Revisiting Proteasome Inhibitors: Molecular Underpinnings of Their Development,Mechanisms of Resistance and Strategies to Overcome Anti-Cancer Drug Resistance

Proteasome inhibitors have shown relevant clinical activity in several hematological malignancies, namely in multiple myeloma and mantle cell lymphoma, improving patient outcomes such as survival and quality of life, when compared with other therapies. However, initial response to the therapy is a challenge as most patients show an innate resistance to proteasome inhibitors, and those that respond to the therapy usually develop late relapses suggesting the development of acquired resistance. The mechanisms of resistance to proteasome inhibition are still controversial and scarce in the literature. In this review, we discuss the development of proteasome inhibitors and the mechanisms of innate and acquired resistance to their activity—a major challenge in preclinical and clinical therapeutics. An improved understanding of these mechanisms is crucial to guiding the design of new and more effective drugs to tackle these devastating diseases. In addition, we provide a comprehensive overview of proteasome inhibitors used in combination with other chemotherapeutic agents, as this is a key strategy to combat resistance.     

Simulation of Organic Liquid Product Deoxygenation through Multistage Countercurrent Absorber/Stripping Using CO2 as Solvent with Aspen-HYSYS: Process Modeling and Simulation

In this work, the deoxygenation of organic liquid products (OLP) obtained through the thermal catalytic cracking of palm oil at 450 °C, 1.0 atmosphere, with 10% (wt.) Na₂CO₃ as a catalyst, in multistage countercurrent absorber columns using supercritical carbon dioxide (SC-CO₂) as a solvent, with an Aspen-HYSYS process simulator, was systematically investigated. In a previous study, the thermodynamic data basis and EOS modeling necessary to simulate the deoxygenation of OLP was presented. This work addresses a new flowsheet, consisting of 03 absorber columns, 10 expansions valves, 10 flash drums, 08 heat exchanges, 01 pressure pump, and 02 make-ups of CO₂, aiming to improve the deacidification of OLP. The simulation was performed at 333 K, 140 bar, and (S/F) = 17; 350 K, 140 bar, and (S/F) = 38; 333 K, 140 bar, and (S/F) = 25. The simulation shows that 81.49% of OLP could be recovered and that the concentrations of hydrocarbons in the extracts of absorber-01 and absorber-02 were 96.95 and 92.78% (wt.) on a solvent-free basis, while the bottom stream of absorber-03 was enriched in oxygenated compounds with concentrations of up to 32.66% (wt.) on a solvent-free basis, showing that the organic liquid products (OLP) were deacidified and SC-CO₂ was able to deacidify the OLP and obtain fractions with lower olefin contents. The best deacidifying condition was obtained at 333 K, 140 bar, and (S/F) = 17.     

Physical Adsorption of H2S Related to the Conservation of Works of Art: The Role of the Pore Structure at Low Relative Pressure

The adsorption isotherms of H₂S in selected adsorbents were determined at 298 K, at relative pressures up to about 0.005, aiming the use of these materials in the removal of that pollutant from the museums atmosphere. The Dubinin-Astakhov equation adjusts very well the experimental results, although one cannot interpret the pre-exponential factor w₀ as the limiting adsorbed amount. The parameter E, related with the adsorption energy, and the parameter n, that can be associated with the surface heterogeneity of the adsorbents, are correlated and the first is also correlated with the adsorbed amounts. It was not found any expectable relationship between the adsorbed amounts and textural parameters of the adsorbents such as the specific surface area or the microporous volume. This points out that the adsorption of H₂S is highly specific. In general, 13X and Y sodium zeolites seem to be the most effective adsorbents, but at lowest tested pressures, near the concentrations found at museums, a pillared clay prepared from a Wyoming montmorillonite seems to be more efficient.     

Spectrometric and theoretical investigation of the structures of Cu and Pb/DTPA complexes

Spectrometric and theoretical tools have been employed in this study in order to elucidate the structures of DTPA (diethylenetriaminepentaacetic acid) complexed to copper and lead. Mass spectrometry allowed determining the 1:1 stoichiometry of metal:ligand, while infrared spectroscopy demonstrated that both N and O are sites for complexation. ¹³C NMR analysis showed the existence of free and complexed carboxyl groups, due to a straight singlet at 180.7 ppm (free carboxylic ¹³C) and to a broad signal at 179.3 ppm (complexed carboxylic ¹³C, ² J _Pb…O=C). A distorted NMR signal were observed for the Cu–DTPA carboxyl group, due to the Cu²⁺ paramagnetism. Based on the spectrometric evidences for the metal–DTPA structures, DFT optimizations were carried out and an octahedral-like arrangement for the Cu complex and a “shell-like” arrangement for the Pb complex, both hexa-coordinated, were then proposed for the structures of the titled compounds.

