EAPB0503, an Imidazoquinoxaline Derivative Modulates SENP3/ARF Mediated SUMOylation,and Induces NPM1c Degradation in NPM1 Mutant AML

Nucleophosmin-1 (NPM1) is a pleiotropic protein involved in numerous cellular processes. NPM1 shuttles between the nucleus and the cytoplasm, but exhibits a predominant nucleolar localization, where its fate and functions are exquisitely controlled by dynamic post-translational modifications (PTM). Sentrin/SUMO Specific Peptidase 3 (SENP3) and ARF are two nucleolar proteins involved in NPM1 PTMs. SENP3 antagonizes ARF-mediated NPM1 SUMOylation, to promote ribosomal biogenesis. In Acute Myeloid Leukemia (AML), NPM1 is frequently mutated, and exhibits an aberrant cytoplasmic localization (NPM1c). NPM1c mutations define a separate AML entity with good prognosis in some AML patients, rendering NPM1c as a potential therapeutic target. SENP3-mediated NPM1 de-SUMOylation induces resistance to therapy in NPM1c AML. Here, we demonstrate that the imidazoquinoxaline EAPB0503 prolongs the survival and results in selective reduction in the leukemia burden of NPM1c AML xenograft mice. Indeed, EAPB0503 selectively downregulates HDM2 expression and activates the p53 pathway in NPM1c expressing cells, resulting in apoptosis. Importantly, we unraveled that NPM1c expressing cells exhibit low basal levels of SUMOylation paralleled with high SENP3 and low ARF basal levels. EAPB0503 reverted these molecular players by inducing NPM1c SUMOylation and ubiquitylation, leading to its proteasomal degradation. EAPB0503-induced NPM1c SUMOylation is concurrent with SENP3 downregulation and ARF upregulation in NPM1c expressing cells. Collectively, these results provide a strong rationale for testing therapies modulating NPM1c post-translational modifications in the management of NPM1c AML.     

pH Responsive Abelmoschus esculentus Mucilage and Administration of Methotrexate: In-Vitro Antitumor and In-Vivo Toxicity Evaluation

The rapid progression in biomaterial nanotechnology apprehends the potential of non-toxic and potent polysaccharide delivery modules to overcome oral chemotherapeutic challenges. The present study is aimed to design, fabricate and characterize polysaccharide nanoparticles for methotrexate (MTX) delivery. The nanoparticles (NPs) were prepared by Abelmoschus esculentus mucilage (AEM) and chitosan (CS) by the modified coacervation method, followed by ultra-sonification. The NPs showed much better pharmaceutical properties with a spherical shape and smooth surface of 213.4–254.2 nm with PDI ranging between 0.279–0.485 size with entrapment efficiency varying from 42.08 ± 1.2 to 72.23 ± 2.0. The results revealed NPs to possess positive zeta potential and a low polydispersity index (PDI). The in-vitro drug release showed a sustained release of the drug up to 32 h with pH-dependence. Blank AEM -CS NPs showed no in-vivo toxicity for a time duration of 14 days, accompanied by high cytotoxic effects of optimized MTX loaded NPs against MCF-7 and MD-MBA231 cells by MTT assay. In conclusion, the findings advocated the therapeutic potential of AEM/CS NPs as an efficacious tool, offering a new perspective for pH-responsive routing of anticancer drugs with tumor cells as a target.     

A Novel Sprague-Dawley Rat Model Presents Improved NASH/NAFLD Symptoms with PEG Coated Vitexin Liposomes

Chronic liver disease (CLD) is a global threat to the human population, with manifestations resulting from alcohol-related liver disease (ALD) and non-alcohol fatty liver disease (NAFLD). NAFLD, if not treated, may progress to non-alcoholic steatohepatitis (NASH). Furthermore, inflammation leads to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Vitexin, a natural flavonoid, has been recently reported for inhibiting NAFLD. It is a lipogenesis inhibitor and activates lipolysis and fatty acid oxidation. In addition, owing to its antioxidant properties, it appeared as a hepatoprotective candidate. However, it exhibits low bioavailability and low efficacy due to its hydrophobic nature. A novel rat model for liver cirrhosis was developed by CCL4/Urethane co-administration. Vitexin encapsulated liposomes were synthesized by the ‘thin-film hydration’ method. Polyethylene glycol (PEG) was coated on liposomes to enhance stability and stealth effect. The diseased rats were then treated with vitexin and PEGylated vitexin liposomes, administered intravenously and orally. Results ascertained the liposomal encapsulation of vitexin and subsequent PEG coating to be a substantial strategy for treating liver cirrhosis through oral drug delivery.     

Occurrence of wax esters and 1-O-alkyl-2,3-diacylglycerols in goat epididymal sperm plasma membrane

Two unusual lipid classes were detected by thin-layer chromatography in the neutral lipids derived from goat cauda-epididymal sperm plasma membrane. The lipids were identified as wax esters and 1-O-alkyl-2,3-diacylglycerols based on chromatographic properties, identity of their hydrolysis products, and infrared/¹H nuclear magnetic resonance spectral evidence. The membrane containedca. 3 and 5 μg/mg protein of wax esters and alkyldiacylglycerols, respectively. The relative proportions of wax esters and alkyldiacylglycerols in the total neutral lipids were 1.5% and 2.4%, respectively. The lipids contained fatty acids with chain lengths of C₁₄ to C₂₂. The major fatty acids of the wax esters were 14∶0, 16∶0, 16∶1ω7, 18∶0 and 18∶1ω9. The fatty acids in alkyldiacylglycerol were 16∶0, 18∶0, 22∶5ω3 and 22∶6ω3. Alkyldiacylglycerol was particularly rich in docosahexaenoic acid 22∶6ω3) representing 30% of the total fatty acids. The alcohols of wax ester were all saturated with C₂₀–C₂₉ carbon chains. The deacylated products derived from alkyldiacylglycerols were identified as hexadecyl, octadecyl and octadec-9′-enyl glycerol ethers.     

