Recent discoveries have shown that venous diseases have a multifactorial etiology. One of the fac... more Recent discoveries have shown that venous diseases have a multifactorial etiology. One of the factors which is definitely involved in this pathologic process is the change in the concentration of oxygen. An increase in the concentration of oxygen, hyperoxia, or reoxygenation following hypoxia, damages the tissues by stepping up the production of free radicals. In addition, a reduction in oxygen concentration, or hypoxia, is also damaging, probably through a reduction in ATP synthesis. From a therapeutic standpoint, the veins, and more particularly the endothelium, must be protected against the impact on the tissue of these changes in oxygen concentration. In this study, the effects of Ginkor Fort were tested on cultured endothelial cells subjected to varying oxygen pressures. The results show that Ginkor Fort can provide good protection of endothelial cells against hyperoxia and hypoxia-reoxygenation. These beneficial effects are probably due to the presence of flavonoids in the Ginko biloba extract; these flavonoids have an anti-oxidant effect. In addition, this substance also protects the cells against hypoxia, possibly by increasing the availability of oxygen for ATP synthesis. This dual protective effect, which is produced by two different mechanisms, may account for the wide spectrum of Ginkor Fort in its use in venous diseases.
Diseases of the cardiovascular system result from a complex mixture of genetic and environmental ... more Diseases of the cardiovascular system result from a complex mixture of genetic and environmental factors. Much has been learned in the remodeling processes in heart and/or arteries during these diseases. Moreover, large epidemiological studies have provided insights in environmental as well genetic risk factors and will continue to unravel new interactions. Progress in defining the cellular and molecular interactions involved, however has been hindered by the disease’s etiological complexity. In addition, although pathological disorders are believed to be due to alterations in gene expression, relatively few modifications are yet reported. This is partly due to the classical, labor-intensive approaches used until now which require a reiteration of the detection procedure for each gene. However, the new techniques recently developed allow the detection of hundreds to thousands genes (DNA microarrays, differential display, SAGE) or proteins (2D gel electrophoresis, protein chips) at one time. It leads to the discovery of unexpected genes whose expression is modified but also to the development of new hypotheses concerning the etiology of the disease. It also provides a useful tool to study the effect of drugs or treatments in patients.
In Western countries, breast cancer incidence and mortality are higher than in Mediterranean coun... more In Western countries, breast cancer incidence and mortality are higher than in Mediterranean countries. These differences have been ascribed to environmental factors but also to late-stage diagnostic and biological specific characteristics. Between September 2002 and September 2005, we collected clinical data by phone counselling 180 French and Mediterranean breast cancer patients and performed microarray experiments. Characteristics of breast cancer in patients from Lebanon, Tunisia and Morocco were more aggressive (more SBR grade III and positive node invasion) and patients were 10 years younger at diagnosis. Sixteen differentially expressed genes such as MMP9, VEGF, PHB1, BRCA1, TFAP2C, GJA1 and TFF1 were also found. Additionally, an up-regulation of cytokeratins KRT8 and KRT18 may indicate a luminal B subtype in "South" (Lebanon, Tunisia and Morocco) tumors while "North" (France) tumors may more frequently be luminal A type. This study allowed the identificat...
International angiology : a journal of the International Union of Angiology, 1997
If venous stasis due to blood stagnation has been recognized to be involved in the development of... more If venous stasis due to blood stagnation has been recognized to be involved in the development of varicose veins, the mechanism linking this situation to the modifications of the venous wall observed in varicoses is still unclear. In order to study this mechanism, human saphenous veins were incubated in normoxic or hypoxic conditions and the interactions between the endothelium and neutrophils were investigated. We observed that many neutrophils adhered to the endothelium of veins incubated in hypoxic conditions rather than in normoxia and that these adherent neutrophils were activated: they released high amounts of superoxide anion and of leukotriene B4. Studies in scanning electron microscopy confirmed the increased neutrophil adherence to the endothelium as well as their activation. These results were then related to the histological observation of varicose veins. These veins show a thickening of the media with extracellular matrix deposit as well as an alteration of the elastic ...
International angiology : a journal of the International Union of Angiology, 1996
Because of their localization at the interface between blood and tissue, endothelial cells are re... more Because of their localization at the interface between blood and tissue, endothelial cells are responsible for the maintenance of vascular homeostasis. They fulfil a series of various functions and constantly interact with circulating leukocytes and with the smooth muscle cells (SMC) present in the media. Any disturbance of their metabolism can thus lead to alterations of the blood vessel functions. We have shown that hypoxia, for example resulting from venous stasis, induces the activation of endothelial cells which then release inflammatory mediators able to activate neutrophils and to induce their infiltration as well as growth factors for SMC. We propose that these processes are the beginning of a cascade of events eventually leading to structural and functional modifications of the venous wall similar to the ones observed in varicose vein wall. The endothelium alterations resulting from venous stasis would thus be the origin of the development of the venous disease. Pharmacolog...
Many findings indicate that the etiology of venous disease is multifactorial. One of the chief fa... more Many findings indicate that the etiology of venous disease is multifactorial. One of the chief factors is certainly the stasis of blood in the lower limbs during long periods of standing. This stasis causes tissue hypoxia which first affects the venous wall. Because of their site at the blood/vein wall interface as well as their fragility, endothelial cells are the first to suffer from lack of oxygen. In order to understand these events, the authors have developed a model of endothelial cells in culture subjected to hypoxia in vitro which imitates conditions encountered clinically. This model was used to test different drugs commonly used in venous pathology. These included GbE, the active ingredient of GINKOR FORT, diosmine and procyanidolic oligomers. It was thus shown that only GbE was not toxic to endothelial cells. Furthermore, GbE was capable of effectively protecting cells subjected to hypoxia. Protection with diosmine was obtained only at concentrations very close to toxic d...
Horseradish peroxidase was conjugated to D-cytochrome b5 by three different two-step methods. The... more Horseradish peroxidase was conjugated to D-cytochrome b5 by three different two-step methods. The yield of conjugates based on the peroxidase enzymatic activity recovered after gel filtration was very low in the glutaraldehyde method, but higher in the N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP) and periodate methods. The molecular size of the conjugates was analyzed by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. Monomeric conjugates were mostly formed via the glutaraldehyde and SPDP methods in the presence of appropriate molar ratios of proteins. Most of the conjugates formed via the periodate method were polymers. The conjugate preparations of the three methods could be incorporated into microsomal membranes. Conjugate polymers, however, appeared less able to be incorporated then monomers. There was a nonpreferential incorporation of free or conjugated D-cytochrome b5 contained in the conjugate preparation of the glutaraldehyde method. In conclusion, t...
One possible mechanism that accounts for the alterations observed in varicose veins is the activa... more One possible mechanism that accounts for the alterations observed in varicose veins is the activation of endothelial cells by ischemia occurring in the leg veins during blood stasis and the cascade of reactions that follows. Because in vitro data suggest that endothelium alteration is a key event in the development of the pathology, it was important to confirm this hypothesis in patients. We used the number of circulating endothelial cells detached from the vascular wall as a criterion of the endothelium injury. We first compared the number of circulating endothelial cells (CECs) in patients with chronic venous insufficiency (CVI) with those of a control population. A twofold increase in the CEC count (1,001+/-127 CEC/ml of plasma compared with 514+/-82 CECs/ml) was observed in CVI patients, which indeed suggests an alteration of the endothelium in this disease. Second, the protective effect of a venotropic drug, Ginkgo biloba extract, troxerutine, and heptaminol (Ginkor Fort), was tested by a randomized double-blind, placebo-controlled clinical trial. In the active-treatment group, the mean values of the CEC count decreased by 14.5% after a 4-week treatment, whereas in the placebo group, the decrease was less (8.4%). The decrease from week 0 to the end of treatment was significantly higher in the active-treatment group than in the placebo group. These results confirm the important role of the endothelium alterations in the development of varicose veins and suggest a potential beneficial action of a venotropic drug on the venous wall.
