The Oxygen Paradox, the French Paradox, and age-related diseases

open46openDavies, Joanna M. S.; Cillard, Josiane; Friguet, Bertrand; Cadenas, Enrique; Cadet, Jean; Cayce, Rachael; Fishmann, Andrew; Liao, David; Bulteau, Anne-Laure; Derbré, Frédéric; Rébillard, Amélie; Burstein, Steven; Hirsch, Etienne; Kloner, Robert A.; Jakowec, Michael; Petzinger, Giselle; Sauce, Delphine; Sennlaub, Florian; Limon, Isabelle; Ursini, Fulvio; Maiorino, Matilde; Economides, Christina; Pike, Christian J.; Cohen, Pinchas; Salvayre, Anne Negre; Halliday, Matthew R.; Lundquist, Adam J.; Jakowec, Nicolaus A.; Mechta-Grigoriou, Fatima; Mericskay, Mathias; Mariani, Jean; Li, Zhenlin; Huang, David; Grant, Ellsworth; Forman, Henry J.; Finch, Caleb E.; Sun, Patrick Y.; Pomatto, Laura C. D.; Agbulut, Onnik; Warburton, David; Neri, Christian; Rouis, Mustapha; Cillard, Pierre; Capeau, Jacqueline; Rosenbaum, Jean; Davies, Kelvin J. A.Davies, Joanna M. S.; Cillard, Josiane; Friguet, Bertrand; Cadenas, Enrique; Cadet, Jean; Cayce, Rachael; Fishmann, Andrew; Liao, David; Bulteau, Anne-Laure; Derbré, Frédéric; Rébillard, Amélie; Burstein, Steven; Hirsch, Etienne; Kloner, Robert A.; Jakowec, Michael; Petzinger, Giselle; Sauce, Delphine; Sennlaub, Florian; Limon, Isabelle; Ursini, Fulvio; Maiorino, Matilde; Economides, Christina; Pike, Christian J.; Cohen, Pinchas; Salvayre, Anne Negre; Halliday, Matthew R.; Lundquist, Adam J.; Jakowec, Nicolaus A.; Mechta-Grigoriou, Fatima; Mericskay, Mathias; Mariani, Jean; Li, Zhenlin; Huang, David; Grant, Ellsworth; Forman, HENRY J.; Finch, Caleb E.; Sun, Patrick Y.; Pomatto, Laura C. D.; Agbulut, Onnik; Warburton, David; Neri, Christian; Rouis, Mustapha; Cillard, Pierre; Capeau, Jacqueline; Rosenbaum, Jean; Davies, Kelvin J. A

Lipid-Induced Peroxidation in the Intestine Is Involved in Glucose Homeostasis Imbalance in Mice

BACKGROUND: Daily variations in lipid concentrations in both gut lumen and blood are detected by specific sensors located in the gastrointestinal tract and in specialized central areas. Deregulation of the lipid sensors could be partly involved in the dysfunction of glucose homeostasis. The study aimed at comparing the effect of Medialipid (ML) overload on insulin secretion and sensitivity when administered either through the intestine or the carotid artery in mice. METHODOLOGY/PRINCIPAL FINDINGS: An indwelling intragastric or intracarotid catheter was installed in mice and ML or an isocaloric solution was infused over 24 hours. Glucose and insulin tolerance and vagus nerve activity were assessed. Some mice were treated daily for one week with the anti-lipid peroxidation agent aminoguanidine prior to the infusions and tests. The intestinal but not the intracarotid infusion of ML led to glucose and insulin intolerance when compared with controls. The intestinal ML overload induced lipid accumulation and increased lipid peroxidation as assessed by increased malondialdehyde production within both jejunum and duodenum. These effects were associated with the concomitant deregulation of vagus nerve. Administration of aminoguanidine protected against the effects of lipid overload and normalized glucose homeostasis and vagus nerve activity. CONCLUSIONS/SIGNIFICANCE: Lipid overload within the intestine led to deregulation of gastrointestinal lipid sensing that in turn impaired glucose homeostasis through changes in autonomic nervous system activity

Post-Translational Modifications Evoked by Reactive Carbonyl Species in Ultraviolet-A-Exposed Skin: Implication in Fibroblast Senescence and Skin Photoaging

