The Gut Microbiome in Depression and Potential Benefit of Prebiotics,Probiotics and Synbiotics: A Systematic Review of Clinical Trials and Observational Studies

An emerging body of literature demonstrates differences in the gut microbiome (GMB) of patients with major depressive disorder (MDD) compared to healthy controls (HC), as well as the potential benefits of prebiotic, probiotic, and synbiotic treatment. We conducted a systematic review of 24 observational studies (n = 2817), and 19 interventional trials (n = 1119). We assessed alpha diversity, beta diversity, and taxa abundance changes in patients with MDD relative to HC, as well as the effect of prebiotics, probiotics, and synbiotics on depressive symptoms in individuals with clinical or subclinical depression. We observed no significant differences in alpha diversity but a significant difference in beta diversity between patients with MDD and HC. There were fluctuations in the abundance of specific taxa in patients with MDD relative to HC. Probiotic and synbiotic, but not prebiotic, treatment showed a modest benefit in reducing depressive symptoms in patients with MDD over four to nine weeks. The GMB profiles of patients with MDD differ significantly from HC, but further studies are needed to elucidate the benefits of prebiotic, probiotic and synbiotic treatments relative to antidepressants and over longer follow-up before these therapies are implemented into clinical practice.     

Glucuronidation of zearalenone,zeranol and four metabolites in vitro: Formation of glucuronides by various microsomes and human UDP‐glucuronosyltransferase isoforms

Glucuronidation constitutes an important pathway in the phase II metabolism of the mycotoxin zearalenone (ZEN) and the growth promotor α‐zearalanol (α‐ZAL, zeranol), but the enzymology of their formation is yet unknown. In the present study, ZEN, α‐ZAL and four of their major phase I metabolites were glucuronidated in vitro using hepatic microsomes from steer, pig, rat and human, intestinal microsomes from humans, and eleven recombinant human UDP‐glucuronosyltransferases (UGTs). After assigning chemical structures to the various glucuronides by using previously published information, the enzymatic activities of the various microsomes and UGT isoforms were determined together with the patterns of glucuronides generated. All six compounds were good substrates for all microsomes studied. With very few exceptions, glucuronidation occurred preferentially at the sterically unhindered phenolic 14‐hydroxyl group. UGT1A1, 1A3 and 1A8 had the highest activities and gave rise to the phenolic glucuronide, whereas glucuronidation of the aliphatic hydroxyl group was mostly mediated by UGT2B7 with low activity. Based on these in vitro data, ZEN, α‐ZAL and their metabolites must be expected to be readily glucuronidated both in the liver and intestine as well as in other extrahepatic organs of humans and various animal species.     

Synapses on the mauthner cell of the goldfish: Thin section,freeze-fracture,and immunocytochemical studies

Large myelinated club ending and small-vesicle bouton synapses on the distal part of the lateral dendrite of the goldfish Mauthner cell were investigated with thin section, freeze-fracture, and immunocytochemical electron microscopic methods. Large myelinated club endings form mixed synapses, having both gap junctions and chemical synaptic junctions. The correlation of the number of gap junction particles (connexons) and the data from electrophysiological studies of single large myelinated club ending synapses suggest that only a small fraction of gap junction channels are open at any given time during electrical synaptic transmission. The chemical synaptic junctions at the large myelinated club ending synapse have large, round synaptic vesicles, indicating that they are excitatory. This result is in agreement with electrophysiological data demonstrating the excitatory nature of this chemical synapse. Freeze-fracture of these excitatory chemical synaptic junctions reveals the presence of the intramembrane particle aggregates in the postsynaptic E face. Small-vesicle boutons form chemical synaptic junctions with small, flat or oval synaptic vesicles. These structural data, in combination with previous electrophysiological studies, suggest that the small-vesicle bouton synapses are inhibitory. In support of this theory, the cytoplasmic side of the postsynaptic membrane of some of these synapses show positive immunocytochemical reaction to monoclonal antibodies against the rat glycine receptor. Freeze-fracture data reveal intramembrane particle aggregates in the postsynaptic P face of some small-vesicle bouton synapses which could possibly represent glycine receptor aggregates.     

Fish‐Microarray: A Miniaturized Platform for Single‐Embryo High‐Throughput Screenings

Small molecule high‐throughput screenings are essential for the fields of drug discovery and toxicology. Such screenings performed on whole animals are more physiologically relevant leading to more predictive results. However, due to challenges in automation, high costs and absence of miniaturized solutions for animal‐based experiments, high throughput screenings based on animal models are still in its infancy. Here a platform for miniaturized high throughput whole‐organism screenings is presented. The new platform is based on patterns of hydrophilic spots separated by superhydrophobic borders. The difference in wettability of spots and borders generates the effect of discontinuous dewetting and allows for formation of arrays of microdroplets that incorporate single fish embryos. Due to the flat border‐less nature of the platform, the system is compatible with single‐step collection of embryos and pipetting‐free parallel addition of chemical libraries using the “sandwiching method.” The system is miniaturized and allows for incubation of embryos in volumes as low as 5 µL. Finally, the platform realizes surface tension based immobilization of single embryos inside of each microcompartment and permits high‐throughput microscopic analysis directly on the platform. Thus, this method combines the advantages of microarrays, such as high‐throughput and simplicity, with the power of in vivo experiments.     

