflammation and depression. Negative emotional processing biases are well-recognised in the aetiology of depression; however potential inflammation-induced alterations in emotional processing remain unexplored. Thus, a series of studies were conducted using human models of immune system activation to examine neuropsychological function. The first study demonstrated that IFN-α treatment in patients with hepatitis C produced negative biases in emotional categorisation, attentional vigilance and a specific effect of enhanced recognition of disgust. The subsequent study found a specific effect of false discrimination of disgusted faces in a healthy volunteer model of inflammatory challenge with typhoid vaccination, however further effects on emotional processing were limited. Typhoid vaccination was also shown to disrupt sleep continuity in ways that may be relevant to depression in the third study. Negative biases were not evident, however, in patients with RA. The final study found that neuropsychological effects of the atypical antidepressant tianeptine were similar to effects following IFN-α, which may be of interest considering tianeptine's purported serotonergic re-uptake enhancing properties and the effects of cytokines on serotonin metabolism. This thesis provides intriguing, yet preliminary, evidence that inflammatory pathways may modulate emotional processing - a mechanism which, if supported, may have future implications for improved identification and treatment of subgroups of depressed patients.

No description available.

Orientador: Pasqual Barretti / Banca: Maria Almerinda Vieira Fernandes Ribeiro Alves / Banca: Jacqueline Costa Teixeira Caramori / Resumo: O risco de morte por doenças cardiovasculares (DCV) em pacientes tratados por hemodiálise (HD) crônica é 10 a 20 vezes maior que o da população geral. Muitos mecanismos têm sido propostos para a gênese das DCV nesses pacientes, como hipervolemia, hipertensão arterial, dislipidemia e elevação do produto cálcio-fósforo, sendo que atualmente a inflamação tem sido apontada como fator de risco independente e associada óbito por essas doenças. Recentemente, a possibilidade da expansão de volume ser uma das causas de inflamação foi considerada e nesse caso, o edema da parede intestinal poderia favorecer a translocação de endotoxinas com conseqüente inflamação. Sabidamente, o acúmulo de volume extracelular na doença renal crônica está associado à retenção de sódio e assim, a redução da concentração de sódio na solução de HD poderia reduzir o volume extracelular e atenuar o estado inflamatório. O objetivo do estudo foi avaliar os efeitos da redução da concentração de sódio na solução de HD sobre a evolução do volume de água corporal e marcadores inflamatórios. Foram incluídos pacientes adultos, tratados regularmente por hemodiálise, com níveis séricos da proteína C reativa (PCR) igual ou maior que 0,7 mg/dl, que foram randomizados em dois grupos: grupo A, constituído de 20 pacientes tratados com a redução da concentração de sódio na solução de HD de 138 mEq/l para 135 mEq/l e grupo B, controle, com 18 pacientes. Na primeira, 8ª e 16ª semanas foram determinados marcadores inflamatórios, bioquímicos, hematológicos, nutricionais, e a quantificação da prescrição dialítica. Quanto às características basais não houve diferenças significantes entre os grupos. Durante o estudo, o grupo A apresentou diminuição significante dos níveis séricos fator de necrose tumoral-α (TNF-α) e interleucina-6 (IL-6) e no grupo B não houve... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The death risk by cardiovascular diseases (CVD) treated in hemodialysis (HD) patients is 10 a 20 times greater than general population. Several pathways have been proposed to explain the CVD origin in these patients, such as hypervolemia, hypertension, lipid disorders and high calcium x phosphorus product; and actually inflammation is considered an independent risk factor associated to death by CVD. Recently, it has been proposed that volume overload could be a cause of inflammation, thus bowel wall edema could favor bacterial endotoxin translocation resulting in systemic inflammation. The extracellular volume overload in chronic kidney diseases is associated to sodium accumulation, thus the reduction of sodium concentration in the HD solutions could reduce the extracellular volume and consequently to attenuate the inflammatory state. The aim of this study was to evaluate the effects of reduction of dialysate sodium concentrations on markers of body water and inflammation. Adult patients on regular HD and C-reactive protein levels ≥ 0, 7 mg/dl were included and randomized in two groups: A, with 20 patients treated by reduction of dialysate sodium concentration from 138 mEq/l to 135 mEq/l and B, control group, with 18 patients. In the first, 8th and 16th weeks inflammatory, biochemical, hematologic, nutritional markers and HD delivers doses were determined. The baseline characteristics were similar between groups. During the study period, there were significant reduction in the serum tumor necrosis factor (TNF-α) e interleukin-6 (IL-6) in the group A, while in group B these markers did not varied significantly. In the treated group there were increase of frequency of muscle cramps and hypotensive episodes, but there were not significant changes in volume markers as well as other laboratory tests. Indeed, the patients were redistributed, in two new groups according to the presence... (Complete abstract click electronic access below) / Mestre

