Methodological Fallacies in the Determination of Serum/Plasma Glutathione Limit Its Translational Potential in Chronic Obstructive Pulmonary Disease

This study aimed to review and critically appraise the current methodological issues undermining the suitability of the measurement of serum/plasma glutathione, both in the total and reduced form, as a measure of systemic oxidative stress in chronic obstructive pulmonary disease (COPD). Fourteen relevant articles published between 2001 and 2020, in 2003 subjects, 1111 COPD patients, and 892 controls, were reviewed. Nine studies, in 902 COPD patients and 660 controls, measured glutathione (GSH) in the reduced form (rGSH), while the remaining five, in 209 COPD patients and 232 controls, measured total GSH (tGSH). In the control group, tGSH ranged between 5.7 and 7.5 µmol/L, whilst in COPD patients, it ranged between 4.5 and 7.4 µmol/L. The mean tGSH was 6.6 ± 0.9 µmol/L in controls and 5.9 ± 1.4 µmol/L in patients. The concentrations of rGSH in the control group showed a wide range, between 0.47 and 415 µmol/L, and a mean value of 71.9 ± 143.1 µmol/L. Similarly, the concentrations of rGSH in COPD patients ranged between 0.49 and 279 µmol/L, with a mean value of 49.9 ± 95.9 µmol/L. Pooled tGSH concentrations were not significantly different between patients and controls (standard mean difference (SMD) = −1.92, 95% CI −1582 to 0.0219; p = 0.057). Depending on whether the mean concentrations of rGSH in controls were within the accepted normal range of 0.5–5.0 µmol/L, pooled rGSH concentrations showed either a significant (SMD = −3.8, 95% CI −2.266 to −0.709; p < 0.0001) or nonsignificant (SMD = −0.712, 95% CI −0.627 to 0.293; p = 0.48) difference. These results illustrate the existing and largely unaddressed methodological issues in the interpretation of the serum/plasma concentrations of tGSH and rGSH in COPD.     

Rosmarinus officinalis L. Leaf Extracts and Their Metabolites Inhibit the Aryl Hydrocarbon Receptor (AhR) Activation In Vitro and in Human Keratinocytes: Potential Impact on Inflammatory Skin Diseases and Skin Cancer

Aryl hydrocarbon receptor (AhR) activation by environmental agents and microbial metabolites is potentially implicated in a series of skin diseases. Hence, it would be very important to identify natural compounds that could inhibit the AhR activation by ligands of microbial origin as 6-formylindolo[3,2-b]carbazole (FICZ), indirubin (IND) and pityriazepin (PZ) or the prototype ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Five different dry Rosmarinus officinalis L. extracts (ROEs) were assayed for their activities as antagonists of AhR ligand binding with guinea pig cytosol in the presence of [³H]TCDD. The methanolic ROE was further assayed towards CYP1A1 mRNA induction using RT-PCR in human keratinocytes against TCDD, FICZ, PZ, and IND. The isolated metabolites, carnosic acid, carnosol, 7-O-methyl-epi-rosmanol, 4′,7-O-dimethylapigenin, and betulinic acid, were assayed for their agonist and antagonist activity in the presence and absence of TCDD using the gel retardation assay (GRA). All assayed ROE extracts showed similar dose-dependent activities with almost complete inhibition of AhR activation by TCDD at 100 ppm. The methanol ROE at 10 ppm showed 99%, 50%, 90%, and 85% inhibition against TCDD, FICZ, IND, and PZ, respectively, in human keratinocytes. Most assayed metabolites exhibited dose-dependent antagonist activity. ROEs inhibit AhR activation by TCDD and by the Malassezia metabolites FICZ, PZ, and IND. Hence, ROE could be useful for the prevention or treatment of skin diseases mediated by activation of AhR.     

Novel Substituted Purine Isosteres: Synthesis,Structure-Activity Relationships and Cytotoxic Activity Evaluation

A number of pyrrolo[2,3-c]pyridines, pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]pyrimidines were designed and synthesized as antiproliferative agents. The target compounds possessed selected substituents in analogous positions on the central scaffold that allowed the extraction of interesting SARs. The cytotoxic activity of the new derivatives was evaluated against prostatic (PC-3) and colon (HCT116) cell lines, and the most potent analogues showed IC₅₀ values in the nM to low µM range, while they were found to be non-toxic against normal human fibroblasts (WI-38). Flow cytometric analysis of DNA content revealed that the most promising derivative 14b caused a statistically significant accumulation of PC-3 cells at G₂/M phase and induced apoptosis in PC-3 cells.     

