A História da Alimentação: balizas historiográficas

Os M. pretenderam traçar um quadro da História da Alimentação, não como um novo ramo epistemológico da disciplina, mas como um campo em desenvolvimento de práticas e atividades especializadas, incluindo pesquisa, formação, publicações, associações, encontros acadêmicos, etc. Um breve relato das condições em que tal campo se assentou faz-se preceder de um panorama dos estudos de alimentação e temas correia tos, em geral, segundo cinco abardagens Ia biológica, a econômica, a social, a cultural e a filosófica!, assim como da identificação das contribuições mais relevantes da Antropologia, Arqueologia, Sociologia e Geografia. A fim de comentar a multiforme e volumosa bibliografia histórica, foi ela organizada segundo critérios morfológicos. A seguir, alguns tópicos importantes mereceram tratamento à parte: a fome, o alimento e o domínio religioso, as descobertas européias e a difusão mundial de alimentos, gosto e gastronomia. O artigo se encerra com um rápido balanço crítico da historiografia brasileira sobre o tema

Regulatory effetcs of ruxolitinib on the expression of inflammation markers and drug-detoxifying proteins

Le ruxolitinib, un inhibiteur de JAK1/2, est actuellement utilisé pour le traitement des syndromes myéloprolifératifs et montre des propriétés anti-inflammatoires. Cependant, les mécanismes cellulaires et moléculaires à l’origine de ses effets restent peu élucidés. Au travers de ces travaux, les effets régulateurs du ruxolitinib sur l'expression de marqueurs de l'inflammation et de protéines de détoxication des médicaments ont été évalués in vitro dans différents types cellulaires. Dans les macrophages humains en culture primaire, le ruxolitinib réprime l’expression de cytokines inflammatoires secondairement induites par la signalisation de l’IFNβ, en réponse au LPS. Similairement, le ruxolitinib inhibe l’expression de protéines de la phase aiguë induites dans les hépatocytes humains en culture primaire et la lignée cellulaire HepaRG. Cet inhibiteur réprime notamment l’expression de la CRP secondairement induite par la signalisation IL6, en réponse au LPS. Aussi, il permet de restaurer l’expression et l’activité de protéines hépatique de détoxication des médicaments réprimées par un stimulus inflammatoire. Dans l’ensemble de ces études, le ruxolitinib montre une efficacité à des concentrations atteintes chez les patients. Ces travaux montrent tout d’abord que par ses propriétés anti-inflammatoires retrouvées dans différents modèles, le ruxolitinib pourrait se montrer intéressant pour le traitement d’un large panel de pathologies inflammatoires. De plus, son utilisation en clinique pourrait nécessiter d’adapter les doses de médicaments associés dont le métabolisme est susceptible d’être modulé par une diminution de l’inflammation par cet inhibiteur de JAK.Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor currently used for the treatment of myeloproliferative neoplasms. It shows anti-inflammatory properties, but the involved molecular and cellular mechanisms remain poorly understood. The regulatory effects of ruxolitinib on the expression of inflammatory markers and drug-detoxifying proteins were investigated in different cellular models through these studies. In human macrophages, ruxolitinib represses the expression of inflammatory cytokines secondarily induced by the IFNβ signalling pathway, in response to LPS. Similarly, ruxolitinib inhibits the expression of acute phase proteins induced in human hepatocytes and in the HepaRG cell line. It also notably represses the expression of CRP secondarily induced by the IL6 signalling pathway, in response to LPS. Moreover, ruxolitinib restores the expression and activity of hepatic drug-detoxifying proteins inhibited in inflammatory conditions. In these studies, ruxolitinib is shown to be efficient at concentrations which can be reached in patients. Altogether, these results show that, firstly, as its anti-inflammatory properties are shown throughout different cellular models, ruxolitinib could be interesting for the treatment of various inflammatory pathologies. Also, clinical use could restore hepatic detoxification capacity for patients suffering from inflammatory diseases and therefor require dose adjustments for associated drugs which metabolism could be regulated by inflammation

Effets régulateurs du ruxolitinib sur l'expression de marqueurs de l'inflammation et de protéines de détoxication des médicaments

Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor currently used for the treatment of myeloproliferative neoplasms. It shows anti-inflammatory properties, but the involved molecular and cellular mechanisms remain poorly understood. The regulatory effects of ruxolitinib on the expression of inflammatory markers and drug-detoxifying proteins were investigated in different cellular models through these studies. In human macrophages, ruxolitinib represses the expression of inflammatory cytokines secondarily induced by the IFNβ signalling pathway, in response to LPS. Similarly, ruxolitinib inhibits the expression of acute phase proteins induced in human hepatocytes and in the HepaRG cell line. It also notably represses the expression of CRP secondarily induced by the IL6 signalling pathway, in response to LPS. Moreover, ruxolitinib restores the expression and activity of hepatic drug-detoxifying proteins inhibited in inflammatory conditions. In these studies, ruxolitinib is shown to be efficient at concentrations which can be reached in patients. Altogether, these results show that, firstly, as its anti-inflammatory properties are shown throughout different cellular models, ruxolitinib could be interesting for the treatment of various inflammatory pathologies. Also, clinical use could restore hepatic detoxification capacity for patients suffering from inflammatory diseases and therefor require dose adjustments for associated drugs which metabolism could be regulated by inflammation.Le ruxolitinib, un inhibiteur de JAK1/2, est actuellement utilisé pour le traitement des syndromes myéloprolifératifs et montre des propriétés anti-inflammatoires. Cependant, les mécanismes cellulaires et moléculaires à l’origine de ses effets restent peu élucidés. Au travers de ces travaux, les effets régulateurs du ruxolitinib sur l'expression de marqueurs de l'inflammation et de protéines de détoxication des médicaments ont été évalués in vitro dans différents types cellulaires. Dans les macrophages humains en culture primaire, le ruxolitinib réprime l’expression de cytokines inflammatoires secondairement induites par la signalisation de l’IFNβ, en réponse au LPS. Similairement, le ruxolitinib inhibe l’expression de protéines de la phase aiguë induites dans les hépatocytes humains en culture primaire et la lignée cellulaire HepaRG. Cet inhibiteur réprime notamment l’expression de la CRP secondairement induite par la signalisation IL6, en réponse au LPS. Aussi, il permet de restaurer l’expression et l’activité de protéines hépatique de détoxication des médicaments réprimées par un stimulus inflammatoire. Dans l’ensemble de ces études, le ruxolitinib montre une efficacité à des concentrations atteintes chez les patients. Ces travaux montrent tout d’abord que par ses propriétés anti-inflammatoires retrouvées dans différents modèles, le ruxolitinib pourrait se montrer intéressant pour le traitement d’un large panel de pathologies inflammatoires. De plus, son utilisation en clinique pourrait nécessiter d’adapter les doses de médicaments associés dont le métabolisme est susceptible d’être modulé par une diminution de l’inflammation par cet inhibiteur de JAK

Potent repression of C-reactive protein (CRP) expression by the JAK1/2 inhibitor ruxolitinib in inflammatory human hepatocytes

International audienceObjective and design - To determine whether inflammatory hepatocytes may constitute primary targets for ruxolitinib, a Janus kinase (JAK) inhibitor, its effects towards expression of hepatic acute-phase proteins, especially C-reactive protein (CRP), were assessed. Materials - Ruxolitinib effects were analysed in primary human hepatocytes and human hepatoma HepaRG cells exposed to various inflammatory stimuli. Results - Ruxolitinib was found to fully inhibit lipopolysaccharide (LPS)-induced CRP secretion and mRNA expression, at concentrations (IC = 12.9 nM) achievable in human blood. It similarly repressed CRP up-regulation due to several Toll-like receptor agonists or pro-inflammatory cytokines [interleukin (IL) 1β, IL6 and tumour necrosis factor α] and counteracted LPS-mediated induction of serum amyloid A, fibrinogen, haptoglobin and serpin. Ruxolitinib was additionally found to block the activation of the IL6/JAK/signal transducer and activator of transcription (STAT) pathway triggered by LPS and whose inhibition by the neutralizing anti-IL6 receptor antibody tocilizumab prevented CRP induction. Conclusion - Ruxolitinib can potently repress induction of CRP in inflammatory human hepatocytes, most likely through targeting the IL6/JAK/STAT signalling cascade. Hepatic production of acute-phase proteins during liver inflammation may, therefore, constitute a target for ruxolitinib

The JAK1/2 Inhibitor Ruxolitinib Reverses Interleukin-6-Mediated Suppression of Drug-Detoxifying Proteins in Cultured Human Hepatocytes

