Molecular Networking for Drug Toxicities Studies: The Case of Hydroxychloroquine in COVID-19 Patients

Using drugs to treat COVID-19 symptoms may induce adverse effects and modify patient outcomes. These adverse events may be further aggravated in obese patients, who often present different illnesses such as metabolic-associated fatty liver disease. In Rennes University Hospital, several drug such as hydroxychloroquine (HCQ) have been used in the clinical trial HARMONICOV to treat COVID-19 patients, including obese patients. The aim of this study is to determine whether HCQ metabolism and hepatotoxicity are worsened in obese patients using an in vivo/in vitro approach. Liquid chromatography high resolution mass spectrometry in combination with untargeted screening and molecular networking were employed to study drug metabolism in vivo (patient’s plasma) and in vitro (HepaRG cells and RPTEC cells). In addition, HepaRG cells model were used to reproduce pathophysiological features of obese patient metabolism, i.e., in the condition of hepatic steatosis. The metabolic signature of HCQ was modified in HepaRG cells cultured under a steatosis condition and a new metabolite was detected (carboxychloroquine). The RPTEC model was found to produce only one metabolite. A higher cytotoxicity of HCQ was observed in HepaRG cells exposed to exogenous fatty acids, while neutral lipid accumulation (steatosis) was further enhanced in these cells. These in vitro data were compared with the biological parameters of 17 COVID-19 patients treated with HCQ included in the HARMONICOV cohort. Overall, our data suggest that steatosis may be a risk factor for altered drug metabolism and possibly toxicity of HCQ.     

Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold‐Hopping Approach

Starting from suvorexant (trade name Belsomra), we successfully identified interesting templates leading to potent dual orexin receptor antagonists (DORAs) via a scaffold‐hopping approach. Structure–activity relationship optimization allowed us not only to improve the antagonistic potency on both orexin 1 and orexin 2 receptors (Ox1 and Ox2, respectively), but also to increase metabolic stability in human liver microsomes (HLM), decrease time‐dependent inhibition of cytochrome P450 (CYP) 3A4, and decrease P‐glycoprotein (Pgp)‐mediated efflux. Compound 80 c [{(1S,6R)‐3‐(6,7‐difluoroquinoxalin‐2‐yl)‐3,8‐diazabicyclo[4.2.0]octan‐8‐yl}(4‐methyl‐[1,1′‐biphenyl]‐2‐yl)methanone] is a potent and selective DORA that inhibits the stimulating effects of orexin peptides OXA and OXB at both Ox1 and Ox2. In calcium‐release assays, 80 c was found to exhibit an insurmountable antagonistic profile at both Ox1 and Ox2, while displaying a sleep‐promoting effect in rat and dog models, similar to that of the benchmark compound suvorexant.     

Effect of Phenolic Acids in Soil under and Between Rows of a Prior Sorghum (Sorghum bicolor) Crop on Germination, Emergence, and Seedling Growth of Peanut (Arachis hypogea)

Sorghum bicolor is an allelopathic crop that reduces the yield of succeeding crops. We have assessed its effect on the germination, emergence, and seedling growth of Arachis hypogea sown in soil that had had a prior sorghum cropping. A. hypogea was sown on rows and interrows of a previous sorghum crop in 1997 and 1998 in Senegal. Seedling establishment (germination rate and seedling weight) was better between rows than on rows of the previous crop. The highest concentrations of phenolic compounds occurred in the rows in 1998, while contents of row and interrow soils were similar in 1997. Vanillic acid was the main component of the six chemicals found in 1997 soils, whereas the 1998 soil samples contained mainly p-hydroxybenzoic acid, p-hydroxybenzaldehyde, vanillic, and p-coumaric acids (10 phenolics identified). The germination of peanut seeds in water (control), soil water extracts, and mixtures of pure phenolics (equivalent to those in 1997 and 1998 soil samples) was tested. All extracts inhibited germination compared to controls, but there was no significant difference among treatments, i.e., the inhibition was the same for seeds in soil solutions and those in the respective phenolic mixtures. Similarly, there were no significant differences among the germination rates in soil water extracts of rows and interrows or in the pure phenolic mixtures of rows and interrows. We propose a geometrical sowing pattern for peanuts between the rows of the previous sorghum crop to escape the latter's "allelopathic heritage."     

A Highly Potent and Cellularly Active β‐Peptidic Inhibitor of the p53/hDM2 Interaction

New and improved : The incorporation of a 6‐chlorotryptophan (6‐Cl‐Trp) into a β‐peptide (M)‐3₁₄ helix leads to a high‐affinity hDM2 inhibitor, as demonstrated by fluorescence fluctuation analysis at single molecule resolution. When conjugated to penetratin, the newly derived hDM2 binder specifically inhibits tumour cell growth in vitro.

