Spontaneous DNA damage to the nuclear genome promotes senescence,redox imbalance and aging

Accumulation of senescent cells over time contributes to aging and age-related diseases. However, what drives senescence in vivo is not clear. Here we used a genetic approach to determine if spontaneous nuclear DNA damage is sufficient to initiate senescence in mammals. Ercc1-/Δ mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1-/Δ mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice. As a consequence, senescent cells accumulated more rapidly in Ercc1-/Δ mice compared to repair-competent animals. However, the levels of DNA damage and senescent cells in Ercc1-/Δ mice never exceeded that observed in old WT mice. Surprisingly, levels of reactive oxygen species (ROS) were increased in tissues of Ercc1-/Δ mice to an extent identical to naturally-aged WT mice. Increased enzymatic production of ROS and decreased antioxidants contributed to the elevation in oxidative stress in both Ercc1-/Δ and aged WT mice. Chronic treatment of Ercc1-/Δ mice with the mitochondrial-targeted radical scavenger XJB-5–131 attenuated oxidative DNA damage, senescence and age-related pathology. Our findings indicate that nuclear genotoxic stress arises, at least in part, due to mitochondrial-derived ROS, and this spontaneous DNA damage is sufficient to drive increased levels of ROS, cellular senescence, and the consequent age-related physiological decline

Conception rationnelle d'un agoniste non peptidique central des récepteurs de la vasopressine et de l'ocytocine pour l'étude des comportements d'attachement

Les récepteurs couplés aux protéines G (RCPG) constituent une classe génomique, structurale et fonctionnelle majeure. La compréhension des interactions ligand-récepteur représente un enjeu thérapeutique et fondamental capital. Nous nous proposions de relever le défi de concevoir rationnellement un agoniste non peptidique d'un RCPG de peptide. Les RCPG de la vasopressine (AVP) et de l'ocytocine (OT) sont notre modèle d'étude. Ces hormones régulent divers aspects du comportement social des mammifères, dont l'attachement. Notre approche combinant modélisation moléculaire et relations structure-activité (RSA) des ligands non peptidiques a été menée en trois temps : 1 consolider le modèle d'interactions ligand-récepteur, 2 explorer les mécanismes de la transition agoniste-antagoniste, 3 concevoir un agoniste central et biodisponible. Les résultats illustrent la subtilité des mécanismes supramoléculaires mis en jeu, avec d'importantes différences entre récepteurs très homologues.G protein-coupled receptors (GPCR) form an important genomic, structural and functional protein class. From a therapeutic as from a fundamental viewpoint, understanding the dynamics of ligand-receptor interactions remains a challenge. Our goal is to rationally design a nonpeptide agonist for a peptide GPCR. Vasopressin (AVP) and oxytocin (OT) receptors represent our model and targets. These hormones are involved in the central control of various aspects of mammals social behaviours, including affect and attachment. Our approach combines molecular modelling and nonpeptide ligands structure-activity relationships (SAR). It was conducted in three steps : 1 to consolidate the ligand-receptor interactions model, 2 to investigate the agonist-antagonist switch mechanisms, 3 to design a central, specific and bioavailable agonist. Results highlight the fine tuning of supramolecular interactions even among highly homologous receptor subtypes.STRASBOURG ILLKIRCH-Pharmacie (672182101) / SudocSudocFranceF

Screening Ionic Solvents for Enhancing the Solubility of Water-Insoluble Natural Dyes

International audienc

Biased Agonist Pharmacochaperones of the AVP V2 Receptor May Treat Congenital Nephrogenic Diabetes Insipidus

X-linked congenital nephrogenic diabetes insipidus (cNDI) results from inactivating mutations of the human arginine vasopressin (AVP) V2 receptor (hV2R). Most of these mutations lead to intracellular retention of the hV2R, preventing its interaction with AVP and thereby limiting water reabsorption and concentration of urine. Because the majority of cNDI-hV2Rs exhibit protein misfolding, molecular chaperones hold promise as therapeutic agents; therefore, we sought to identify pharmacochaperones for hV2R that also acted as agonists. Here, we describe high-affinity nonpeptide compounds that promoted maturation and membrane rescue of L44P, A294P, and R337X cNDI mutants and restored a functional AVP-dependent cAMP signal. Contrary to pharmacochaperone antagonists, these compounds directly activated a cAMP signal upon binding to several cNDI mutants. In addition, these molecules displayed original functionally selective properties (biased agonism) toward the hV2R, being unable to recruit arrestin, trigger receptor internalization, or stimulate mitogen-activated protein kinases. These characteristics make these hV2R agonist pharmacochaperones promising therapeutic candidates for cNDI

LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism

International audienceOxytocin (OT) and its receptor (OT-R) are implicated in the etiology of autism spectrum disorders (ASD), and OT-R is a potential target for therapeutic intervention. Very few nonpeptide oxytocin agonists have currently been reported. Their molecular and in vivo pharmacology remain to be clarified, and none of them has been shown to be efficient in improving social interaction in animal models relevant to ASD. In an attempt to rationalize the design of centrally active nonpeptide full agonists, we studied in a systematic way the structural determinants of the affinity and efficacy of representative ligands of the V-1a and V-2 vasopressin receptor subtypes (V-1a-R and V-2-R) and of the oxytocin receptor. Our results confirm the subtlety of the structure affinity and structure efficacy relationships around vasopressin/oxytocin receptor ligands and lead however to the first nonpeptide OT receptor agonist active in a mouse model of ASD after peripheral ip administration

Two strategies for the development of mitochondrion-targeted small molecule radiation damage mitigators

PURPOSE: To evaluate the effectiveness of mitigation of acute ionizing radiation damage by mitochondrion-targeted small molecules.\ud \ud METHODS AND MATERIALS: We evaluated the ability of nitroxide-linked alkene peptide isostere JP4-039, the nitric oxide synthase inhibitor-linked alkene peptide esostere MCF201-89, and the p53/mdm2/mdm4 protein complex inhibitor BEB55 to mitigate radiation effects by clonogenic survival curves with the murine hematopoietic progenitor cell line 32D cl 3 and the human bone marrow stromal (KM101) and pulmonary epithelial (IB3) cell lines. The p53-dependent mechanism of action was tested with p53(+/+) and p53(-/-) murine bone marrow stromal cell lines. C57BL/6 NHsd female mice were injected i.p. with JP4-039, MCF201-89, or BEB55 individually or in combination, after receiving 9.5 Gy total body irradiation (TBI).\ud \ud RESULTS: Each drug, JP4-039, MCF201-89, or BEB55, individually or as a mixture of all three compounds increased the survival of 32D cl 3 (p = 0.0021, p = 0.0011, p = 0.0038, and p = 0.0073, respectively) and IB3 cells (p = 0.0193, p = 0.0452, p = 0.0017, and p = 0.0019, respectively) significantly relative to that of control irradiated cells. KM101 cells were protected by individual drugs (p = 0.0007, p = 0.0235, p = 0.0044, respectively). JP4-039 and MCF201-89 increased irradiation survival of both p53(+/+) (p = 0.0396 and p = 0.0071, respectively) and p53(-/-) cells (p = 0.0007 and p = 0.0188, respectively), while BEB55 was ineffective with p53(-/-) cells. Drugs administered individually or as a mixtures of all three after TBI significantly increased mouse survival (p = 0.0234, 0.0009, 0.0052, and 0.0167, respectively).\ud \ud CONCLUSION: Mitochondrial targeting of small molecule radiation mitigators decreases irradiation-induced cell death in vitro and prolongs survival of lethally irradiated mice.\ud \u