The C-Jun N-Terminal Kinase Inhibition in Intracerebral Hemorrhage

Background: In intracerebral hemorrhage (ICH), a subtype of stroke, the bloodentry into the brain triggers toxicity resulting in a strong loss of neurons andinflammation. Water content is also increases leading to growing intracranial pressure,which worsens neurological outcome. C-Jun N-terminal kinases (JNKs) areactivated in response to stress stimuli. Specific inhibition of JNK by a TAT-coupledpeptide (XG-102) mediates neuroprotection in several models of ischemic stroke.Recently, we have noted that the JNK pathway is also activated in a mouse modelof ICH, raising the question of the efficacy of XG-102 in this model.Method: ICH was induced in the mouse by intrastriatal injection of bacterialcollagenase (0,1U). Three hours later, animals received an i.v. injection of XG-102(100μg/kg). The neuroscore was assessed using a scale (from 0 to 9) based on 3behavioral tests performed daily. Then, mice were sacrificed at 6h, 24h, 48h and 5dafter ICH and histological studies performed.Results: XG-102 significantly improves neurological outcome at 24h (mean score:1,8±1.4 vs 3,4±1.8, p<0.01). Analysis of the lesion volume revealed a significantdecrease of the lesion area in the treated group at 48h (29±11 mm3 vs 39±5 mm3,p = 0.04). XG-102 mainly inhibits the edema component of the lesion. Indeed, asignificant decrease of the brain swelling was observed in treated animals at 48h(14±13% vs 26±9%, p=0.04) and 5d (-0,3±4.5% vs 5,1±3.6%, p=0.01).Conclusions: Inhibition of the JNK pathway by XG-102 appears to lead to asignificant decrease of the cerebral edema in the ICH model providing a furtherbeneficial effect of the XG-102 treatment. This result is of interest becausecurrently, clinical treatment for brain edema is limited. Importantly, the beneficialeffects observed with XG-102 in both stroke models open the possibility to rapidlytreat patients before identifying the stroke subtype by imaging.

The CAP1/Prss8 catalytic triad is not involved in PAR2 activation and protease nexin-1 (PN-1) inhibition.

Serine proteases, serine protease inhibitors, and protease-activated receptors (PARs) are responsible for several human skin disorders characterized by impaired epidermal permeability barrier function, desquamation, and inflammation. In this study, we addressed the consequences of a catalytically dead serine protease on epidermal homeostasis, the activation of PAR2 and the inhibition by the serine protease inhibitor nexin-1. The catalytically inactive serine protease CAP1/Prss8, when ectopically expressed in the mouse, retained the ability to induce skin disorders as well as its catalytically active counterpart (75%, n=81). Moreover, this phenotype was completely normalized in a PAR2-null background, indicating that the effects mediated by the catalytically inactive CAP1/Prss8 depend on PAR2 (95%, n=131). Finally, nexin-1 displayed analogous inhibitory capacity on both wild-type and inactive mutant CAP1/Prss8 in vitro and in vivo (64% n=151 vs. 89% n=109, respectively), indicating that the catalytic site of CAP1/Prss8 is dispensable for nexin-1 inhibition. Our results demonstrate a novel inhibitory interaction between CAP1/Prss8 and nexin-1, opening the search for specific CAP1/Prss8 antagonists that are independent of its catalytic activity.-Crisante, G., Battista, L., Iwaszkiewicz, J., Nesca, V., Mérillat, A.-M., Sergi, C., Zoete, V., Frateschi, S., Hummler, E. The CAP1/Prss8 catalytic triad is not involved in PAR2 activation and protease nexin-1 (PN-1) inhibition.

The dexamethasone-induced inhibition of proliferation, migration, and invasion in glioma cell lines is antagonized by macrophage migration inhibitory factor (MIF) and can be enhanced by specific MIF inhibitors.