International audienceThe inflammatory cytokine interleukin (IL)-6, which basically activates the Janus kinase (JAK)/ signal transducer and activator of transcription (STAT) signaling pathway, is well known to repress expression of hepatic cytochromes P-450 (P450s) and transporters. Therapeutic proteins, like monoclonal antibodies targeting IL-6 or its receptor, have consequently been demonstrated to restore full hepatic detoxification capacity, which results in inflammatory disease-related drug-drug interactions (idDDIs). In the present study, we investigated whether ruxolitinib, a small drug acting as a JAK1/2 inhibitor and currently used in the treatment of myeloproliferative neoplasms, may also counteract the repressing effects of IL-6 toward hepatic detoxifying systems. Ruxolitinib was found to fully inhibit IL-6-mediated repression of P450 (CYP1A2, CYP2B6, and CYP3A4) and transporter (NTCP, OATP1B1, and OCT1) mRNA levels in primary human hepatocytes and differentiated hepatoma HepaRG cells. Such effects were dose-dependent, with ruxolitinib EC50 values around 1.0-1.2 μM and thus close to ruxolitinib plasma levels that can be reached in patients. Moreover, they were associated with concomitant restoration of P450 and drug transporter activities in IL-6-exposed HepaRG cells. By contrast, ruxolitinib failed to suppress the repression of drug-detoxifying protein mRNA levels caused by IL-1β The JAK inhibitor and anti-rheumatoid arthritis compound tofacitinib was additionally found to reverse IL-6-mediated suppression of P450 and transporter mRNA expressions. Taken together, our results demonstrated that small drugs acting as JAK inhibitors, like ruxolitinib, counteract IL-6-mediated repression of drug-metabolizing enzymes and drug transporters in cultured human hepatocytes. These JAK inhibitors may consequently be hypothesized to restore hepatic detoxification capacity for patients suffering from inflammatory diseases, which may in turn cause idDDIs

Repression of interferon β-regulated cytokines by the JAK1/2 inhibitor ruxolitinib in inflammatory human macrophages

International audienceRuxolitinib is a Janus kinase (JAK) 1/2 inhibitor, currently used in the treatment of myeloproliferative neoplasms. It exerts potent anti-inflammatory activity, but the involved molecular and cellular mechanisms remain poorly understood. In order to gain insights about this point, ruxolitinib effects towards expression of main inflammatory cytokines were studied in human macrophages, which constitute a key-cell type implicated in inflammation. Analysis of mRNA expression of cytokines (n=84) by PCR array indicated that, among those induced by the pro-inflammatory stimulus lipopolysaccharide (LPS) (n=44), 61.4% (n=27) were repressed by 5μM ruxolitinib. The major inflammatory cytokines, interleukin (IL) 6 and tumor necrosis factor α, were notably down-regulated by ruxolitinib at both the mRNA and protein level. Other repressed cytokines included IL27 and the chemokines CCL2, CXCL9, CXCL10 and CXCL11, but not IL1β. The interferon (IFN) β/JAK/signal transducer and activator of transcription (STAT) pathway, well-activated by LPS in human macrophages as demonstrated by increased secretion of IFNβ, STAT1 phosphorylation, and up-regulation of reference IFNβ-responsive genes, was concomitantly blocked by the JAK inhibitor. Most of cytokines targeted by ruxolitinib were shown to be regulated by IFNβ in a JAK-sensitive manner. In addition, counteracting the IFNβ/JAK/STAT cascade using a blocking monoclonal antibody directed against IFNβ receptor resulted in a similar profile of cytokine repression to that observed in response to the JAK inhibitor. Overall, these data provide evidence for ruxolitinib-mediated repression of inflammatory cytokines in human macrophages through inhibition of the LPS/IFNβ/JAK/STAT signalling pathway, which probably contributes to the anti-inflammatory effects of the JAK inhibitor

mRNA Expression and Activity of Nucleoside Transporters in Human Hepatoma HepaRG Cells

The HepaRG cell line is a highly differentiated human hepatoma cell line, displaying the expression of various drug transporters. However, functional expression of nucleoside transporters remains poorly characterized in HepaRG cells, although these transporters play a key role in hepatic uptake of antiviral and anticancer drugs. The present study was, therefore, designed to characterize the expression, activity and regulation of equilibrative (ENT) and concentrative (CNT) nucleoside transporter isoforms in differentiated HepaRG cells. These cells were found to exhibit a profile of nucleoside transporter mRNAs similar to that found in human hepatocytes, i.e., notable expression of ENT1, ENT2 and CNT1, with very low or no expression of CNT2 and CNT3. ENT1 activity was, next, demonstrated to be the main uridine transport activity present in HepaRG cells, like in cultured human hepatocytes. Various physiological factors, such as protein kinase C (PKC) activation or treatment by inflammatory cytokines or hepatocyte growth factor (HGF), were additionally found to regulate expression of ENT1, ENT2 and CNT1; PKC activation and HGF notably concomitantly induced mRNA expression and activity of ENT1 in HepaRG cells. Overall, these data suggest that HepaRG cells may be useful for analyzing cellular pharmacokinetics of nucleoside-like drugs in human hepatic cells, especially of those handled by ENT1