From Orphan Drugs to Adopted Therapies: Advancing C3-Targeted Intervention to the Clinical Stage

Complement dysregulation is increasingly recognized as an important pathogenic driver in a number of clinical disorders. Complement-triggered pathways intertwine with key inflammatory and tissue destructive processes that can either increase the risk of disease or exacerbate pathology in acute or chronic conditions. The launch of the first complement-targeted drugs in the clinic has undeniably stirred the field of complement therapeutic design, providing new insights into complement\u27s contribution to disease pathogenesis and also helping to leverage a more personalized, comprehensive approach to patient management. In this regard, a rapidly expanding toolbox of complement therapeutics is being developed to address unmet clinical needs in several immune-mediated and inflammatory diseases. Elegant approaches employing both surface-directed and fluid-phase inhibitors have exploited diverse components of the complement cascade as putative points of therapeutic intervention. Targeting C3, the central hub of the system, has proven to be a promising strategy for developing biologics as well as small-molecule inhibitors with clinical potential. Complement modulation at the level of C3 has recently shown promise in preclinical primate models, opening up new avenues for therapeutic intervention in both acute and chronic indications fueled by uncontrolled C3 turnover. This review highlights recent developments in the field of complement therapeutics, focusing on C3-directed inhibitors and alternative pathway (AP) regulator-based approaches. Translational perspectives and considerations are discussed, particularly with regard to the structure-guided drug optimization and clinical advancement of a new generation of C3-targeted peptidic inhibitors

ECONOMIA COMPARTILHADA E MODO DE PRODUÇÃO CAPITALISTA NO CONTEXTO DOS APLICATIVOS DE ENTREGA

RESUMOAlgumas das características da economia compartilhada podem gerar novas dinâmicas nas relações de trabalho, por isso se faz importante entender se esse novo modelo de economia pode reforçar a precarização do trabalho. Por meio de entrevistas semiestruturadas com cinco entregadores vinculados a diferentes aplicativos de entrega de comida, o artigo buscou compreender se as empresas de aplicativos perpetuam práticas do modo de produção capitalista a partir da exploração da atividade de entregador. As análises foram realizadas a partir das categorias, a priori, de motivação, rotina, vantagens e desvantagens de realizar a atividade de entregador, ciência dos direitos trabalhistas, relacionamento com as empresas e a perspectiva de futuro em relação à atividade e a empregos formais. Como resultado foi possível identificar que mesmo que a economia compartilhada traga muitos ganhos para plataformas inovadoras, existe um contexto de forte desigualdade por trás do crescimento econômico que questiona o pilar social da sustentabilidade.Palavras-chave: Economia compartilhada. Modo de produção capitalista. Entregadores. Aplicativos. Bicicleta. ABSTRACTSome of the sharing economy characteristics generate new work relationships. Therefore, it is important to understand whether this new economic model can reinforce the already precarious nature of work. Through semi-structured interviews with five bike messengers from different delivery applications, the article sought to understand if application companies perpetuate the capitalist mode of production practices through the exploitation of the delivery activity. Analyses were carried out based on a priori categories related to motivation, routine, advantages, and disadvantages of performing the activity of delivery, awareness of labor rights, relationship with companies, and the future perspective of the activity and formal jobs. As a result, it was possible to identify that even though the sharing economy brings many gains for innovative platforms, there is a context of inequality behind this economic growth that questions the social pillar of sustainability.Keywords: Sharing economy. Capitalist mode of production. Deliveries. Applications. Bike messenger

Complement-Dependent Mechanisms and Interventions in Periodontal Disease

Periodontitis is a prevalent inflammatory disease that leads to the destruction of the tooth-supporting tissues. Current therapies are not effective for all patients and this oral disease continues to be a significant public health and economic burden. Central to periodontal disease pathogenesis is a reciprocally reinforced interplay between microbial dysbiosis and destructive inflammation, suggesting the potential relevance of host-modulation therapies. This review summarizes and discusses clinical observations and pre-clinical intervention studies that collectively suggest that complement is hyperactivated in periodontitis and that its inhibition provides a therapeutic benefit. Specifically, interception of the complement cascade at its central component, C3, using a locally administered small peptidic compound (Cp40/AMY-101) protected non-human primates from induced or naturally occurring periodontitis. These studies indicate that C3-targeted intervention merits investigation as an adjunctive treatment of periodontal disease in humans

The evolution and appearance of c3 duplications in fish originate an exclusive teleost c3 gene form with anti- inflammatory activity