Orientador: Clélia Akiko Hiruma-Lima / Resumo: A dor é um dos principais indicadores de enfermidade. Ela é uma sensação desagradável, complexa e extremamente subjetiva, relacionada a algum estímulo lesivo ou potencialmente lesivo ao organismo. Quando esses estímulos danificam tecidos do organismo a resposta inflamatória é iniciada. Essa resposta é necessária para a resolução de diversos danos e essencial para a defesa do organismo. A inflamação é uma resposta vascular realizada por mediadores inflamatórios. Se houver falha neste processo pode haver a perda da função tecidual. A abordagem mais comum para reduzir a dor e a inflamação é através do uso de medicamentos anti-inflamatórios não esteroidais (AINEs). Entretanto, o uso destes fármacos sem as devidas orientações, ou por longos períodos, pode levar ao aparecimento de sérias reações adversas como as úlceras pépticas. Uma alternativa para o tratamento da dor e inflamação é o uso de espécies vegetais com propriedades medicinais. Nesse contexto, a espécie Arrabidaea brachypoda é uma espécie medicinal comumente utilizada nas regiões sudeste e nordeste brasileira para o tratamento de cálculo renal e dores nas articulações. Considerando a utilização popular da planta, o objetivo do projeto foi avaliar a ação antinociceptiva e anti-inflamatória do extrato diclorometano das raízes de A. brachypoda (DEAB) em modelos experimentais in vivo e seus mecanimos de ação. Neste trabalho avaliamos a toxicidade aguda do DEAB e também o efeito desse extrato sobre a performance motora dos a... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

Orientador: Gisele Fabrino Machado / Banca: Valéria Marçal Felix de Lima / Banca: Flávia Lombardi Lopes / Banca: Paulo Ricardo Dell'Amerina Rocha / Banca: Monica Regina Vendrame Amarante / Resumo: A leishmaniose visceral (LV) é uma doença parasitária que apresenta distribuição mundial e que pode afetar homens e animais, sendo que o cão é considerado o principal hospedeiro da doença. Cães infectados pelo parasito Leishmania podem apresentar-se assintomáticos ou com desordens generalizadas, incluindo alterações neurológicas. Existem alguns relatos do acometimento do encéfalo durante a infecção, mas a neuropatogenia da doença não foi completamente elucidada. Há evidências do comprometimento das barreiras encefálicas e da presença do DNA do parasito no encéfalo. Os receptores tipo Toll (TLRs) são sensores do sistema imune inato capazes de detectar padrões moleculares associados aos patógenos (PAMPs), desencadeando uma resposta inflamatórias com produção de diversos mediadores inflamatórios, incluindo citocinas. Desta forma, o objetivo deste estudo foi avaliar o perfil de expressão gênica dos Tolls 1-10, assim como a produção de citocinas pró-inflamatórias TNF-α, IFN-γ, IL-1β e IL-6 no encéfalo e no baço de cães com leishmaniose visceral. No baço houve aumento de expressão gênica de TLR-5 e TLR-9, enquanto no encéfalo houve aumento de TLR-4 em uma pequena população de cães infectados. Em relação às citocinas, todas as citocinas foram detectadas nos dois tecidos avaliados, com excessão de IL-6. Nos cães infectados, TNF-α e IL-1β estavam presentes em maiores concentrações no encéfalo e no baço, respectivamente. Este estudo fornece suporte para explicar o envolvimento de TLRs ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract:Visceral leishmaniasis (VL) is a parasitic disease that presents world distribution, affecting humans and animals. Dogs are considered the main hosts of the disease. Infected dogs with the Leishmania parasite can be asymptomatic or present generalized disorders, including neurological alterations. There are some reports of brain commitment during infection. Nevertheless, neuropathogenesis of VL is not completely elucidated. There are evidences of brain barriers breakdown and of the presence of Leishmania DNA in the brain. Toll-like receptors (TLRs) are innate immune sensors capable of detecting pathogen-associated molecular patterns (PAMPs), trigger an inflammatory response with production of several inflammatory mediators, including cytokines. Therefore, the aim of this study was to evaluate gene expression profile of TLRs1-10, along with the production of proinflammatory cytokines in both brain and spleen in dogs with VL. In spleen there was an upregulation of TLR-5 and TLR-9 while in the brain there was up-regulation of TLR- 4 in a few number of infected animals. Regarding cytokines, all cytokines were detected in both tissues, except IL-6. In the infected dogs, TNF-α and IL-1β were present at higher concentrations in the brain and spleen, respectively. This study provides support to explain the involvement of TLRs in VL and our data confirm the brain as an affected organ in this disease / Doutor