Protein adsorption on the mesoporous molecular sieve silicate SBA-15: effects of pH and pore size

A mesoporous molecular sieve silicate, SBA-15, with three pore sizes (38.1 A, 77.3 A, and 240 A) has been synthesized using a non-ionic, tri-block copolymer as a template in a sol-gel method. The effects of synthesis conditions on the pore size and pore-size distribution of this adsorbent have been described. The adsorption of proteins on these crystalline, ordered, materials has been studied. The kinetics of adsorption and equilibrium capacity have been probed with three proteins of different dimensions. The effects of electrostatic interactions and protein size are illustrated. It has been shown that SBA-15 materials can be tailored to show size selectivity for proteins, and very high capacities (450 mg/g) can be obtained. Furthermore, the rates of adsorption are shown to be dependent on the pore size, protein structure and solution pH.     

Organic-Inorganic Sol-Gel Hybrids with Ionic Properties

Summary.  A hybrid silicon precursor (ICS-PPG) obtained by reaction of 3-isocyanatopropyltriethoxy silane with poly-(propyleneglycol)-bis-(2-aminopropyl ether) was recognized as a potential host for various salts and molecular species. It has been used for electrochromic, gasochromic, photovoltaic, and fuel cell applications. This focuses on proton conducting gels (PWA/ICS-PPG, SiWA/ICS-PPG, and W-PTA/ICS-PPG) obtained after the incorporation of polyoxometalates in the ICS-PPG host. IR spectroscopic measurements are used to reveal the entrapment, the aggregation, and the interactions of W-PTA, PWA, or SiWA with the sol-gel derived network. The proton conductivity of the composites, measured using impedance spectroscopy, increases with increasing concentration of the polyoxometalates from 10⁻⁶ to 10⁻³ S/cm. Received June 23, 2000. Accepted (revised) September 18, 2000     

Lecithin organogels used as bioactive compounds carriers. A microdomain properties investigation

Organogels were obtained by adding small amounts of water to a solution of lecithin in organic solvents. Either isooctane or isopropyl palmitate and isopropyl myristate were used as the continuous organic phase of the gels. EPR spectroscopy using both DSA membrane-sensitive and lipophilic spin probes was applied to define the dynamic structure of the surfactant monolayer and the continuous oil phase of lecithin organogels. It was found that by increasing the water quantity, an increase of the polar head area per lecithin molecule was induced, and as a consequence the total interface expanded. It was found that the use of esters as organic solvents induced a decrease of the size of the dispersed structures. The interconnection of the aqueous microdomains and their dynamics were monitored by both static and time-resolved fluorescence quenching spectroscopy using Ru(bipy)32+ as fluorophore and Fe(CN)63- as quencher. It was found that the rates of inter- and/or intra-micellar exchange of water molecules were very slow because they appeared quite immobilized close to the lecithin polar heads. According to the results of the dynamic studies, appropriate organogels were formulated and used to incorporate model bioactive compounds with medicinal or cosmetic interest such as caffeine and theophylline. When these systems were tested for trans-membrane diffusion, they showed a 24 h permeation of 20% and 35%, respectively.     

Discovery of 5-Methylthiazole-Thiazolidinone Conjugates as Potential Anti-Inflammatory Agents: Molecular Target Identification and In Silico Studies

A series of previously synthesized 5-benzyliden-2-(5-methylthiazole-2-ylimino)thiazoli- din-4-one were evaluated for their anti-inflammatory activity on the basis of PASS predictive outcomes. The predictive compounds were found to demonstrate moderate to good anti-inflammatory activity, and some of them displayed better activity than indomethacin used as the reference drug. Structure–activity relationships revealed that the activity of compounds depends not only on the nature of the substituent but also on its position in the benzene ring. The most active compounds were selected to investigate their possible mechanism of action. COX and LOX activity were determined and found that the title compounds were active only to COX-1 enzymes with an inhibitory effect superior to the reference drug naproxen. As for LOX inhibitory activity, the derivatives failed to show remarkable LOX inhibition. Therefore, COX-1 has been identified as the main molecular target for the anti-inflammatory activity of our compounds. The docking study against COX-1 active site revealed that the residue Arg 120 was found to be responsible for activity. In summary, the 5-thiazol-based thiazolidinone derivatives have been identified as a novel class of selective COX-1 inhibitors.     

A classification of isometry groups of homogeneous 3‐manifolds

We classify pairs where M is a 3‐dimensional simply connected smooth manifold and G a Lie group acting on M transitively, effectively with compact isotropy group.