Noureddine Zebda - Academia.edu (original) (raw)
Papers by Noureddine Zebda
Journal of Neurochemistry, 2009
The 5‐HT3 receptor is a member of the ‘Cys‐loop’ family of ligand‐gated ion channels that mediate... more The 5‐HT3 receptor is a member of the ‘Cys‐loop’ family of ligand‐gated ion channels that mediate fast excitatory and inhibitory transmission in the nervous system. Current evidence points towards native 5‐HT3 receptors originating from homomeric assemblies of 5‐HT3A or heteromeric assembly of 5‐HT3A and 5‐HT3B. Novel genes encoding 5‐HT3C, 5‐HT3D, and 5‐HT3E have recently been described but the functional importance of these proteins is unknown. In the present study, in silico analysis (confirmed by partial cloning) indicated that 5‐HT3C, 5‐HT3D, and 5‐HT3E are not human–specific as previously reported: they are conserved in multiple mammalian species but are absent in rodents. Expression profiles of the novel human genes indicated high levels in the gastrointestinal tract but also in the brain, Dorsal Root Ganglion (DRG) and other tissues. Following the demonstration that these subunits are expressed at the cell membrane, the functional properties of the recombinant human subunits were investigated using patch clamp electrophysiology. 5‐HT3C, 5‐HT3D, and 5‐HT3E were all non‐functional when expressed alone. Co‐transfection studies to determine potential novel heteromeric receptor interactions with 5‐HT3A demonstrated that the expression or function of the receptor was modified by 5‐HT3C and 5‐HT3E, but not 5‐HT3D. The lack of distinct effects on current rectification, kinetics or pharmacology of 5‐HT3A receptors does not however provide unequivocal evidence to support a direct contribution of 5‐HT3C or 5‐HT3E to the lining of the ion channel pore of novel heteromeric receptors. The functional and pharmacological contributions of these novel subunits to human biology and diseases such as irritable bowel syndrome for which 5‐HT3 receptor antagonists have major clinical usage, therefore remains to be fully determined.
The FASEB Journal, Apr 1, 2012
Allergology International, 2000
ABSTRACT It has recently been shown that vascular endothelial growth factor (VEGF) enhances vascu... more ABSTRACT It has recently been shown that vascular endothelial growth factor (VEGF) enhances vascular permeability and that mast cells produce VEGF, suggesting the involvement of VEGF in allergic diseases. In the present study we quantitatively analyzed VEGF in the nasal lavage fluid of patients with nasal allergy. We performed nasal antigen challenge with Japanese cedar pollen antigen in 10 healthy adult volunteers and in 10 cedar pollen IgE-positive patients with nasal allergy. In all patients with nasal allergy, VEGF and histamine levels in the nasal lavage fluid reached a peak 30 min after antigen challenge, then returned to prechallenge values 2 h after antigen challenge. In these patients, the histamine level increased three-fold, while the VEGF level increased 10-fold. However, in all healthy adult volunteers, VEGF and histamine levels did not increase. A stronger correlation was noted between the ratio of decreased nasal cavity volume and the ratio of increased VEGF levels (R = 0.823; P P
The Journal of Cell Biology, 2000
In metastatic rat mammary adenocarcinoma cells, cell motility can be induced by epidermal growth ... more In metastatic rat mammary adenocarcinoma cells, cell motility can be induced by epidermal growth factor. One of the early events in this process is the massive generation of actin barbed ends, which elongate to form filaments immediately adjacent to the plasma membrane at the tip of the leading edge. As a result, the membrane moves outward and forms a protrusion. To test the involvement of ADF/cofilin in the stimulus-induced barbed end generation at the leading edge, we inhibited ADF/cofilin's activity in vivo by increasing its phosphorylation level using the kinase domain of LIM-kinase 1 (GFP-K). We report here that expression of GFP-K in rat cells results in the near total phosphorylation of ADF/cofilin, without changing either the G/F-actin ratio or signaling from the EGF receptor in vivo. Phosphorylation of ADF/cofilin is sufficient to completely inhibit the appearance of barbed ends and lamellipod protrusion, even in the continued presence of abundant G-actin. Coexpression ...
