11 research outputs found
Structural Analysis of Human Serum Albumin in Complex with the Fibrate Drug Gemfibrozil
Gemfibrozil (GEM) is an orally administered lipid-regulating fibrate derivative drug sold under the brand name Lopid®, among others. Since its approval in the early 80s, GEM has been largely applied to treat hypertriglyceridemia and other disorders of lipid metabolism. Though generally well tolerated, GEM can alter the distribution and the free, active concentration of some co-administered drugs, leading to adverse effects. Most of them appear to be related to the ability of GEM to bind with high affinity human serum albumin (HSA), the major drug-carrier protein in blood plasma. Here, we report the crystal structure of HSA in complex with GEM. Two binding sites have been identified, namely Sudlow’s binding sites I (FA7) and II (FA3–FA4). A comparison of the crystal structure of HSA in complex with GEM with those of other previously described HSA–drug complexes enabled us to appreciate the analogies and differences in their respective binding modes. The elucidation of the molecular interaction between GEM and HSA might offer the basis for the development of novel GEM derivatives that can be safely and synergistically co-administered with other drugs, enabling augmented therapeutic efficacies
Covalent immobilization of delipidated human serum albumin on poly(pyrrole-2-carboxylic) acid film for the impedimetric detection of perfluorooctanoic acid
The immobilization of biomolecules at screen printed electrodes for biosensing applications is still an open challenge. To enrich the toolbox of bioelectrochemists, graphite screen printed electrodes (G-SPE) were modified with an electropolymerized film of pyrrole-2-carboxilic acid (Py-2-COOH), a pyrrole derivative rich in carboxylic acid functional groups. These functionalities are suitable for the covalent immobilization of biomolecular recognition layers. The electropolymerization was first optimized to obtain stable and conductive polymeric films, comparing two different electrolytes: sodium dodecyl sulphate (SDS) and sodium perchlorate. The G-SPE modified with Py-2-COOH in 0.1 M SDS solution showed the required properties and were further tested. A proof-of-concept study for the development of an impedimetric sensor for perfluorooctanoic acid (PFOA) was carried out using the delipidated human serum albumin (hSA) as bioreceptor. The data interpretation was supported by size exclusion chromatography and small-angle X-ray scattering (SEC-SAXS) analysis of the bioreceptor-target complex and the preliminary results suggest the possibility to further develop this biosensing strategy for toxicological and analytical studies
Nanocoated fiber label-free biosensing for perfluorooctanoic acid detection by lossy mode resonance
The determination of per- and polyfluoroalkyl substances (PFAS) in environmental samples, such as drinking
waters, requires the design of high performing and versatile sensing strategies. Label-free biosensing platforms
based on specialty fiber optics are a valid option to face this challenge. Among them, lossy mode resonance
(LMR) fiber optic biosensors are showing remarkable performance in terms of detection limit, selectivity, and
reproducibility. The detection of small molecules, such as perfluorooctanoic acid (PFOA), can be achieved with
the help of well-designed biological recognition layers. In this study, the biosensing potentialities of a label-free
LMR-assisted optical platform based on nanocoated fibers are investigated. Delipidated human serum albumin
(hSA) was used as biological recognition layer for PFOA in aqueous solution. Different fiber functionalization
protocols based on the covalent immobilization of hSA were tested. The conformational changes related to the
formation of hSA/PFOA complex were followed via optical monitoring of LMR spectral shift, showing a trend
that can be modeled with Langmuir adsorption isotherm. These results confirmed the potentiality of LMR-based
fiber biosensors for the detection of small molecules, such as PFOA, in synthetic samples
The Neogene-Quaternary geodynamic evolution of the central Calabrian Arc: A case study from the western Catanzaro Trough basin
Structural Analysis of Human Serum Albumin in Complex with the Fibrate Drug Gemfibrozil
Gemfibrozil (GEM) is an orally administered lipid-regulating fibrate derivative drug sold under the brand name Lopid®, among others. Since its approval in the early 80s, GEM has been largely applied to treat hypertriglyceridemia and other disorders of lipid metabolism. Though generally well tolerated, GEM can alter the distribution and the free, active concentration of some co-administered drugs, leading to adverse effects. Most of them appear to be related to the ability of GEM to bind with high affinity human serum albumin (HSA), the major drug-carrier protein in blood plasma. Here, we report the crystal structure of HSA in complex with GEM. Two binding sites have been identified, namely Sudlow’s binding sites I (FA7) and II (FA3–FA4). A comparison of the crystal structure of HSA in complex with GEM with those of other previously described HSA–drug complexes enabled us to appreciate the analogies and differences in their respective binding modes. The elucidation of the molecular interaction between GEM and HSA might offer the basis for the development of novel GEM derivatives that can be safely and synergistically co-administered with other drugs, enabling augmented therapeutic efficacies
Investigation of the Interaction between Human Serum Albumin and Branched Short-Chain Perfluoroalkyl Compounds
The current trend dealing with the production of per- and polyfluoroalkyl substances (PFASs) involves the shifting toward branched short-chain fluorinated compounds known as new-generation PFASs. A key aspect to be clarified, to address the adverse health effects associated with the exposure to PFASs, is their binding mode to human serum albumin (hSA), the most abundant protein in plasma. In this study, we investigated the interaction between hSA and two representative branched short-chain PFASs, namely, HPFO-DA and C6O4. In-solution studies revealed that both compounds bind hSA with affinities and stoichiometries lower than that of the legacy long-chain perfluoroalkyl compound PFOA. Competition experiments using hSA-binding drugs with known site-selectivity revealed that both HPFO-DA and C6O4 bound to pockets located in subdomain IIIA. The crystal structure of hSA in complex with HPFO-DA unveiled the presence of two binding sites. The characterization and direct comparison of hSA interactions with new-generation PFASs may be key elements for the understanding of the toxicological impact of these compounds
Anthracycline Metabolism and Toxicity in Human Myocardium: Comparisons between Doxorubicin, Epirubicin, and a Novel Disaccharide Analogue with a Reduced Level of Formation and [4Fe-4S] Reactivity of Its Secondary Alcohol Metabolite
Investigation of the Interaction between Human Serum Albumin and Branched Short-Chain Perfluoroalkyl Compounds
The current trend
dealing with the production of per- and polyfluoroalkyl
substances (PFASs) involves the shifting toward branched short-chain
fluorinated compounds known as new-generation PFASs. A key aspect
to be clarified, to address the adverse health effects associated
with the exposure to PFASs, is their binding mode to human serum albumin
(hSA), the most abundant protein in plasma. In this study, we investigated
the interaction between hSA and two representative branched short-chain
PFASs, namely, HPFO-DA and C6O4. In-solution studies revealed that
both compounds bind hSA with affinities and stoichiometries lower
than that of the legacy long-chain perfluoroalkyl compound PFOA. Competition
experiments using hSA-binding drugs with known site-selectivity revealed
that both HPFO-DA and C6O4 bound to pockets located in subdomain IIIA.
The crystal structure of hSA in complex with HPFO-DA unveiled the
presence of two binding sites. The characterization and direct comparison
of hSA interactions with new-generation PFASs may be key elements
for the understanding of the toxicological impact of these compounds
A database of the coseismic effects following the 30 October 2016 Norcia earthquake in Central Italy
We provide a database of the coseismic geological surface effects following the Mw 6.5 Norcia earthquake that hit central Italy on 30 October 2016. This was one of the strongest seismic events to occur in Europe in the past thirty years, causing complex surface ruptures over an area of >400 km2. The database originated from the collaboration of several European teams (Open EMERGEO Working Group; about 130 researchers) coordinated by the Istituto Nazionale di Geofisica e Vulcanologia. The observations were collected by performing detailed field surveys in the epicentral region in order to describe the geometry and kinematics of surface faulting, and subsequently of landslides and other secondary coseismic effects. The resulting database consists of homogeneous georeferenced records identifying 7323 observation points, each of which contains 18 numeric and string fields of relevant information. This database will impact future earthquake studies focused on modelling of the seismic processes in active extensional settings, updating probabilistic estimates of slip distribution, and assessing the hazard of surface faulting