Ca2+ signaling plays a pivotal role in the control of cellular homeostasis and aberrant regulatio... more Ca2+ signaling plays a pivotal role in the control of cellular homeostasis and aberrant regulation of Ca2+ fluxes have a strong impact on cellular functioning. As a consequence of this ubiquitous role, Ca2+ signaling dysregulation is involved in the pathophysiology of multiple diseases including cancer. Indeed, multiple studies have highlighted the role of Ca2+ fluxes in all the steps of cancer progression. In particular, the transfer of Ca2+ at the ER-mitochondrial contact sites, also known as mitochondrial associated membranes (MAMs), has been shown to be crucial for cancer cell survival. One of the proteins enriched at this site is the sigma-1 receptor (S1R), a protein that has been described as a Ca2+-sensitive chaperone that exerts a protective function in cells in various ways, including the modulation of Ca2+ signaling. Interestingly, S1R is overexpressed in many types of cancer even though the exact mechanisms by which it promotes cell survival are not fully elucidated. This...
To control capillary bleeding, surgeons may use absorbable hemostatic agents, such as Surgicel® a... more To control capillary bleeding, surgeons may use absorbable hemostatic agents, such as Surgicel® and TachoSil®. Due to their slow resorption, their persistence in situ can have a negative impact on tissue repair in the resected organ. To avoid complications and obtain a hemostatic agent that promotes tissue repair, a zinc-supplemented calcium alginate compress was developed: HEMO-IONIC®. This compress is non-absorbable and is therefore removed once hemostasis has been achieved. After demonstrating the hemostatic efficacy and stability of the blood clot obtained with HEMO-IONIC, the impact of Surgicel, TachoSil, and HEMO-IONIC on cell activation and tissue repair were compared (i) in vitro on endothelial cells, which are essential to tissue repair, and (ii) in vivo in a mouse skin excision model. In vitro, only HEMO-IONIC maintained the phenotypic and functional properties of endothelial cells and induced their migration. In comparison, Surgicel was found to be highly cytotoxic, and TachoSil inhibited endothelial cell migration. In vivo, only HEMO-IONIC increased angiogenesis, the recruitment of cells essential to tissue repair (macrophages, fibroblasts, and epithelial cells), and accelerated maturation of the extracellular matrix. These results demonstrate that a zinc-supplemented calcium alginate, HEMO-IONIC, applied for 10 min at the end of surgery and then removed has a long-term positive effect on all phases of tissue repair.
Receptor-mediated production of inositol 1,4,5-trisphosphate (InsP3) initiates Ca2 + release and ... more Receptor-mediated production of inositol 1,4,5-trisphosphate (InsP3) initiates Ca2 + release and is responsible for cytosolic Ca2 oscillations. InsP3 oscillations have also been observed in some cells. One of the enzymes controlling InsP3 catabolism, the InsP3 3-kinase, is stimulated by Ca2 ; this regulation is presumably part of the reason for InsP3 oscillations that have been observed in some cells. Here, we investigate the possible role of Ca2-activated InsP3 catabolism on the characteristics of the InsP3-induced Ca2 + oscillations. Numerical simulations show that if it is assumed that the Ca2-independent InsP3 catabolism is predominant, Ca2 + oscillations remain qualitatively unchanged although the relative amplitude of the oscillations in InsP3 concentrations becomes minimal. We tested this prediction in hepatocytes by masking the Ca2-dependent InsP3 catabolism by 3-kinase through the injection of massive amounts of InsP3 5-phosphatase, which is not stimulated by Ca2 . We ¢nd t...
Les effets de differents acides biliaires sur le ca² ⁺ cellulaire ont ete examines dans des suspe... more Les effets de differents acides biliaires sur le ca² ⁺ cellulaire ont ete examines dans des suspensions d'hepatocytes isoles de rats. Les acides biliaires taurolithocholate et lithocholate qui inhibent la secretion biliaire in vivo augmentent le ca² ⁺ ionize cytosolique de 150 a 700 nM en 20 secondes et stimulent l'efflux de ca² ⁺ cellulaire. Cet effet est dose-dependant (EC50 de 16-18 micromoles/1). Il est independant du ca² ⁺ extracellulaire et resulte d'une mobilisation rapide de ca² ⁺ depuis un compartiment interne (0. 8 a 1 nmol/mg de proteines). Ce compartiment est le meme que celui permeabilise par la vasopressine, via la production d'inositol (1, 4, 5) tiphosphate (IP3). Cependant, au contraire de l’hormone, les deux acides biliaires ne stimulent pas la synthese d’IP3. Dans les hepatocytes traites a la saponine, le taurolithocholate et le lithocholate provoquent une brusque liberation de ca² ⁺ (en 20 sec, avec un EC50 a 16-18 µM) depuis un compartiment non mi...
