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See detailHIV-1 protease inhibitors do not interfere with provirus transcription and host cell apoptosis induced by combined treatment TNF-alpha plus TSA
Vandergeeten, Claire ULg; Quivy, Vincent; Moutschen, Michel ULg et al

in Biochemical Pharmacology (2007), 73(11), 1738-1748

HIV-1 latency represents a major hurdle to the complete eradication of the virus from patients under highly active anti-retroviral therapy (HAART) regimens. One solution to this problem would be to ... [more ▼]

HIV-1 latency represents a major hurdle to the complete eradication of the virus from patients under highly active anti-retroviral therapy (HAART) regimens. One solution to this problem would be to eliminate the latently infected cellular reservoirs by forcing gene expression in presence of HAART to prevent spreading of the infection by the newly synthesized viruses. Many studies have reported that a combination of a histone deacetylase inhibitor (HDACi) (i.e. TSA, NaBut, Valproic acid,...) with a pro-inflammatory cytokine (i.e. TNF alpha, IL-1,...) reactivates in a synergistic manner HIV-1 transcription in latently infected cells. The aim of the present study was to determine whether HIV-1 protease inhibitors (PIs) used in HAART (such as Saquinavir, Indinavir, Nelfinavir, Lopinavir, Ritonavir and Amprenavir) could interfere with the potential purge of the cellular reservoirs induced by a combined treatment involving TSA and TNF alpha. We showed, in two HIV-1 latently infected cell lines (ACH-2 and U1) that all PIs efficiently inhibited release of mature viral particles but did neither affect cell apoptosis nor NF-kappa B induction and HIV-1 transcription activation following combined treatment with TNF alpha + TSA. This study is encouraging in the fight against HIV-1 and shows that PIs should be compatible with an inductive adjuvent therapy for latent reservoir reduction/elimination in association with efficient HAART regimens. (c) 2007 Elsevier Inc. All rights reserved. [less ▲]

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See detailBiomarker discovery for inflammatory bowel disease, using proteomic serum profiling
Meuwis, Marie-Alice ULg; Fillet, Marianne ULg; Geurts, Pierre ULg et al

in Biochemical Pharmacology (2007), 73(9), 1422-1433

Crohn's disease and ulcerative colitis known as inflammatory bowel diseases (IBD) are chronic immuno-inflammatory pathologies of the gastrointestinal tract. These diseases are multifactorial, polygenic ... [more ▼]

Crohn's disease and ulcerative colitis known as inflammatory bowel diseases (IBD) are chronic immuno-inflammatory pathologies of the gastrointestinal tract. These diseases are multifactorial, polygenic and of unknown etiology. Clinical presentation is non-specific and diagnosis is based on clinical, endoscopic, radiological and histological criteria. Novel markers are needed to improve early diagnosis and classification of these pathologies. We performed a study with 120 serum samples collected from patients classified in 4 groups (30 Crohn, 30 ulcerative colitis, 30 inflammatory controls and 30 healthy controls) according to accredited criteria. We compared protein sera profiles obtained with a Surface Enhanced Laser Desorption Ionization-Time of Flight-Mass Spectrometer (SELDI-TOF-MS). Data analysis with univariate process and a multivariate statistical method based on multiple decision trees algorithms allowed us to select some potential biomarkers. Four of them were identified by mass spectrometry and antibody based methods. Multivariate analysis generated models that could classify samples with good sensitivity and specificity (minimum 80%) discriminating groups of patients. This analysis was used as a tool to classify peaks according to differences in level on spectra through the four categories of patients. Four biomarkers showing important diagnostic value were purified, identified (PF4, MRP8, FIBA and Hpalpha2) and two of these: PF4 and Hpalpha2 were detected in sera by classical methods. SELDI-TOF-MS technology and use of the multiple decision trees method led to protein biomarker patterns analysis and allowed the selection of potential individual biomarkers. Their downstream identification may reveal to be helpful for IBD classification and etiology understanding. [less ▲]

