Conformational Switching of a Foldamer in a Multicomponent System by pH-Filtered Selection between Competing Noncovalent Interactions

Biomolecular systems are able to respond to their chemical environment through reversible, selective, noncovalent intermolecular interactions. Typically, these interactions induce conformational changes that initiate a signaling cascade, allowing the regulation of biochemical pathways. In this work, we describe an artificial molecular system that mimics this ability to translate selective noncovalent interactions into reversible conformational changes. An achiral but helical foldamer carrying a basic binding site interacts selectively with the most acidic member of a suite of chiral ligands. As a consequence of this noncovalent interaction, a global absolute screw sense preference, detectable by ¹³C NMR, is induced in the foldamer. Addition of base, or acid, to the mixture of ligands competitively modulates their interaction with the binding site, and reversibly switches the foldamer chain between its left and right-handed conformations. As a result, the foldamer–ligand mixture behaves as a biomimetic chemical system with emergent properties, functioning as a “proton-counting” molecular device capable of providing a tunable, pH-dependent conformational response to its environment

G6PD protects from oxidative damage and improves healthspan in mice

Reactive oxygen species (ROS) are constantly generated by cells and ROS-derived damage contributes to ageing. Protection against oxidative damage largely relies on the reductive power of NAPDH, whose levels are mostly determined by the enzyme glucose-6-phosphate dehydrogenase (G6PD). Here, we report a transgenic mouse model with moderate overexpression of human G6PD under its endogenous promoter. Importantly, G6PD-Tg micehave higher levels of NADPH, lower levels of ROS-derived damage, and better protection from ageing-associated functional decline, including extended median lifespan in females. The G6PD transgene has no effect on tumour development, even after combining with various tumour-prone genetic alterations. We conclude that a modest increase in G6PD activity is beneficial for healthspan through increased NADPH levels and protection from the deleterious effects of ROS

Overexpression of G6PD as a model of robustness

Frailty is a major geriatric syndrome that has been associated to oxidative stress. The antioxidant system is largely based on the reducing power of NADPH, whose levels are mainly determined by the enzyme glucose-6-phosphate dehydrogenase (G6PD). Material and methods:Using old female Tg-mice overexpressing G6PD (18 to 26 months old), we measured frailty and different muscle parameters: oxidative stress, cross-sectional area (CSA), markers regulating protein synthesis, mitochondrial dynamics, and apoptosis. Results: Our results show that 18–24 months old G6PD-Tg animals performed better in the motor coordination and grip strength test than the WT. We also found lower changes in body weight and improved performance in the running speed in the G6PD-Tg mice. Taking into account the five frailty components, we found that the percentage of mice considered as frail was higher in the WT than in the G6PD-Tg group. G6PD-Tg mice exhibited higher GSH over GSSG ratio, reduced apoptosis (Bax/Bcl2), lower intramuscular adipocyte markers (FABP4, PDGFR α) and a higher mitochondrial content (COXIV) than the WT. Conclusion. Our results show that the overexpression of G6PD prevents frailty in 18 to 26 months old mice modulating the oxidative stress and markers of muscle quality

Bénéfices de l'allopurinol dans la prévention de l'atrophie musculaire induite par l'immobilisation

National audienceno abstrac

Modificaciones hematológicas inducidas por eritropoyetina frente a hipoxia normobárica intermitente Hematologic changes induced by erythropoietin versus intermittent normobaric hypoxia

&lt;p align="justify"&gt;Publicaciones recientes reflejan la preocupaci&amp;oacute;n de las autoridades antidopaje por el uso de sistemas simuladores de altitud y la posibilidad de considerarlos m&amp;eacute;todos dopantes. El objetivo de nuestro estudio fue el de comparar las modificaciones hematol&amp;oacute;gicas inducidas por dos tratamientos con eritropoyetina recombinante humana (rHuEpo) a diferentes dosis, frente a un protocolo de hipoxia normob&amp;aacute;rica intermitente (HNI) en un modelo animal. &lt;br /&gt;Veinticuatro ratas Wistar macho j&amp;oacute;venes fueron divididas en 3 grupos experimentales: grupo sometido a HNI (12h pO2 12% /12h pO2 21%) (n=8); grupo tratado con una dosis de 300 UI de rHuEpo (n=8) y grupo tratado con 500 UI de rHuEpo (n=8). Se extrajeron dos muestras de sangre a cada uno de los grupos experimentales (antes y despu&amp;eacute;s de los tratamientos). Nuestros resultados muestran incrementos muy similares, y estad&amp;iacute;sticamente significativos, en los valores de hemoglobina, de hematocrito y de reticulocitos, tanto en el grupo HNI como en el grupo tratado con 300 UI de rHuEpo tras los 15 d&amp;iacute;as de tratamiento. El tratamiento con 500 UI de rHuEpo produjo un incremento significativamente mayor. &lt;br /&gt;La principal conclusi&amp;oacute;n de nuestro estudio es que las modificaciones de los par&amp;aacute;metros hematol&amp;oacute;gicos obtenidas mediante un protocolo de HNI son similares a las obtenidas con un tratamiento con 300 UI de rHuEpo.&lt;br /&gt;Palabras clave: Hemoglobina, hematocrito, reticulocitos, dopaje&lt;/p&gt;<br>Recent publications reflect the anti-doping authorities&amp;rsquo; concern about the use of altitude simulator systems, since these technologies could be considered as doping methods. The major aim of our study was to compare the effect of two different rHuEpo treatments with a normobaric intermittent hypoxic (NIH) protocol regarding the modifications of hemoglobin, hematocrit and reticulocytes values in an animal model. Although these hematological parameters are of secondary nature, some international sport federations currently exclude athletes, who show aberrant values of these parameters, from competition.&lt;br /&gt;Twenty-four young male Wistar rats (3 months and ~300g weight) were randomly divided in 3 experimental groups: normobaric intermittent hypoxic group&amp;nbsp; (12h pO2 12% /12h pO2 21%) (n=8); the group treated with 300 UI of rHuEpo (n=8) and the group treated with 500 UI of rHuEpo (n=8).The rHuEpo was administered subcutaneously 3 times/week. All the treatments lasted 15 days. Two blood samples were obtained in every experimental group. The first one before the treatments and the second one 15 days after the treatments. &lt;br /&gt;Our results show similar and statistically significant increments in the hemoglobin, hematocrit and reticulocytes values after 15 days of treatment with 300 UI of rHuEpo or NIH. The treatment with 500 UI of rHuEpo induced a higher increase in the hematological parameters determined in our study when compared with the other treatments (NIH and rHuEpo 300 UI). &lt;br /&gt;The main conclusion of our study is that the hematological modifications achieved with a NIH protocol were comparable with those that imply a treatment with 300 UI of rHuEpo.&lt;br /&gt;Key Words: Hemoglobin, hematocrit, reticulocytes, dopin