Glioblastomas (GBMs) are the most frequent and malignant brain tumors in adults. Glucocorticoids (GCs) are routinely used in the treatment of GBMs for their capacity to reduce the tumor-associated edema. Few in vitro studies have suggested that GCs inhibit the migration and invasion of GBM cells through the induction of MAPK phosphatase 1 (MKP-1). Macrophage migration inhibitory factor (MIF), an endogenous GC antagonist is up-regulated in GBMs. Recently, MIF has been involved in tumor growth and migration/invasion and specific MIF inhibitors have been developed on their capacity to block its enzymatic tautomerase activity site. In this study, we characterized several glioma cell lines for their MIF production. U373 MG cells were selected for their very low endogenous levels of MIF. We showed that dexamethasone inhibits the migration and invasion of U373 MG cells, through a glucocorticoid receptor (GR)- dependent inhibition of the ERK1/2 MAPK pathway. Oppositely, we found that exogenous MIF increases U373 MG migration and invasion through the stimulation of the ERK1/2 MAP kinase pathway and that this activation is CD74 independent. Finally, we used the Hs 683 glioma cells that are resistant to GCs and produce high levels of endogenous MIF, and showed that the specific MIF inhibitor ISO-1 could restore dexamethasone sensitivity in these cells. Collectively, our results indicate an intricate pathway between MIF expression and GC resistance. They suggest that MIF inhibitors could increase the response of GBMs to corticotherapy.

Les clavecinistes français des XVIIe et XVIIIe siècles / d'Anglebert, d'Andrieu, J.- Ph. Rameau... [et al.], comp. ; Isabelle Nef, clav.

Comprend : Allemande, gavotte, menuet / J.- H. d'Anglebert, comp. ; Isabelle Nef, clav. ; Le ramage, Les amours, L'hymen / Jean-François Dandrieu, comp. ; Isabelle Nef, clav. ; L'entretien des muses / Jean-Philippe Rameau, comp. ; Isabelle Nef, clav. ; Chaconne / Louis Couperin, comp. ; Isabelle Nef, clav. ; Allemande, courante, sarabande / Jacques Champion de Chambonnières, comp. ; Isabelle Nef, clav. ; La rare / Jacques Champion de Chambonnières, comp. ; Isabelle Nef, clav. ; Musette / Louis Claude Daquin, comp. ; Isabelle Nef, clav. ; Tambourin / Louis Claude Daquin, comp. ; Isabelle Nef, clav. ; Les bergères / Louis Claude Daquin, comp. ; Isabelle Nef, clav. ; Chaconne / J.- H. d'Anglebert, comp. ; Isabelle Nef, clav. ; Les roseaux / François Couperin, comp. ; Isabelle Nef, clav. ; Les petits moulins à vent / François Couperin, comp. ; Isabelle Nef, clav.

Inhibition of lymphocyte mediated cytotoxicity by perforin antisense oligonucleotides.

The granule/perforin exocytosis model of CTL mediated cytolysis proposes that CTL, upon recognition of the specific targets, release the cytolytic, pore-forming protein perforin into the intercellular space which then mediates the cytotoxic effect. However, direct evidence for the involvement of perforin is still lacking, and indeed, recent results even seem incompatible with the model. To determine directly the role of perforin in CTL cytotoxicity, perforin antisense oligonucleotides were exogenously added during the stimulation of mouse spleen derived T cells and human peripheral blood lymphocytes (PBL), respectively. Perforin protein expression in lymphocytes was reduced by up to 65%, and cytotoxicity of stimulated T cells by as much as 69% (5.7-fold). These results provide the first experimental evidence for a crucial role of perforin in lymphocyte mediated cytotoxicity.

Hemodynamic and biochemical consequences of renin inhibition by infusion of CGP 38560A in normal volunteers.

Hemodynamic and biochemical effects of the new renin inhibitor CGP 38560A (molecular weight 826) were tested in 15 healthy volunteers after a single-blind, randomized, placebo-controlled protocol. At a 2-week interval, groups of five subjects received a 30-minute infusion of either 5% dextrose or CGP 38560A 50, 125, or 250 micrograms/kg. Blood pressure, heart rate, plasma renin activity, active and total renin, angiotensin-(1-8)octapeptide (angiotensin II), and aldosterone were sequentially measured up to 3 hours from the onset of the infusion. There was no consistent change in blood pressure or heart rate. Plasma renin activity and angiotensin II decreased dose dependently, and peak suppression was observed at the end of the infusion of CGP 38560A and after the 250-micrograms/kg dose. Plasma renin activity fell from 1.0 +/- 0.19 (mean +/- SEM) to less than 0.05 ng/ml/hr in all five subjects (p less than 0.001), and angiotensin II fell from 7.7 +/- 1.2 to 2.6 +/- 0.9 femtomole/ml (p less than 0.01). Active renin rose fourfold from 24 +/- 1.9 to 98 +/- 14 pg/ml (p less than 0.001) at the end of the infusion of the high dose. Plasma angiotensin II returned toward its initial values much faster than plasma renin activity and active renin. In conclusion, CGP 38560A was well tolerated. It induced a dose-dependent decrease in angiotensin II and plasma renin activity and a long-lasting and dose-dependent rise in active renin. The doses used did not reduce plasma angiotensin II maximally despite reduction of plasma renin activity to unmeasurable levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Estimativa da acidez potencial pelo método do pH SMP em solos do estado do Rio de Janeiro