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See detailNF-kappa B activation by reactive oxygen species: Fifteen years later
Gloire, Geoffrey ULg; Legrand-Poels, Sylvie ULg; Piette, Jacques ULg

in Biochemical Pharmacology (2006), 72(11), 1493-1505

The transcription factor NF-kappa B plays a major role in coordinating innate and adaptative immunity, cellular proliferation, apoptosis and development. Since the discovery in 1991 that NF-kappa B maybe ... [more ▼]

The transcription factor NF-kappa B plays a major role in coordinating innate and adaptative immunity, cellular proliferation, apoptosis and development. Since the discovery in 1991 that NF-kappa B maybe activated by H(2)o(2), several laboratories have put a considerable effort into dissecting the molecular mechanisms underlying this activation. Whereas early studies revealed an atypical mechanism of activation, leading to I kappa B alpha Y42 phosphorylation independently Of I kappa B kinase (IKK), recent findings suggest that H2O2 activates NF-kappa B mainly through the classical IKK-dependent pathway. The molecular mechanisms leading to IKK activation are, however, cell-type specific and will be presented here. In this review, we also describe the effect of other ROS (HOCl and O-1(2)) and reactive nitrogen species on NF-kappa B activation. Finally, we critically review the recent data highlighting the role of ROS in NF-kappa B activation by proinflammatory cytokines (TNF-alpha and IL-1 beta) and lipopolysaccharide (LPS), two major components of innate immunity. (c) 2006 Elsevier Inc. All rights reserved. [less ▲]

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See detailNF-kappa B activation by double-strand breaks
Habraken, Yvette ULg; Piette, Jacques ULg

in Biochemical Pharmacology (2006), 72(9), 1132-1141

Cellular response to DNA damage is complex and relies on the simultaneous activation of different networks. It involves DNA damage recognition, repair, and induction of signalling cascades leading to cell ... [more ▼]

Cellular response to DNA damage is complex and relies on the simultaneous activation of different networks. It involves DNA damage recognition, repair, and induction of signalling cascades leading to cell cycle checkpoint activation, apoptosis, and stress related responses. The fate of damaged cells depends on the balance between pro- and antiapoptotic signals. in this decisive life or death choice, the transcription factor NF-kappa B has emerged as a prosurvival actor in most cell types. As corollary, it appears to be associated with tumorigenic process and resistance to therapeutic strategies as it protects cancerous cells from death. in this review, we will focus on NF-kappa B activation by double-strand breaks inducing agents, such as ionizing radiation and DNA topoisomerase I and II inhibitors routinely used in cancer therapy. Coinciding with the 20th anniversary of the NF-kappa B discovery, major steps of the DSB-triggered cascade have been recently identified. Two parallel cascades are necessary for NF-kappa B activation. The first one depends on ATM (activated by double-strand breaks) and the second on PIDD (activated by an unknown stress signal). The phosphorylation of NEMO by ATM is the point of convergence of these two cascades. The identification of ATM/NEMO complex as the long searched "nuclear to cytoplasm" signal leading to IKK activation is also a major piece of the puzzle. The knowledge of the precise steps leading to DSB-initiated NF kappa B activation will allow the development of specific blocking compounds reducing its prosurvival function. (c) 2006 Elsevier Inc. All rights reserved. [less ▲]

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See detailDeregulated NF-kappa B activity in haematological malignancies
Keutgens, Aurore ULg; Robert, Isabelle ULg; Viatour, Patrick ULg et al

in Biochemical Pharmacology (2006), 72(9), 1069-1080

The NF-kappa B family of transcription factors plays key roles in the control of cell proliferation and apoptosis. Constitutive NF-kappa B activation is a common feature for most haematological ... [more ▼]

The NF-kappa B family of transcription factors plays key roles in the control of cell proliferation and apoptosis. Constitutive NF-kappa B activation is a common feature for most haematological malignancies and is therefore believed to be a crucial event for enhanced proliferation and survival of these malignant cells. In this review, we will describe the molecular mechanisms underlying NF-kappa B deregulation in haematological malignancies and will highlight what is still unclear in this field, 20 years after the discovery of this transcription factor. (c) 2006 Elsevier Inc. All rights reserved. [less ▲]

