Network strategies to understand the aging process and help age-related drug design

Recent studies have demonstrated that network approaches are highly appropriate tools to understand the extreme complexity of the aging process. The generality of the network concept helps to define and study the aging of technological, social networks and ecosystems, which may give novel concepts to cure age-related diseases. The current review focuses on the role of protein-protein interaction networks (interactomes) in aging. Hubs and inter-modular elements of both interactomes and signaling networks are key regulators of the aging process. Aging induces an increase in the permeability of several cellular compartments, such as the cell nucleus, introducing gross changes in the representation of network structures. The large overlap between aging genes and genes of age-related major diseases makes drugs which aid healthy aging promising candidates for the prevention and treatment of age-related diseases, such as cancer, atherosclerosis, diabetes and neurodegenerative disorders. We also discuss a number of possible research options to further explore the potential of the network concept in this important field, and show that multi-target drugs (representing "magic-buckshots" instead of the traditional "magic bullets") may become an especially useful class of age-related future drugs.Comment: an invited paper to Genome Medicine with 8 pages, 2 figures, 1 table and 46 reference

OCUPAÇÃO IRREGULAR: OS ENTRAVES AO PROCESSO DE REGULARIZAÇÃO FUNDIÁRIA EM GOIÂNIA - O Residencial JK.

Made available in DSpace on 2016-08-10T10:49:51Z (GMT). No. of bitstreams: 1 GLADES MARIA DE JESUS DA SILVA SOARES.pdf: 34738059 bytes, checksum: 31cca2a56f989c45052ddde1e3dd31fd (MD5) Previous issue date: 2013-03-14This research seeks to understand the relationship between the occupations of town formal and informal, having as its object of study the process of irregular occupation in the city of Goiânia, and the restrictions of regularization of these possessions. The occupations are irregular phenomena in urban growth in Brazil and reflection of this reality in Goiânia, that the last ten years there has been an increase of more than 50,000 irregular occupations. Thus, faced with such a perspective, this paper is of a dialectical approach of urban space in Goiânia, in order to investigate the barriers of the regularization process, which derive other social problems such as violence, social exclusion, and urban segregation social. In such aspects and the full regularization process comprises three aspects: urban, environmental and legal which involve different public institutions that need to be coordinated and integrated, making the management of these actions, one of the main barriers for effective regularization, which has as main objective, to recover the land from the city, making it perform its function social. In this sense, the research finds that urban planning needs to engage with this conception of town, so the applicability of urban instruments is effectively guided in order to value the human person and not primarily urban space, and are aiming to obtain information on socio-spatial diversity and its complexities in social relations, such as temporality, specificity of relations, the progression to historicities understand and explain each existing group, taking into consideration all the experiences, setting the understanding of social relations of possessions so elucidated. Only then will it be possible to think that the regularization in the city of Goiânia effectively and fully.A presente pesquisa busca compreender as relações entre as ocupações formal e informal da cidade, tendo como objeto de estudo o processo de ocupação irregular no Município de Goiânia, bem como os entraves da regularização dessas posses. As ocupações irregulares urbanas são fenômenos em crescimento no Brasil, e Goiânia reflete essa realidade. Constata-se um aumento de mais de 50.000 ocupações irregulares nos últimos dez anos. Diante de tal perspectiva, a presente dissertação reveste-se de uma abordagem dialética do espaço urbano em Goiânia, de forma a investigar os entraves do processo de regularização, dos quais decorrem outros problemas sociais, tais como: violência, exclusão social, segregação urbana e social. Ressalte-se que o processo de regularização plena compreende três dimensões urbanística, ambiental e jurídica , as quais envolvem ações de diferentes instituições públicas de uma maneira coordenada e integrada. Quando isto não acontece, surgem entraves para a efetivação da regularização fundiária, que tem como objetivo principal recuperar o ordenamento da cidade, fazendo com que ela cumpra a sua função social. Neste sentido, a presente pesquisa constata que o planejamento urbano necessita dialogar com esta concepção de cidade, para que a aplicação dos instrumentos urbanísticos seja efetivamente norteada de forma a valorizar a pessoa humana e não prioritariamente o espaço urbano. Esse diálogo deve também objetivar a coleta de informações sobre a diversidade socioespacial e suas complexidades nas relações sociais, como temporalidade, especificidades das relações, progressão das historicidades para compreender e explicar cada grupo existente, levando em consideração todas as experiências vividas e configurando a compreensão das relações sociais das posses de forma elucidada. Só a partir daí será possível pensar a regularização fundiária no município de Goiânia de forma efetiva e plena. Para tal, será utilizada teoria consistente centrada em Lefebvre (1980), Villaça (1995) e Santos (1995)