Chronic non-healing wounds commonly present in patients with diabetes. These wounds are characterised by elevated numbers of immature leukocytes and M1 macrophages and reduced numbers of endothelial cells and M2 macrophages, impairing wound healing resolution. Topical treatment of murine diabetic wounds with a Hoxa3 gene expression vector redresses the balance of inflammatory and pro-healing cells within the lesion, reducing excessive inflammation and rescuing the wound healing phenotype. In this thesis I present experiments to further understanding of how diabetes alters the macrophage phenotype and how this may cause the decreased endothelial cell and M2 macrophage numbers in the diabetic wound. In vitro culture was used to characterize the intrinsic changes of diabetic macrophages isolated from the environmental effects of the diabetic wound milieu. These same systems were used to develop a cell culture system for the promotion of monocytic to endothelial transdifferentiation. Finally the in vitro macrophage culture system was used to assess the effects of Hoxa3 treatment upon diabetic macrophages and how Hoxa3 transcriptional activity in macrophages may contribute to the restoration of wound healing. In vitro cultured diabetic macrophages were observed to raise an increased response to classical and alternative activation signals that may contribute to the excessive inflammatory state of diabetic cutaneous wounds. Treatment of these macrophages for four days with a Hoxa3 conditioned medium protein transduction system upregulated the expression of the plasminogen activator urokinase receptor gene Plaur and enhanced the expression of macrophage maturation markers. These macrophages also exhibit an enhanced response to classical activation stimuli, a reduced alternative activation response. In an in vitro neovascularisation assay Hoxa3 treated macrophages inhibit vessel growth. These effects of Hoxa3 treatment of diabetic macrophages are unexpected based on the rescue of the inflammatory phenotype with Hoxa3 treatment of diabetic wounds. Non-diabetic macrophages were also treated for four days with a Hoxa3 conditioned medium and exhibited upregulation of macrophage maturation markers. These macrophages showed no difference in activation state polarisation compared to macrophages grown in a control conditioned medium but did upregulate activation markers in unstimulated cells. This may be indicative of a priming for response to low levels of activation stimuli. The Hoxa3 treated non-diabetic cells also promoted the formation of vessel networks in a neovascularisation co-culture assay, possibly through the promotion of angiogenesis. These results suggest that diabetes directly effects the maturation and inflammatory phenotype of macrophages and that Hoxa3 treatment rescues the impaired maturation phenotype and may stimulate macrophage populations to a pro-angiogenic state.

