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.     

Biodegradable composites with improved barrier properties and transparency from the impregnation of PLA to bacterial cellulose membranes

Poly(lactic acid) (PLA) was impregnated in bacterial cellulose (BC) membranes. BC/PLA films were prepared by solvent casting and mechanical, optical and barrier properties, and biodegradation process were investigated. The transparency of processed films was higher than that of neat BC and increased with PLA content. Moreover, the incorporation of PLA to BC enhanced significantly the water vapor barrier properties of the BC membranes. The bionanocomposites contained a high percentage of cellulose due to the impregnation method that leads to the film with a BC content of 94%, which practically maintains the excellent mechanical properties of BC. However, when increasing the PLA content in the bionanocomposites the mechanical properties decreased slightly with respect to BC. Biodegradation under real soil conditions was determined indirectly through the study of the visual degradation and disintegration, demonstrating that the bionanocomposites were degraded faster than the neat PLA. The successful production of BC/PLA bionanocomposites suggested the possible application of them for active food packaging. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43669.     

Polypyrrole materials doped with weakly coordinating anions: influence of substituents and the fate of the doping anion during the overoxidation process

The influence of weakly coordinating anions with different shapes and substituents has been studied to get the overoxidation resistance limit of the material, ORL. The anions utilized are derivatives of [Co(C₂B₉H₁₁)₂]⁻, [B₁₂H₁₂]²⁻ and [B₁₂H₁₁NH₃]⁻. The following tendencies have been established (1) boron cluster monoanions are to date the anions that offer the highest stability to overoxidation of PPy doped materials (2) the ORL stability of the material can not be attributed only to the shape of the cluster (3) monoanionic clusters are far superior than dianionic to get an ORL rise (4) cluster charge density reduction results in ORL rise as has been observed in [Co(C₂B₉H₁₁)₂]⁻ after incorporation of electron-withdrawing substituents with no electron back-donation (5) globular, rigid and large monoanions are less suitable for enhanced ORL values than elongated and non-rigid species (6) adequate anion's substitution produce a rise in the ORL of the material, thus polyether side-arms are beneficial with [Co(C₂B₉H₁₁)₂]⁻, whereas, T-shaped methylaryl groups are appealing in [B₁₂H₁₁NH₃]⁻ based materials, respectively, (7) substituents on the anions usually imply higher difficulty in the materials' growth. The high boron contents in these materials has permitted to learn on the fate of the doping anions during the overoxidation process. There is a built-up of the concentration of the doping anion in the electrolyte near surface area, whereas, a depletion is observed in the nearest inner layers.     

Are Chemical Compounds Important for Soybean Resistance to <Emphasis Type="Italic">Anticarsia gemmatalis</Emphasis>?

The identification and quantification of flavonoids (rutin and genistin) present in extracts of soybean genotypes, and their effects on the biology and physiology of Anticarsia gemmatalis Hübner (Lep.: Noctuidae) were studied. Analysis of covariance and bicoordinate utilization plots were used to remove the effect of feeding time from pupal weight and consumption as well as to separate pre- and postingestive effects of treatment on A. gemmatalis growth. Genotypes PI 274454, PI 227687, and “IAC-100” extracts in general, caused higher mortality, negatively influenced initial larval and pupal weight, and elongated larval cycle. Larvae fed on the “IAC-100” extract diet ingested larger amounts of food per unit of time, but were less efficient in its conversion to biomass. Leaf extracts of PI 227687 had the largest concentration of rutin (quercitin 3-O-rhamnosylglucoside), followed by PI 274454, and “IAC-100”; PI 74454 also had the highest genistin (genistein 7-O-glucoside) content. The susceptible cultivar “BR-16” showed only a kaempferol-based flavonoid in its chemical profile, indicating that after successive crosses, secondary compounds responsible for plant defenses were eliminated. Genotypes PI 274454, PI 227687, and “IAC-100” showed accentuated resistance characteristics and were considered inadequate sources for the development of A. gemmatalis. Considering rutin and genistin concentration in these genotypes, it is suggested that flavonoids are important factors conferring resistance to A. gemmatalis.     

Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects over 6 million people worldwide. Development of new drugs to treat this disease remains a priority since those currently available have variable efficacy and frequent adverse effects, especially during the long regimens required for treating the chronic stage of the disease. T. cruzi modulates the host cell-metabolism to accommodate the cell cytosol into a favorable growth environment and acquire nutrients for its multiplication. In this study we evaluated the specific anti-T. cruzi activity of nine bio-energetic modulator compounds. Notably, we identified that 17-DMAG, which targets the ATP-binding site of heat shock protein 90 (Hsp90), has a very high (sub-micromolar range) selective inhibition of the parasite growth. This inhibitory effect was also highly potent (IC₅₀ = 0.27 μmol L⁻¹) against the amastigote intracellular replicative stage of the parasite. Moreover, molecular docking results suggest that 17-DMAG may bind T. cruzi Hsp90 homologue Hsp83 with good affinity. Evaluation in a mouse model of chronic T. cruzi infection did not show parasite growth inhibition, highlighting the difficulties encountered when going from in vitro assays onto preclinical drug developmental stages.     

Early-Life Development of the Bifidobacterial Community in the Infant Gut

The establishment of the gut microbiota poses implications for short and long-term health. Bifidobacterium is an important taxon in early life, being one of the most abundant genera in the infant intestinal microbiota and carrying out key functions for maintaining host-homeostasis. Recent metagenomic studies have shown that different factors, such as gestational age, delivery mode, or feeding habits, affect the gut microbiota establishment at high phylogenetic levels. However, their impact on the specific bifidobacterial populations is not yet well understood. Here we studied the impact of these factors on the different Bifidobacterium species and subspecies at both the quantitative and qualitative levels. Fecal samples were taken from 85 neonates at 2, 10, 30, 90 days of life, and the relative proportions of the different bifidobacterial populations were assessed by 16S rRNA–23S rRNA internal transcribed spacer (ITS) region sequencing. Absolute levels of the main species were determined by q-PCR. Our results showed that the bifidobacterial population establishment is affected by gestational age, delivery mode, and infant feeding, as it is evidenced by qualitative and quantitative changes. These data underline the need for understanding the impact of perinatal factors on the gut microbiota also at low taxonomic levels, especially in the case of relevant microbial populations such as Bifidobacterium. The data obtained provide indications for the selection of the species best suited for the development of bifidobacteria-based products for different groups of neonates and will help to develop rational strategies for favoring a healthy early microbiota development when this process is challenged.