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See detailHistomycologie de la biodiversité des onychomycoses
PIERARD, Gérald ULg; ARRESE ESTRADA, Jorge ULg; QUATRESOOZ, Pascale ULg

in Baran, R.; PIERARD, Gérald (Eds.) Onychomycoses (2004)

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See detailHistomycologie unguéale
Arrese Estrada, Jorge ULg; Quatresooz, Pascale ULg; Franchimont, Claudine ULg et al

in Annales de Dermatologie et de Vénéréologie (2003), 130

The diversity of onychomycoses is large when the disease is scrutinized using traditional, fluorescence or confocal microscopy. Histomycology is a non-invasive assessment performed on nail clippings. The ... [more ▼]

The diversity of onychomycoses is large when the disease is scrutinized using traditional, fluorescence or confocal microscopy. Histomycology is a non-invasive assessment performed on nail clippings. The location of and the density in fungal cells is variable. In some instances, these aspects remain clinically unsuspected. In vivo confocal microscopy can bring the same information. Computerized image analysis of histological sections is the most performant means for quantifying the fungal load. Immunohistochemistry brings information about the identity of the fungus or the association of different fungi present in the nail plate. Mixed infections may be unifocal or located at different levels in the nail apparatus. The viability of fungi as assessed by vital stains can be assessed under the microscope and quantified by flow cytometry. The different facets of nail histomycology are complementary and shed some light on aspects sometimes unsuspected of onychomycoses. [less ▲]

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See detailHistone deacetylase 4 is required for TGF beta 1-induced myofibroblastic differentiation
Glenisson, Wendy; Castronovo, Vincenzo ULg; Waltregny, David ULg

in Biochimica et Biophysica Acta-Molecular Cell Research (2007), 1773(10), 1572-1582

Transforming Growth Factor beta 1 (TGF beta 1) is a crucial cytokine triggering myofibroblastic (MF) differentiation, a process involved in tissue healing as well as in pathologic conditions such as ... [more ▼]

Transforming Growth Factor beta 1 (TGF beta 1) is a crucial cytokine triggering myofibroblastic (MF) differentiation, a process involved in tissue healing as well as in pathologic conditions such as fibrosis and cancer. Together with cell shape modifications, TGF beta 1-mediated differentiation of fibroblasts into myofibroblasts is characteristically associated with the neo-expression of smooth muscle alpha-actin (alpha-SMA), a cytoskeletal protein that enhances their contractile activity. Several cellular differentiation programs have been linked to epigenetic regulation of gene expression, including gene methylation and historic acetylation. Herein, we sought to investigate the role of histone deacetylases (HDAC) in TGF beta 1-induced MY differentiation. We found that TSA, a global inhibitor of class I and class II HDACs, prevented alpha-SMA transcript and protein expression and morphological changes mediated by TGF beta 1 in cultured human skin fibroblasts. In order to identify the HDAC(s) participating in MF differentiation, the impact of specific HDAC silencing (HDAC1 through HDAC8) using RNA interference was investigated in fibroblasts exposed to TGF beta 1. Among the eight HDACs tested, silencing of HDAC4, HDAC6, and HDAC8 expression impaired TGF beta 1-induced alpha-SMA expression. HDAC4 silencing most efficiently abrogated alpha-SMA expression and also prevented TGF beta 1-mediated morphological changes. Forced down-regulation of HDAC4 stimulated the expression of 5'-TG-3'-Interacting Factor (TGIF) and TGIF2 homeoproteins, two known endogenous repressors of the TGF beta signaling pathway, but not of the inhibitory Smad7. Collectively, these data suggest that HDAC4 is an essential epigenetic regulator of MF differentiation and unveil HDAC4 as a potential target for treating MF-related disorders. (C) 2007 Published by Elsevier B.V. [less ▲]

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See detailHistone deacetylase 5 is a regulator of S phase progression
Peixoto, Paul ULg; Pirotte, Sophie ULg; Matheus, Nicolas ULg et al

Poster (2011, February 05)

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See detailHistone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation.
Godin, Juliette ULg; Dompierre, Jim; Charrin, Bénédicte et al

in Journal of Neuroscience (2007), 27(13)

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See detailHistone deacetylase 7 is involved in the control of angiogenesis by regulating platelet-derived growth factor-β
Mottet, Denis; Bellahcene, Akeila ULg; Deroanne, Christophe et al

Conference (2006)

