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Labrie M.,INRS Institute Armand Frappier | St-Pierre Y.,INRS Institute Armand Frappier
Cellular and Molecular Life Sciences | Year: 2013

Matrix metalloproteinase 9 (MMP-9) is one of the most studied enzymes in cancer. MMP-9 can cleave proteins of the extracellular matrix and a large number of receptors and growth factors. Accordingly, its expression must be tightly regulated to avoid excessive enzymatic activity, which is associated with disease progression. Although we know that epigenetic mechanisms play a central role in controlling mmp-9 gene expression, predicting how epigenetic drugs could be used to suppress mmp-9 gene expression is not trivial because epigenetic drugs also regulate the expression of key proteins that can tip the balance towards activation or suppression of MMP-9. Here, we review how our understanding of the biology and expression of MMP-9 could be exploited to augment clinical benefits, most notably in terms of the prevention and management of degenerative diseases and cancer. © 2012 Springer Basel.


Villemur R.,INRS Institute Armand Frappier
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2013

In this report, a complete description of Desulfitobacterium hafniense strain PCP-1 is presented. The D. hafniense strain PCP-1 was isolated from a methanogenic consortium for its capacity to dehalogenate pentachlorophenol (PCP) into 3-chlorophenol. This strain is also capable of dehalogenating several other chloroaromatic compounds and tetrachloroethene into trichloroethene. Four gene loci encoding putative chlorophenol-reductive dehalogenases (CprA2 to CprA5) were detected, and the products of two of these loci have been demonstrated to dechlorinate different chlorinated phenols. Strain PCP-1 was used in laboratory-scale bioprocesses to degrade PCP present in contaminated environments. Desulfitobacterium hafniense PCP-1 is an excellent candidate for the development of efficient bioprocesses to degrade organohalide compounds © 2013 The Author(s) Published by the Royal Society. All rights reserved.


Caza M.,INRS Institute Armand Frappier | Lepine F.,INRS Institute Armand Frappier | Dozois C.M.,INRS Institute Armand Frappier
Molecular Microbiology | Year: 2011

Extraintestinal pathogenic Escherichia coli (ExPEC) use siderophores to sequester iron during infection. Enterobactin and salmochelins are catecholate siderophores produced by some ExPEC strains and other pathogenic enterobacteria. Siderophore export and synthesis mutants of avian ExPEC strain χ7122 were tested in a chicken infection model. In single-strain infections, siderophore-negative (ΔentDΔiuc), ΔentS and ΔentSΔiroC export mutants were attenuated in tissues and blood, whereas the ΔiroC export mutant was only attenuated in blood. Interestingly, the ΔentD mutant, producing only aerobactin, retained full virulence, and loss of entD in the ΔentSΔiroC mutant restored virulence. LC-MS/MS quantification of siderophores in export mutants demonstrated that loss of entS impaired enterobactin and mono-glucosylated enterobactin secretion, whereas loss of iroC impaired di- and tri-glucosylated enterobactin secretion. Loss of entS and/or iroC resulted in intracellular accumulation and increased secretion of siderophore monomers. Catecholate siderophore export mutants also demonstrated decreased fitness in a co-challenge infection model. By contrast, catecholate siderophore synthesis mutants (ΔentD and ΔiroB) competed as well as the wild-type strain. Results establish that EntS and IroC mediate specific export of catecholate siderophores and the role of these exporters for ExPEC virulence is contingent on enterobactin synthesis, which is not required when other siderophores like aerobactin are functional. © 2011 Blackwell Publishing Ltd.


Villemur R.,INRS Institute Armand Frappier
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

In this report, a complete description of Desulfitobacterium hafniense strain PCP-1 is presented. The D. hafniense strain PCP-1 was isolated from a methanogenic consortium for its capacity to dehalogenate pentachlorophenol (PCP) into 3-chlorophenol. This strain is also capable of dehalogenating several other chloroaromatic compounds and tetrachloroethene into trichloroethene. Four gene loci encoding putative chlorophenol-reductive dehalogenases (CprA2 to CprA5) were detected, and the products of two of these loci have been demonstrated to dechlorinate different chlorinated phenols. Strain PCP-1 was used in laboratory-scale bioprocesses to degrade PCP present in contaminated environments. Desulfitobacterium hafniense PCP-1 is an excellent candidate for the development of efficient bioprocesses to degrade organohalide compounds.