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See detailExtending the nuclear roles of I kappa B kinase subunits
Gloire, Geoffrey ULg; Dejardin, Emmanuel ULg; Piette, Jacques ULg

in Biochemical Pharmacology (2006), 72(9), 1081-1089

The transcription factor NF-kappa B plays a key role in a wide variety of cellular processes such as innate and adaptive immunity, cellular proliferation, apoptosis and development. In unstimulated cells ... [more ▼]

The transcription factor NF-kappa B plays a key role in a wide variety of cellular processes such as innate and adaptive immunity, cellular proliferation, apoptosis and development. In unstimulated cells, NF-kappa B is sequestered in the cytoplasm through its tight association with inhibitory proteins called I kappa BS, comprising notably I kappa B alpha. A key step in NF-kappa B activation is the phosphorylation Of I kappa B alpha by the so-called I kappa B kinase (IKK) complex, which targets the inhibitory protein for proteasomal degradation and allows the freed NF-kappa B to enter the nucleus where it can transactivate its target genes. The IKK complex is composed of two catalytic subunits called IKK alpha and IKK beta, and a regulatory subunit called NEMO/IKK gamma. Despite their key role in mediating I kappa B alpha phosphorylation in the cytoplasm, recent works have provided evidence that IKK subunits also translocate into the nucleus to regulate NF-kappa B-dependent and -independent gene expression, paving the way of a novel and exciting field of research. In this review, we will describe the current knowledge in that research area. (c) 2006 Elsevier Inc. All rights reserved. [less ▲]

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See detailThe alternative NF-kappa B pathway from biochemistry to biology: Pitfalls and promises for future drug development
Dejardin, Emmanuel ULg

in Biochemical Pharmacology (2006), 72(9), 1161-1179

The past two decades have led to a tremendous work on the transcription factor NF-kappa B and its molecular mechanisms of activation. The nuclear translocation of NF-kappa B is controlled by two main ... [more ▼]

The past two decades have led to a tremendous work on the transcription factor NF-kappa B and its molecular mechanisms of activation. The nuclear translocation of NF-kappa B is controlled by two main pathways: the classical and the alternative NF-kappa B pathways. The classical NF-kappa B pathway activates the IKK complex that controls the inducible degradation Of Most I kappa B family members that are I kappa B alpha, I kappa B beta, I kappa B epsilon and p105. The alternative NF-kappa B pathway induces p100 processing and p52 generation through the activation of at least two kinases, which are NIK and IKK alpha. Genetic studies have shown that IKK gamma is dispensable for the alternative pathway, which suggests the existence of an alternative IKK alpha-containing complex. It is noteworthy that activation of particular p52 heterodimers like p52/RelB requires solely the alternative pathway while activation of p52/p65 or p52/c-Rel involves a "hybrid pathway". Among others, LT beta R, BAFF-R, CD40 and RANK have the ability to induce the alternative pathway. The latter plays some roles in biological functions controlled by these receptors, which are the development of secondary lymphoid organs, the proliferation, survival and maturation of B cell, and the osteoclastogenesis. Exacerbated activation of the alternative pathway is potentially associated to a wide range of disorders like rheumatoid arthritis, ulcerative colitis or B cell lymphomas. Therefore, inhibitors of the alternative pathway could be valuable tools for the treatment of inflammatory disorders and cancers. (c) 2006 Elsevier Inc. All rights reserved. [less ▲]

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See detail20 years of NF-kappa B
Chariot, Alain ULg

in Biochemical Pharmacology (2006), 72(9), 1051-1053

We are celebrating this year 20 years of research dedicated to the transcription factor NF-kB. From 1986, the year of its initial identification as a DNA-binding activity for the enhancer of the ... [more ▼]

