Search

The skin is the organ that is most susceptible to the impact of the exposome. Located at the interface with the external environment, it protects internal organs through the barrier function of the epidermis. It must adapt to the consequences of the harmful effects of solar radiation, the various chemical constituents of atmospheric pollution, and wounds associated with mechanical damage: oxidation, cytotoxicity, inflammation, and so forth. In this biological context, a capacity to adapt to the various stresses caused by the exposome is essential; otherwise, more or less serious conditions may develop accelerated aging, pigmentation disorders, atopy, psoriasis, and skin cancers. Nrf2-controlled pathways play a key role at this level. Nrf2 is a transcription factor that controls genes involved in oxidative stress protection and detoxification of chemicals. Its involvement in UV protection, reduction of inflammation in processes associated with healing, epidermal differentiation for barrier function, and hair regrowth, has been demonstrated. The modulation of Nrf2 in the skin may therefore constitute a skin protection or care strategy for certain dermatological stresses and disorders initiated or aggravated by the exposome. Nrf2 inducers can act through different modes of action. Keap1-dependent mechanisms include modification of the cysteine residues of Keap1 by (pro)electrophiles or prooxidants, and disruption of the Keap1-Nrf2 complex. Indirect mechanisms are suggested for numerous phytochemicals, acting on upstream pathways, or via hormesis. While developing novel and safe Nrf2 modulators for skin care may be challenging, new avenues can arise from natural compounds-based molecular modeling and emerging concepts such as epigenetic regulation., (© 2022 The Authors. BioFactors published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)

An efficient, divergent, and straightforward access to novel C-glycosides has been developed, namely, α-hydroxy carboxamide and carboxylic acid derivatives, via a green and scalable process from unprotected carbohydrates. The method involves condensation of 1,3-dimethylbarbituric acid with unprotected sugars followed by subsequent barbiturate oxidative cleavage in the same pot. Further expanding of the chemistry led to the development of efficient entries to diastereoisomerically pure C-glycosyl-α-hydroxy esters or amides through nucleophilic attack on a readily available and versatile key lactone intermediate.

Oxytocin (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.

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 -/∆ mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1 -/∆ mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice. As a consequence, senescent cells accumulated more rapidly in Ercc1 -/∆ mice compared to repair-competent animals. However, the levels of DNA damage and senescent cells in Ercc1 -/∆ mice never exceeded that observed in old WT mice. Surprisingly, levels of reactive oxygen species (ROS) were increased in tissues of Ercc1 -/∆ 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 -/∆ and aged WT mice. Chronic treatment of Ercc1 -/∆ 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., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

The overall objective was to identify an accurate computational electronic method to virtually screen phenolic compounds through their antioxidant and free-radical scavenging activity. The impact of a key parameter of the density functional theory (DFT) approach was studied. Performances of the 21 most commonly used exchange-correlation functionals are thus detailed in the evaluation of the main energetic parameters related to the activities of two prototype antioxidants, namely quercetin and edaravone, is reported. These functionals have been chosen among those belonging to three different families of hybrid functionals, namely global, range separated, and double hybrids. Other computational parameters have also been considered, such as basis set and solvent effects. The selected parameters, namely bond dissociation enthalpy (BDE), ionization potential (IP), and proton dissociation enthalpy (PDE) allow a mechanistic evaluation of the antioxidant activities of free radical scavengers. Our results show that all the selected functionals provide a coherent picture of these properties, predicting the same order of BDEs and PDEs. However, with respect to the reference values, the errors found at CBS-Q3 level significantly vary with the functional. Although it is difficult to evidence a global trend from the reported data, it clearly appears that LC-ωPBE, M05-2X, and M06-2X are the most suitable approaches for the considered properties, giving the lowest cumulative mean absolute errors. These methods are therefore suggested for an accurate and fast evaluation of energetic parameters related to an antioxidant activity via free radical scavenging.

More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub-Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine-based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT-451840 [(S,E)-N-(4-(4-acetylpiperazin-1-yl)benzyl)-3-(4-(tert-butyl)phenyl)-N-(1-(4-(4-cyanobenzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)