The etiology of most neurodegenerative diseases of the central nervous system remains unknown and likely involves a combination of genetic susceptibility and environmental triggering factors. Given that exposure to numerous infectious pathogens occurs during childhood, and that some viral infections can lead to neurodegeneration and demyelination, it is conceivable that some viruses may act as triggering factors in neuropathogenesis. We have previously shown that the prototype OC43 strain of the common cold-associated human respiratory coronavirus has the capacity to infect human neuronal and glial cells and does persist in human brains. Moreover, it has neuroinvasive properties in susceptible BALB/c mice, where it leads to a chronic encephalitis with accompanying disabilities. Here, we show that mutations in the viral spike glycoprotein, reproducibly acquired during viral persistence in human neural cell cultures, led to a drastically modified virus-induced neuropathology in BALB/c mice, characterized by flaccid paralysis and demyelination. Even though infection by both mutated and wild-type viruses led to neuroinflammation, the modified neuropathogenesis induced by the mutated virus was associated with increased viral spread and significantly more CD4+ and CD8+ T-lymphocyte infiltration into the central nervous system, as well as significantly increased levels of the proinflammatory cytokine interleukin (IL)-6 and the chemokine CCL2 (monocyte chemoattractant protein [MCP]-1). Moreover, recombinant virus harboring the S glycoprotein mutations retained its neurotropism, productively infecting neurons. Therefore, interaction of a human respiratory coronavirus with the central nervous system may modulate virus and host factors resulting in a modified neuropathogenesis in genetically susceptible individuals.


Arango Duque G.,INRS Institute Armand Frappier | Arango Duque G.,Center for Host Parasite Interactions | Descoteaux A.,INRS Institute Armand Frappier | Descoteaux A.,Center for Host Parasite Interactions
Current Opinion in Microbiology | Year: 2015

Macrophages are cells of the immune system that mediate processes ranging from phagocytosis to tissue homeostasis. Leishmania has evolved ingenious ways to adapt to life in the macrophage. The GP63 metalloprotease, which disables key microbicidal pathways, has recently been found to disrupt processes ranging from antigen cross-presentation to nuclear pore dynamics. New studies have also revealed that Leishmania sabotages key metabolic and signaling pathways to fuel parasite growth. Leishmania has also been found to induce DNA methylation to turn off genes controlling microbicidal pathways. These novel findings highlight the multipronged attack employed by Leishmania to subvert macrophage function. © 2015 .


Tremblay J.,INRS Institute Armand Frappier | Deziel E.,INRS Institute Armand Frappier
BMC Genomics | Year: 2010

Background: The bacterium Pseudomonas aeruginosa is capable of three types of motilities: swimming, twitching and swarming. The latter is characterized by a fast and coordinated group movement over a semi-solid surface resulting from intercellular interactions and morphological differentiation. A striking feature of swarming motility is the complex fractal-like patterns displayed by migrating bacteria while they move away from their inoculation point. This type of group behaviour is still poorly understood and its characterization provides important information on bacterial structured communities such as biofilms. Using GeneChip® Affymetrix microarrays, we obtained the transcriptomic profiles of both bacterial populations located at the tip of migrating tendrils and swarm center of swarming colonies and compared these profiles to that of a bacterial control population grown on the same media but solidified to not allow swarming motility.Results: Microarray raw data were corrected for background noise with the RMA algorithm and quantile normalized. Differentially expressed genes between the three conditions were selected using a threshold of 1.5 log2-fold, which gave a total of 378 selected genes (6.3% of the predicted open reading frames of strain PA14). Major shifts in gene expression patterns are observed in each growth conditions, highlighting the presence of distinct bacterial subpopulations within a swarming colony (tendril tips vs. swarm center). Unexpectedly, microarrays expression data reveal that a minority of genes are up-regulated in tendril tip populations. Among them, we found energy metabolism, ribosomal protein and transport of small molecules related genes. On the other hand, many well-known virulence factors genes were globally repressed in tendril tip cells. Swarm center cells are distinct and appear to be under oxidative and copper stress responses.Conclusions: Results reported in this study show that, as opposed to swarm center cells, tendril tip populations of a swarming colony displays general down-regulation of genes associated with virulence and up-regulation of genes involved in energy metabolism. These results allow us to propose a model where tendril tip cells function as «scouts» whose main purpose is to rapidly spread on uncolonized surfaces while swarm center population are in a state allowing a permanent settlement of the colonized area (biofilm-like). © 2010 Tremblay and Déziel; licensee BioMed Central Ltd.


Lamarche M.G.,INRS Institute Armand Frappier | Deziel E.,INRS Institute Armand Frappier
PLoS ONE | Year: 2011

Bacterial cells have evolved the capacity to communicate between each other via small diffusible chemical signals termed autoinducers. Pseudomonas aeruginosa is an opportunistic pathogen involved, among others, in cystic fibrosis complications. Virulence of P. aeruginosa relies on its ability to produce a number of autoinducers, including 4-hydroxy-2-alkylquinolines (HAQ). In a cell density-dependent manner, accumulated signals induce the expression of multiple targets, especially virulence factors. This phenomenon, called quorum sensing, promotes bacterial capacity to cause disease. Furthermore, P. aeruginosa possesses many multidrug efflux pumps conferring adaptive resistance to antibiotics. Activity of some of these efflux pumps also influences quorum sensing. The present study demonstrates that the MexEF-OprN efflux pump modulates quorum sensing through secretion of a signalling molecule belonging to the HAQ family. Moreover, activation of MexEF-OprN reduces virulence factor expression and swarming motility. Since MexEF-OprN can be activated in infected hosts even in the absence of antibiotic selective pressure, it could promote establishment of chronic infections in the lungs of people suffering from cystic fibrosis, thus diminishing the immune response to virulence factors. Therapeutic drugs that affect multidrug efflux pumps and HAQ-mediated quorum sensing would be valuable tools to shut down bacterial virulence. © 2011 Lamarche, Déziel.


Belkacemi A.,INRS Institute Armand Frappier
Expert reviews in molecular medicine | Year: 2011

Curcumin, the phytochemical agent in the spice turmeric, which gives Indian curry its yellow colour, is also a traditional Indian medicine. It has been used for millennia as a wound-healing agent and for treating a variety of ailments. The antioxidant, anti-inflammatory, antiproliferative and other properties of curcumin have only recently gained the attention of modern pharmacology. The mechanism of action of curcumin is complex and multifaceted. In part, curcumin acts by activating various cytoprotective proteins that are components of the phase II response. Over the past decade, research with curcumin has increased significantly. In vitro and in vivo studies have demonstrated that curcumin could target pathways involved in the pathophysiology of Alzheimer disease (AD), such as the β-amyloid cascade, tau phosphorylation, neuroinflammation or oxidative stress. These findings suggest that curcumin might be a promising compound for the development of AD therapy. However, its insolubility in water and poor bioavailability have limited clinical trials and its therapeutic applications. To be effective as a drug therapy, curcumin must be combined with other drugs, or new delivery strategies need to be developed.


Matte C.,INRS Institute Armand Frappier | Descoteaux A.,INRS Institute Armand Frappier
Infection and Immunity | Year: 2010

The protozoan parasite Leishmania donovani, the etiological agent of visceral leishmaniasis, is renowned for its capacity to sabotage macrophage functions and signaling pathways stimulated by activators such as gamma interferon (IFN-γ). Our knowledge of the strategies utilized by L. donovani to impair macrophage responsiveness to IFN-γ remains fragmentary. In the present study, we investigated the impact of an infection by the amastigote stage of L. donovani on IFN-γ responses and signaling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in mouse bone marrow-derived macrophages. The levels of IFN-γ-induced expression of major histocompatibility complex class II and inducible nitric oxide synthase (iNOS) were strongly reduced in L. donovani amastigote-infected macrophages. As the expression of those genes is mediated by the transcription factors STAT1α and IFN regulatory factor 1 (IRF-1), we investigated their activation in amastigote-infected macrophages treated with IFN-γ. We found that whereas STAT1α protein levels and the levels of phosphorylation on Tyr701 and Ser727 were normal, IRF-1 expression was inhibited in infected macrophages. This inhibition of IRF-1 expression correlated with a defective nuclear translocation of STAT1α, and further analyses revealed that the IFN-γ-induced STAT1α association with the nuclear transport adaptor importin-α5 was compromised in L. donovani amastigote-infected macrophages. Taken together, our results provide evidence for a novel mechanism used by L. donovani amastigotes to interfere with IFN-γ-activated macrophage functions and provide a better understanding of the strategies deployed by this parasite to ensure its intracellular survival. Copyright © 2010, American Society for Microbiology. All Rights Reserved.

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