We are celebrating this year 20 years of research dedicated to the transcription factor NF-kB. From 1986, the year of its initial identification as a DNA-binding activity for the enhancer of the immunoglobulin k light-chain in activated B cells by David Baltimore and colleagues [1] to 2006, almost 20000 papers related to this transcription factor were published, which means three reports per day. This amazing amount of data generated over the years and throughout the world reflects the critical roles played by NF-kB in biology. It is indeed increasingly difficult to find circumstances where NF-kB is not involved at one point. One reason is due to the amazing amount of signals that can activate NF-kB. They include bacterial, viral and fungal products but also inflammatory cytokines, oxidative stress and therapeutically used drugs (as reviewed by Y. Habraken and J. Piette in this issue) and are listed in Tom Gilmore’s website (www.nf-kb.org) (Boston University). Another reason is due to the functional kB sites found in about one hundred genes [2]. These numerous NF-kB target genes play critical roles in cell survival and proliferation, as well as in innate and adaptive immunity, which reflects the essential role of this transcription factor in physiology and diseases. [less ▲]

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See detailCan NF-kappaB be a target for novel and efficient anti-cancer agents?
Olivier, Sabine ULg; Robe, Pierre ULg; Bours, Vincent ULg

in Biochemical Pharmacology (2006), 72(9), 1054-1068

Since the discovery of the NF-kappaB transcription factor in 1986 and the cloning of the genes coding for NF-kappaB and IkappaB proteins, many studies demonstrated that this transcription factor can, in ... [more ▼]

Since the discovery of the NF-kappaB transcription factor in 1986 and the cloning of the genes coding for NF-kappaB and IkappaB proteins, many studies demonstrated that this transcription factor can, in most cases, protect transformed cells from apoptosis and therefore participate in the onset or progression of many human cancers. Molecular studies demonstrated that ancient widely used drugs, known for their chemopreventive or therapeutic activities against human cancers, inhibit NF-kappaB, usually among other biological effects. It is therefore considered that the anti-cancer activities of NSAIDs (non-steroidal anti-inflammatory drugs) or glucocorticoids are probably partially related to the inhibition of NF-kappaB and new clinical trials are being initiated with old compounds such as sulfasalazine. In parallel, many companies have developed novel agents acting on the NF-kappaB pathway: some of these agents are supposed to be NF-kappaB specific (i.e. IKK inhibitors) while others have wide-range biological activities (i.e. proteasome inhibitors). Today, the most significant clinical data have been obtained with bortezomib, a proteasome inhibitor, for the treatment of multiple myeloma. This review discusses the preclinical and clinical data obtained with these various drugs and their putative future developments. [less ▲]

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See detailPeripheral benzodiazepine receptor (PBR) ligand cytotoxicity unrelated to PBR expression
Hans, Grégory ULg; Wislet, Sabine ULg; Lallemend, François et al

in Biochemical Pharmacology (2005), 69(5), 819-830

Some synthetic ligands of the peripheral-type benzodiazepine receptor (PBR), an 18 kDa protein of the outer mitochondrial membrane, are cytotoxic for several tumor cell lines and arise as promising ... [more ▼]

Some synthetic ligands of the peripheral-type benzodiazepine receptor (PBR), an 18 kDa protein of the outer mitochondrial membrane, are cytotoxic for several tumor cell lines and arise as promising chemotherapeutic candidates. However, conflicting results were reported regarding the actual effect of these drugs on cellular survival ranging from protection to toxicity. Moreover, the concentrations needed to observe such a toxicity were usually high, far above the affinity range for their receptor, hence questioning its specificity. In the present study, we have shown that micromolar concentrations of FGIN-1-27 And Ro 5-4864, two chemically unrelated PBR ligands are toxic for both PBR-expressing SK-N-BE neuroblastoma cells and PBR-deficient Jurkat lymphoma cells. We have thereby demonstrated that the cytotoxicity of these drugs is unrelated to their PBR-binding activity. Moreover, Ro 54864-induced cell death differed strikingly between both cell types, being apoptotic in Jurkat cells while necrotic in SK-N-BE cells. Again, this did not seem to be related to PBR expression since Ro 5-4864-induced death of PBR-transfected Jurkat cells remained apoptotic. Taken together, our results show that PBR is unlikely to mediate all the effects of these PBR ligands. They however confirm that some of these ligands are very effective cytotoxic drugs towards various cancer cells, even for reputed chemoresistant tumors such as neuroblastoma, and, surprisingly, also for PBR-lacking tumor cells. (C) 2004 Elsevier Inc. All rights reserved. [less ▲]

