Paricalcitol reduces peritoneal fibrosis in mice through the activation of regulatory T cells and reduction in IL-17 production

Fibrosis is a significant health problem associated with a chronic inflammatory reaction. The precise mechanisms involved in the fibrotic process are still poorly understood. However, given that inflammation is a major causative factor, immunomodulation is a possible therapeutic approach to reduce fibrosis. The vitamin D receptor (VDR) that is present in all hematopoietic cells has been associated with immunomodulation. We investigated whether the intraperitoneal administration of paricalcitol, a specific activator of the VDR, modulates peritoneal dialysis fluid (PDF)-induced peritoneal fibrosis. We characterized the inflammatory process in the peritoneal cavity of mice treated or not treated with paricalcitol and analyzed the ensuing fibrosis. The treatment reduced peritoneal IL-17 levels, which strongly correlated with a significantly lower peritoneal fibrotic response. In vitro studies demonstrate that both CD4+ and CD8+ regulatory T cells appear to impact the regulation of IL-17. Paricalcitol treatment resulted in a significantly increased frequency of CD8+ T cells showing a regulatory phenotype. The frequency of CD4+ Tregs tends to be increased, but it did not achieve statistical significance. However, paricalcitol treatment increased the number of CD4+ and CD8+ Treg cells in vivo. In conclusion, the activation of immunological regulatory mechanisms by VDR signaling could prevent or reduce fibrosis, as shown in peritoneal fibrosis induced by PDF exposure in mice.This study was supported by RETICS 06/0016 (VFM, RS) and FIS PI 09/0064 (RS) from the Fondo de Investigaciones Sanitarias (Health Research Fund). MLC was funded by SAF 2013-47611-R, SAF 2010-21249, and SAF 2007-61201 from the Ministerio de Economía y competitividad. MRO was supported by RETICS 12/0021,S2012DMD2321 from the Comunidad Autónoma de Madrid, PI 11/01854 from Fondo Investigaciones Sanitarias. GTGM was supported by Renal Foundation Íñigo Álvarez de Toledo, FIBHULP, and by Severo Ochoa FoundationPeer Reviewe

Análise de desempenho econômico da produção orgânica de leite: estudo de caso no Distrito Federal

Neste trabalho, objetivou-se analisar economicamente a produção orgânica de leite. Para esta avaliação foram utilizados os dados obtidos em uma propriedade certificada como orgânica, localizada no Distrito Federal, durante os períodos de 2002 e 2003. A Renda Líquida (RL) por litro de leite foi positiva no ano de 2002 e negativa no de 2003, considerando-se o preço do leite a R$0,40/ L, (preço histórico pago ao produtor de leite convencional na região), apresentando resultados positivos com o preço simulado de R$ 0,80/L (preço pago aos produtores orgânicos nas Regiões Sul e Sudeste do país). Os índices de produtividade foram semelhantes aos observados nas propriedades convencionais. A produção orgânica de leite pode ser uma alternativa economicamente viável para a pecuária, desde que haja uma remuneração superior à praticada para o leite convencional

Treatment with Natalizumab in Relapsing–Remitting Multiple Sclerosis Patients Induces Changes in Inflammatory Mechanism

Natalizumab is a widely accepted drug for the relapsing–remitting subtype of multiple sclerosis (RRMS). The present longitudinal exploratory study in RRMS patients analyzes the effects of natalizumab treatment on the levels of pro-inflammatory and anti-inflammatory cytokine protein levels and also the frequency and suppressor function of regulatory T cells. Flow cytometry was used to determine cytokines and regulatory T cell frequency while regulatory T cell suppressor function was assayed in vitro at different time-points after starting with natalizumab. Results showed serum levels of pro-inflammatory interferon gamma and interleukin (IL)-12p70, as well as anti-inflammatory IL-4 and IL-10, were elevated just a few hours or days after first IV infusion of natalizumab. Interestingly, other cytokines like IL-5 or IL-13 were also elevated while pro-inflammatory IL-17, IL-2, and IL-1β increased only after a long-term treatment, suggesting different immune mechanisms. In contrast, we did not observe any effect of natalizumab treatment on regulatory T cell frequency or activity. In conclusion, these results suggest natalizumab has other immunological effects beyond VLA-4 interaction and inhibition of CNS extravasation, the relevance of which is as yet unknown and warrants further investigation