     

4,4‐Dimethyl‐ and Diastereomeric 4‐Hydroxy‐4‐methyl‐ (2S)‐Glutamate Analogues Display Distinct Pharmacological Profiles at Ionotropic Glutamate Receptors and Excitatory Amino Acid Transporters

Subtype‐selective ligands are of great interest to the scientific community, as they provide a tool for investigating the function of one receptor or transporter subtype when functioning in its native environment. Several 4‐substituted (S)‐glutamate (Glu) analogues were synthesized, and altogether this approach has provided important insight into the structure–activity relationships (SAR) for ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs), as well as the excitatory amino acid transporters (EAATs). In this work, three 4,4‐disubstituted Glu analogues 1 – 3 , which are hybrid structures of important 4‐substituted Glu analogues 4 – 8 , were investigated at iGluRs and EAATs. Collectively, their pharmacological profiles add new and valuable information to the SAR for the iGluRs and EAAT1–3.     

Rheological characterization of starch derivatives/polycaprolactone blends processed by reactive extrusion

Linear viscoelastic, steady shear behaviors, and morphologies of starch formate/poly(ε-caprolactone) (PCL) blends, compatibilized by oligomers and obtained by reactive extrusion, have been investigated as a function of formic acid (FA)/starch ratio, nature, and molecular weight of the oligomer. The rheological properties of these blends have been compared with those of a commercial starch-based thermoplastic, namely Mater-Bi® ZF03UA. In presence of FA, starch is destructured to starch formate and oligomers are used as plasticizers. The linear viscoelastic response of blends is quite similar to that of nanocomposite materials: the low frequency behavior is attributed to a percolated network of destructured starch particles, and the high frequency behavior is that of the polymer matrix. The viscosity curve presents a profile characterized by two plateau regions, at low and high shear rates. The plateau region at low shear rates corresponds to the viscous response of the blend while that observed at high shear rates can be attributed to the PCL matrix. The compatibilization is enhanced in the presence of starch formate and increases with increasing the oligomer molecular weight. The use of PCL oligomer was shown to improve this compatibilization effect. POLYM. ENG. SCI., 2008. © 2008 Society of Plastics Engineers     

Intergranular Oxidation of Nickel-Base Alloys: Potentialities of Focused Ion Beam Tomography

Oxidation of Metals - The present work focuses on the intergranular oxidation of Alloy 600 and its weld material Alloy 82 after exposure in simulated primary water at 340–360 °C...     

Great enhancement of mechanical features in PLA based composites containing aligned few layer graphene (FLG), the effect of FLG loading,size, and dispersion on mechanical and thermal properties

Four series of polylactide (PLA) based composite films containing horizontally aligned few layer graphene (FLG) flakes of high aspect ratio and adsorbed albumin are prepared. The mechanical and thermal properties varies with percentage, dispersion degree and size of FLG flakes. Great improvement up to 290% and 360% of tensile modulus and strength respectively were obtained for the composite containing high lateral size of FLG at 0.17% wt, and up to 60% and 80% for the composite with very well dispersed 0.02% wt FLG. The composites of PLA and PEG-PLLA containing very well dispersed FLG flakes at 0.07% wt are ductile showing enhancement of elongation at break up to respectively 80% and 88%. Relatively high electrical conductivity, 5 × 10⁻³ S/cm, is measured for PLA film charged with 3% of FLG.     

Thermal stability and crystallisation of a Zr55Cu30Al10Ni5 bulk metallic glass studied by in situ ultrasonic echography

An original in situ ultrasonic echography technique was used to study the thermal stability and crystallisation of a Zr₅₅Cu₃₀Al₁₀Ni₅ bulk metallic glass between RT and 630 °C. Changes in Young's modulus with temperature were reported allowing to study the supercooled-liquid state and the crystallisation process. Investigations of viscoelastic properties gave information on the correlation factor (hierarchically correlated motion theory) and three distinct crystallisation stages were observed. Their kinetics were studied using Voigt's and Reuss' approximations for a two-phase material and comparisons with the Johnson–Mehl–Avrami–Kolmogorov theory allowed us to consider a mixed surface/internal nucleation for the first stage and a surface nucleation for the two last stages.     

Potential influence of microorganisms on the corrosion of carbon steel in the French high- and intermediate-level long-lived radioactive waste disposal context

In the context of the high-level radioactive waste disposal CIGEO, the corrosion rate due to microbially influenced corrosion (MIC) has to be evaluated. In France, it is envisaged to dispose of high- and intermediate-level long-lived radioactive waste at a depth of 500 m in a deep geological disposal, drilled in the Callovo-Oxfordian claystone (Cox) formation. To do so, a carbon steel casing will be inserted inside disposal cells, which are horizontal tunnels drilled in the Cox. A specific cement grout will be injected between the carbon steel casing and the claystone. A study was conducted to evaluate the possibility of MIC on carbon steel in the foreseeable high radioactive waste disposal. The corrosiveness of various environments was investigated at 50°C and 80°C with or without microorganisms enriched from samples of Andra's underground research laboratory. The monitoring of corrosion during the experiments was ensured using gravimetric method and real-time corrosion monitoring using sensors based on the measurements of the electrical resistance. The corrosion data were completed with microbiological analyses including cultural and molecular characterizations.