Eric Boulanger

Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42.

Cellular migration is a fundamental process linked to diverse pathological states such as diabetes and its complications, atherosclerosis, inflammation, and cancer. The receptor for advanced glycation end products (RAGE) is a multiligand cell surface macromolecule which binds distinct ligands that accumulate in these settings. RAGE-ligand interaction evokes central changes in key biological properties of cells, including proliferation, generation of inflammatory mediators, and migration. Although RAGE-dependent signal transduction is critically dependent on its short cytoplasmic domain, to date the proximate mechanism by which this RAGE domain engages and stimulates cytoplasmic signaling pathways has yet to be identified. Here we show that the RAGE cytoplasmic domain interacts with Diaphanous-1 (Dia-1) both in vitro and in vivo. We employed the human RAGE cytoplasmic domain as “bait” in the yeast two-hybrid assay and identified the formin homology (FH1) domain of Dia-1 as a potential binding partner of this RAGE domain. Immunoprecipitation studies revealed that the RAGE cytoplasmic domain interacts with the FH1 domain of Dia-1. Down-regulation of Dia-1 expression by RNA interference blocks RAGE-mediated activation of Rac-1 and Cdc42 and, in parallel, RAGE ligand-stimulated cellular migration. Taken together, these findings indicate that the interaction of the RAGE cytoplasmic domain with Dia-1 is required to transduce extracellular environmental cues evoked by binding of RAGE ligands to their cell surface receptor, a chief consequence of which is Rac-1 and Cdc42 activation and cellular migration. Because RAGE and Dia-1 are implicated in the regulation of inflammatory, vascular, and transformed cell migration, these findings highlight this interaction as a novel target for therapeutic intervention in inflammation, atherosclerosis, diabetes, and cancer.

Soluble receptor for advanced glycation end products: a new biomarker in diagnosis and prognosis of chronic inflammatory diseases

The formation of advanced glycation end products (AGEs) is a result of the non-enzymatic reaction between sugars and free amino groups of proteins. AGEs, through interacting with their specific receptor for AGEs (RAGE), result in activation of pro-inflammatory states and are involved in numerous pathologic situations. The soluble form of RAGE (sRAGE) is able to act as a decoy to avoid interaction of RAGE with its pro-inflammatory ligands (AGEs, HMGB1, S100 proteins). sRAGE levels have been found to be decreased in chronic inflammatory diseases including atherosclerosis, diabetes, renal failure and the aging process. The use of measuring circulating sRAGEs may prove to be a valuable vascular biomarker and in this review, we describe the implications of sRAGE in inflammation and propose that this molecule may represent a future therapeutic target in chronic inflammatory diseases.

Underuse of Oral Anticoagulation for Individuals with Atrial Fibrillation in a Nursing Home Setting in France: Comparisons of Resident Characteristics and Physician Attitude

To describe the characteristics of nursing home residents diagnosed with atrial fibrillation (AF) and eligible for oral anticoagulants who did not receive these drugs and to detail the conditions that physicians who decide not to prescribe anticoagulants take into account.

How Can Diet Affect the Accumulation of Advanced Glycation End-Products in the Human Body?

The accumulation of advanced glycation end products (AGEs) is associated with the complications of diabetes, kidney disease, metabolic disorders and degenerative diseases. It is recognized that the pool of glycation products found in the human body comes not only from an endogenous formation, but also from a dietary exposure to exogenous AGEs. In recent years, the development of pharmacologically-active ingredients aimed at inhibiting endogenous glycation has not been successful. Since the accumulation of AGEs in the human body appears to be progressive throughout life, an early preventive action against glycation could be effective through dietary adjustments or supplementation with purified micronutrients. The present article provides an overview of current dietary strategies tested either in vitro, in vivo or both to reduce the endogenous formation of AGEs and to limit exposure to food AGEs.

Abnormal Mitochondrial cAMP/PKA Signaling Is Involved in Sepsis-Induced Mitochondrial and Myocardial Dysfunction

Adrenergic receptors couple to Gs-proteins leading to transmembrane adenylyl cyclase activation and cytosolic cyclic adenosine monophosphate (cAMP) production. Cyclic AMP is also produced in the mitochondrial matrix, where it regulates respiration through protein kinase A (PKA)-dependent phosphorylation of respiratory chain complexes. We hypothesized that a blunted mitochondrial cAMP-PKA pathway would participate in sepsis-induced heart dysfunction. Adult male mice were subjected to intra-abdominal sepsis. Mitochondrial respiration of cardiac fibers and myocardial contractile performance were evaluated in response to 8Br-cAMP, PKA inhibition (H89), soluble adenylyl cyclase inhibition (KH7), and phosphodiesterase inhibition (IBMX; BAY60-7550). Adenosine diphosphate (ADP)-stimulated respiratory rates of cardiac fibers were reduced in septic mice. Compared with controls, stimulatory effects of 8Br-cAMP on respiration rates were enhanced in septic fibers, whereas inhibitory effects of H89 were reduced. Ser-58 phosphorylation of cytochrome c oxidase subunit IV-1 was reduced in septic hearts. In vitro, incubation of septic cardiac fibers with BAY60-7550 increased respiratory control ratio and improved cardiac MVO2 efficiency in isolated septic heart. In vivo, BAY60-7550 pre-treatment of septic mice have limited impact on myocardial function. Mitochondrial cAMP-PKA signaling is impaired in the septic myocardium. PDE2 phosphodiesterase inhibition by BAY60-7550 improves mitochondrial respiration and cardiac MVO2 efficiency in septic mice.