Desempenho de bezerros aleitados com soro de queijo em associação ao colostro

O objetivo deste trabalho foi avaliar o desempenho de bezerros mestiços, aleitados com soro de queijo em associação ao colostro. Foram utilizados 24 bezerros Holandês x Zebu, distribuídos em delineamento inteiramente casualizado, com três tratamentos e oito repetições. Os tratamentos consistiram de: leite integral, 50% de leite integral + 50% de soro de queijo, e 30% de colostro + 70% de soro de queijo. O desenvolvimento dos bezerros foi avaliado até os 60 dias de idade, por meio de pesagens semanais e mensurações corporais. Para a estimativa de consumo, foram feitas medições diárias de consumo da dieta sólida, pelo método oferta/sobra. O desempenho econômico foi avaliado pelo cálculo de indicadores de custos e receitas, e de medidas de resultados econômicos. Não houve influência da dieta líquida sobre o consumo de matéria seca e sobre as médias de medidas corporais dos bezerros. Foram observadas diferenças significativas no ganho de peso dos animais na segunda e na quarta semanas de vida. A dieta com colostro apresentou o maior lucro adicional em comparação ao tratamento controle. A associação do soro de queijo ao colostro é a opção mais vantajosa economicamente, já que a substituição de 100% do leite por esses subprodutos não prejudicou o desempenho dos animais

Paricalcitol reduces peritoneal fibrosis in mice through the activation of regulatory T cells and reduction in IL-17 production.

Fibrosis is a significant health problem associated with a chronic inflammatory reaction. The precise mechanisms involved in the fibrotic process are still poorly understood. However, given that inflammation is a major causative factor, immunomodulation is a possible therapeutic approach to reduce fibrosis. The vitamin D receptor (VDR) that is present in all hematopoietic cells has been associated with immunomodulation. We investigated whether the intraperitoneal administration of paricalcitol, a specific activator of the VDR, modulates peritoneal dialysis fluid (PDF)-induced peritoneal fibrosis. We characterized the inflammatory process in the peritoneal cavity of mice treated or not treated with paricalcitol and analyzed the ensuing fibrosis. The treatment reduced peritoneal IL-17 levels, which strongly correlated with a significantly lower peritoneal fibrotic response. In vitro studies demonstrate that both CD4+ and CD8+ regulatory T cells appear to impact the regulation of IL-17. Paricalcitol treatment resulted in a significantly increased frequency of CD8+ T cells showing a regulatory phenotype. The frequency of CD4+ Tregs tends to be increased, but it did not achieve statistical significance. However, paricalcitol treatment increased the number of CD4+ and CD8+ Treg cells in vivo. In conclusion, the activation of immunological regulatory mechanisms by VDR signaling could prevent or reduce fibrosis, as shown in peritoneal fibrosis induced by PDF exposure in mice

Paricalcitol reduced peritoneal membrane fibrosis, inflammation and ultrafiltration failure in mice exposed to PDF.

<p>A) Paraffin sections of the peritoneal membrane from the 3 groups were stained with Masson's trichrome. B) Thickening of the peritoneal membrane was determined by morphometric analysis. C) Peritoneal permeability was determined by net ultrafiltration. D) The presence of inflammatory and mesothelial cells was determined by the expression of CD45 (green) and cytokeratin (red), respectively, in frozen sections of peritoneal membrane representative of each group. A green arrow indicates hematopoietic cells. A red arrow indicates mesothelial cells. E) The angiogenesis was determined by the expression of CD31 (green). Cytokeratin-positive cells are stained in red. The color balance was equally adjusted in immunofluorescence using Photoshop V10 for Mac (Abobe Systems Incorporated, US). n≥5 in each group. Statistical significance was determined using the Mann-Whitney test. *<i>P</i><.05; ***<i>P</i><.001.</p