1,721,190 research outputs found
An updated view of translocator protein (TSPO)
Full text linkDecades of study on the role of mitochondria in living cells have evidenced the importance of the 18 kDa mitochondrial translocator protein (TSPO), first discovered in the 1977 as an alternative binding site for the benzodiazepine diazepam in the kidneys. This protein participates in a variety of cellular functions, including cholesterol transport, steroid hormone synthesis, mitochondrial respiration, permeability transition pore opening, apoptosis, and cell proliferation. Thus, TSPO has become an extremely attractive subcellular target for the early detection of disease states that involve the overexpression of this protein and the selective mitochondrial drug delivery. This special issue was programmed with the aim of summarizing the latest findings about the role of TSPO in eukaryotic cells and as a potential subcellular target of diagnostics or therapeutics. A total of 9 papers have been accepted for publication in this issue, in particular, 2 reviews and 7 primary data manuscripts, overall describing the main advances in this field
Editorial: What does it take to cure the brain? Studies towards genes, proteins, processes, and rehabilitation
Full text linkEditorial on the Research Topic
What does it take to cure the brain? Studies toward genes, proteins,
processes, and rehabilitatio
A mechanistic and kinetic study of the beta-lactone hydrolysis of Salinosporamide A (NPI-0052), a novel proteasome inhibitor
No full textThe aim of the present study was to investigate the mechanism of aqueous degradation of Salinosporamide A (NPI-0052; 1), a potent proteasome inhibitor that is currently in Phase I clinical trials for the treatment of cancer and is characterized by a unique beta-lactone-gamma-lactam bicyclic ring structure. The degradation of 1 was monitored by HPLC and by both low- and high-resolution mass spectral analyses. Apparent first-order rate constants for the degradation at 25 degrees C were determined in aqueous buffer solutions (ionic strength 0.15 M adjusted with NaCl) at various pH values in the range of 1 to 9. Degradation kinetics in water and in deuterium oxide were compared as a mechanistic probe. The studies were performed at pH (pD) 4.5 at 25 degrees C. To further confirm the reaction mechanism, the degradation was also performed in O-18-enriched water and the degradation products subjected to HPLC separation prior to mass spectral analysis. Solubility and stability in (SBE)(7m)-beta-cyclodextrin (Captisol) solutions were also determined. The hydrolytic degradation of 1, followed by both HPLC and LC/MS, showed that the drug in aqueous solutions gives a species with a molecular ion consistent with the beta-lactone hydrolysis product (NPI-2054; 2). This initial degradant further rearranges to a cyclic ether (NPI-2055; 3) via an intramolecular nucleophilic displacement reaction. The kinetic results showed that the degradation of 1 was moderately buffer catalyzed (general base) and the rate constants were pH independent in the range of 1-5 and base dependent above pH 6.5. No acid catalysis was observed. The kinetic deuterium solvent isotope effect (KSIE) was 3.1 (k(H)/k(D)) and a linear proton inventory plot showed that the rate-determining step involved only a single proton transfer. This suggested that a neighboring hydroxyl group (as opposed to a second water molecule) facilitated water attack at pD 4.5. Mass spectral analysis from the O-18-labeling studies proved that the mechanism involves acyl-oxygen bond cleavage and not a carbonium ion mechanism. 1 is unstable in water (t(90%) <= 33 min at pH <5) and degrades via beta-lactone hydrolysis involving a normal ester hydrolysis mechanism (addition-elimination) resulting in acyl-oxygen bond cleavage. Captisol solubilized and stabilized 1 in aqueous solutions. (c) 2007 Wiley-Liss, Inc
Nanoformulations for drug delivery: safety, toxicity, and efficacy
No full textThis chapter presents an outline of the recent available information regarding safety, toxicity, and efficacy of nano drug delivery systems. Of particular importance is the evaluation of several key factors to design nontoxic and effective nanoformulations. Among them, we focus on nanostructure materials and synthesis methods, mechanisms of interactions with biological systems, treatment of nanoparticles, manufacture impurities, and nanostability. Emphasis is given to in silico, in vitro, and in vivo models used to assess and predict the toxicity of these new formulations. Additionally, some examples of in vitro and in vivo studies of specific nanoderivatives are also presented in this chapter
Mucoadhesive nanoparticles of Eudragit RS 100/cyclodextrin intended for transmucosal routes for peptides
No full textSynthesis and biological evaluation of some peripheral benzodiazepine receptor ligand-cytarabine conjugates for delivery to human lymphoma cell lines
No full textDetermination of pKa and Hydration Constants for a Series of α-Keto-Carboxylic Acids Using Nuclear Magnetic Resonance Spectrometry
Full text linkThe determination of the acid-base dissociation constants, and thus the pKa values, of α-keto acids such as pyruvic acid is complex because of the existence of these acids in their hydrated and nonhydrated or oxo state. Equilibria involved in the hydration and dehydration of the α-keto group of pyruvic acid and three other α-keto acids, 3-methyl-2-oxobutanoic acid, 4-methyl-2-oxopentanoic acid, and 2-oxo-2-phenylacetic acid, were investigated by proton and carbon nuclear magnetic resonance spectrometry, at constant ionic strength, 0.15, and 25°C. Dissociation constants for the oxo (pKaoxo) and hydrated (pKahyd) acids of each compound were estimated from the change in the degree of hydration with changes in pH and directly from the changes in chemical shifts of various hydrogen and carbons nuclei with pH. α-Keto acids showed greater hydration in their acidic forms than their carboxylate forms. The degree of hydration was sensitive to steric and electronic/resonance factors. As expected, the oxo forms of the acids were stronger acids compared with their hydrated analogs, and their dissociation constants were also sensitive to steric and electronic factors
A mechanistic and kinetic study of the β-lactone hydrolysis of Salinosporamide A (NPI-0052), a novel proteasome inhibitor
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