Design, synthesis and structure-activity evaluation of novel 2-pyridone-based inhibitors of a-synuclein aggregation with potentially improved BBB permeability

The treatment of Parkinson''s disease (PD), the second most common neurodegenerative human disorder, continues to be symptomatic. Development of drugs able to stop or at least slowdown PD progression would benefit several million people worldwide. SynuClean-D is a low molecular weight 2-pyridone-based promising drug candidate that inhibits the aggregation of a-synuclein in human cultured cells and prevents degeneration of dopaminergic neurons in a Caenorhabditis elegans model of PD. Improving SynuClean-D pharmacokinetic/pharmacodynamic properties, performing structure/activity studies and testing its efficacy in mammalian models of PD requires the use of gr-amounts of the compound. However, not enough compound is on sale, and no synthetic route has been reported until now, which hampers the molecule progress towards clinical trials. To circumvent those problems, we describe here an efficient and economical route that enables the synthesis of SynuClean-D with good yields as well as the synthesis of SynuClean-D derivatives. Structure-activity comparison of the new compounds with SynuClean-D reveals the functional groups of the molecule that can be disposed of without activity loss and those that are crucial to interfere with a-synuclein aggregation. Several of the derivatives obtained retain the parent''s compound excellent in vitro anti-aggregative activity, without compromising its low toxicity. Computational predictions and preliminary testing indicate that the blood brain barrier (BBB) permeability of SynuClean-D is low. Importantly, several of the newly designed and obtained active derivatives are predicted to display good BBB permeability. The synthetic route developed here will facilitate their synthesis for BBB permeability determination and for efficacy testing in mammalian models of PD. © 2021 The Author

Photo-acclimatory thresholds anticipate sudden shifts in seagrass ecosystem state under reduced light conditions

Seagrass ecosystems usually respond in a nonlinear fashion to increasing pressures and environmental changes. Feedback mechanisms operating at the ecosystem level and involving multiple interactions among the seagrass meadow, its associated community and the physical environment are known to play a major role in such nonlinear responses. Phenotypic plasticity may also be important for buffering these ecological thresholds (i.e., regime shifts) as many physiological processes show nonlinear responses to gradual environmental changes, conferring the appearance of resistance before the effects at the organism and population levels are visible. However, the potential involvement of plant plasticity in driving catastrophic shifts in seagrass ecosystems has not yet been assessed. In this study, we conducted a manipulative 6-month light-gradient experiment in the field to capture nonlinearities of the physiological and population responses of the seagrass Cymodocea nodosa to gradual light reduction. The aim was to explore if and how the photo-acclimatory responses of shaded plants are translated to the population level and, hence, to the ecosystem level. Results showed that the seagrass population was rather stable under increasing shading levels through the activation of multilevel photo-acclimative responses, which are initiated with light reduction and modulated in proportion to shading intensity. The activation of photo-physiological and metabolic compensatory responses allowed shaded plants to sustain nearly constant plant productivity (metabolic carbon balance) along a range of shading levels before losing linearity and starting to decline. The species then activated plant- and meadow-scale photo-acclimative responses and drew on its energy reserves (rhizome carbohydrates) to confer additional population resilience. However, when the integration of all these buffering mechanisms failed to counterbalance the effects of extreme light limitation, the population collapsed, giving place to a phase shift from vegetated to bare sediments with catastrophic ecosystem outcomes. Our findings evidence that ecological thresholds in seagrass ecosystems under light limitation can be explained by the role of species’ compensatory responses in modulating population-level responses. The thresholds of these plastic responses anticipate the sudden loss of seagrass meadows with the potential to be used as early warning indicators signalling the imminent collapse of the ecosystem, which is of great value for the real-world management of seagrass ecosystems.En prens

Selective targeting of human and animal pathogens of the helicobacter genus by flavodoxin inhibitors: Efficacy, synergy, resistance and mechanistic studies

Antimicrobial resistant (AMR) bacteria constitute a global health concern. Helicobacter py-lori is a Gram-negative bacterium that infects about half of the human population and is a major cause of peptic ulcer disease and gastric cancer. Increasing resistance to triple and quadruple H. pylori eradication therapies poses great challenges and urges the development of novel, ideally narrow spectrum, antimicrobials targeting H. pylori. Here, we describe the antimicrobial spectrum of a family of nitrobenzoxadiazol-based antimicrobials initially discovered as inhibitors of flavodoxin: an essential H. pylori protein. Two groups of inhibitors are described. One group is formed by nar-row-spectrum compounds, highly specific for H. pylori, but ineffective against enterohepatic Helico-bacter species and other Gram-negative or Gram-positive bacteria. The second group includes ex-tended-spectrum antimicrobials additionally targeting Gram-positive bacteria, the Gram-negative Campylobacter jejuni, and most Helicobacter species, but not affecting other Gram-negative pathogens. To identify the binding site of the inhibitors in the flavodoxin structure, several H. pylori-flavodoxin variants have been engineered and tested using isothermal titration calorimetry. An initial study of the inhibitors capacity to generate resistances and of their synergism with antimicrobials commonly used in H. pylori eradication therapies is described. The narrow-spectrum inhibitors, which are ex-pected to affect the microbiota less dramatically than current antimicrobial drugs, offer an oppor-tunity to develop new and specific H. pylori eradication combinations to deal with AMR in H. pylori. On the other hand, the extended-spectrum inhibitors constitute a new family of promising antimi-crobials, with a potential use against AMR Gram-positive bacterial pathogens. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Conocimiento objetivo y subjetivo de los consumidores españoles sobre el pescado

Product knowledge has been recognised as an important factor influencing consumer decision making. The aim of this study was to assess Spanish consumers’ knowledge about fish as well as their relationship with certain socio-demographic characteristics. Objective and subjective knowledge were measured by means of 5 and 4 items respectively. Overall results revealed the existence of a certain lack of knowledge about fish, although some differences were observed depending on gender, age, education level, region of residence and growing up region (coastal or interior). A positive relationship between objective and subjective knowledge was also detected

Re-examining the role of the gut microbiota in the conversion of the lipid-lowering statin monacolin K (lovastatin) into its active β-hydroxy acid metabolite

Monacolin K (MK, lovastatin), a naturally occurring statin, only exerts lipid-lowering effects in its active β-hydroxy acid form (MKA). This activation was thought to be mediated by the gut microbiota (GM). We report here for the first time that the GM does not convert MK into MKA (a spontaneous pH-dependent conversion) but catabolises MKA. The GM might hamper the lipid-lowering effects by degrading the active metabolite MKA.The research reported in this article has been supported by the Project AGL2015-73744-JIN (MINECO, Spain).We acknowledge support of the publication fee by the CSIC Open Access Support Initiative through its Unit of Information Resources for Research (URICI

NMR Spectroscopic Identification of Urolithin G, a Novel Trihydroxy Urolithin Produced by Human Intestinal Enterocloster Species. Supporting Information

Figure S1. 1H NMR spectra of urolithin D, urolithin C, urolithin M7, urolithin G, urolithin A, and isourolithin A in AcN-d3 and in DMSO-d6. *Signals from hydroxyl protons; Figure S2. 13C NMR spectrum (zoom from d = 110–115 ppm) of urolithin G in AcN-d3 and DMSO-d6. C2 and C7 were clearly separated in AcN-d3, while they appeared very close in the DMSO-d6 spectrumPeer reviewe