Photoaging is an accelerated form of aging resulting from skin exposure to ultraviolet (UV) radiation. UV-A radiation deeply penetrates the dermis and triggers the generation of reactive oxygen species (ROS) which promotes damage to DNA, lipids and proteins. Lipid peroxidation results from the oxidative attack of polyunsaturated fatty acids which generate a huge amount of lipid peroxidation products, among them reactive carbonyl species (RCS) such as α, β-unsaturated hydroxyalkenals (e.g., 4-hydroxynonenal), acrolein or malondialdehyde. These highly reactive agents form adducts on free NH2 groups and thiol residues on amino acids in proteins and can also modify DNA and phospholipids. The accumulation of RCS-adducts leads to carbonyl stress characterized by progressive cellular and tissular dysfunction, inflammation and toxicity. RCS-adducts are formed in the dermis of skin exposed to UV-A radiation. Several RCS targets have been identified in the dermis, such as collagen and elastin in the extracellular matrix, whose modification could contribute to actinic elastosis lesions. RCS-adducts may play a role in fibroblast senescence via the modification of histones, and the sirtuin SIRT1, leading to an accumulation of acetylated proteins. The cytoskeleton protein vimentin is modified by RCS, which could impair fibroblast motility. A better identification of protein modification and carbonyl stress in the dermis may help to develop new treatment approaches for preventing photoaging

Effet protecteur des acides gras contre le stress oxydatif : Implication en physiopathologie vasculaire

Oxidative stress play a major role in the genesis and the evolution of vascular pathologies. Recent data suggest that redox mechanisms are involved in the signaling network of vascular cells and the physiology of the vascular wall. Experimental cell models allow to analyse the biological effect of pro-oxidants, and the regulation exerted by antioxidants and cytoprotective agents. Fatty acids play a complex role in atherosclerosis, since they exhibit both anti and proatherogenic properties, as function of their concentration and insaturation level. Beside their role in cell metabolism and mitochondrial b-oxidation, fatty acids activate various signaling pathways, and could modulate intracellular oxidative stress via an uncoupling effect on mitochondria. We report here that fatty acids protect against mitochondrial oxidative stress by activating cellular glutathione peroxidase (GPX) activity. This effect is independent of the chain length and unsaturation level. EGF receptor is activated by fatty acids and involved in their protective effect against mitochondrial oxidative stress and GPX activation, and similar protective results are observed with EGF. Oleic acid and EGF protect DNA against the formation of 8oxodG lesions occurring subsequently to oxidative stress. Taken together, this new ‘antioxidant’ and cytoprotective property of fatty acids and EGF could participate to the stabilization of atherosclerotic plaque, and the more general anti-atherogenic properties of oleic acid

Effet protecteur des acides gras contre le stress oxydatif : Implication en physiopathologie vasculaire

Oxidative stress play a major role in the genesis and the evolution of vascular pathologies. Recent data suggest that redox mechanisms are involved in the signaling network of vascular cells and the physiology of the vascular wall. Experimental cell models allow to analyse the biological effect of pro-oxidants, and the regulation exerted by antioxidants and cytoprotective agents. Fatty acids play a complex role in atherosclerosis, since they exhibit both anti and proatherogenic properties, as function of their concentration and insaturation level. Beside their role in cell metabolism and mitochondrial b-oxidation, fatty acids activate various signaling pathways, and could modulate intracellular oxidative stress via an uncoupling effect on mitochondria. We report here that fatty acids protect against mitochondrial oxidative stress by activating cellular glutathione peroxidase (GPX) activity. This effect is independent of the chain length and unsaturation level. EGF receptor is activated by fatty acids and involved in their protective effect against mitochondrial oxidative stress and GPX activation, and similar protective results are observed with EGF. Oleic acid and EGF protect DNA against the formation of 8oxodG lesions occurring subsequently to oxidative stress. Taken together, this new ‘antioxidant’ and cytoprotective property of fatty acids and EGF could participate to the stabilization of atherosclerotic plaque, and the more general anti-atherogenic properties of oleic acid

Signalisation apototique induite par les LDL oxydées Implication dans l’athérosclérose

The balance between vascular cell proliferation vs apoptosis plays a key role in vessel wall remodeling. Intimal migration and proliferation of smooth muscle cells (SMC), and secretion of extracellular matrix are involved in fibrous cap formation and plaque stability, whereas apoptosis of vascular cells may contribute to the erosion and instability of the plaque leading to its rupture and subsequent thrombus formation. LDL become atherogenic after undergoing oxidation within the vascular wall. Oxidized LDL (oxLDL) and oxidized lipids exhibit complex biological properties involved in endothelial dysfunction, SMC migration and proliferation, inflammation, and apoptosis. Oxidized LDL-induced apoptosis involves the extrinsic propapoptotic pathway (linked to Fas/Fas ligand) in lymphocytes, and the intrinsic mitochondrial apoptotic pathway, involving bcl-2 family members, cytochrome C release, and the terminal executive caspase-3 pathway, as well as the mitochondrial apoptotic factor AIF, in vascular cells. The apoptotic signaling of oxLDL is mediated in part by an intense and sustained rise of cytosolic calcium. The mechanisms regulating the balance between proliferation and apoptosis triggered by oxLDL and their role in vivo in atherosclerotic plaque progression remains to be clarified

Modulation du stress oxydant intracellulaire par des facteurs infectieux et métaboliques (implication dans la prolifération / mort cellulaire des cellules vasculaires au cours de l athérosclérose)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF