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.     

Endosperm α 1,4—α 1,6 Glucopolysaccharides Utilization During Germination of Sweet Corn and Other Maize Genotypes

The quantity variations and the structural changes of the α 1,4 —α 1,6 glucopolysaccharides contained in the endosperm of sweet corn, waxy and amylose extender maize genotypes, were studied during early germination. The α 1,4 —α 1,6 glucopolysaccharides were fractionated according to their branching degree. The results obtained showed that: the degradation pattern of the α 1,4 —α 1,6 glucopolysaccharides was similar for the different corn genotypes studied. In addition, soluble dextrins or partial degradation products were not detected, but reducing sugars were accumulated. Furthermore, the structure of the remaining polysaccharides was similar to those present in the non germinating seed. These results led us to propose that once a polysaccharide molecule was used as the substrate by degradative enzymes during germination, that molecule was totally degraded.     

Diet Prevents Social Stress-Induced Maladaptive Neurobehavioural and Gut Microbiota Changes in a Histamine-Dependent Manner

Exposure to repeated social stress may cause maladaptive emotional reactions that can be reduced by healthy nutritional supplementation. Histaminergic neurotransmission has a central role in orchestrating specific behavioural responses depending on the homeostatic state of a subject, but it remains to be established if it participates in the protective effects against the insults of chronic stress afforded by a healthy diet. By using C57BL/6J male mice that do not synthesize histamine (Hdc^−/−) and their wild type (Hdc^+/+) congeners we evaluated if the histaminergic system participates in the protective action of a diet enriched with polyunsaturated fatty acids and vitamin A on the deleterious effect of chronic stress. Behavioural tests across domains relevant to cognition and anxiety were performed. Hippocampal synaptic plasticity, cytokine expression, hippocampal fatty acids, oxylipins and microbiota composition were also assessed. Chronic stress induced social avoidance, poor recognition memory, affected hippocampal long-term potentiation, changed the microbiota profile, brain cytokines, fatty acid and oxylipins composition of both Hdc^−/− and Hdc^+/+ mice. Dietary enrichment counteracted stress-induced deficits only in Hdc^+/+ mice as histamine deficiency prevented almost all the diet-related beneficial effects. Interpretation: Our results reveal a previously unexplored and novel role for brain histamine as a mediator of many favorable effects of the enriched diet. These data present long-reaching perspectives in the field of nutritional neuropsychopharmacology.     

Macrophage-Mediated Melanoma Reduction after HP-NAP Treatment in a Zebrafish Xenograft Model

The Helicobacter pylori Neutrophil Activating Protein (HP-NAP) is endowed with immunomodulatory properties that make it a potential candidate for anticancer therapeutic applications. By activating cytotoxic Th1 responses, HP-NAP inhibits the growth of bladder cancer and enhances the anti-tumor activity of oncolytic viruses in the treatment of metastatic breast cancer and neuroendocrine tumors. The possibility that HP-NAP exerts its anti-tumor effect also by modulating the activity of innate immune cells has not yet been explored. Taking advantage of the zebrafish model, we examined the therapeutic efficacy of HP-NAP against metastatic human melanoma, limiting the observational window to 9 days post-fertilization, well before the maturation of the adaptive immunity. Human melanoma cells were xenotransplanted into zebrafish embryos and tracked in the presence or absence of HP-NAP. The behavior and phenotype of macrophages and the impact of their drug-induced depletion were analyzed exploiting macrophage-expressed transgenes. HP-NAP administration efficiently inhibited tumor growth and metastasis and this was accompanied by strong recruitment of macrophages with a pro-inflammatory profile at the tumor site. The depletion of macrophages almost completely abrogated the ability of HP-NAP to counteract tumor growth. Our findings highlight the pivotal role of activated macrophages in counteracting melanoma growth and support the notion that HP-NAP might become a new biological therapeutic agent for the treatment of metastatic melanomas.     

Colloidal processing of Al2O3-doped zirconia ceramics with CaO–P2O5–SiO2 glass as additive

Well-dispersed concentrated aqueous suspensions of Al₂O₃-doped Y-TZP (AY-TZP), AY-TZP with 5.4 vol% of CaO–P₂O₅–SiO₂ (CaPSi) glass (AY-TZP5) and 10.5 vol% CaPSi glass (AY-TZP10), with ammonium polyacrylate (NH₄PA) dispersant were prepared to produce slip cast compacts. The rheological properties of 35 and 40 vol% slips were studied. The densification, microstructure as well as hardness and fracture toughness were investigated as a function of CaPSi glass content at 1300°C-1500°C. The optimum NH₄PA concentration of 35 vol% AY-TZP5 and AY-TZP10 slips at pH ~9 was found to be about 43% and 67% greater than that of AY-TZP slips; this behavior was related to the greater amounts of Ca²⁺ ions leached out from the CaPSi glass surface. The viscosity of stabilized 40 vol% slips with NH₄PA attained a minimum value at 5.4 vol% CaPSi glass addition, and resulted in a more dense packing of cast samples. AY-TZP5 can be sintered at a lower temperature (1300°C) compared to that of AY-TZP. AY-TZP5 exhibited a fine microstructure of tetragonal ZrO₂ (grain sizes below 0.3 µm), and ZrSiO₄–Ca₂P₂O₇ particles homogeneously distributed within the zirconia matrix. It presented similar fracture toughness and a slightly lower hardness compared to those of AY-TZP.     

Amylose is not Strictly Linear

Amyloses from selected corn starches were used to measure the glucoses involved in the branching points. The number of glucose α 1,6 glycosidically linked were determined by two different methods: 1) The enzymatic one measures directly quantiatively and specifically the glucoses α, 1,6 linked. 2) The other, a chemical one that measures the different n-methylated glucoses involved in the terminal, α 1,4 linked and α1,6 linked positions. The results obtained through both methodologies clearly indicate a good correlation. Amylose is not linear. It has very small proportion of branches and they are α1,6 glycosidically linked.     

Novel Tacrine‐Grafted Ugi Adducts as Multipotent Anti‐Alzheimer Drugs: A Synthetic Renewal in Tacrine–Ferulic Acid Hybrids

Herein we describe the design, multicomponent synthesis, and biological, molecular modeling and ADMET studies, as well as in vitro PAMPA‐blood–brain barrier (BBB) analysis of new tacrine–ferulic acid hybrids (TFAHs). We identified (E)‐3‐(hydroxy‐3‐methoxyphenyl)‐N‐{8[(7‐methoxy‐1,2,3,4‐tetrahydroacridin‐9‐yl)amino]octyl}‐N‐[2‐(naphthalen‐2‐ylamino)2‐oxoethyl]acrylamide (TFAH 10 n ) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC₅₀=68.2 nM ), strong antioxidant activity (4.29 equiv trolox in an oxygen radical absorbance capacity (ORAC) assay), and good β‐amyloid (Aβ) anti‐aggregation properties (65.6 % at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, as determined by PAMPA‐BBB assay. Notably, even when tested at very high concentrations, TFAH 10 n easily surpasses the other TFAHs in hepatotoxicity profiling (59.4 % cell viability at 1000 μM ), affording good neuroprotection against toxic insults such as Aβ_1–40, Aβ_1–42, H₂O₂, and oligomycin A/rotenone on SH‐SY5Y cells, at 1 μM . The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer′s disease.     

Multi‐element characterisation of carob,fig and almond liqueurs by MP‐AES

Carob pod, fig and almond liqueurs are produced in various Mediterranean regions. This work reports the mineral content of these traditional beverages and evaluates the influence of the raw material. Twenty‐five fruit liqueurs from 16 producers were analysed. A simple open‐vessel sample mineralization by wet digestion using nitric acid–hydrogen peroxide (1:1) was used before spectrometric analysis. Nine essential elements (Cu, Ca, Mg, Na, K, Fe, Zn, Mn and P) and two non‐essentials (Cd and Pb) were quantified by microwave plasma–atomic emission spectrometry (MP‐AES). Carob liqueur presented the broader profile of minerals and was the only fruit liqueur containing iron (72.7% of samples), phosphorous, manganese and low levels of lead (in two of the 11 samples). Conversely, almond liqueurs contained the lowest mineral content with only five elements detected. Fruit liqueurs showed variability in mineral content even within the same liqueur, presumably as a consequence of the different manufacturing processes. Despite this variability, application of principal component analysis to essential mineral concentrations (K, Na, Ca, Mg, Mn, Fe and Zn) resulted in satisfactory classification (PC1 and PC2 accounting for 78.5% of the total variance) of the Portuguese liqueurs evaluated. Copyright © 2018 The Institute of Brewing & Distilling     

Applying bibliometric mapping in a high level science policy context

Bibliometric maps have the potential to become useful tools for science policy issues. The complexity of the structures, however, makes it often very difficult to interpret the results. In this study, we present a case study in which we use the bibliometric mapping results to address a high level science policy issue of research efficiency. By revealing the results in an alternative way, we increased the utility of bibliometric mapping within the science policy context. Moreover, by including additional information to the entities in the landscape, we provide useful input for the research potential.