Molecules that inhibit Aβ misfolding have received considerable attention in view of their potential use in the prevention or treatment of Alzheimer's disease. We designed a peptide‐porphyrin conjugate incorporating two recognition sites enabling it to interact strongly with the Aβ42 peptide. The inhibitory effect on Aβ42 fibril formation was determined in aqueous solution by a variety of spectroscopic techniques including UV‐vis, fluorescence, Circular Dichroism, Dynamic Light Scattering, Maldi‐Time of Flight‐Mass Spectrometry and Nuclear Magnetic Resonance Spectroscopy. A working mechanism of the antifibrillogenic action of the conjugate was proposed based on the experimental observations. The neuroprotective activity of the conjugate was also inferred by using primary neuronal or neuron‐like differentiated SH‐SY5Y cell cultures.
Inhibition of the initial stages of amyloid-β peptide self-assembly is a key approach in drug development for Alzheimer’s disease, in which soluble and highly neurotoxic low molecular weight oligomers are produced and aggregate in the brain over time. Here we report a high-throughput method based on ion mobility mass spectrometry and multivariate statistical analysis to rapidly select statistically significant early-stage species of amyloid-β1-40 whose formation is inhibited by a candidate theranostic agent. Using this method, we have confirmed the inhibition of a Zn-porphyrin-peptide conjugate in the early self-assembly of Aβ40 peptide. The MS/MS fragmentation patterns of the species detected in the samples containing the Zn-porphyrin-peptide conjugate suggested a porphyrin-catalyzed oxidation at Met-35(O) of Aβ40. We introduce ion mobility MS combined with multivariate statistics as a systematic approach to perform data analytics in drug discovery/amyloid research that aims at the evaluation of the inhibitory effect on the Aβ early assembly in vitro models at very low concentration levels of Aβ peptides.
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This study analyses the seasonal trend of polychlorinated biphenyls (PCB) concentrations in air and soil from a high-altitude mountain pasture in the Italian Alps. PCB concentrations in soil were generally comparable to background levels and were lower than those previously measured in the same area. Only CB-209 unexpectedly showed high concentrations with respect to the other congeners. GC-MS-MS identification was very clear, rising a new problem of increasing PCB contamination concerning only CB-209, which is not present in commercial mixtures used in the past in Italy and Europe. Considering all of the congeners, seasonal PCB trends were observed both in air and in soil that were related to the temperature and precipitation measured specifically in the study area. Highly significant relationships were found between the temperature-normalised concentrations in soil and the precipitation amounts. A north/south enrichment factor was present only in soil with rapid early summer revolatilisation kinetics from soil to air and autumn redeposition events from air to soil. Fugacity ratio calculations confirmed these trends. Surface soils respond rapidly to meteorological variables, while subsurface soils respond much more slowly. Seasonal trends were different for the northern and southern sides of the mountain. A detailed picture of the interactions among temperature, precipitation, mountain aspects and soil features was obtained.
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