AJP: Gastrointestinal and Liver Physiology, 2009
P2Y receptors have been reported to modulate gastrointestinal functions. The newest family member... more P2Y receptors have been reported to modulate gastrointestinal functions. The newest family member is the nucleotide-sugar receptor P2Y14. P2ry14 mRNA was detected throughout the rat gut, with the highest level being in the forestomach. We investigated the role of the receptor in stomach motility using cognate agonists and knockout (KO) mice. In rat isolated forestomach, 100 μM UDP-glucose and 100 μM UDP-galactose both increased the baseline muscle tension (BMT) by 6.2 ± 0.6 and 1.6 ± 0.6 mN ( P < 0.05, n = 3–4), respectively, and the amplitude of contractions during electrical field stimulation (EFS) by 3.7 ± 1.7 and 4.3 ± 2.5 mN ( P < 0.05, n = 3–4), respectively. In forestomach from wild-type (WT) mice, 100 μM UDP-glucose increased the BMT by 1.0 ± 0.1 mN ( P <0.05, n = 6) but this effect was lost in the KO mice (change of −0.1 ± 0.1 mN, n = 6). The 100 μM UDP-glucose also increased the contraction amplitude during EFS in this tissue from the WT animals (0.9 ± 0.4 mN, P &...
AJP: Lung Cellular and Molecular Physiology, 2013
Endothelial cells, master gatekeepers of the cardiovascular system, line its inner boundary from ... more Endothelial cells, master gatekeepers of the cardiovascular system, line its inner boundary from the heart to distant capillaries constantly exposed to blood flow. Interendothelial signaling and the monolayers adhesion to the underlying collagen-rich basal lamina are key in physiology and disease. Using neutron scattering, we report the first ever interfacial structure of endothelial monolayers under dynamic flow conditions mimicking the cardiovascular system. Endothelial adhesion (defined as the separation distance ℓ between the basal cell membrane and solid boundary) is explained using developed interfacial potentials and intramembrane segregation of specific adhesion proteins. Our method provides a powerful tool for the biophysical study of cellular layer adhesion strength in living tissues.
Grace a un modele animal adequat d'etude de la metastase spontanee, nous avons montre que les... more Grace a un modele animal adequat d'etude de la metastase spontanee, nous avons montre que les melanocytes humains metastatiques expriment des disaccharides gal1-3 gal nac non sialyles. De tels disaccharides, reconnus par la lectine pna (peanut agglutinin), ont egalement ete mis en evidence chez l'homme dans les melanomes primitifs malins. De plus, la presence de cellules pna#+ est correlee au niveau d'invasion locale et a l'epaisseur de la tumeur qui conditionnent le risque de metastase chez les patients. Deux glycoproteines de poids moleculaires respectifs 140 kda (magp1) et 110-120 kda (magp2) portent ces disaccharides gal1-3galnac non sialyles dans les cellules metastatiques et masques par des residus acides sialiques dans leurs homologues non metastatiques. Dans les cellules metastatiques, le deficit en sialylation des glycoproteines est accompagne d'une alteration de la sialylation des gangliosides qui se traduit par une deficience en disialogangliosides (gd...
Abstract. In metastatic rat mammary adenocarcinoma cells, cell motility can be induced by epiderm... more Abstract. In metastatic rat mammary adenocarcinoma cells, cell motility can be induced by epidermal growth factor. One of the early events in this process is the massive generation of actin barbed ends, which elongate to form filaments immediately adjacent to the plasma membrane at the tip of the leading edge. As a result, the membrane moves outward and forms a protrusion. To test the involvement of ADF/cofilin in the stimulus-induced barbed end generation at the leading edge, we inhibited ADF/cofilin’s activity in vivo by increasing its phosphorylation level using the kinase domain of LIM-kinase 1 (GFP-K). We report here that expression of GFP-K in rat cells results in the near total phosphorylation of ADF/cofilin, without changing either the G/F-actin ratio or signaling from the EGF receptor in vivo. Phosphorylation of ADF/cofilin is sufficient to completely inhibit the appearance of barbed ends and lamellipod protrusion, even in the continued presence of abundant G-actin. Coexpre...
Circulation research, Jan 21, 2017
Oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) generates a group... more Oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) generates a group of bioactive oxidized phospholipid products with a broad range of biological activities. Barrier-enhancing and anti-inflammatory effects of OxPAPC on pulmonary endothelial cells are critical for prevention of acute lung injury caused by bacterial pathogens or excessive mechanical ventilation. Anti-inflammatory properties of OxPAPC are associated with its antagonistic effects on Toll-like receptors and suppression of RhoA GTPase signaling. Because OxPAPC exhibits long-lasting anti-inflammatory and lung-protective effects even after single administration in vivo, we tested the hypothesis that these effects may be mediated by additional mechanisms, such as OxPAPC-dependent production of anti-inflammatory and proresolving lipid mediator, lipoxin A4 (LXA4). Mass spectrometry and ELISA assays detected significant accumulation of LXA4 in the lungs of OxPAPC-treated mice and in conditioned medi...