A extração da acidez potencial com acetato de cálcio 0,5 mol L-1 é um método amplamente utilizado nos laboratórios de análises de solo no Brasil. Neste trabalho, foram analisadas cento e duas amostras de solos do Estado do Rio de Janeiro, em 1996, visando obter a curva de calibração entre a acidez potencial e o pH de equilíbrio da suspensão de solo com solução-tampão (pH SMP). Os resultados demonstraram que a acidez potencial pode ser estimada por meio da curva de regressão da solução-tampão SMP (R² = 0,90**). Também foi observada correlação significativa entre o pH de equilíbrio da suspensão de acetato de cálcio 0,5 mol L-1 e o pH SMP.

pH como un trazador de la variabilidad biogeoquímica en el Sistema de Humboldt

Se analizó información sobre parámetros biogeoquímicos como pH, CO2 parcialmente disuelto, clorofila-a, oxígeno, salinidad y temperatura, obtenidos en el Sistema de Humboldt frente a Perú en los años 2007-2009, a fin de comprender la importancia del pH como una variable clave para trazar la variabilidad biogeoquímica del Sistema de Afloramiento de Humboldt. Las Aguas Costeras Frías (ACF) ricas en nutrientes evidencian una relación inversa con el pH, en ese sentido valores de 7,6 a 8,0 se encontraron asociados a la ocurrencia de eventos de afloramiento; en condiciones frías como La Niña 2007 el pH predominante se encuentra por debajo de 8,0, y en el caso de las Aguas Subtropicales Superficiales presentan un pH entorno a 8,3. La productividad en los veranos se incrementa debido a factores como la intensidad de luz generándose núcleos de clorofila-a superiores a 10,0 μg.L-1; como constituyentes de la reacción bioquímica de fotosíntesis se tiene en cuenta la forma inmediata del compuesto CO2 y el consumo de iones hidronio; en situaciones extremas de fertilización, se tiene elevado pH entre 8,2 e inclusive 9,0, en donde los contenidos de oxígeno disuelto superan los 6,0 mL.L-1.

Estimativa de H + AL pelo pH SMP em solos do Rio Grande do Sul e de Santa Catarina

A capacidade de troca de cátions (CTC) e a proporção dos principais cátions retidos nas cargas negativas do solo são de grande importância para a caracterização química e para o diagnóstico da fertilidade do solo. Essas características, juntamente com o Al, o Ca e o Mg trocáveis, foram incluídas na análise de solo realizada pelos laboratórios oficiais do Rio Grande do Sul e de Santa Catarina, a partir de 1994. Este trabalho avaliou a relação entre o valor de H + Al e o pH SMP, visando estabelecer uma equação para a estimativa do valor de H + Al (acidez potencial), o qual pode ser utilizado no cálculo da CTC (método da soma de cátions trocáveis). O trabalho foi realizado nos laboratórios de solos da Universidade de Passo Fundo (UPF) e da Universidade Federal do Rio Grande do Sul (UFRGS), em 1995, constando da determinação do teor de H + Al, extraído com acetato de cálcio 1,0 mol L-1, pH 7,0, e do pH SMP em um grupo de 113 amostras de solo. Os resultados obtidos foram reunidos com os de outros pesquisadores, procedendo-se à análise de regressão para um conjunto de 250 amostras representativas de solos dos dois estados. Observou-se relação significativa entre o valor de H + Al e o pH SMP. Concluiu-se que as equações log (H + Al) = 3,9014 - 0,391 SMP (R² = 0,90) ou ln (H + Al) = 8,9832 - 0,9004 SMP (R² = 0,90), com os valores de H + Al expressos em mmol c dm-3, podem ser utilizadas para a estimativa do teor de H + Al pelo uso do pH SMP.

Fluxo difusivo de zinco em amostras de solo influenciado por textura, íon acompanhante e pH do solo

O fluxo difusivo (difusão) é a forma mais importante de transporte de zinco no solo, dada sua baixa concentração na solução. Este trabalho teve como objetivo avaliar o fluxo difusivo de Zn em amostras de um solo de textura argilosa (Latossolo Vermelho-Escuro - LE), outro de textura média (Podzólico Vermelho-Amarelo - PV) e um terceiro de textura arenosa (Latossolo Vermelho-Amarelo - LV), submetidos a níveis de pH: pH natural (4,38) e 5,40, para o LE; natural (4,87) e 6,00, para o PV, e somente pH natural (4,64), para o LV, e a três fontes de Zn (ZnCl2, ZnEDTA e ZnSO4) nas doses de 0, 20 e 40 mg dm-3 de Zn. As unidades experimentais constituíram-se de 400 cm³ de amostras de solo, colocadas em câmaras feitas de tubos de PVC, com 10 cm de diâmetro e 5 cm de altura, contendo, cada câmara, uma lâmina de resina trocadora de cátions ácido forte (modelo CR61CZR IONICS, Inc) como dreno de Zn, nas dimensões de 2,0 x 5,0 cm, colocada à profundidade de 2,5 cm no meio da câmara. As amostras, umedecidas até a capacidade de campo, foram incubadas por um período de 15 dias à temperatura de 24 ± 4ºC. Após esse período, as lâminas foram retiradas, realizando-se a extração do Zn adsorvido às lâminas de resina. O pH do solo demonstrou ser fator de grande importância no controle do fluxo difusivo do Zn, acarretando-lhe grande diminuição quando da elevação de pH. De modo geral, o fluxo difusivo de Zn foi menor com o aumento do teor de argila do solo. O fluxo difusivo de Zn foi maior, nos três solos, quando a fonte utilizada foi ZnCl2.

Cis association of Ly49A with MHC class I restricts natural killer cell inhibition.

Natural killer (NK) cell function is negatively regulated by inhibitory receptors interacting with major histocompatibility complex class I molecules expressed on target cells. Here we show that the inhibitory Ly49A NK cell receptor not only binds to its H-2D(d) ligand expressed on potential target cells (in trans) but also is constitutively associated with H-2D(d) in cis (on the same cell). Cis association and trans interaction occur through the same binding site. Consequently, cis association restricts the number of Ly49A receptors available for binding of H-2D(d) on target cells and reduces NK cell inhibition through Ly49A. By lowering the threshold at which NK cell activation exceeds NK cell inhibition, cis interaction allows optimal discrimination of normal and abnormal host cells.

Influência do pH na sorção de imazaquin em um Latossolo Vermelho Acriférrico

O herbicida imazaquin é uma molécula orgânica com grupos funcionais ionizáveis, sendo sua sorção dependente do pH e da carga elétrica líquida do solo. Neste trabalho, foi estudada a sorção do imazaquin nas camadas superficiais e subsuperficiais de um Latossolo Vermelho Acriférrico típico textura muito argilosa, considerando quatro diferentes valores de pH. Com uso de moléculas radiomarcadas com carbono-14, determinou-se a quantidade sorvida pela diferença entre a quantidade aplicada e a remanescente em solução. Os resultados foram ajustados à equação de Freundlich, para determinação do coeficiente de sorção (Kf). De maneira geral, o herbicida apresentou baixa sorção no solo. Nas amostras coletadas nas duas profundidades, a sorção diminuiu com a elevação do pH. Para um mesmo valor de pH, a sorção foi maior no horizonte subsuperficial do que no superficial, sendo a carga líquida positiva resultante do baixo teor de matéria orgânica e dos elevados conteúdos de óxidos de ferro e de alumínio. Quando a carga elétrica líquida do solo foi positiva, não foi possível predizer a sorção de imazaquin, considerando apenas a especiação da molécula e a sua partição na fração orgânica do solo.