Thalidomide modulates Mycobacterium leprae-induced NF-κB pathway and lower cytokine response

AbstractIt is widely accepted that tumor necrosis factor alpha (TNF-α) plays a critical role in the development of tissue and nerve damage in leprosy and during the reactional episodes of acute inflammation. Thalidomide (N-α-phthalimidoglutarimide), a drug used to treat leprosy reaction, modulates immune response, inhibits inflammation and NF-κB activity. Here we investigated whether thalidomide inhibits NF-κB activation induced by Mycobacterium leprae, p38 and ERK1/2 MAPK activation. EMSA and supershift assays were performed to investigate NF-κB activation in response to M. leprae and its modulation following in vitro treatment with thalidomide. Luciferase assay was assayed in transfected THP-1 cells to determine NF-κB transcriptional activity. Flow cytometry and immunofluorescence were used to investigate p65 accumulation in the nucleus. Immunoblotting was used to investigate p38 and ERK1/2 phosphorylation. Following activation of PBMC and monocytes with M. leprae, the formation and nuclear localization of NF-κB complexes composed mainly of p65/p50 and p50/p50 dimers was observed. Induction of NF-κB activation and DNA binding activity was inhibited by thalidomide. The drug also reduced M. leprae-induced TNF-α production and inhibited p38 and ERK1/2 activation. Definition of the activation mechanisms in cells stimulated with M. leprae can lead to the development of new therapy applications to modulate NF-κB activation and to control the inflammatory manifestations due to enhanced TNF-α response as observed in leprosy and in leprosy reactions

Efeitos indiscriminado do uso de esteroides anabólicos androgênico no sistema cardiovascular / The effects of indiscriminate use of androgenic anabolic steroids on the cardiovascular system

Os esteroides androgênicos anabolizantes (AAS), isto é, o hormônio natural da testosterona e seus parentes sintéticos são substâncias com características tanto androgênicas, responsáveis pelo desenvolvimento e manutenção das características masculinas, quanto anabolizantes, responsáveis pelo estímulo da hipertrofia muscular. Entre os muitos efeitos colaterais da terapia hormonal com AAS, destacam-se problemas no sistema cardiovascular. A partir disto, o presente trabalho tem como objetivo realizar uma revisão da literatura sobre os principais efeitos dos esteroides anabólicos androgênicos no sistema cardiovascular a partir de estudos experimentais.  Os artigos utilizados para esta revisão foram publicados no período de 2010 a 2020 nas bases de dados Pubmed, Scielo e em periódicos independentes. As consultas foram realizadas por intermédio dos seguintes termos: "androgenic anabolic", "the cardiovascular system", "blood flow" "anabolic steroids/adverse effects". Após a triagem por título e resumo, 26 artigos foram selecionados. Os resultados desta revisão permitiram ratificar que o uso de esteroides anabolizantes pode causar alterações estruturais e funcionais da musculatura cardíaca decorrente ao seu uso, por efeitos diretos e/ou indiretos, podendo provocar e perpetuar doenças cardiovasculares

Imposto de renda e indenização: análise da evolução jurisprudencial nos Tribunais Superiores = Income tax and indemnification: analysis of jurisprudential evolution in the Superior Courts

- Relatório de Pesquisa Realizada pelos Membros do Grupo 1 de Pesquisa do “IBDT Jovem”

O Papel do NF-KB e da fagocitose de células apoptóticas na patogênese da hanseníase

Submitted by Tatiana Oliveira ([email protected]) on 2012-06-05T18:34:39Z No. of bitstreams: 1 Tatiana Oliveira Fulco.pdf: 6352891 bytes, checksum: 35625276b78761742a718df841963873 (MD5)Made available in DSpace on 2012-06-05T18:34:39Z (GMT). No. of bitstreams: 1 Tatiana Oliveira Fulco.pdf: 6352891 bytes, checksum: 35625276b78761742a718df841963873 (MD5) Previous issue date: 2010Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.Estudos anteriores de nosso grupo demonstraram que o Mycobacterium leprae induz apoptose de monócitos humanos por uma via dependente de proteasoma. No presente trabalho nós demonstramos que o M. leprae induz a produção de TNFa e induz apoptose de monócitos por uma via dependente de NF-?B. A talidomida, utilizada no tratamento do Eritema Nodoso Hansênico, possui atividade anti-TNF por um mecanismo ainda não completamente elucidado. Nós demonstramos que a Talidomida suprime a produção de TNF por uma via dependente de p38 MAPK e NF-?B. O papel da remoção de células apoptóticas também foi avaliado. Apesar de macrófagos ativados pela via alternativa ou Mf2 possuírem maior capacidade de associação com o M. leprae quando comparados a macrófagos ativados pela via clássica ou Mf1, o estímulo com células apoptóticas levou ao aumento na associação do M. leprae em macrófagos Mf1, mas não Mf2. Esse aumento na associação do M. leprae com macrófagos Mf1 estimulados com células apoptóticas está associado ao aumento da expressão gênica de COX-2 e elevados níveis de PGE2, IL-10 e TGF-ß, com redução dos níveis de IL-6 e IL-15. Em conjunto, tais dados sugerem que na presença de células apoptóticas, macrófagos pró-inflamatórios estimulados com o M. leprae, desviam para um fenótipo antiinflamatório o que pode explicar o estabelecimento da infecção em pacientes com a forma tuberculóide da doençaPrevious studies o four group revealed that Mycobacterium. leprae induces apoptosis of human monocytes by a proteasome-dependent pathway. In the present work we demonstrated that M. leprae induces TNFa and apoptosis by a NF-?B-dependent pathway. Thalidomide, drug used in treatment of erithema nodosum leprosum, has been described by its anti-TNFa activity although the mechanism is not fully understood. We demonstrated that thalidomide suppress TNFa production by p38 MAPK and NF-?B – dependent pathways. The role of apoptotic cell clearance was also evaluated. Although macrophages activated by alternative pathway or Mf2 have increased phagocytic activity when compared to macrophages activated by classical pathway or Mf1, apoptotic cell uptake increased the association of M. leprae with Mf1 but not Mf2. The increase in M. leprae association with apoptotic cell stimulated Mf1 is associated with the increased COX-2 gene expression and higher levels of PGE2, IL-10 and TGF-ß, with reduced levels of IL-6 and IL-15. Together, these data suggest that in the presence of apoptotic cells, M. leprae stimulated pro-inflammatory macrophages deviates to an anti-inflammatory phenotype that could explain the establishment of M. leprae infection in patients with the tuberculoid form of the diseas

Toxicological Potential of the FDA-Approved Treatment against Monkeypox. Comment on Zovi et al. Pharmacological Agents with Antiviral Activity against Monkeypox Infection. <i>Int. J. Mol. Sci</i>. 2022, <i>23</i>, 15941

Recently, some drugs were approved to control Monkeypox (MPX), among them tecovirimat. This was recently approved by regulatory agencies around the world, the paper of Zovi et al entitled Pharmacological Agents with Antiviral Activity against Monkeypox Infection highlight it as safe and effective, although the safety data are still not very robust. In this Comment, we present some theoretical evaluations of its safety, considering that for use in humans it is essential to have a rich scientific literature in the area. After a series of analyses, a potential risk of liver, respiratory and kidney damage was found in addition to carcinogenic potential. Thus, while we agree that there is a need for rapid responses to infection, we reinforce that well-designed and adequately powered studies should not only focus on investigating the pharmacological efficacy of tecovirimat but also demonstrate its safety in humans. Therefore, in this Comment, we present some concerns that may help in formulating a safer treatment for patients infected with Monkeypox virus (MPXV)

Integração inovadora entre empresas incubadas e universidades para geração contínua de vantagens competitivas em ambientes dinâmicos