TLR2-dependent Modulation of Osteoclastogenesis by Porphyromonas gingivalis through Differential Induction of NFATc1 and NF-κB*

Osteolytic diseases, including rheumatoid arthritis, osteomyelitis, and periodontitis, are usually associated with bacterial infections. However, the precise mechanisms by which bacteria induce bone loss still remain unclear. Evidence exists that Toll-like receptor (TLR) signaling regulates both inflammation and bone metabolism and that the receptor activator of NF-κB ligand (RANKL) and its receptor RANK are the key regulators for bone remodeling and for the activation of osteoclasts. Here, we investigate the direct effects of the periodontal pathogen Porphyromonas gingivalis on osteoclast differentiation and show that P. gingivalis differentially modulates RANKL-induced osteoclast formation contingent on the state of differentiation of osteoclast precursors. In addition, although an optimal induction of cytokines by P. gingivalis is dependent on TLR2 and TLR4, as well as myeloid differentiation factor 88 and Toll/IL-1R domain-containing adaptor-inducing IFN-β, P. gingivalis utilizes TLR2/ myeloid differentiation factor 88 in modulating osteoclast differentiation. P. gingivalis modulates RANKL-induced osteoclast formation by differential induction of NFATc1 and c-Fos. More importantly, RANKL-mediated lineage commitment also has an impact on P. gingivalis-induced cytokine production. RANKL inhibits P. gingivalis-induced cytokine production by down-regulation of TLR/NF-κB and up-regulation of NFATc1. Our findings reveal novel aspects of the interactions between TLR and RANK signaling and provide a new model for understanding the mechanism underlying the pathogenesis of bacteria-mediated bone loss

Hyperlipidemia impaired innate immune response to periodontal pathogen Porphyromonas gingivalis in Apolipoprotein E knockout mice

A finely-tuned innate immune response plays a pivotal role in protecting host against bacterial invasion during periodontal disease progression. Hyperlipidemia has been suggested to exacerbate periodontal health condition. However, the underlying mechanism has not been addressed. In the present study, we investigated the effect of hyperlipidemia on innate immune responses to periodontal pathogen Porphyromonas gingivalis infection. Apolipoprotein E-deficient and wild-type mice at the age of 20 weeks were used for the study. Peritoneal macrophages were isolated and subsequently used for the study of viable P. gingivalis infection. ApoE−/− mice demonstrated inhibited iNOS production and impaired clearance of P. gingivalis in vitro and in vivo; furthermore, ApoE−/− mice displayed disrupted cytokine production pattern in response to P. gingivalis, with a decreased production of tumor necrosis factor-α, interleukin-6 (IL-6), IL-1β and monocyte chemotactic protein-1. Microarray data demonstrated that Toll-like receptor (TLR) and NOD-like receptor (NLR) pathway were altered in ApoE−/− mice macrophages; further analysis of pattern recognition receptors (PRRs) demonstrated that expression of triggering receptors on myeloid cells-1 (TREM-1), an amplifier of the TLR and NLR pathway, was decreased in ApoE−/− mice macrophages, leading to decreased recruitment of NF-κB onto the promoters of the TNF-α and IL-6. Our data suggest that in ApoE−/− mice hyperlipidemia disrupts the expression of PRRs, and cripples the host’s capability to generate sufficient innate immune response to P. gingivalis, which may facilitate immune evasion, subgingival colonization and establishment of P. gingivalis in the periodontal niche