abstract: Studies have demonstrated that anthocyanins can function as antioxidants, reduce inflammation, and improve dyslipidemia. Tart cherries are anthocyanin-rich, making them particularly attractive as a functional food to improve cardiovascular disease (CVD) risk. There have been few published studies to date examining the impact of tart cherries on biomarkers of dyslipidemia and inflammation, particularly in overweight and obese individuals at high risk for these conditions. This study evaluated the effect of consuming 100% tart cherry juice daily on blood lipids including total cholesterol, low-density lipoprotein cholesterol (LDL-C), calculated very low density lipoprotein cholesterol (VLDL-C), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), and the CVD risk ratios, as well as the inflammatory biomarkers interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), C-reactive protein (CRP), monocyte chemotactic protein-1 (MCP-1), and erythrocyte sedimentation rate (ESR) following a 4-week period. Based on the high anthocyanin content of tart cherries, it was hypothesized that the lipid and inflammatory profiles would be significantly improved following the intervention. A total of 26 men and women completed this 4-week randomized, single-blind, placebo-controlled, crossover study. Participants were randomized to drink either 8 ounces of placebo beverage or tart cherry juice daily for 4 weeks. Following a 4-week washout period, the alternate beverage was consumed. Ultimately, this investigation demonstrated no statistically significant alterations in any of the lipid or inflammatory biomarkers when analyzed across time and between interventions (p > 0.05). As expected, glucose and insulin parameters remained stable over the duration of the study, as well as self-reported physical activity level, total calorie consumption, and macronutrient intake. However, trans-fat was reported to be significantly higher during the cherry arm of the study as compared to the placebo arm (p < 0.05), potentially confounding other results. Although the results of this study were equivocal, it is feasible that a higher dose, longer treatment duration, or more susceptible target population may be required to elicit significant effects. Consequently, further investigation is necessary to clarify this research. / Dissertation/Thesis / M.S. Nutrition 2012

Elevation of VEGFR-3, the primary mediator of lymphangiogenesis (i.e., new lymphatic vessel formation), is frequently associated with inflammation related to chronic disease and cancer. In the latter case, VEGFR-3 dependent lymphangiogenesis induced by inflamed tumors increases the incidence of distant metastasis, leading to decreased patient survival. However, the molecular mechanisms underlying inflammation-induced VEGFR-3 elevation and lymphangiogenesis are currently unknown. Two potential candidate genes that may regulate expression of VEGFR-3 are Prox1, the primary mediator of embryonic lymphangiogenesis, and NF-κB, the key intracellular regulator of inflammation-induced transcription. We hypothesized that the key inflammatory mediator, NF-κB, regulates transcription of key mediators of lymphangiogenesis, VEGFR-3 and Prox1. We further hypothesized that inflammation-induced elevation of VEGFR-3 and Prox1 are essential steps required for robust lymphangiogenesis in response to inflammation. The three primary goals of this study were to (1) delineate the time-course of events leading to inflammation-induced lymphangiogenesis in vivo; (2) clone and characterize the VEGFR-3 promoter and identify factors regulating VEGFR-3 expression in vitro; and (3) characterize the lymphatic phenotype of NF-κB p50 knockout mice. To begin testing these hypotheses, we used a mouse model of peritonitis to characterize induction of lymphangiogenesis and expression kinetics of NF-κB, Prox1 and VEGFR-3. In vivo time-course analysis of inflammation-induced lymphangiogenesis showed activation of NF-κB followed by sequential upregulation of Prox1 and VEGFR-3 that preceded lymphangiogenesis by 4 and 2 days, respectively. Characterization of the VEGFR-3 promoter by luciferase-reporter and ChIP assays showed direct activation by Prox1, NF-κB p50 and p65 transcription factors. This also revealed that Prox1 and NF-κB p50 bind in close proximity and synergistically activate the VEGFR-3 promoter. Characterization of p50 knockout mice revealed significantly decreased lymphatic vessel density in several organs that corresponded to reduced VEGFR-3 and Prox1 expression. Activation of NF-κB by inflammatory stimuli also elevated expression of NF-κB, Prox1 and VEGFR-3 in cultured lymphatic endothelial cells, which enhanced proliferation and migration in response to the VEGFR-3-specific ligand, VEGF-C152S. Collectively, our findings suggest that induction of the NF-κB pathway by inflammatory stimuli activates Prox1, and both NF-κB and Prox1 activate the VEGFR-3 promoter leading to increased receptor expression in lymphatic endothelial cells. This, in turn, enhances the responsiveness of pre-existing lymphatic endothelium to VEGFR-3 binding factors, VEGF-C and VEGF-D, ultimately resulting in robust lymphangiogenesis.