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See detailSodium nitroprusside-induced osteoblast apoptosis is mediated by long chain ceramide and is decreased by raloxifene.
Olivier, Sabine ULg; Fillet, Marianne ULg; Malaise, Michel ULg et al

in Biochemical Pharmacology (2005), 69(6), 891-901

Release of high levels of nitric oxide (NO) is associated with osteoblastic cell death. The mechanisms of NO-induced cytotoxicity are not well documented and it is presently not known if estrogenic ... [more ▼]

Release of high levels of nitric oxide (NO) is associated with osteoblastic cell death. The mechanisms of NO-induced cytotoxicity are not well documented and it is presently not known if estrogenic compounds prevent this effect. We studied the role of ceramides in cell death induced by the NO donor sodium nitroprusside (SNP) and we tested the possibility that 17beta-estradiol, the anti-estrogen ICI 182.780 and two selective estrogen receptor modulators raloxifene and tamoxifen modify osteoblastic cell apoptosis. SNP dose-dependently decreased MC3T3-E1 osteoblast viability, increased NO production in the culture media and enhanced the release of intracellular ceramides C22 and C24. Cell death induced by SNP was partially inhibited when MC3T3-E1 cells were pretreated with raloxifene and tamoxifen but was not modified when the cells were pretreated with 17beta-estradiol or ICI 182.780. Cell death induced by SNP resulted from apoptosis as demonstrated by Annexin-V and propidium iodide labeling and a reduction of SNP-induced MC3T3-E1 apoptosis was confirmed in the presence of raloxifene and tamoxifen. SNP induction of C22 and C24 production was inhibited by a pretreatment with raloxifene but not with 17beta-estradiol. Moreover, the synthetic ceramide C24 (0.75 and 1microM) decreased MC3T3-E1 cell viability and osteoblast cell death induced by C24 was partially decreased by raloxifene and to a lesser extent by 17beta-estradiol. These data demonstrate that SNP-induced cell death is mediated by the long chain ceramides C22 and C24 and that raloxifene protected osteoblast from apoptosis induced by SNP, an effect that might be relevant to its pharmacological properties on bone remodeling. [less ▲]

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See detailPro-inflammatory properties for thiazolidinediones.
Desmet, Christophe ULg; Warzée, Barbara ULg; Gosset, Philippe et al

in Biochemical Pharmacology (2005), 69(2), 255-265

Thiazolidinediones (TZDs) are pharmacological ligands of the peroxisome proliferator-activated receptor (PPAR)-gamma that are extensively used in the treatment of type II diabetes. Recently, an anti ... [more ▼]

Thiazolidinediones (TZDs) are pharmacological ligands of the peroxisome proliferator-activated receptor (PPAR)-gamma that are extensively used in the treatment of type II diabetes. Recently, an anti-inflammatory potential for TZDs has been suggested, based on observations that these compounds may inhibit pro-inflammatory cytokine expression in vitro and may attenuate the inflammatory response in vivo. Here, we show that the TZDs rosiglitazone (RSG) and troglitazone (TRO) do not inhibit the inflammatory response to tumor necrosis factor (TNF)-alpha in various epithelial cell types. On the contrary, both RSG and TRO significantly potentiated TNF-alpha-induced production of granulocyte/macrophage-colony-stimulating factor, interleukin (IL)-6 and/or IL-8 in these cells. This increase in pro-inflammatory cytokine expression was functionally significant as supernatants from cells co-treated with TNF-alpha and TZDs displayed increased neutrophil pro-survival activity when compared with supernatants from cells treated with TNF-alpha alone. Additionally, it was shown that TZDs enhance cytokine expression at the transcriptional level, but that the pro-inflammatory effects of TZDs are independent on PPARgamma, nuclear factor kappaB or mitogen-activated protein kinase activation. Our study shows that TZDs may potentiate the inflammatory response in epithelial cells, a previously unappreciated effect of these compounds [less ▲]

