A pro-inflammatory intestinal microbiome is characteristic of Parkinson's disease (PD). Prebiotic fibers change the microbiome and this study sought to understand the utility of prebiotic fibers for ...use in PD patients. The first experiments demonstrate that fermentation of PD patient stool with prebiotic fibers increased the production of beneficial metabolites (short chain fatty acids, SCFA) and changed the microbiota demonstrating the capacity of PD microbiota to respond favorably to prebiotics. Subsequently, an open-label, non-randomized study was conducted in newly diagnosed, non-medicated (n = 10) and treated PD participants (n = 10) wherein the impact of 10 days of prebiotic intervention was evaluated. Outcomes demonstrate that the prebiotic intervention was well tolerated (primary outcome) and safe (secondary outcome) in PD participants and was associated with beneficial biological changes in the microbiota, SCFA, inflammation, and neurofilament light chain. Exploratory analyses indicate effects on clinically relevant outcomes. This proof-of-concept study offers the scientific rationale for placebo-controlled trials using prebiotic fibers in PD patients. ClinicalTrials.gov Identifier: NCT04512599.
A series of syringaldehyde imines with para-substituted anilines have been synthesized in a good yield, and their crystal structures have been analyzed. The orientation of the syringaldehyde hydroxyl ...group plays in important role in the intermolecular hydrogen-bonding pattern of the molecules. The O–H…N hydrogen bonding interactions primarily determine the three-dimensional packing of the molecules, even though they make up a relatively small percentage of intermolecular interactions in the molecules. The three structures with the p-hydroxy group cis to the imine group give hydrogen-bonded zigzag chains in the monoclinic crystals, while the structure with a trans hydroxy group crystallize in a hexagonal space group (R3¯) and form hydrogen-bonded hexamers. The hexagonal structure also displays Br…Br interactions, forming additional hexameric clusters. The analysis of published p-hydroxyphenyl imine crystal structures from the Cambridge Crystallographic Database revealed patterns in the length of the hydrogen bonding interactions based on steric congestion around the hydroxyl group.
Alzheimer's disease (AD) is a devastating neurological disorder for which soluble oligomers of the peptide amyloid-β (Aβ) are now recognized as the neurotoxic species. Metal-based therapeutics are ...uniquely suited to target Aβ, with ruthenium-based (Ru) complexes emerging as propitious candidates. Recently, azole-based Ru(III) complexes were observed to modulate the aggregation of Aβ in solution, where the inclusion of a primary amine proximal to the ligand coordination site improved the activity of the complexes. To advance these structure-activity relationships, a series of oxazole-based Ru complexes were prepared and evaluated for their ability to modulate Aβ aggregation. From these studies, a lead candidate,
, emerged that had superior activity relative to its azole predecessors in modulating the aggregation of soluble Aβ and diminishing its cytotoxicity. Further evaluation of
demonstrated its ability to disrupt formed Aβ aggregates, resulting in smaller amorphous species. Because altering both sides of the aggregation equilibrium for Aβ has not been previously suggested for metal-based complexes for AD, this work represents an exciting new avenue for improved therapeutic success.
Treatment of β-hydroxy-α-p-methoxyphenoxy carboxylic acids derived from the asymmetric glycolate aldol addition reaction with p-nitrobenzenesulfonyl chloride yielded divergent results depending on ...the nature of the β-substituent of the carboxylic acid. Substrates bearing either alkyl substituents (R = -n-butyl, -n-octyl, -benzyl, isopropyl, -tert-butyl) or aryl systems bearing electron-withdrawing substituents (R = -p-C6H4Cl, -p-C6H4Br, -p-C6H4NO2) yielded β-lactones. In contrast, α-p-methoxyphenoxy-β-hydroxycarboxylic acids bearing electron-donating aryl groups or the sterically demanding 2-naphthyl group formed (Z)-alkenes.
Alzheimer's disease (AD) is the most common form of dementia, characterized by extracellular protein deposits, comprised primarily of the peptide amyloid-beta (Aβ), are a pathological indicator of ...the disease. Commonly known as Aβ plaques, these deposits contain a relatively high concentration of metals, making metallotherapeutics uniquely suited to target soluble Aβ, thereby limiting its aggregation and cytotoxicity. Ruthenium-based complexes are promising candidates for advancement, as the complex PMRU20 (2-aminothiazolium trans-RuCl4(2-aminothiazole)2) and several thiazole-based derivatives were found to prevent the aggregation of Aβ, with hydrogen-bonding functional groups improving their performance. Further investigation into the impact of the heteroatom in the azole ring on the activity of Ru complexes was achieved through the synthesis and evaluation of a small set of imidazole-based compounds. The ability of the complexes to prevent the aggregation of Aβ was determined where the same sample was subjected to analysis by three complementary methods: ThT fluorescence, dynamic light scattering (DLS), and transmission electron microscopy (TEM). It was found that hydrophobic interactions, along with hydrogen-bonding via the imidazole nitrogen heteroatom, promoted interactions with the Aβ peptide, thereby limiting its aggregation. Furthermore, it was found that having rapid and sequential exchange proved detrimental as it resulted in a decreased association with Aβ. These results highlight important considerations between a balance of intermolecular interactions and ligand exchange kinetics in the design of further therapeutic candidates.