Esse artigo apresenta uma abordagem de integração entre startups e universidade, tendo como objetivos: (i) difundir práticas gerenciais inovadoras em empresas ligadas à incubadoras de empresas, (ii) estreitar a relação entre teoria e prática no ensino da Administração sobretudo em ambiente dinâmicos, (iii) criar um ambiente propício ao desenvolvimento das competências dos alunos do curso de Administração em um enfoque de aprendizagem pela ação, ao mesmo tempo que os empresários das empresas incubadas possam refletir sobre seus processos de gestão. Tal intento é alcançado por meio de uma abordagem construtivista de aprendizagem ativa, com participação ativa dos alunos de graduação de um curso de administração, sob supervisão de um professor-facilitador e dos empresários das startups. Esse artigo apresenta resultados de casos exploratórios que visam entender problemas gerenciais de empresas incubadas na incubadora MIDI Tecnológico e propõe modelos de decisão para os empresários a partir de seus valores e preferências. Essa pesquisa apresenta inovação no aspecto gerencial, onde é apresentado o uso da abordagem Lean Startup junto ao apoio à decisão construtivista, para avaliar e criar alternativas de ações no tocante ao desenvolvimento de produto e mercado. E em adição, esse trabalho também apresenta uma abordagem de integração inovadora entre empresas incubadas e universidades, onde a primeira pode se valer de conhecimento gerenciais presentes nos cursos de administração para melhorar seu desempenho, bem como os acadêmicos podem se valer da aprendizagem vivencial para aplicar conhecimentos que precisarão ser melhor explorados durante sua vida acadêmica e profissional

In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives

Abstract Background Plasmodium falciparum has shown multidrug resistance, leading to the necessity for the development of new drugs with novel targets, such as the synthesis of isoprenic precursors, which are excellent targets because the pathway is different in several steps when compared with the human host. Naphthoquinone derivatives have been described as potentially promising for the development of anti-malarial leader molecules. In view of that, the focus in this work is twofold: first, evaluate the in vitro naphthoquinone antiplasmodial activity and cytotoxicity; secondly, investigate one possible action mechanism of two derivatives of hydroxy-naphthoquinones. Results The two hydroxy-naphthoquinones derivatives have been tested against P. falciparum in vitro, using strains of parasites chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2), causing 50% inhibition of parasite growth with concentrations that varied from 7 to 44.5 μM. The cell viability in vitro against RAW Cell Line displayed IC50 = 483.5 and 714.9 μM, whereas, in primary culture tests using murine macrophages, IC50 were 315.8 and 532.6 μM for the two selected compounds, causing no haemolysis at the doses tested. The in vivo acute toxicity assays exhibited a significant safety margin indicated by a lack of systemic and behavioural toxicity up to 300 mg/kg. It is suggested that this drug seems to inhibit the biosynthesis of isoprenic compounds, particularly the menaquinone and tocopherol. Conclusions These derivatives have a high potential for the development of new anti-malarial drugs since they showed low toxicity associated to a satisfactory antiplasmodial activity and possible inhibition of a metabolic pathway distinct from the pathways found in the mammalian host

TST conversions and systemic interferon-gamma increase after methotrexate introduction in psoriasis patients.

BackgroundTuberculosis screening in psoriasis patients is complex due to the immunological alterations associated with psoriasis, the presence of comorbidities, and the effect of immunosuppressive treatment. However, it is not established whether the results of screening tests are affected by these factors in psoriasis patients.ObjectivesTo determine whether there is a change in the results of the tuberculin skin test (TST) or the interferon-gamma release assay (IGRA) in psoriasis patients living in tuberculosis (TB)-endemic area after 12 weeks of methotrexate (MTX) treatment and to investigate the association of the test results with clinical and inflammatory markers.MethodsForty-five patients were selected for a prospective single-arm self-controlled study and followed for at least 18 months. The TST, IGRA, Psoriasis Area and Severity Index (PASI), and inflammatory factors (erythrocyte sedimentation rate (ESR), C-reactive protein, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha levels), were determined before and after 12 weeks of oral 15 mg per week MTX administration and compared. The associations between the IGRA and TST results were verified before and after treatment according to inflammatory factors and clinical characteristics (age, blood glucose, weight, body mass index, disease duration, and PASI).ResultsWe collected data on 25 patients who completed the full course of therapy and the follow-up. None of the patients developed TB. TST positivity was significantly elevated at week 12 (25% baseline vs 44% at week 12, P ConclusionsIn addition to the classic booster effect, TST conversions in patients using MTX can occur due to an increase in IFN-γ. However, it is not possible to exclude true TST conversions. Therefore, other diagnostic methods, like IGRA or chest tomography, should be used when the TST has intermediate results