La transduction des messages hormonaux en signaux calciques est un des moyens dont disposent les ... more La transduction des messages hormonaux en signaux calciques est un des moyens dont disposent les cellules pour communiquer. A l’etat de repos, la concentration cytosolique en Ca2+ libre est maintenue a un niveau tres bas (100 a 200 nM). Des mouvements de Ca2+ de faible amplitude depuis le milieu extracellulaire et/ou depuis les compartiments intracellulaires de stockage sont ainsi capables de creer un mode de codage hautement elabore des messages hormonaux. Ce type de transduction est utilise par de nombreux agonistes pour assurer ou reguler de multiples fonctions comme la secretion, la contraction ou encore la division cellulaire. Le foie est un organe cible pour de nombreuses hormones mobilisant le Ca2+ intracellulaire. Cependant, bien que les mecanismes de transduction soient de mieux en mieux disseques, l’impact physiologique de cette voie de signalisation reste souvent speculatif dans cet organe. Les techniques d’imagerie cellulaire ont permis d’analyser les signaux calciques a l’echelon cellulaire et subcellulaire. Dans l’hepatocyte, ces signaux sont oscillants et leur frequence est dependante de la concentration en agoniste. L’elevation de la concentration de Ca2+ generee par une hormone peut etre propagee aux cellules adjacentes sous la forme de vagues calciques intercellulaires. Dans la plupart des systemes etudies (cellules epitheliales ou gliales), la propagation orientee d’une vague calcique resulte de la diffusion d’un second messager a l’ensemble des cellules via les jonctions communicantes. Dans le foie, ce mecanisme ne peut pas rendre compte de la propagation des vagues calciques. Il existe en fait un gradient de sensibilite aux agonistes entre hepatocytes adjacents au sein de systemes multicellulaires fraichement isoles resultant d’une heterogeneite graduelle du nombre de recepteurs hormonaux le long des travees hepatocytaires. Des fonctions telles que la secretion biliaire et la contraction canaliculaire pourraient etre orientees dans le lobule hepatique par ce type de vagues calciques interhepatocytaires.
Sigma receptor 1 (SigR1) is an endoplasmic reticulum resident integral membrane protein whose fun... more Sigma receptor 1 (SigR1) is an endoplasmic reticulum resident integral membrane protein whose functions remain unclear. Although the liver shows the highest expression of SigR1, its role in this organ is unknown. SigR1 is overexpressed in many cancers and its expression is correlated to hormonal status in hormone-dependent cancers. To better understand the role of SigR1 in hepatocytes we focused our work on the regulation of its expression in tumoral liver. In this context, hepatocellular adenomas, benign hepatic tumors associated with estrogen intake are of particular interest. The expression of SigR1 mRNA was assessed in hepatocellular adenoma (HCA) patients using qPCR. The impact of estrogen on the expression of SigR1 was studied in vivo (mice) and in vitro (HepG2 and Huh7 cells). The effect of HNF1α on the expression of SigR1 was studied in vivo by comparing wild type mice to HNF1 knockout mice. Estrogen enhanced SigR1 expression through its nuclear receptor ERα. HNF1α mutated H...
Ca2+ oscillations, a widespread mode of cell signaling, were reported in non-excitable cells for ... more Ca2+ oscillations, a widespread mode of cell signaling, were reported in non-excitable cells for the first time more than 25 years ago. Their fundamental mechanism, based on the periodic Ca2+ exchange between the endoplasmic reticulum and the cytoplasm, has been well characterized. However, how the kinetics of cytosolic Ca2+ changes are related to the extent of a physiological response remains poorly understood. Here, we review data suggesting that the downstream targets of Ca2+ are controlled not only by the frequency of Ca2+ oscillations but also by the detailed characteristics of the oscillations, such as their duration, shape, or baseline level. Involvement of non-endoplasmic reticulum Ca2+ stores, mainly mitochondria and the extracellular medium, participates in this fine tuning of Ca2+ oscillations. The main characteristics of the Ca2+ exchange fluxes with these compartments are also reviewed.