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See detailProstaglandin E2 induces the expression of functional inhibitory CD94/NKG2A receptors in human CD8+ T lymphocytes by a cAMP-dependent protein kinase A type I pathway.
Zeddou, Mustapha ULg; Greimers, Roland ULg; de Valensart, Nicolas et al

in Biochemical Pharmacology (2005), 70(5), 714-24

The CD94/NKG2A heterodimer is a natural killer receptor (NKR), which inhibits cell-mediated cytotoxicity upon interaction with MHC class I gene products. It is expressed by NK cells and by a small ... [more ▼]

The CD94/NKG2A heterodimer is a natural killer receptor (NKR), which inhibits cell-mediated cytotoxicity upon interaction with MHC class I gene products. It is expressed by NK cells and by a small fraction of activated T cells, predominantly of CD8+ phenotype. Abnormal upregulation of the CD94/NKG2A inhibitory NKR on cytotoxic T cells (CTLs) could be responsible for a failure of immunosurveillance in cancer or HIV infection. In an attempt to identify the mechanisms leading to inhibitory NKR upregulation on T cells, we analyzed the expression of the CD94/NKG2A heterodimer on human CTLs activated with anti-CD3 mAb in the presence of PGE2 or with 8-CPT-cAMP, an analogue of cyclic AMP. As previously described, anti-CD3 mAb-mediated activation induced the expression of CD94/NKG2A on a small fraction of CD8+ T cells. Interestingly, when low concentrations of PGE2 or 8-CPT-cAMP were present during the culture, the proportion of CD8+ T cells expressing CD94/NKG2A was two- to five-fold higher. This upregulation was partially prevented by PKA inhibitors, such as KT5720 and Rp-8-Br-cAMP (type I selective). We also report that cAMP induces upregulation of NKG2A at the mRNA level. We further demonstrated that cross-linking of CD94 on CD8+ T cells expressing the CD94/NKG2A heterodimer inhibits their cytotoxic activity in a bispecific antibody redirected lysis assay. Our findings clearly demonstrate that the PGE2/cAMP/PKA type I axis is involved in the expression of CD94/NKG2A receptor on human CD8+ T lymphocytes. [less ▲]

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See detailCell death and growth arrest in response to photodynamic therapy with membrane-bound photosensitizers
Piette, Jacques ULg; Volanti, Cédric ULg; Vantieghem, Annelies et al

in Biochemical Pharmacology (2003), 66(8), 1651-1659

Photodynamic therapy (PDT) is a treatment for cancer and for certain benign conditions that is based on the use of a photosensitizer and light to produce reactive oxygen species in cells. Many of the ... [more ▼]

Photodynamic therapy (PDT) is a treatment for cancer and for certain benign conditions that is based on the use of a photosensitizer and light to produce reactive oxygen species in cells. Many of the photosensitizers currently used in PDT localize in different cell compartments such as mitochondria, lysosomes, endoplasmic reticulum and generate cell death by triggering necrosis and/or apoptosis. Efficient cell death is observed when light, oxygen and the photosensitizer are not limiting ("high dose PDT"). When one of these components is limiting ("low dose PDT"), most of the cells do not immediately undergo apoptosis or necrosis but are growth arrested with several transduction pathways activated. This commentary will review the mechanism of apoptosis and growth arrest mediated by two important PDT agents. i.e. pyropheophorbide and hypericin. (C) 2003 Elsevier Inc. All rights reserved. [less ▲]

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See detailEffects of rhein on human articular chondrocytes in alginate beads
Sanchez, Christelle ULg; Mathy-Hartert, Marianne; Deberg, Michelle ULg et al

in Biochemical Pharmacology (2003), 65(3), 377-388

This study was designed to investigate the effects of them, the active metabolite of diacerhein, on the metabolic functions of human chondrocytes cultured in alginate beads. Enzymatically isolated ... [more ▼]