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See detailHistone Deacetylase 7 Regulates Cell Survival and TCR Signaling in CD4/CD8 Double-Positive Thymocytes.
Kasler, Herbert G; Young, Bryan D; Mottet, Denis ULg et al

in Journal of Immunology (2011), 186(8), 4782-93

CD4/CD8 double-positive thymocytes express the transcriptional repressor histone deacetylase (HDAC)7, a class IIa HDAC that is exported from the cell nucleus after TCR engagement. Through signal-dependent ... [more ▼]

CD4/CD8 double-positive thymocytes express the transcriptional repressor histone deacetylase (HDAC)7, a class IIa HDAC that is exported from the cell nucleus after TCR engagement. Through signal-dependent nuclear export, class IIa HDACs such as HDAC7 mediate signal-dependent changes in gene expression that are important to developmental fate decisions in multiple tissues. We report that HDAC7 is exported from the cell nucleus during positive selection in mouse thymocytes and that it regulates genes mediating the coupling between TCR engagement and downstream events that determine cell survival. Thymocytes lacking HDAC7 are inefficiently positively selected due to a severely shortened lifespan and exhibit a truncated repertoire of TCR Jalpha segments. The expression of multiple important mediators and modulators of the response to TCR engagement is altered in HDAC7-deficient thymocytes, resulting in increased tonic MAPK activity that contributes to the observed loss of viability. Remarkably, the activity of protein kinase D, the kinase that mediates nuclear export of HDAC7 in response to TCR signaling, is also increased in HDAC7-deficient thymocytes, suggesting that HDAC7 nuclear export governs a self-sustaining autoexcitatory loop. These experiments add to the understanding of the life/death decision in thymic T cell development, define a novel function for class IIa HDACs, and point to a novel feed-forward mechanism whereby these molecules regulate their own state and mediate stable developmental transitions. [less ▲]

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See detailHistone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis
Mottet, Denis ULg; Bellahcene, Akeila ULg; Pirotte, Sophie ULg et al

in Circulation Research (2007), 101(12), 1237-1246

Global inhibition of class I and II histone deacetylases (HDACs) impairs angiogenesis. Herein, we have undertaken the identification of the specific HDAC(s) with activity that is necessary for the ... [more ▼]

Global inhibition of class I and II histone deacetylases (HDACs) impairs angiogenesis. Herein, we have undertaken the identification of the specific HDAC(s) with activity that is necessary for the development of blood vessels. Using small interfering RNAs, we observed that HDAC7 silencing in endothelial cells altered their morphology, their migration, and their capacity to form capillary tube-like structures in vitro but did not affect cell adhesion, proliferation, or apoptosis. Among several factors known to be involved in angiogenesis, platelet-derived growth factor-B (PDGF-B) and its receptor (PDGFR-beta) were the most upregulated genes following HDAC7 silencing. We demonstrated that their increased expression induced by HDAC7 silencing was partially responsible for the inhibition of endothelial cell migration. In addition, we have also shown that treatment of endothelial cells with phorbol 12-myristate 13-acetate resulted in the exportation of HDAC7 out of the nucleus through a protein kinase C/protein kinase D activation pathway and induced, similarly to HDAC7 silencing, an increase in PDGF-B expression, as well as a partial inhibition of endothelial cell migration. Collectively, these data identified HDAC7 as a key modulator of endothelial cell migration and hence angiogenesis, at least in part, by regulating PDGF-B/PDGFR-beta gene expression. Because angiogenesis is required for tumor progression, HDAC7 may represent a rational target for therapeutic intervention against cancer. [less ▲]

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See detailHistone deacetylase HDAC7 as a key regulator of the angiogenic process
Mottet, Denis; Bellahcene, Akeila ULg; Waltregny, David ULg et al

Poster (2006, January 20)

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See detailHistone deacetylase HDAC8 associates with smooth muscle alpha-actin and is essential for smooth muscle cell contractility
Waltregny, David ULg; Glenisson, Wendy; Tran, Syv Li et al

in FASEB Journal (2005), 19(8), 966-968

Although originally characterized as nuclear enzymes controlling the stability of nucleosomes, histone deacetylases (HDACs) may also exert their activity within the cytosol. Recently, we have demonstrated ... [more ▼]

