59 research outputs found
The mechanisms of humic substances self-assembly with biological molecules: The case study of the prion protein
Humic substances (HS) are the largest constituent of soil organic matter and are considered as a key component of the terrestrial ecosystem. HS may facilitate the transport of organic and inorganic molecules, as well as the sorption interactions with environmentally relevant proteins such as prions. Prions enter the environment through shedding from live hosts, facilitating a sustained incidence of animal prion diseases such as Chronic Wasting Disease and scrapie in cervid and ovine populations, respectively. Changes in prion structure upon environmental exposure may be significant as they can affect prion infectivity and disease pathology. Despite its relevance, the mechanisms of prion interaction with HS are still not completely understood. The goal of this work is to advance a structural-level picture of the encapsulation of recombinant, non-infectious, prion protein (PrP) into different natural HS. We observed that PrP precipitation upon addition of HS is mainly driven by a mechanism of âsalting-outâ whereby PrP molecules are rapidly removed from the solution and aggregate in insoluble adducts with humic molecules. Importantly, this process does not alter the protein folding since insoluble PrP retains its α-helical content when in complex with HS. The observed ability of HS to promote PrP insolubilization without altering its secondary structure may have potential relevance in the context of âprion ecologyâ. These results suggest that soil organic matter interacts with prions possibly without altering the protein structures. This may facilitate prions preservation from biotic and abiotic degradation leading to their accumulation in the environment
Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease
BACKGROUND:
The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease.
METHODS:
In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina.
RESULTS:
At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91).
CONCLUSIONS:
Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .)
Aggregation and disaggregation of humic supramolecular assemblies by NMR diffusion ordered spectroscopy (DOSY-NMR)
Diffusion ordered nuclear magnetic resonance spectroscopy
(DOSY-NMR) was applied to a number of fulvic (FA) and humic
(HA) acids of different origin. Spectral separation achieved
by DOSY based on diffusion coefficients (D), and correlated to
molecular sizes by calibration standards, showed that
carbohydrates had the largest molecular size in FA, whereas
alkyl or aromatic components were the most slowly diffusing
moieties in HA. At increasing concentrations, these components
had invariably lower D values in DOSY spectra for all humic
samples, thereby indicating an aggregation into apparently larger
associations, whose increased hydrodynamic radius was
confirmed by viscosity measurements. When humic solutions
werebroughtfromalkalinetoacidicpH(3.6),componentsdiffusivity
detected by DOSY increased significantly, suggesting a
decreaseofaggregationandmolecularsize.Ageneralcomparison
of HA and FA molecular sizes was achieved by multivariate
statistical analysis. While a larger extent of aggregation and
disaggregation was observed for HA than for FA, no aggregation
wasdetected,undersimilar conditions, foratruemacropolymeric
standard. Such difference in diffusion between a polymeric
molecule and humic samples, is in line with the supramolecular
nature of humic matter. The possible formation of humic
micelles was also investigated by both changes of diffusivity
in DOSY spectra and shift of 1H NMR signals. Except for HA of
peat and soil origin, revealing a self-assembling in micellelike
structures at the 4 mg mL-1 concentration, no other humic
sample showed evidence of critical micelle concentration
(cmc) up to 20 mg mL-1. These results indicated that DOSYNMRspectroscopy
is a useful technique to evaluate components
of different molecular size in natural humic superstructures
High-power gradient diffusion NMR spectroscopy for the rapid assessment of extra-virgin olive oil adulteration
Host-Guest Interactions between 2,4-Dichlorophenol and Humic Substances As Evaluated by H-1 NMR Relaxation and Diffusion Ordered Spectroscopy
Rates of oxidative coupling of humic phenolic monomers catalyzed by a biomimetic iron-porphyrin
Enhanced Molecular Dimension of a Humic Acid Induced by Photooxidation Catalyzed by Biomimetic Metalporphyrins
Oligomerization of Humic Phenolic Monomers by Oxidative Coupling under Biomimetic Catalysis
Three humic phenolic monomers, catechol (CAT), caffeic
acid (CAFF), and p-coumaric acid (COUM), were subjected
to oxidative coupling catalyzed by biomimetic watersoluble
iron-porphyrin (Fe(TDCPPS)Cl) in either separate
or mixed solution, and the reaction products were
characterized by gas chromatography-mass spectrometry
(GC-MS) and electrospray-mass spectrometry (ESIMS).
The GC-MS analysis proved the formation of C-C
and C-O dimers, whereas the ESI-MS/MS analysis also
suggested trimerization for all the monomers and
tetramerization for CAT. On the basis of mass spectra,
molecular structures were assigned to the observed oligomers.
In the phenolic separate solutions, dimers represented
about 65%, 44%, and 30% of reaction products for CAT, CAFF,
and COUM, respectively, whereas trimers were from 4
to 5%. A relevant part of the products were unidentified
oligomers and several degradation compounds, mostly
aromatic aldehydes and alcohols and aromatic or aliphatic
carboxylic acids. When all three humic phenolic monomers
underwent the catalyzed coupling reaction in one mixed
solution, 14% of the reaction products were identified as
C-C dimers of CAT. Although no other C-O dimers of CAT,
nor any dimers of COUM and CAFF, could be identified,
some other structurally unknown oligomers were present
among the reaction products of the mixed solution.
However, no oligomers larger than tetramers were formed
in either separate or mixed solutions. This work indicates
the essential role of biomimetic metal-porphyrins in
catalyzing the oxidative coupling of humic phenolic monomers
in aqueous media, thereby promoting the polymerization
of natural organic matter
Molecular changes occurring during micro-oxygenation of an aglianico red wine as observed by NMR spectroscopy
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