This study was designed to investigate the effects of them, the active metabolite of diacerhein, on the metabolic functions of human chondrocytes cultured in alginate beads. Enzymatically isolated ostcoarthritic (OA) chondrocytes were cultured in alginate beads in a well-defined culture medium for 12 days. Rhein was tested in a range of concentrations comprised between 10(-7) and 4 x 10(-5) M, in the presence or absence of 10(-10) M IL-1beta. Interleukin (IL)-6 and -8, macrophage inflammatory protein (MIP-1beta), stromelysin-1 (MMP-3), aggrecan (AGG), tissue inhibitor of metalloproteinases-1 (TIMP-1), prostaglandin E-2 (PGE(2)) and nitric oxide (NO) productions were assayed. Cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) mRNA steady-state levels were also quantified. In the basal condition, 10(-5) M them increased by 46.5% the production of AGG, decreased by 17-30% the production of IL-6, MMP-3, NO and MIP-1beta but enhanced by 50% the production of PGE2(.) IL-1beta increased IL-6, IL-8, MIP-1beta, NO, PGE(2) and MMP-3 productions, but inhibited AGG and TIMP-1 synthesis. Rhein partially reversed the effect of IL-1beta on TIMP-1 and NO production, had no effect on AGG, IL-6 and MIP-1P production, but upregulated the IL-1beta stimulated PGE(2) production. The COX-2 and iNOS mRNA levels and IL-8 production were not modified by rhein. Overall, these results contribute to explain the clinical efficiency of rhein and give new information on its mechanisms of action. (C) 2002 Elsevier Science Inc. All rights reserved. [less ▲]

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See detailMechanisms involved in exogenous C2- and C6-ceramide-induced cancer cell toxicity.
Fillet, Marianne ULg; Bentires-Alj, Mohamed; Deregowski, Valérie et al

in Biochemical Pharmacology (2003), 65(10), 1633-42

Ceramides are important intracellular second messengers that play a role in the regulation of cell growth, differentiation, and programmed cell death. To determine whether ceramides can mediate the ... [more ▼]

Ceramides are important intracellular second messengers that play a role in the regulation of cell growth, differentiation, and programmed cell death. To determine whether ceramides can mediate the apoptosis of HCT116 and OVCAR-3 cancer cells, exogenous C2-, C6-, and C16-ceramides were used to mimic the endogenous lipid increase that follows a large variety of stresses. C2- and C6-ceramides (cell-permeable ceramide analogs), but not C16-ceramide, induced nuclear factor-kappaB (NF-kappaB) DNA-binding, caspase-3 activation, poly(ADP-ribose) polymerase degradation, and mitochondrial cytochrome c release, indicating that apoptosis occurs through the caspase cascade and the mitochondrial pathway. No difference in survival was observed between control cells and cells expressing mutated IkappaBalpha and treated with the permeable ceramides. This suggests that, at least in these cell lines, stable NF-kappaB inhibition did not modify the ceramide-induced cytotoxicity pathway. C6-ceramide also induced a double block in G1 and G2, thus emptying the S phase. [less ▲]

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See detailMatrix and serine protease expression during leukemic cell differentiation induced by aclacinomycin and all-trans-retinoic acid
Devy, L.; Hollender, P.; Munaut, Carine ULg et al

in Biochemical Pharmacology (2002), 63(2), 179-189

In myeloid leukemia, immature leukemic cells are able to egress into peripheral blood to infiltrate extra-medullary organs. We therefore analyzed the migrating and invasive potential of human HL-60 and ... [more ▼]

In myeloid leukemia, immature leukemic cells are able to egress into peripheral blood to infiltrate extra-medullary organs. We therefore analyzed the migrating and invasive potential of human HL-60 and NB4 cell lines, representative of acute myelogenous leukemia, their ability to express matrix metalloproteases (MMPs), tissue inhibitors of metalloproteases (TIMPs) and urokinase plasminogen activator (uPA) in response to differentiating agents. Granulocytic differentiation by all-trans-retinoic acid (ATRA) and aclacinomycin (ACLA) strongly increased HL-60 and NB4 cell migration and invasion. At mRNA and protein levels, these cell lines produced significant amounts of MMP-9 (HL-60 < NB4). Granulocytic differentiation by ACLA increased both pro and active forms of MMP-9 whereas ATRA decreased them and stimulated uPA mRNAs. TIMP-1, the physiological MMP inhibitor, increased during granulocytic differentiation whereas TIMP-2 did not significantly vary. Use of Batimastat and aprotinin suggests that ATRA was active by modulating the uPA system while ACLA interfered with MMP expression. In conclusion, our data demonstrate that HL-60 and NB4 cells express MMPs and uPA which are differentially regulated by the differentiating agents ATRA and ACLA and suggest the clinical usefulness of MMPs and serine protease inhibitors in the prophylaxis and treatment of the ATRA syndrome. (C) 2002 Elsevier Science Inc. All rights reserved. [less ▲]