12 páginas, 6 figuras, 3 tablas.-- This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedThe complement system acts as a first line of defense and promotes organism homeostasis by modulating the fates of diverse physiological processes. Multiple copies of component genes have been previously identified in fish, suggesting a key role for this system in aquatic organisms. Herein, we confirm the presence of three different previously reported complement c3 genes (c3.1, c3.2, c3.3) and identify five additional c3 genes (c3.4, c3.5, c3.6, c3.7, c3.8) in the zebrafish genome. Additionally, we evaluate the mRNA expression levels of the different c3 genes during ontogeny and in different tissues under steady-state and inflammatory conditions. Furthermore, while reconciling the phylogenetic tree with the fish species tree, we uncovered an event of c3 duplication common to all teleost fishes that gave rise to an exclusive c3 paralog (c3.7 and c3.8). These paralogs showed a distinct ability to regulate neutrophil migration in response to injury compared with the other c3 genes and may play a role in maintaining the balance between inflammatory and homeostatic processes in zebrafishThis work has been funded by the project CSD2007-00002 “Aquagenomics” from the Spanish Ministerio de Ciencia e Innovación, the ITN 289209 “FISHFORPHARMA” (EU) and project 201230E057 from the Agencia Estatal Consejo Superior de Investigaciones Científicas (CSIC).Peer reviewe

Complement system in dendritic cell differentiation and maturation.

O papel do complemento na modulação da resposta de células dendríticas não é bem entendido. Neste trabalho observamos que estas células produzirem proteínas do complemento e que o componente C3 regula positivamente a expressão de DC-SIGN, HLA-DR, CD1a, CD80 e CD86 e a produção de IL-6 e IL-12 por células dendríticas humanas. Também observamos, em modelo murino, menor expressão de MHC-II em células dendríticas C5aR-/-, a qual está associada com menor expressão do transativador de MHC-II; menor expressão de moléculas coestimuladoras nas células C3aR-/-, C5aR-/- e C5L2-/- e menor produção de IL-12p40, IL-12p70 e IL-6 em resposta a ligantes de TLR2 pelas células C3aR-/- e C5aR-/-. Conseqüentemente, a ausência de sinal pelos C3aR e C5aR, regula negativamente a habilidade destas células na indução da resposta de linfócitos T CD4+, modificando os níveis de proliferação e citocinas produzidas. De maneira conjunta, observamos participação do complemento na diferenciação e maturação de células dendríticas e no desenvolvimento da resposta imune adaptativa.The role of complement in the modulation of dendritic cells functions remains elusive. Here we show that these cells are able to produce complement proteins and that complement C3 upregulates the expression of DC-SIGN, HLA-DR, CD1a, CD80 and CD86 and the production of IL-6 e IL-12 by human dendritic cells. We also observed, in a mouse model, lower expression of MHC-II in C5aR-/- dendritic cells, which is correlated to lower expression of MHC-II transactivator; lower expression of costimmulatory molecules in C3aR-/-, C5aR-/- and C5L2-/- cells and lower production of IL-12p40, IL-12p70 and IL-6 by C3aR-/- and C5aR-/- cells in response to TLR2 stimulation. In consequence to the absence of C3aR and/or C5aR signaling we observed that these cells have lower ability to induce CD4+ T cells proliferation and production of Th1 cytokines. Together our data show a participation of complement in dendritic cell differentiation and maturation and in the polarization of adaptative immune responses

The renaissance of complement therapeutics

The increasing number of clinical conditions that involve a pathological contribution from the complement system - many of which affect the kidneys - has spurred a regained interest in therapeutic options to modulate this host defence pathway. Molecular insight, technological advances, and the first decade of clinical experience with the complement-specific drug eculizumab, have contributed to a growing confidence in therapeutic complement inhibition. More than 20 candidate drugs that target various stages of the complement cascade are currently being evaluated in clinical trials, and additional agents are in preclinical development. Such diversity is clearly needed in view of the complex and distinct involvement of complement in a wide range of clinical conditions, including rare kidney disorders, transplant rejection and haemodialysis-induced inflammation. The existing drugs cannot be applied to all complement-driven diseases, and each indication has to be assessed individually. Alongside considerations concerning optimal points of intervention and economic factors, patient stratification will become essential to identify the best complement-specific therapy for each individual patient. This Review provides an overview of the therapeutic concepts, targets and candidate drugs, summarizes insights from clinical trials, and reflects on existing challenges for the development of complement therapeutics for kidney diseases and beyond