Implication of advanced glycation end products (Ages) and their receptor (Rage) on myocardial contractile and mitochondrial functions

Advanced glycation end products (AGEs) play an important role for the development and/or progression of cardiovascular diseases, mainly through induction of oxidative stress and inflammation. AGEs are a heterogeneous group of molecules formed by non-enzymatic reaction of reducing sugars with amino acids of proteins, lipids and nucleic acids. AGEs are mainly formed endogenously, while recent studies suggest that diet constitutes an important exogenous source of AGEs. The presence and accumulation of AGEs in various cardiac cell types affect extracellular and intracellular structure and function. AGEs contribute to a variety of microvascular and macrovascular complications through the formation of cross-links between molecules in the basement membrane of the extracellular matrix and by engaging the receptor for advanced glycation end products (RAGE). Activation of RAGE by AGEs causes up regulation of the transcription factor nuclear factor-κB and its target genes. of the RAGE engagement stimulates oxidative stress, evokes inflammatory and fibrotic reactions, which all contribute to the development and progression of devastating cardiovascular disorders. This review discusses potential targets of glycation in cardiac cells, and underlying mechanisms that lead to heart failure with special interest on AGE-induced mitochondrial dysfunction in the myocardium.

Vieillissement rénal : facteurs de risque et néphroprotection

Renal failure in the elderly is currently underestimated and presents a real challenge for the public health system. Kidney function must be routinely assessed by creatinine clearance, estimated with either the Cockcroft and Gault formula or the simplified MDRD formula, which appears especially appropriate for the elderly. Normal kidney aging is related to tissue and functional changes that make older patients very vulnerable to environmental modifications. Numerous factors can accelerate the impairment of rental function during aging. Some of them cannot be modified: sex, genome, and initial kidney disease. Most of them can be managed or treated: hypertension, diabetes mellitus, obesity, smoking, dyslipidemia, proteinuria, and the presence of oxidation and glycation products. Chronic renal failure in the elderly must be managed early with strict treatment targets to avoid the development of end-stage renal disease. Inhibitors of the renin-angiotensin-aldosterone system play an essential role in optimizing nephroprotection: control of hypertension, diabetes complications, and proteinuria. They should be prescribed very carefully in older patients. Age is not a prerequisite for consultations with nephrologists, which should take place early so that nephroprotection can still be useful.

Relationship between Pisa syndrome and cholinesterase inhibitor use for elderly adults with Alzheimer's disease.

Management Advisor Committee Meeting on the Benefit/Risk of Salmon Calcitonin for the Treatment of Postmenopausal Osteoporosis Briefing Book, 2013 [on-line]. Available at http://www.fda.gov/downloads/Advisory Committees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugs AdvisoryCommittee/UCM341781.pdf Accessed March 21, 2014. 5. European Medicines Agency. Assessment report for calcitonin containing medicinal products. United Kingdom: European Medicines Agency, 2013 [on-line]. Available at http://www.ema.europa.eu/docs/en_GB/document_lib rary/Referrals_document/Calcitonin_31/WC500146172.pdf Accessed March 21, 2014. 6. Wells G, Krause D, Chernoff J et al. Does calcitonin cause cancer? (abstract SA0401). J Bone Miner Res 2013;28(Suppl 1) [on-line]. Available at http:// www.asbmr.org/education/2013-abstracts Accessed March 21, 2014. 7. Food and Drug Administration Center for Drug Evaluation and Research. Minutes for the March 5, 2013 Joint Meeting of the Advisory Committee for Reproductive Health Drugs (ACRHD) and the Drug Safety and Risk Management Advisory Committee (DSaRM) [on-line]. Available at http:// www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM351017.pdf Access ed March 21, 2014.

Targeting Oxidative Stress and Mitochondrial Dysfunction in the Treatment of Impaired Wound Healing: A Systematic Review

Wound healing is a well-tuned biological process, which is achieved via consecutive and overlapping phases including hemostasis, inflammatory-related events, cell proliferation and tissue remodeling. Several factors can impair wound healing such as oxygenation defects, aging, and stress as well as deleterious health conditions such as infection, diabetes, alcohol overuse, smoking and impaired nutritional status. Growing evidence suggests that reactive oxygen species (ROS) are crucial regulators of several phases of healing processes. ROS are centrally involved in all wound healing processes as low concentrations of ROS generation are required for the fight against invading microorganisms and cell survival signaling. Excessive production of ROS or impaired ROS detoxification causes oxidative damage, which is the main cause of non-healing chronic wounds. In this context, experimental and clinical studies have revealed that antioxidant and anti-inflammatory strategies have proven beneficial in the non-healing state. Among available antioxidant strategies, treatments using mitochondrial-targeted antioxidants are of particular interest. Specifically, mitochondrial-targeted peptides such as elamipretide have the potential to mitigate mitochondrial dysfunction and aberrant inflammatory response through activation of nucleotide-binding oligomerization domain (NOD)-like family receptors, such as the pyrin domain containing 3 (NLRP3) inflammasome, nuclear factor-kappa B (NF-κB) signaling pathway inhibition, and nuclear factor (erythroid-derived 2)-like 2 (Nrf2).

AGE, RAGE, and Diabetic Nephropathy

Diabetes is a disease that is present worldwide and which is associated with a large number of potential complications including chronic kidney disease (CKD). Several factors have been implicated in the development of the latter, including advanced glycation end-products (AGEs), which are formed from the interaction between sugar and proteins. AGE toxicity may be triggered via different mechanisms, especially by receptor binding. Immunohistochemical studies have demonstrated the presence of AGEs in all renal structures (vessels, glomeruli, tubules, and the interstitium). They appear to be involved in the exacerbation of renal injury observed during diabetic nephropathy. At present, no specific treatment is yet available, although several therapeutic approaches are under development.