The adsorption of lysozymes: A model system

Hen egg white lysozyme was adsorbed onto clean borosilicate glass and n-pentyl silane-treated glass surfaces. Both modified (reductively methylated) and native lysozyme were studied. Variable angle X-ray photoelectron spectroscopy (VA-XPS) suggested differences in the nature of the adsorbed layer depending on substrate properties, as well as on degree of methylation of the protein. Adsorbed film thickness (as measured in the dehydrated state by XPS) ranged from 14 Å on hydrophilic glass to 25 Å on the hydrophobic surface. Degree of surface coverage ranged from 45% on the hydrophobic to 69% on the hydrophilic surface. The results suggest that lysozyme unfolds to a greater extent and covers more surface on the hydrophilic glass, possibly due to strong electrostatic interactions at the pH 7.4 conditions used in the study. An analysis of the surface structure of native hen lysozyme by molecular graphics has also been performed, suggesting that adsorption on hydrophobic surfaces should occur via the hydrophobic patch opposite the enzyme active site cleft. A comparison with human lysozyme has also been made using total internal reflection fluorescence (TIRF) spectroscopy to measure protein adsorption on model surfaces. The two proteins have significantly different interfacial properties.     

Study of Blood Porphyrin Spectral Profile for Diagnosis of Chronic Renal Failure

The progression to end-stage renal failure is independent of the initial pathogenic mechanism. Metabolic acidosis is a common consequence of chronic renal failure that results from inadequate ammonium excretion and decreased tubular bicarbonate reabsorption. Protoporphyrin IX (PpIX) is the immediate metabolic precursor of the heme molecule. The purpose of this study was to evaluate the levels of erythrocytes protoporphyrin IX at an animal model during progressive renal disease. A total of 36 eight-week-old male Wistar rats were divided into six groups: Normal, 4 and 8 weeks after 5/6 nephrectomy (NX). Renal function was evaluated by creatinine clearance and plasma creatinine levels. The autofluorescence of erythrocytes porphyrin of healthy and NX rats was analyzed using fluorescence spectroscopy. Emission spectra were obtained by exciting the samples at 405 nm. Significant differences between normal and NX rats autofluorescence shape occurred in the 600–700 nm spectral region. A correlation was observed between emission band intensity at 635 nm and progression of renal disease.     

The effect of power bleaching actived by several light sources on enamel microhardness

The purpose of this study was to evaluate the influence of different light sources for in-office bleaching on surface microhardness of human enamel. One hundred and five blocks of third molars were distributed among seven groups. The facial enamel surface of each block was polished and baseline Knoop microhardness of enamel was assessed with a load of 25 g for 5 s. Subsequently, the enamel was treated with 35% hydrogen peroxide bleaching agent and photo-activated with halogen light (group A) during 38 s, LED (group B) during 360 s, and high intensity diode laser (group C) during 4 s. The groups D (38 s), E (360 s), and F (4 s) were treated with the bleaching agent without photo-activated. The control (group G) was only kept in saliva without any treatment. Microhardness was reassessed after 1 day of the bleaching treatment, and after 7 and 21 days storage in artificial saliva. The mean percentage and standard deviation of microhardness in Knoop Hardness Number were: A 97.8 ± 13.1 KHN; B 95.5 ± 12.7 KHN; C 84.2 ± 13.6 KHN; D 128.6 ± 20.5 KHN; E 133.9 ± 14.2 KHN; F 123.9 ± 14.2 KHN; G 129.8 ± 18.8 KHN. Statistical analysis (p < 0.05; Tukey test) showed that microhardness percentage values were significantly lower in the groups irradiated with light when compared with the non-irradiated groups. Furthermore, the non-irradiated groups showed that saliva was able to enhance the microhardness during the measurement times. The enamel microhardness was decreased when light sources were used during the bleaching process and the artificial saliva was able to increase microhardness when no light was used.     

Interaction of Candida parapsilosis isolates with human hair and nail surfaces revealed by scanning electron microscopy analysis

Candida parapsilosis is found frequently as commensal organism on epithelial tissues, and is also an increasing cause of nosocomial infection. Scanning electron microscope (SEM) observations were used to analyse the capability of C. parapsilosis cells to adhere and grow as biofilm on human natural substrates and to compare the adherence pattern of isolates exhibiting distinct phenotypes. Cells from the crepe phenotype are predominantly elongated and form pseudohyphae whereas cells from the smooth phenotype are yeast-shaped, either in liquid cultures or on human nail and hair surfaces. The electron micrographs revealed that C. parapsilosis cells from the smooth phenotype adhered in higher number to both surfaces compared to the observed for the crepe phenotype. SEM analysis of human hair surface revealed that cells from the smooth phenotype appear as clumped blastoconidia of uniform morphology embedded in a flocculent extracellular material forming biofilm. The extracellular material and biofilm were seeing in a less extension in the crepe phenotype. A distinct adherence pattern was observed when human nail was used as substrate. Here C. parapsilosis cells seem to be linked to surface structures of human nail plate. Fibrillar extracellular material was observed connecting neighbouring cells as well as nail surface.