Glucuronidation of curcuminoids by human microsomal and recombinant UDP-glucuronosyltransferases

Glucuronidation is an important pathway in the metabolism of curcumin, but the isoforms of uridine-5'-diphosphoglucuronosyltransferase (UGT) involved are not known. Here, we report on the glucuronidation of the three natural curcuminoids and their major phase I metabolites with microsomes from human liver and intestine as well as with human recombinant UGTs. Microsomes from human liver generated predominantly the phenolic and small amounts of the alcoholic glucuronide of each curcuminoid, whereas intestinal microsomes formed only the phenolic conjugates but with higher activities. The phenolic glucuronidation of the curcuminoids was predominantly catalyzed by hepatic UGT1A1 and intestinal UGT1A8 and 1A10, whereas UGT1A9, 2B7, and 1A8 exhibited high activities for hexahydro-curcuminoids. UGT1A9 was able to form the alcoholic glucuronide of each curcuminoid in addition to the phenolic conjugate. These data suggest that the gastrointestinal tract contributes substantially to the glucuronidation of curcuminoids in humans, which may have important implications for their pharmacokinetic fate in vivo.     

Sinusoidal nonlinearity in wavelength-sweeping interferometry

We report the influence of the nonlinearities in the wavelength-sweeping speed on the resulting interferometric signals in an absolute distance interferometer. The sweeping signal is launched in the reference and target interferometers from an external cavity laser source. The experimental results demonstrate a good resolution in spite of the presence of nonlinearities in the wavelength sweep. These nonlinearities can be modeled by a sum of sinusoids. A simulation is then implemented to analyze the influence of their parameters. It shows that a sinusoidal nonlinearity is robust enough to give a good final measurement uncertainty through a Fourier transform technique. It can be concluded that an optimal value of frequency and amplitude exists in the case of a sinusoidal nonlinearity.     

Dicyanovinyl–Substituted Oligothiophenes: Structure‐Property Relationships and Application in Vacuum‐Processed Small Molecule Organic Solar Cells

Efficient synthesis of a series of terminally dicyanovinyl (DCV)‐substituted oligothiophenes, DCVnT 1–6, without solubilizing side chains synthesized via a novel convergent approach and their application as electron donors in vacuum‐processed m‐i‐p‐type planar and p‐i‐n‐type bulk heterojunction organic solar cells is described. Purification of the products via gradient sublimation yields thermally highly stable organic semiconducting materials in single crystalline quality which allows for X‐ray structure analysis. Important insights into the packing features and intermolecular interactions of these promising solar cell materials are provided. Optical absorption spectra and electrochemical properties of the oligomers are investigated and valuable structure–property relationships deduced. Photovoltaic devices incorporating DCVnTs 4–6 showed power conversion efficiencies up to 2.8% for planar and 5.2% for bulk heterojunction organic solar cells under full sun illumination (mismatch corrected simulated AM 1.5G sunlight). The 5.2% efficiency shown here represents one of the highest values ever reported for organic vacuum‐deposited single heterojunction solar cells.     

Absorption and metabolism of the mycotoxin zearalenone and the growth promotor zeranol in Caco-2 cells in vitro

Scope: Zearalenone (ZEN) and α‐zearalanol (α‐ZAL, zeranol) were studied in differentiated Caco‐2 cells and in the Caco‐2 Millicell^® system in vitro to simulate their in vivo intestinal absorption and metabolism in humans. Methods and results: In addition to metabolic reduction/oxidation, extensive conjugation with glucuronic acid and sulfate of the parent compounds and their phase I metabolites was observed. The positional isomers of the glucuronides and sulfates were unambiguously identified: Sulfonation occurred specifically at the 14‐hydroxyl group, whereas glucuronidation was less specific and, in addition to the preferred 14‐hydroxyl group, involved the 16‐ and 7‐hydroxyl groups. Using the Caco‐2 Millicell^® system, an efficient transfer of the glucuronides and sulfates of ZEN and α‐ZAL and their phase I metabolites into both the basolateral and the apical compartment was observed after apical administration. The apparent permeability coefficients (P_app values) of ZEN, α‐ZAL and the ZEN metabolite α‐zearalenol were determined, using an initial apical concentration of 20 μM and a permeation time of 1 h. Conclusion: According to the P_app values, the three compounds are expected to be extensively and rapidly absorbed from the intestinal lumen in vivo and reach the portal blood both as aglycones and as glucuronide and sulfate conjugates in humans.