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See detailIn vitro and in vivo effects of new insulin releasing agents
Nguyen, Q. A.; Antoine, M. H.; Ouedraogo, R. et al

in Biochemical Pharmacology (2002)

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See detailIs HIF-1alpha a pro- or an anti-apoptotic protein?
Piret, Jean-Pascal; Mottet, Denis ULg; Raes, Martine et al

in Biochemical Pharmacology (2002), 64(5-6), 889-92

Hypoxia-inducible factor-1 (HIF-1) is the major transcription factor specifically activated by hypoxia. It induces the expression of different genes whose products play an adaptive role for hypoxic cells ... [more ▼]

Hypoxia-inducible factor-1 (HIF-1) is the major transcription factor specifically activated by hypoxia. It induces the expression of different genes whose products play an adaptive role for hypoxic cells and tissues. Besides these protective responses, HIF-1 and/or hypoxia have also been shown to be either anti-apoptotic or pro-apoptotic, according to the cell type and experimental conditions. More severe or prolonged hypoxia rather induces apoptosis that is, at least in part, initiated by the direct association of HIF-1alpha and p53 and p53-induced gene expression. On the other hand, HIF-1alpha dimerized with ARNT, as an active transcription factor, can protect cells from apoptosis induced by several conditions. This review is aimed to describe the different mechanisms that account for these opposite effects of HIF-1alpha. [less ▲]

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See detailS Phase Dependence and Involvement of Nf-Kappab Activating Kinase to Nf-Kappab Activation by Camptothecin
Habraken, Yvette ULg; Piret, Bernard; Piette, Jacques ULg

in Biochemical Pharmacology (2001), 62(5), 603-16

Camptothecin (CPT) and derivatives are topoisomerase I poisons currently used as anticancer drugs. Their cytotoxicity is maximal for cells in S phase. Using asynchronous and S phase-synchronized HeLa ... [more ▼]

Camptothecin (CPT) and derivatives are topoisomerase I poisons currently used as anticancer drugs. Their cytotoxicity is maximal for cells in S phase. Using asynchronous and S phase-synchronized HeLa cells, we showed that both the nuclear factor-kappaB (NF-kappaB) activation and its transcriptional activity, induced by CPT treatment, are enhanced in S phase cells. After CPT treatment, NF-kappaB activation reached a maximum within 2-3 hr and was still detectable after 24 hr. The nature of the complex evolved with time, forming mostly p50/p65 after 2 hr to almost exclusively p52 after 24 hr. In HeLa cells, the different steps of the induction were readily observable in S phase synchronized cells, whereas they were barely noticeable in a randomly growing cell population. The signal progressed through the activation of the IKK complex, the phosphorylation of IkappaBalpha, and the degradation of phosphorylated-IkappaBalpha and -IkappaBbeta. The stable expression of wild-type HA-tagged-IkappaBalpha or mutated HA-tagged-IkappaBalpha (S32,36A) allowed us to confirm the essential role of Ser32 and Ser36. NF-kappaB-activating kinase (NIK) could play a role upstream of the IKK complex, as the transient expression of a kinase inactive mutant NIK(K429,430A) abolished the activation of NF-kappaB by CPT. A kinase inactive mutant of mitogen-activated protein/ERK kinase kinase 1 (MEKK1), another kinase susceptible of acting upstream of the signalsome, did not. Cytotoxicity studies with clonal populations expressing different amounts of wild-type or mutated IkappaBalpha revealed that the overexpression of wild-type IkappaBa in large amount increases the sensitivity of HeLa cells to CPT more efficiently than a lower level of expression of non-phosphorylable IkappaBalpha. [less ▲]

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