J Neurochem, 2009
5-HT 3 receptors are therapeutically important members of the superfamily of Cys-loop ligand-gate... more 5-HT 3 receptors are therapeutically important members of the superfamily of Cys-loop ligand-gated ion channels which includes the nicotinic acetylcholine receptors (nAChRs), GABA A , GABA C and glycine receptors (Reeves and Lummis 2002; Peters et al. 2005). The 5-HT 3 receptor exists as a pentameric ring of subunits that form an integral ion channel along the central axis. To date, functional channels composed of a homomeric assembly of 5-HT 3A (Maricq et al. 1991; Miyake et al. 1995); or heteromeric assembly of 5-HT 3A and 5-HT 3B subunits (5-HT 3AB) (Davies et al. 1999) have been described. Each exhibits distinct channel characteristics (single channel conductance, rectification), but little difference in pharmacology, at least in terms of responses to 5hydroxytryptamine (5-HT) or 5-HT 3 receptor antagonists (Reeves and Lummis 2002; Peters et al. 2005), although small differences in responses to tubocurarine or picrotoxin are observed (Davies et al. 1999; Brady et al. 2001; Das and Dillon 2003). These findings do not, however, explain the apparent pharmacological diversity of responses mediated by the 5-HT 3 receptor within native tissues.
Invasion & metastasis, 1995
Malignant transformation is associated with alterations in both cell-cell and cell-matrix interac... more Malignant transformation is associated with alterations in both cell-cell and cell-matrix interactions. The E2 and C5 clones, derived from the human colon adenocarcinoma LoVo cell line, show, respectively, low and high metastatic capacity as experimental xenografts in vivo. In this study, we have assessed the adhesion and spreading of E2 and C5 cells on basement membrane laminin, expression of the laminin receptor integrins alpha 6 beta 1 and alpha 6 beta 4 and expression of gelatinolytic and plasminogen-dependent activities. On days 5 and 7 after subcutaneous grafting to immunosuppressed newborn rats, well-differentiated E2 tumors displayed a polarized expression of these integrin subunits, with the exception of the beta 1 subunit which remained pericellular. In contrast, C5 tumors were unorganized and the three integrin subunits remained nonpolarized and pericellular. Flow cytometry results showed that the expression of alpha 6 beta 1 and alpha 1 beta 4 integrins was weaker in the...
Journal of Neurochemistry, 2009
The 5‐HT3 receptor is a member of the ‘Cys‐loop’ family of ligand‐gated ion channels that mediate... more The 5‐HT3 receptor is a member of the ‘Cys‐loop’ family of ligand‐gated ion channels that mediate fast excitatory and inhibitory transmission in the nervous system. Current evidence points towards native 5‐HT3 receptors originating from homomeric assemblies of 5‐HT3A or heteromeric assembly of 5‐HT3A and 5‐HT3B. Novel genes encoding 5‐HT3C, 5‐HT3D, and 5‐HT3E have recently been described but the functional importance of these proteins is unknown. In the present study, in silico analysis (confirmed by partial cloning) indicated that 5‐HT3C, 5‐HT3D, and 5‐HT3E are not human–specific as previously reported: they are conserved in multiple mammalian species but are absent in rodents. Expression profiles of the novel human genes indicated high levels in the gastrointestinal tract but also in the brain, Dorsal Root Ganglion (DRG) and other tissues. Following the demonstration that these subunits are expressed at the cell membrane, the functional properties of the recombinant human subunits were investigated using patch clamp electrophysiology. 5‐HT3C, 5‐HT3D, and 5‐HT3E were all non‐functional when expressed alone. Co‐transfection studies to determine potential novel heteromeric receptor interactions with 5‐HT3A demonstrated that the expression or function of the receptor was modified by 5‐HT3C and 5‐HT3E, but not 5‐HT3D. The lack of distinct effects on current rectification, kinetics or pharmacology of 5‐HT3A receptors does not however provide unequivocal evidence to support a direct contribution of 5‐HT3C or 5‐HT3E to the lining of the ion channel pore of novel heteromeric receptors. The functional and pharmacological contributions of these novel subunits to human biology and diseases such as irritable bowel syndrome for which 5‐HT3 receptor antagonists have major clinical usage, therefore remains to be fully determined.