Synopsis for Graphical Abstract.
The mechanism of action of ruthenium(III) therapeutics where ligand exchange precedes coordination to the amyloid-beta peptide via histidine imidazoles. Display omitted
•Aqueous ligand exchange is accelerated with electron donating substituents.•Coordination of the ruthenium(III) complexes to amyloid-beta via histidine imidazole.•The prepared ruthenium(III) complexes modulate the aggregation of amyloid-beta.•Hydrophobic ligand substitution improves inhibition of amyloid-beta aggregation.
Females of many species obtain benefits by mating polyandrously, and often prefer novel males over previous mates. However, how do females recognise previous mates, particularly in the face of ...cognitive constraints? Female crickets appear to have evolved a simple but effective solution: females imbue males with their own cuticular hydrocarbons (CHCs) at mating and utilise chemosensory self‐referencing to recognise recent mates. Female CHC profiles exhibited significant additive genetic variation, demonstrating that genetically unique chemical cues are available to support chemosensory self‐referencing. CHC profiles of males became more similar to those of females after mating, indicating physical transfer of CHCs between individuals during copulation. Experimental perfuming of males with female CHCs resulted in a female aversion to males bearing chemical cues similar to their own. Chemosensory self‐referencing, therefore, could be a widespread mechanism by which females increase the diversity of their mating partners.
Oxidopyrylium-alkene 5 + 2 cycloaddition conjugate addition cascade (C3) sequences are described. Intramolecular cycloadditions involving terminal alkenes, enals, and enones were investigated. ...Substrates with tethers of varying lengths delivered five- and six-membered carbocycles and heterocycles thus demonstrating the scope and limitation of the cycloaddition–conjugate addition cascade. Several experiments and theoretical calculations provide evidence for the proposed mechanistic pathway.
Unique reactivity of anti- and syn-acetoxypyranones was observed in oxidopyrylium-alkene 5 + 2 cycloadditions. The subtle interplay between the corresponding acetoxypyranone conformation and steric ...bulk of tertiary amine bases causes syn-acetoxypyranones to undergo 5 + 2 cycloaddition appreciably faster than anti-acetoxypyranones. Additionally, the efficiency of a cascade process that afforded a novel tetracyclic lactol was determined to be dependent on the relative stereochemistry of each diastereomer, the amine base utilized, and the addition of water.
The cobalt(III) complex, mer-Co(tpy)(phen)Cl(PF6)2, was synthesized via a one-pot synthesis and fully characterised; then utilised to photocatalytically produce hydrogen under acidic conditions.
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•A cobalt(III) complex, Co(tpy)(phen)Cl(PF6)2, was synthesized and characterized.•The crystal structure has a monoclinic crystal system with a C2/c space group.•The complex displayed good electrocatalytic and photocatalytic properties.•A turnover frequency of 3300 mmol H2 mol-1CAT min−1 was observed over a 3 h period.
Co(tpy)(phen)Cl(PF6)2•0.25CH3CN (where tpy = 2,2′;6′,2″-terpyridine and phen = 1,10-phenanthroline) was prepared from a one pot mixture involving stoichiometric quantities of tpy and phen. The structure of Co(tpy)(phen)Cl(PF6)2•0.25CH3CN was confirmed by elemental analysis, high resolution mass spectroscopy (HRMS), various spectroscopic analyses, and X-ray crystallography. Density functional theory calculations were also carried out. The crystal structure of Co(tpy)(phen)Cl(PF6)2•0.25CH3CN, which was grown from acetonitrile, revealed a monoclinic crystal system with a C2/c space group. The cyclic voltammogram which was acquired in acetonitrile revealed reversible CoIII/II, CoII/I, and CoI/0 mixed with ligand-based redox couples at E½ = +0.35, –0.81, and –1.37 V (vs Ag/AgCl), respectively. In the presence of p-cyanoanillinium tetrafluoroborate with acetonitrile as the solvent, Co(tpy)(phen)Cl(PF6)2•0.25CH3CN displayed electrocatalytic hydrogen evolution activity at a 830 mV overpotential, as evidenced by a catalytic wave which was observed in the voltammogram, and by the detection of hydrogen in the headspace of the reaction vessel of a controlled potential electrolysis experiment. Photocatalytic hydrogen evolution studies with Co(tpy)(phen)Cl(PF6)2•0.25CH3CN produced a turnover frequency (TOF) of 3300 mmol H2 mol−1CAT min−1 when compared to Co(dmgH)2(py)Cl (where dmgH = dimethylglyoximato), which had a TOF of 4500 mmol H2.mol−1CAT min−1 under the same conditions. Co(tpy)(phen)Cl(PF6)2•0.25CH3CN produced a turnover number (TON) of 79 when compared to 141 for Co(dmgH)2Cl(py) in DMF in ca 3 h.
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