Impaired dendritic cell differentiation and maturation in the absence of C3

Human monocytes can be differentiated into immature dendritic cells (DCs) in the presence of serum and cytokines. One of the main functions of immature DCs is to capture and process antigens. Following maturation, they differentiate into antigen presenting cells. The role of complement in the differentiation process from monocytes towards immature DCs remains elusive. Here we demonstrate that complement 3 (C3) has a regulatory impact on the expression of specific DC surface molecules and DC-derived cytokine production during DC differentiation. We isolated human adherent peripheral blood mononuclear cells, which were cultured in the presence of GM-CSF plus IL-4 in medium supplemented with normal human serum or C3 deficient serum. The lack of C3 during DC differentiation negatively impacted the expression of C-type lectin receptor DC-SIGN, the antigen presenting molecules HLA-DR and CD1a, and the costimulatory molecules CD80 and CD86. Further, the spontaneous production of IL-6 and IL-12 was reduced in the absence of C3. Moreover, the maturation of immature DCs in response to LPS challenge was impaired in the absence of C3 as evidenced by reduced MHC-II, co-stimulatory molecule expression as well as modulated IL-12 and TNF-alpha production. Collectively, our results provide evidence for a novel role of C3 as a critical cofactor in human DC differentiation and maturation. (C) 2007 Elsevier Ltd. All rights reserved

Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery

Complement dysregulation underlies several inflammatory disorders, and terminal complement inhibition has thus far afforded significant clinical gains. Nonetheless, emerging pathologies, fueled by complement imbalance and therapy-skewing genetic variance, underscore the need for more comprehensive, disease-tailored interventions. Modulation at the level of C3, a multifaceted orchestrator of the complement cascade, opens up prospects for broader therapeutic efficacy by targeting multiple pathogenic pathways modulated by C3-triggered proinflammatory crosstalk. Notably, C3 intervention is emerging as a viable therapeutic strategy for renal disorders with predominantly complement-driven etiology, such as C3 glomerulopathy (C3G). Using C3G as a paradigm, we argue that concerns about the feasibility of long-term C3 intervention need to be placed into perspective and weighed against actual therapeutic outcomes in prospective clinical trials

DIVERSIDADE FUNCIONAL DA VEGETAÇÃO ARBÓREA E ARBUSTIVA EM CERRADO EM DIFERENTES ESTÁGIOS EM REGENERAÇÃO NO NORDESTE DO BRASIL

We seek to answer: Will functional metrics have a greater relationship with species richness in the conserved area? Will we find higher values ​​of functional metrics in the conserved area? Will the average values ​​of functional traits be higher for conserved areas and similar between areas undergoing regeneration? Will the areas present differences in functional composition, with turnover being more preponderant for functional beta diversity? We selected two areas with different regeneration times (18 and 35 years) and one preserved area and implemented a 50x50 m plot. We collected functional traits from 24 tree-shrub species from which the following were measured: leaf thickness, dry and fresh leaf mass, leaf area, specific leaf area and wood density. Only functional richness and species richness were related to species richness. We verified a difference in divergence and functional dispersion between the areas undergoing regeneration, the conserved areas presented the highest average values ​​and the 35-year-old areas the lowest values. We evidenced a difference in the functional composition between the regenerating and conserved areas. The turnover value was 0.7101 and the nesting value was 0.150. The regeneration time and agricultural practice influence the functional composition, where we found that turnover is the most preponderant component for functional beta diversity.  Buscamos responder: As métricas funcionais apresentarão maior relação com riqueza de espécies na área conservada? Encontraremos maiores valores das métricas funcionais na área conservada? As médias dos valores dos traços funcionais serão maiores para áreas conservadas e similares entre as áreas em regeneração? As áreas apresentarão diferenças na composição funcional sendo o turnover mais preponderante para a diversidade beta funcional? Selecionamos duas áreas com diferentes tempos de regeneração (18 e 35 anos) e uma conservada e implantamos uma parcela de 50x50 m. Coletamos traços funcionais de 24 espécies arbóreo-arbustivas das quais foram medidos: espessura da folha, massa seca e fresca da folha, área foliar, área foliar específica e densidade da madeira. Somente riqueza funcional e riqueza em espécies apresentaram relação com riqueza em espécies. Verificamos diferença na divergência e dispersão funcional entre as áreas em regeneração, as áreas conservadas apresentaram os maiores valores das médias e as áreas 35 anos os menores valores. Evidenciamos diferença na composição funcional entre as áreas em regeneração e conservada. O valor do turnover foi 0,7101 e do aninhamento 0,150. O tempo de regeneração e prática agrícola influenciam na composição funcional, onde verificamos que o turnover é o componente mais preponderante para diversidade beta funcional