Recent discoveries have shown that venous diseases have a multifactorial etiology. One of the fac... more Recent discoveries have shown that venous diseases have a multifactorial etiology. One of the factors which is definitely involved in this pathologic process is the change in the concentration of oxygen. An increase in the concentration of oxygen, hyperoxia, or reoxygenation following hypoxia, damages the tissues by stepping up the production of free radicals. In addition, a reduction in oxygen concentration, or hypoxia, is also damaging, probably through a reduction in ATP synthesis. From a therapeutic standpoint, the veins, and more particularly the endothelium, must be protected against the impact on the tissue of these changes in oxygen concentration. In this study, the effects of Ginkor Fort were tested on cultured endothelial cells subjected to varying oxygen pressures. The results show that Ginkor Fort can provide good protection of endothelial cells against hyperoxia and hypoxia-reoxygenation. These beneficial effects are probably due to the presence of flavonoids in the Ginko biloba extract; these flavonoids have an anti-oxidant effect. In addition, this substance also protects the cells against hypoxia, possibly by increasing the availability of oxygen for ATP synthesis. This dual protective effect, which is produced by two different mechanisms, may account for the wide spectrum of Ginkor Fort in its use in venous diseases.
Diseases of the cardiovascular system result from a complex mixture of genetic and environmental ... more Diseases of the cardiovascular system result from a complex mixture of genetic and environmental factors. Much has been learned in the remodeling processes in heart and/or arteries during these diseases. Moreover, large epidemiological studies have provided insights in environmental as well genetic risk factors and will continue to unravel new interactions. Progress in defining the cellular and molecular interactions involved, however has been hindered by the disease’s etiological complexity. In addition, although pathological disorders are believed to be due to alterations in gene expression, relatively few modifications are yet reported. This is partly due to the classical, labor-intensive approaches used until now which require a reiteration of the detection procedure for each gene. However, the new techniques recently developed allow the detection of hundreds to thousands genes (DNA microarrays, differential display, SAGE) or proteins (2D gel electrophoresis, protein chips) at one time. It leads to the discovery of unexpected genes whose expression is modified but also to the development of new hypotheses concerning the etiology of the disease. It also provides a useful tool to study the effect of drugs or treatments in patients.
In Western countries, breast cancer incidence and mortality are higher than in Mediterranean coun... more In Western countries, breast cancer incidence and mortality are higher than in Mediterranean countries. These differences have been ascribed to environmental factors but also to late-stage diagnostic and biological specific characteristics. Between September 2002 and September 2005, we collected clinical data by phone counselling 180 French and Mediterranean breast cancer patients and performed microarray experiments. Characteristics of breast cancer in patients from Lebanon, Tunisia and Morocco were more aggressive (more SBR grade III and positive node invasion) and patients were 10 years younger at diagnosis. Sixteen differentially expressed genes such as MMP9, VEGF, PHB1, BRCA1, TFAP2C, GJA1 and TFF1 were also found. Additionally, an up-regulation of cytokeratins KRT8 and KRT18 may indicate a luminal B subtype in "South" (Lebanon, Tunisia and Morocco) tumors while "North" (France) tumors may more frequently be luminal A type. This study allowed the identificat...
International angiology : a journal of the International Union of Angiology, 1997
If venous stasis due to blood stagnation has been recognized to be involved in the development of... more If venous stasis due to blood stagnation has been recognized to be involved in the development of varicose veins, the mechanism linking this situation to the modifications of the venous wall observed in varicoses is still unclear. In order to study this mechanism, human saphenous veins were incubated in normoxic or hypoxic conditions and the interactions between the endothelium and neutrophils were investigated. We observed that many neutrophils adhered to the endothelium of veins incubated in hypoxic conditions rather than in normoxia and that these adherent neutrophils were activated: they released high amounts of superoxide anion and of leukotriene B4. Studies in scanning electron microscopy confirmed the increased neutrophil adherence to the endothelium as well as their activation. These results were then related to the histological observation of varicose veins. These veins show a thickening of the media with extracellular matrix deposit as well as an alteration of the elastic ...