Although originally characterized as nuclear enzymes controlling the stability of nucleosomes, histone deacetylases (HDACs) may also exert their activity within the cytosol. Recently, we have demonstrated that HDAC8, a class I HDAC, is a novel, prominently cytosolic marker of smooth muscle differentiation. As HDAC8 displays a striking stress fiber-like pattern of distribution and is coexpressed in vivo with smooth muscle alpha-actin (alpha-SMA) and smooth muscle myosin heavy chain, we have explored the possible participation of this HDAC in smooth muscle cytoskeleton regulation. Cell fractionation assays performed with primary human smooth muscle cells (HSMCs) showed that HDAC8, in contrast to HDAC1 and HDAC3, was enriched in cytoskeleton-bound protein fractions and insoluble cell pellets, suggesting an association of HDAC8 with the cystoskeleton. Coimmunoprecipitation experiments using HSMCs, NIH-3T3 cells, and human prostate tissue lysates further demonstrated that HDAC8 associates with alpha-SMA but not with beta-actin. HDAC8 silencing through RNA interference strongly reduced the capacity of HSMCs to contract collagen lattices. Mock transfections had no effect on HSMC contractily, and transfections with small interfering RNAs (siRNAs) specific for HDAC6, a cytosolic HDAC that functions as an alpha-tubulin deacetylase, resulted in a weak contraction inhibition. Although mock- and HDAC6 siRNA-transfected HSMCs showed no noticeable morphological changes, HDAC8 siRNA-transfected HSMCs displayed a size reduction with diminished cell spreading after replating. Altogether, our findings indicate that HDAC8 associates with the smooth muscle actin cytoskeleton and may regulate the contractile capacity of smooth muscle cells. [less ▲]

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See detailHistone deacetylase HDAC8 associates with smooth muscle alpha–actin and is essential for smooth muscle cell contractility
Glénisson, Wendy; Waltregny, David ULg; Tran, Syv Li et al

Conference (2006)

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See detailHistone deacetylase HDAC8 associates with smooth muscle alpha–actin and is essential for smooth muscle cell contractility
Glénisson, Wendy; Waltregny, David ULg; Tran, Syv Li et al

Conference (2005)

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See detailHistone deacetylase inhibitor trichostatin A sustains sodium pervanadate-induced NF-kappa B activation by delaying IkappaBalpha mRNA resynthesis : comparison with tumor necrosis factor alpha
Horion, Julie ULg; Gloire, Geoffrey ULg; El Mjiyad, Nadia et al

in Journal of Biological Chemistry (2007), 282(21), 15383

NF-kappaB is a crucial transcription factor tightly regulated by protein interactions and post-translational modifications, like phosphorylation and acetylation. A previous study has shown that ... [more ▼]

NF-kappaB is a crucial transcription factor tightly regulated by protein interactions and post-translational modifications, like phosphorylation and acetylation. A previous study has shown that trichostatin A (TSA), a histone deacetylase inhibitor, potentiates tumor necrosis factor (TNF) alpha-elicited NF-kappaB activation and delays IkappaBalpha cytoplasmic reappearance. Here, we demonstrated that TSA also prolongs NF-kappaB activation when induced by the insulino-mimetic pervanadate (PV), a tyrosine phosphatase inhibitor that initiates an atypical NF-kappaB signaling. This extension is similarly correlated with delayed IkappaBalpha cytoplasmic reappearance. However, whereas TSA causes a prolonged IKK activity when addedtoTNFalpha, it does notwhenaddedtoPV.Instead, quantitative reverse transcriptase-PCR revealed a decrease of ikappabalphamRNAlevel after TSA addition to PV stimulation. This synthesis deficit of the inhibitor could explain the sustained NF-kappaB residence in the nucleus. In vivo analysis by chromatin immunoprecipitation assays uncovered that, forPVinduction but not forTNFalpha, the presence of TSA provokes several impairments on the ikappabalphapromoter: (i) diminution of RNA Pol II recruitment; (ii) reduced acetylation and phosphorylation of histone H3-Lys14 and -Ser10, respectively; (iii) decreased presence of phosphorylated p65-Ser536; and (iv) reduction of IKKalphabinding. The recruitment of these proteins on the icam-1 promoter, another NF-kappaB-regulated gene, is not equally affected, suggesting a promoter specificity of PV with TSA stimulation. Taken together, these data suggest that TSA acts differently depending on the NF-kappaB pathway and the targeted promoter in question. This indicates that one overall histone deacetylase role is to inhibit NF-kappaB activation by molecular mechanisms specific of the stimulus and the promoter. [less ▲]

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See detailHistone deacetylase mediated transcriptional activation reduces proviral loads in HTLV-1 associated myelopathy/tropical spastic paraparesis patients.
Lezin, Agnes; Gillet, Nicolas ULg; Olindo, Stephane et al

in Blood (2007), 110(10), 3722-8

Epigenetic modifications of chromatin may play a role in maintaining viral latency and thus persistence of the human T-lymphotropic virus type 1 (HTLV-1), which is responsible for HTLV-associated ... [more ▼]

Epigenetic modifications of chromatin may play a role in maintaining viral latency and thus persistence of the human T-lymphotropic virus type 1 (HTLV-1), which is responsible for HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A major determinant of disease progression is increased peripheral blood proviral load (PVL), possibly via the accumulation of infected cells in the central nervous system (CNS) creating a damaging inflammatory response. Current therapeutic approaches that focus on reducing either cell proliferation, viral replication, or tissue invasion are still unsatisfactory. Contrasting with these inhibitory strategies, we evaluated the efficacy of a novel approach aimed, paradoxically, at activating viral gene expression to expose virus-positive cells to the host immune response. We used valproate (VPA), a histone deacetylase inhibitor that has been used for decades as a chronic, safe treatment for epileptic disorders. Based on in vitro and in vivo data, we provide evidence that transient activation of the latent viral reservoir causes its collapse, a process that may alleviate the condition of HAM/TSP. This represents the first such approach to treating HAM/TSP, using gene activation therapy to tilt the host-pathogen balance in favor of an existing antiviral response. This trial is registered at http://clinicaltrials.gov/as no. NCT00519181. [less ▲]

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See detailHistone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling
Deroanne, Christophe ULg; Bonjean, Karine; Servotte, Sandrine et al

in Oncogene (2002), 21(3), 427-436

Angiogenesis is a complex biological process involving the coordinated modulation of many genes. Histone deacetylases (HDAC) are a growing family of enzymes that mediate the availability of chromatin to ... [more ▼]

Angiogenesis is a complex biological process involving the coordinated modulation of many genes. Histone deacetylases (HDAC) are a growing family of enzymes that mediate the availability of chromatin to the transcriptional machinery. Trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA), two HDAC inhibitors known to relieve gene silencing, were evaluated as potential antiangiogenic agents. TSA and SAHA were shown to prevent vascular endothelial growth factor (VEGF)-stimulated human umbilical cord endothelial cells (HUVEC) from invading a type I collagen gel and forming capillary-like structures. SAHA and TSA inhibited the VEGF-induced formation of a CD31-positive capillary-like network in embryoid bodies and inhibited the VEGF-induced angiogenesis in the CAM assay. TSA also prevented, in a dose-response relationship, the sprouting of capillaries from rat aortic rings. TSA inhibited in a dose-dependent and reversible fashion the VEGF-induced expression of VEGF receptors, VEGFR1, VEGFR2, and neuropilin-1. TSA and SAHA upregulated the expression by HUVEC of semaphorin III, a recently described VEGF competitor, at both mRNA and protein levels. This effect was specific to endothelial cells and was not observed in human fibroblasts neither in vascular smooth muscle cells. These observations provide a conspicuous demonstration that HDAC inhibitors are potent anti-angiogenic factors altering VEGF signaling. [less ▲]

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See detailHistone deacetylases: anti-angiogenic targets in cancer therapy.
Mottet, Denis ULg; Castronovo, Vincenzo ULg

in Current Cancer Drug Targets (2010), 10(8), 898-913

Judah Folkman was the first in 1971 to observe and report that cancer growth and dissemination were dependent on angiogenesis - the formation of new blood vessels from pre-existing vasculature. For almost ... [more ▼]

Judah Folkman was the first in 1971 to observe and report that cancer growth and dissemination were dependent on angiogenesis - the formation of new blood vessels from pre-existing vasculature. For almost 40 years, this concept has inspired generations of researchers to identify anti-angiogenic molecules that could be used therapeutically to stop blood vessels formation and starve tumors of nutrients and oxygen. Tumor angiogenesis requires complex cellular and molecular interactions between endothelial and cancer cells. In response to external stimuli such as hypoxia, cancer cells secrete pro-angiogenic factors into the extracellular matrix that activate the surrounding endothelial cells to proliferate, migrate and form new blood vessels. So, vascularization of malignant lesions depends on the expression of specific genes in both endothelial and tumor cells and accumulating evidences shows that several members of the histone deacetylase (HDAC) family play key roles in the regulation of these genes. Indeed, numerous in vitro and in vivo studies demonstrated that inhibitors of HDAC modulate angiogenic gene expression in both endothelial and cancer cells and disturb the delicate and complex balance between the collective action of pro-angiogenic factors and angiogenesis inhibitors. Thus, HDAC are currently recognized as promising targets for the development of anti-cancer drugs. This review is an effort to present and discuss the role, functions and mechanisms of action of HDAC during tumor-driven angiogenesis as well as a brief summary of the clinical status of the main HDAC inhibitors (HDACi) currently under development in cancer therapy. [less ▲]

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See detailHistone Deacetylases: Target Enzymes for Cancer Therapy
Mottet, Denis ULg; Castronovo, Vincenzo ULg

in Clinical & Experimental Metastasis (2007)

Epigenic regulation of gene transcription has recently been the subject of a fast growing interest particularly in the field of cancer. Enzymatic acetylation and deacetylation of the epsilon-amino groups ... [more ▼]

Epigenic regulation of gene transcription has recently been the subject of a fast growing interest particularly in the field of cancer. Enzymatic acetylation and deacetylation of the epsilon-amino groups of lysine residues from nucleosomal histones, represents major molecular epigenic mechanisms controlling gene expression. Histone deacetylases (HDACs) and histone acetyl transferases (HAT) represent the two families of enzymes in charge of the control of the level of acetylation of the histone tails. By removing the acetyl groups that abrogate the positive charge of the lysine residues that maintain the histone tails attached to DNA, HDACs repress transcription. In mammals, these latter enzymes form three groups of related enzymes based on their sequence homology and are classified as HDACs I, II and III. Global inhibition of the HDACs I and II groups results in cell growth arrest and apoptosis of cancer cells and alters tumor growth in in vivo experimental models. Their surprisingly low general toxicity and their impressive efficiency in preclinical cancer models has led to consider HDAC inhibitors as very promising new anticancer pharmacological agents. In this review, we attempt to give a comprehensive overview of the role and the involvement of HDAC in carcinogenesis as well as the current progress on the development of HDAC general and specific inhibitors as new cancer therapies. [less ▲]

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See detailLes histones desacetylases : nouvelles cibles pour les therapies anti-cancereuses.
Mottet, Denis ULg; Castronovo, Vincenzo ULg

in Medecine Sciences : M/S (2008), 24(8-9), 742-6

Circa twenty-five years ago, cancer research was dominated by the concept that the origin of cancer was genetic. Thousands of genetic alterations have indeed been identified involving more than hundred ... [more ▼]

Circa twenty-five years ago, cancer research was dominated by the concept that the origin of cancer was genetic. Thousands of genetic alterations have indeed been identified involving more than hundred different genes in cancer development. Today, the model has evolved: it has been demonstrated that malignancies can be initiated not only through genetic alterations but also through epigenetic deregulations. By altering the expression of gene involved in cell regulation, epigenetic alterations, such as histone acetylation, play a key role in the initiation and progression of neoplasm. It has been shown that an imbalance between the acelylated and deacetylated status of chromatin is significantly involved in the acquisition of a malignant phenotype. Thus, the modulation of the histone acetylation level by histone deacetylase (HDAC) inhibitors could lead to a genetic re-programmation in cancer cells that would favor apoptosis and prevent proliferation. The potential therapeutic value of several HDAC inhibitors for cancer patients has been evaluated in clinical assays with very promising outcome. Indeed, the first inhibitors available for patients has been recently approved for cancer patients tracing the way for a new class of promising anti-cancer therapy modalities. [less ▲]

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See detailHistopathological comparison of two mouse-adapted influenza A strains in mice.
Garigliany, Mutien-Marie ULg; Habyarimana, Adélite; Cornet, Anne et al

Conference (2008, October)

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See detailHistopathological diagnosis of a type vii mucopolysaccharidosis after pregnancy termination.
Delbecque, Katty ULg; Gaillez, Stephanie ULg; Schaaps, Jean-Pierre ULg

in Fetal & Pediatric Pathology (2009), 28(1), 1-8

Type VII mucopolysaccharidosis is a very rare recessive lysosomal storage disease. We diagnosed a type VII MPS in a case of severe fetal hydrops after pregnancy termination at 23 weeks of gestation. The ... [more ▼]

Type VII mucopolysaccharidosis is a very rare recessive lysosomal storage disease. We diagnosed a type VII MPS in a case of severe fetal hydrops after pregnancy termination at 23 weeks of gestation. The diagnosis was suspected on histopathological examination by the presence of foam cells in many viscera and foamy placental Hofbauer cells. Enzyme assay on cultured amniotic cells showed a markedly deficient beta-glucuronidase activity, thus confirming the diagnosis. This report shows the importance of a precise necropsy diagnosis in nonimmune hydrops because of putative implications for genetic counseling and prenatal diagnosis in subsequent pregnancies. [less ▲]

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