Ca2+ signaling plays a pivotal role in the control of cellular homeostasis and aberrant regulatio... more Ca2+ signaling plays a pivotal role in the control of cellular homeostasis and aberrant regulation of Ca2+ fluxes have a strong impact on cellular functioning. As a consequence of this ubiquitous role, Ca2+ signaling dysregulation is involved in the pathophysiology of multiple diseases including cancer. Indeed, multiple studies have highlighted the role of Ca2+ fluxes in all the steps of cancer progression. In particular, the transfer of Ca2+ at the ER-mitochondrial contact sites, also known as mitochondrial associated membranes (MAMs), has been shown to be crucial for cancer cell survival. One of the proteins enriched at this site is the sigma-1 receptor (S1R), a protein that has been described as a Ca2+-sensitive chaperone that exerts a protective function in cells in various ways, including the modulation of Ca2+ signaling. Interestingly, S1R is overexpressed in many types of cancer even though the exact mechanisms by which it promotes cell survival are not fully elucidated. This...
To control capillary bleeding, surgeons may use absorbable hemostatic agents, such as Surgicel® a... more To control capillary bleeding, surgeons may use absorbable hemostatic agents, such as Surgicel® and TachoSil®. Due to their slow resorption, their persistence in situ can have a negative impact on tissue repair in the resected organ. To avoid complications and obtain a hemostatic agent that promotes tissue repair, a zinc-supplemented calcium alginate compress was developed: HEMO-IONIC®. This compress is non-absorbable and is therefore removed once hemostasis has been achieved. After demonstrating the hemostatic efficacy and stability of the blood clot obtained with HEMO-IONIC, the impact of Surgicel, TachoSil, and HEMO-IONIC on cell activation and tissue repair were compared (i) in vitro on endothelial cells, which are essential to tissue repair, and (ii) in vivo in a mouse skin excision model. In vitro, only HEMO-IONIC maintained the phenotypic and functional properties of endothelial cells and induced their migration. In comparison, Surgicel was found to be highly cytotoxic, and TachoSil inhibited endothelial cell migration. In vivo, only HEMO-IONIC increased angiogenesis, the recruitment of cells essential to tissue repair (macrophages, fibroblasts, and epithelial cells), and accelerated maturation of the extracellular matrix. These results demonstrate that a zinc-supplemented calcium alginate, HEMO-IONIC, applied for 10 min at the end of surgery and then removed has a long-term positive effect on all phases of tissue repair.
Receptor-mediated production of inositol 1,4,5-trisphosphate (InsP3) initiates Ca2 + release and ... more Receptor-mediated production of inositol 1,4,5-trisphosphate (InsP3) initiates Ca2 + release and is responsible for cytosolic Ca2 oscillations. InsP3 oscillations have also been observed in some cells. One of the enzymes controlling InsP3 catabolism, the InsP3 3-kinase, is stimulated by Ca2 ; this regulation is presumably part of the reason for InsP3 oscillations that have been observed in some cells. Here, we investigate the possible role of Ca2-activated InsP3 catabolism on the characteristics of the InsP3-induced Ca2 + oscillations. Numerical simulations show that if it is assumed that the Ca2-independent InsP3 catabolism is predominant, Ca2 + oscillations remain qualitatively unchanged although the relative amplitude of the oscillations in InsP3 concentrations becomes minimal. We tested this prediction in hepatocytes by masking the Ca2-dependent InsP3 catabolism by 3-kinase through the injection of massive amounts of InsP3 5-phosphatase, which is not stimulated by Ca2 . We ¢nd t...
Les effets de differents acides biliaires sur le ca² ⁺ cellulaire ont ete examines dans des suspe... more Les effets de differents acides biliaires sur le ca² ⁺ cellulaire ont ete examines dans des suspensions d'hepatocytes isoles de rats. Les acides biliaires taurolithocholate et lithocholate qui inhibent la secretion biliaire in vivo augmentent le ca² ⁺ ionize cytosolique de 150 a 700 nM en 20 secondes et stimulent l'efflux de ca² ⁺ cellulaire. Cet effet est dose-dependant (EC50 de 16-18 micromoles/1). Il est independant du ca² ⁺ extracellulaire et resulte d'une mobilisation rapide de ca² ⁺ depuis un compartiment interne (0. 8 a 1 nmol/mg de proteines). Ce compartiment est le meme que celui permeabilise par la vasopressine, via la production d'inositol (1, 4, 5) tiphosphate (IP3). Cependant, au contraire de l’hormone, les deux acides biliaires ne stimulent pas la synthese d’IP3. Dans les hepatocytes traites a la saponine, le taurolithocholate et le lithocholate provoquent une brusque liberation de ca² ⁺ (en 20 sec, avec un EC50 a 16-18 µM) depuis un compartiment non mi...