International angiology : a journal of the International Union of Angiology, 1996
Because of their localization at the interface between blood and tissue, endothelial cells are re... more Because of their localization at the interface between blood and tissue, endothelial cells are responsible for the maintenance of vascular homeostasis. They fulfil a series of various functions and constantly interact with circulating leukocytes and with the smooth muscle cells (SMC) present in the media. Any disturbance of their metabolism can thus lead to alterations of the blood vessel functions. We have shown that hypoxia, for example resulting from venous stasis, induces the activation of endothelial cells which then release inflammatory mediators able to activate neutrophils and to induce their infiltration as well as growth factors for SMC. We propose that these processes are the beginning of a cascade of events eventually leading to structural and functional modifications of the venous wall similar to the ones observed in varicose vein wall. The endothelium alterations resulting from venous stasis would thus be the origin of the development of the venous disease. Pharmacolog...
Many findings indicate that the etiology of venous disease is multifactorial. One of the chief fa... more Many findings indicate that the etiology of venous disease is multifactorial. One of the chief factors is certainly the stasis of blood in the lower limbs during long periods of standing. This stasis causes tissue hypoxia which first affects the venous wall. Because of their site at the blood/vein wall interface as well as their fragility, endothelial cells are the first to suffer from lack of oxygen. In order to understand these events, the authors have developed a model of endothelial cells in culture subjected to hypoxia in vitro which imitates conditions encountered clinically. This model was used to test different drugs commonly used in venous pathology. These included GbE, the active ingredient of GINKOR FORT, diosmine and procyanidolic oligomers. It was thus shown that only GbE was not toxic to endothelial cells. Furthermore, GbE was capable of effectively protecting cells subjected to hypoxia. Protection with diosmine was obtained only at concentrations very close to toxic d...
Horseradish peroxidase was conjugated to D-cytochrome b5 by three different two-step methods. The... more Horseradish peroxidase was conjugated to D-cytochrome b5 by three different two-step methods. The yield of conjugates based on the peroxidase enzymatic activity recovered after gel filtration was very low in the glutaraldehyde method, but higher in the N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP) and periodate methods. The molecular size of the conjugates was analyzed by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. Monomeric conjugates were mostly formed via the glutaraldehyde and SPDP methods in the presence of appropriate molar ratios of proteins. Most of the conjugates formed via the periodate method were polymers. The conjugate preparations of the three methods could be incorporated into microsomal membranes. Conjugate polymers, however, appeared less able to be incorporated then monomers. There was a nonpreferential incorporation of free or conjugated D-cytochrome b5 contained in the conjugate preparation of the glutaraldehyde method. In conclusion, t...
One possible mechanism that accounts for the alterations observed in varicose veins is the activa... more One possible mechanism that accounts for the alterations observed in varicose veins is the activation of endothelial cells by ischemia occurring in the leg veins during blood stasis and the cascade of reactions that follows. Because in vitro data suggest that endothelium alteration is a key event in the development of the pathology, it was important to confirm this hypothesis in patients. We used the number of circulating endothelial cells detached from the vascular wall as a criterion of the endothelium injury. We first compared the number of circulating endothelial cells (CECs) in patients with chronic venous insufficiency (CVI) with those of a control population. A twofold increase in the CEC count (1,001+/-127 CEC/ml of plasma compared with 514+/-82 CECs/ml) was observed in CVI patients, which indeed suggests an alteration of the endothelium in this disease. Second, the protective effect of a venotropic drug, Ginkgo biloba extract, troxerutine, and heptaminol (Ginkor Fort), was tested by a randomized double-blind, placebo-controlled clinical trial. In the active-treatment group, the mean values of the CEC count decreased by 14.5% after a 4-week treatment, whereas in the placebo group, the decrease was less (8.4%). The decrease from week 0 to the end of treatment was significantly higher in the active-treatment group than in the placebo group. These results confirm the important role of the endothelium alterations in the development of varicose veins and suggest a potential beneficial action of a venotropic drug on the venous wall.
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