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This work demonstrates for the first time that binding of various compounds within subdomain IB of human serum albumin (HSA) provokes characteristic changes in the near-UV circular dichroism (CD) spectrum of the protein. It can be inferred from the spectroscopic features of difference ellipticity signals and from CD displacement experiments that tyrosine residues located in subdomain IB are the source of the observed spectral alterations. It is proposed that inclusion of some ligand molecules (bile acids, dehydroepiandrosterone sulfate, steroidal terpenes, fatty acids, ibuprofen, and gemfibrozil) into the pocket of subdomain IB disrupts the Tyr138-Tyr161 interhelical π-π stacking interaction, which is reflected in the CD spectrum. This phenomenon can be utilized for the CD detection of subdomain IB specific binding of endo- as well as exogenous agents and to study the drug binding associated local conformational adaptation of the HSA molecule. © 2013 American Chemical Society. Source

Du L.,CAS Institute of Chemistry | Huang S.,CAS Institute of Chemistry | Zhuang Q.,CAS Institute of Chemistry | Jia H.,CAS Institute of Chemistry | And 4 more authors.

The detection of free radicals and related species has attracted significant attention in recent years because of their critical roles in physiological and pathological processes. Among the methods for the detection of free radicals, electron spin resonance (ESR) coupled with the use of the spin trapping technique has been an effective approach for characterization and quantification of these species due to its high specificity. However, its application in biological systems, especially in in vivo systems, has been greatly limited partially due to the low reaction rate between the currently available spin traps with biological radicals. To overcome this drawback, we herein report the first example of nitrone functionalized gold nanoparticles (Au@EMPO) as highly efficient spin traps in which the thiolated EMPO (2-(ethoxycarbonyl)-2-methyl-3,4-dihydro-2H-pyrrole 1-oxide) derivative was self-assembled on gold nanoparticles. Kinetic studies showed that Au@EMPO has a 137-fold higher reaction rate constant with OH than PBN (N-tert-butyl-α- phenylnitrone). Owing to the high rate of trapping OH by Au@EMPO as well as the high stability of the resulting spin adduct (t1/2 ∼ 56 min), Au@EMPO affords 124-fold higher sensitivity for OH than EMPO. Thus, this new nanospin trap shows great potential in trapping the important radicals such as OH in various biological systems and provides a novel strategy to design spin traps with much improved properties. © 2013 The Royal Society of Chemistry. Source

Hoell A.,Helmholtz Center Berlin | Varga Z.,Institute of Molecular Pharmacology | Raghuwanshi V.S.,Humboldt University of Berlin | Krumrey M.,Physikalisch - Technische Bundesanstalt | And 2 more authors.
Journal of Applied Crystallography

The formation and growth of nanosized CaF2 crystallites by heat treatment of an oxyfluoride glass of composition 7.65Na2O-7.69K2O-10.58CaO-12.5CaF2-5. 77Al2O3-55.8SiO2 (wt%) was investigated using anomalous small-angle X-ray scattering (ASAXS). A recently developed vacuum version of the hybrid pixel detector Pilatus 1M was used for the ASAXS measurements below the Ca K-edge of 4038 eV down to 3800 eV. ASAXS investigation allows the determination of structural parameters such as size and size distribution of nanoparticles and characterizes the spatial distribution of the resonant element, Ca. The method reveals quantitatively that the growing CaF2 crystallites are surrounded by a shell of lower electron density. This depletion shell of growing thickness hinders and finally limits the growth of CaF2 crystallites. Moreover, in samples that were annealed for 10 h and more, additional very small heterogeneities (1.6 nm diameter) were found. © 2014 International Union of Crystallography. Source

Zsila F.,Institute of Molecular Pharmacology
Molecular Pharmaceutics

According to the conventional view, noncovalent association of small molecules with human serum albumin (HSA) occurs principally at the so-called Sudlow's sites located in subdomain IIA and IIIA. By employing a circular dichroism (CD) spectroscopic approach, it is shown that biliverdin is the specific CD label of an additional drug binding area in subdomain IB. CD competition experiments disclosed the entrapment of a diverse assortment of acidic, neutral, and basic molecules within subdomain IB including anticancer agents (camptothecin, doxorubicin, daunorubicin, teniposide, suramin, tyrosine kinase inhibitors), anticoagulants (dicoumarol), various steroids (bile acids, carbenoxolone), nonsteroidal antiinflammatory drugs, natural substances (aristolochic acid, glycyrrhetinic acid), and synthetic dyes (methyl orange, azocarmine B). These finding imply that subdomain IB can be considered as the third major drug binding region of HSA featured with promiscuous ligand recognition ability. Additionally, subdomain IB is allosterically coupled with the Sudlow's sites, the ligand binding of which is shown to alter the HSA binding mode and affinity of biliverdin and hemin. Brief case studies are presented to illustrate how the evaluation of spectral changes of tetrapyrrole CD probes gains new insight into the HSA binding properties of endogenous as well as pharmaceutical compounds. © 2013 American Chemical Society. Source

Heja L.,Institute of Molecular Pharmacology
Current Medicinal Chemistry

Although glial proliferation of the epileptic loci is recognized for more than a century in certain focal epilepsies, the role of astrocytes in epileptic conditions is receiving significant attention only in recent years. The present review will highlight current knowledge about the various ways astrocytes control neuronal excitability and contribute to genesis, maintenance and suppression of seizures. Besides the widely recognized astrocytic tasks like glutamate clearance, the role of gliotransmission, glutamate, GABA and ATP release as well as gap junctional communication will also be discussed along with the contribution of blood-brain barrier dysfunction, inflammatory pathways and alterations in mircoRNA expression profile to epilepsy. The mechanisms described will help to understand the astrocytic mechanisms contributing to the antiepileptic effect of existing anti-epileptic drugs (AEDs) and current therapeutic strategies and also signifies the potential of specific astrocyte-based AED development. © 2014 Bentham Science Publishers. Source

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