The FASEB Journal, Apr 1, 2012
Allergology International, 2000
ABSTRACT It has recently been shown that vascular endothelial growth factor (VEGF) enhances vascu... more ABSTRACT It has recently been shown that vascular endothelial growth factor (VEGF) enhances vascular permeability and that mast cells produce VEGF, suggesting the involvement of VEGF in allergic diseases. In the present study we quantitatively analyzed VEGF in the nasal lavage fluid of patients with nasal allergy. We performed nasal antigen challenge with Japanese cedar pollen antigen in 10 healthy adult volunteers and in 10 cedar pollen IgE-positive patients with nasal allergy. In all patients with nasal allergy, VEGF and histamine levels in the nasal lavage fluid reached a peak 30 min after antigen challenge, then returned to prechallenge values 2 h after antigen challenge. In these patients, the histamine level increased three-fold, while the VEGF level increased 10-fold. However, in all healthy adult volunteers, VEGF and histamine levels did not increase. A stronger correlation was noted between the ratio of decreased nasal cavity volume and the ratio of increased VEGF levels (R = 0.823; P P
The Journal of Cell Biology, 2000
In metastatic rat mammary adenocarcinoma cells, cell motility can be induced by epidermal growth ... more In metastatic rat mammary adenocarcinoma cells, cell motility can be induced by epidermal growth factor. One of the early events in this process is the massive generation of actin barbed ends, which elongate to form filaments immediately adjacent to the plasma membrane at the tip of the leading edge. As a result, the membrane moves outward and forms a protrusion. To test the involvement of ADF/cofilin in the stimulus-induced barbed end generation at the leading edge, we inhibited ADF/cofilin's activity in vivo by increasing its phosphorylation level using the kinase domain of LIM-kinase 1 (GFP-K). We report here that expression of GFP-K in rat cells results in the near total phosphorylation of ADF/cofilin, without changing either the G/F-actin ratio or signaling from the EGF receptor in vivo. Phosphorylation of ADF/cofilin is sufficient to completely inhibit the appearance of barbed ends and lamellipod protrusion, even in the continued presence of abundant G-actin. Coexpression ...
AJP: Gastrointestinal and Liver Physiology, 2009
P2Y receptors have been reported to modulate gastrointestinal functions. The newest family member... more P2Y receptors have been reported to modulate gastrointestinal functions. The newest family member is the nucleotide-sugar receptor P2Y14. P2ry14 mRNA was detected throughout the rat gut, with the highest level being in the forestomach. We investigated the role of the receptor in stomach motility using cognate agonists and knockout (KO) mice. In rat isolated forestomach, 100 μM UDP-glucose and 100 μM UDP-galactose both increased the baseline muscle tension (BMT) by 6.2 ± 0.6 and 1.6 ± 0.6 mN ( P < 0.05, n = 3–4), respectively, and the amplitude of contractions during electrical field stimulation (EFS) by 3.7 ± 1.7 and 4.3 ± 2.5 mN ( P < 0.05, n = 3–4), respectively. In forestomach from wild-type (WT) mice, 100 μM UDP-glucose increased the BMT by 1.0 ± 0.1 mN ( P <0.05, n = 6) but this effect was lost in the KO mice (change of −0.1 ± 0.1 mN, n = 6). The 100 μM UDP-glucose also increased the contraction amplitude during EFS in this tissue from the WT animals (0.9 ± 0.4 mN, P &...
AJP: Lung Cellular and Molecular Physiology, 2013
Endothelial cells, master gatekeepers of the cardiovascular system, line its inner boundary from ... more Endothelial cells, master gatekeepers of the cardiovascular system, line its inner boundary from the heart to distant capillaries constantly exposed to blood flow. Interendothelial signaling and the monolayers adhesion to the underlying collagen-rich basal lamina are key in physiology and disease. Using neutron scattering, we report the first ever interfacial structure of endothelial monolayers under dynamic flow conditions mimicking the cardiovascular system. Endothelial adhesion (defined as the separation distance ℓ between the basal cell membrane and solid boundary) is explained using developed interfacial potentials and intramembrane segregation of specific adhesion proteins. Our method provides a powerful tool for the biophysical study of cellular layer adhesion strength in living tissues.
Grace a un modele animal adequat d'etude de la metastase spontanee, nous avons montre que les... more Grace a un modele animal adequat d'etude de la metastase spontanee, nous avons montre que les melanocytes humains metastatiques expriment des disaccharides gal1-3 gal nac non sialyles. De tels disaccharides, reconnus par la lectine pna (peanut agglutinin), ont egalement ete mis en evidence chez l'homme dans les melanomes primitifs malins. De plus, la presence de cellules pna#+ est correlee au niveau d'invasion locale et a l'epaisseur de la tumeur qui conditionnent le risque de metastase chez les patients. Deux glycoproteines de poids moleculaires respectifs 140 kda (magp1) et 110-120 kda (magp2) portent ces disaccharides gal1-3galnac non sialyles dans les cellules metastatiques et masques par des residus acides sialiques dans leurs homologues non metastatiques. Dans les cellules metastatiques, le deficit en sialylation des glycoproteines est accompagne d'une alteration de la sialylation des gangliosides qui se traduit par une deficience en disialogangliosides (gd...