La transduction des messages hormonaux en signaux calciques est un des moyens dont disposent les ... more La transduction des messages hormonaux en signaux calciques est un des moyens dont disposent les cellules pour communiquer. A l’etat de repos, la concentration cytosolique en Ca2+ libre est maintenue a un niveau tres bas (100 a 200 nM). Des mouvements de Ca2+ de faible amplitude depuis le milieu extracellulaire et/ou depuis les compartiments intracellulaires de stockage sont ainsi capables de creer un mode de codage hautement elabore des messages hormonaux. Ce type de transduction est utilise par de nombreux agonistes pour assurer ou reguler de multiples fonctions comme la secretion, la contraction ou encore la division cellulaire. Le foie est un organe cible pour de nombreuses hormones mobilisant le Ca2+ intracellulaire. Cependant, bien que les mecanismes de transduction soient de mieux en mieux disseques, l’impact physiologique de cette voie de signalisation reste souvent speculatif dans cet organe. Les techniques d’imagerie cellulaire ont permis d’analyser les signaux calciques a l’echelon cellulaire et subcellulaire. Dans l’hepatocyte, ces signaux sont oscillants et leur frequence est dependante de la concentration en agoniste. L’elevation de la concentration de Ca2+ generee par une hormone peut etre propagee aux cellules adjacentes sous la forme de vagues calciques intercellulaires. Dans la plupart des systemes etudies (cellules epitheliales ou gliales), la propagation orientee d’une vague calcique resulte de la diffusion d’un second messager a l’ensemble des cellules via les jonctions communicantes. Dans le foie, ce mecanisme ne peut pas rendre compte de la propagation des vagues calciques. Il existe en fait un gradient de sensibilite aux agonistes entre hepatocytes adjacents au sein de systemes multicellulaires fraichement isoles resultant d’une heterogeneite graduelle du nombre de recepteurs hormonaux le long des travees hepatocytaires. Des fonctions telles que la secretion biliaire et la contraction canaliculaire pourraient etre orientees dans le lobule hepatique par ce type de vagues calciques interhepatocytaires.
Sigma receptor 1 (SigR1) is an endoplasmic reticulum resident integral membrane protein whose fun... more Sigma receptor 1 (SigR1) is an endoplasmic reticulum resident integral membrane protein whose functions remain unclear. Although the liver shows the highest expression of SigR1, its role in this organ is unknown. SigR1 is overexpressed in many cancers and its expression is correlated to hormonal status in hormone-dependent cancers. To better understand the role of SigR1 in hepatocytes we focused our work on the regulation of its expression in tumoral liver. In this context, hepatocellular adenomas, benign hepatic tumors associated with estrogen intake are of particular interest. The expression of SigR1 mRNA was assessed in hepatocellular adenoma (HCA) patients using qPCR. The impact of estrogen on the expression of SigR1 was studied in vivo (mice) and in vitro (HepG2 and Huh7 cells). The effect of HNF1α on the expression of SigR1 was studied in vivo by comparing wild type mice to HNF1 knockout mice. Estrogen enhanced SigR1 expression through its nuclear receptor ERα. HNF1α mutated H...
Ca2+ oscillations, a widespread mode of cell signaling, were reported in non-excitable cells for ... more Ca2+ oscillations, a widespread mode of cell signaling, were reported in non-excitable cells for the first time more than 25 years ago. Their fundamental mechanism, based on the periodic Ca2+ exchange between the endoplasmic reticulum and the cytoplasm, has been well characterized. However, how the kinetics of cytosolic Ca2+ changes are related to the extent of a physiological response remains poorly understood. Here, we review data suggesting that the downstream targets of Ca2+ are controlled not only by the frequency of Ca2+ oscillations but also by the detailed characteristics of the oscillations, such as their duration, shape, or baseline level. Involvement of non-endoplasmic reticulum Ca2+ stores, mainly mitochondria and the extracellular medium, participates in this fine tuning of Ca2+ oscillations. The main characteristics of the Ca2+ exchange fluxes with these compartments are also reviewed.
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