Abstract. In metastatic rat mammary adenocarcinoma cells, cell motility can be induced by epiderm... more Abstract. In metastatic rat mammary adenocarcinoma cells, cell motility can be induced by epidermal growth factor. One of the early events in this process is the massive generation of actin barbed ends, which elongate to form filaments immediately adjacent to the plasma membrane at the tip of the leading edge. As a result, the membrane moves outward and forms a protrusion. To test the involvement of ADF/cofilin in the stimulus-induced barbed end generation at the leading edge, we inhibited ADF/cofilin’s activity in vivo by increasing its phosphorylation level using the kinase domain of LIM-kinase 1 (GFP-K). We report here that expression of GFP-K in rat cells results in the near total phosphorylation of ADF/cofilin, without changing either the G/F-actin ratio or signaling from the EGF receptor in vivo. Phosphorylation of ADF/cofilin is sufficient to completely inhibit the appearance of barbed ends and lamellipod protrusion, even in the continued presence of abundant G-actin. Coexpre...
Circulation research, Jan 21, 2017
Oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) generates a group... more Oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) generates a group of bioactive oxidized phospholipid products with a broad range of biological activities. Barrier-enhancing and anti-inflammatory effects of OxPAPC on pulmonary endothelial cells are critical for prevention of acute lung injury caused by bacterial pathogens or excessive mechanical ventilation. Anti-inflammatory properties of OxPAPC are associated with its antagonistic effects on Toll-like receptors and suppression of RhoA GTPase signaling. Because OxPAPC exhibits long-lasting anti-inflammatory and lung-protective effects even after single administration in vivo, we tested the hypothesis that these effects may be mediated by additional mechanisms, such as OxPAPC-dependent production of anti-inflammatory and proresolving lipid mediator, lipoxin A4 (LXA4). Mass spectrometry and ELISA assays detected significant accumulation of LXA4 in the lungs of OxPAPC-treated mice and in conditioned medi...
J Neurochem, 2009
5-HT 3 receptors are therapeutically important members of the superfamily of Cys-loop ligand-gate... more 5-HT 3 receptors are therapeutically important members of the superfamily of Cys-loop ligand-gated ion channels which includes the nicotinic acetylcholine receptors (nAChRs), GABA A , GABA C and glycine receptors (Reeves and Lummis 2002; Peters et al. 2005). The 5-HT 3 receptor exists as a pentameric ring of subunits that form an integral ion channel along the central axis. To date, functional channels composed of a homomeric assembly of 5-HT 3A (Maricq et al. 1991; Miyake et al. 1995); or heteromeric assembly of 5-HT 3A and 5-HT 3B subunits (5-HT 3AB) (Davies et al. 1999) have been described. Each exhibits distinct channel characteristics (single channel conductance, rectification), but little difference in pharmacology, at least in terms of responses to 5hydroxytryptamine (5-HT) or 5-HT 3 receptor antagonists (Reeves and Lummis 2002; Peters et al. 2005), although small differences in responses to tubocurarine or picrotoxin are observed (Davies et al. 1999; Brady et al. 2001; Das and Dillon 2003). These findings do not, however, explain the apparent pharmacological diversity of responses mediated by the 5-HT 3 receptor within native tissues.
Invasion & metastasis, 1995
Malignant transformation is associated with alterations in both cell-cell and cell-matrix interac... more Malignant transformation is associated with alterations in both cell-cell and cell-matrix interactions. The E2 and C5 clones, derived from the human colon adenocarcinoma LoVo cell line, show, respectively, low and high metastatic capacity as experimental xenografts in vivo. In this study, we have assessed the adhesion and spreading of E2 and C5 cells on basement membrane laminin, expression of the laminin receptor integrins alpha 6 beta 1 and alpha 6 beta 4 and expression of gelatinolytic and plasminogen-dependent activities. On days 5 and 7 after subcutaneous grafting to immunosuppressed newborn rats, well-differentiated E2 tumors displayed a polarized expression of these integrin subunits, with the exception of the beta 1 subunit which remained pericellular. In contrast, C5 tumors were unorganized and the three integrin subunits remained nonpolarized and pericellular. Flow cytometry results showed that the expression of alpha 6 beta 1 and alpha 1 beta 4 integrins was weaker in the...