Photocatalytic degradation of diclofenac using hybrid MIL-53(Al)@TiO2 and MIL-53(Al)@ZnO catalysts

In this work, TiO₂ and ZnO were incorporated successfully into a MIL-53(Al) metal–organic framework (MOF) to form nanocomposites via a facile post-modification technique. The hybrid MIL-53(Al)@TiO₂ and MIL-53(Al)@ZnO were characterized by several characterization tests. The X-ray diffraction (XRD), Fourier-transform infrared (FTIR), and field-emission scanning electron microscopy (FE-SEM) analyses showed evidence of the successful incorporation of TiO₂ and ZnO within the MIL-53(Al) framework. The thermal gravimetric analysis (TGA) analysis demonstrated the excellent thermal stability of MIL-53(Al)@TiO₂ and MIL-53(Al)@ZnO, while diffuse reflectance spectroscopy (DRS) determined the direct optical band gaps of MIL-53(Al)@ZnO and MIL-53(Al)@TiO₂ to be 3.24 and 3.34 eV, respectively. The composites were also tested for the photocatalytic degradation of diclofenac (DCF) as a micropollutant. The DCF degradation efficiency of the photocatalysts was ranked in the following order: MIL-53(Al)@TiO₂ > MIL-53(Al) > TiO₂ > ZnO > MIL-53(Al)@ZnO. The incorporation of TiO₂ enhanced the optical properties of MIL-53 (Al), which was confirmed with the superior photodegradation efficiency of MIL-53(Al)@TiO₂ (>85% in 2 h) as compared to the pristine MIL-53(Al) (around 80% in 2 h). The improvement in the photodegradation of the hybrid-MOF is mostly associated with the possible dual function of the adsorption and photodegradation mechanisms. The reusability of MIL-53(Al) and its composites was inspected over 3 cycles of photodegradation experiments with DCF. The photocatalytic activity of MIL-53(Al)@TiO₂ remained unchanged (>90%), while for MIL-53(Al) and MIL-53(Al)@ZnO a slight drop was observed over three cyclic degradation experiments. Fluorescence measurements revealed that the hydroxyl radical is an important reactive oxygen species produced by all the photocatalysts that aid in the photodegradation of DCF. Furthermore, the kinetic modelling of the photoreaction identified a second-order kinetics for all catalysts. Experiments with scavengers showed that hydroxyl radicals played a major role in the photocatalytic process, and it was found that only 2 h of treatment was sufficient to obtain a considerable chemical oxygen demand (COD) reduction of 58%.     

Kinetics and isotherm studies for the adsorption of boron from water using titanium dioxide

Boron is a necessary element for plants that are generally found in the ground and seawater, but it can also be poisonous in large doses. Contamination of water with boric acid or borate ions is a global concern. Due to the absence of the chemical charge that boron possesses, its removal is often difficult. To investigate boron's adsorption characteristics, kinetic, isotherm, and isothermal studies were performed. The adsorption of boron was shown to be a pH-dependent mechanism, with the best results at around pH 9.0. About 47% of the boron from a solution of 50 mg L⁻¹ was removed using 5 g titanium dioxide in 30 min. It was also demonstrated that boron adsorption kinetics increased with temperature, which is best described by the pseudo-second-order kinetic model (R² > 0.98) and also fits well with Elovich and pseudo-first-order models (R² > 0.94) at pH 9.0. Equilibrium was reached in about 40 min for all the samples. The film boundary layer diffusion step limits the rate. Experimental results correspond well to the Freundlich isotherm (R² = 0.95–0.99). Langmuir and Temkin's isotherms also fitted reasonably well (R² = 0.94–0.98). The Freundlich and Langmuir constants indicate favourable adsorption. The Gibbs free energy (ΔG) values increased negatively (from −11.47 to −15.63 kJ mol⁻¹) with increasing temperature, signifying a feasible and spontaneous process. The enthalpy change (ΔH) value of about 30.35 kJ mol⁻¹ indicated endothermic physical adsorption. The results indicate that titanium dioxide is an excellent and safe adsorbent for the removal of boron from water.     

Adsorption desalination of chloride ions on composite natural–synthetic materials: An approach for the reduction of chlorine corrosion in electrodeionization units

The release of chlorine in the electrodeionization (EDI) unit causes corrosion in the EDI unit, damaging ion exchange membranes and creating a safety risk for the workers. In this work, adsorption desalination of Cl^? ions on low-cost composite synthetic–natural Jordanian materials were investigated as an approach to prevent the release of corrosive chlorine gas at the positive electrode. The percentage removal reaches 25% at 25 min shaking time to 55% at 120 min, in a single batch experiment. The values of ΔH⁰, ΔS⁰, and ΔG⁰ indicate the favorability of physisorption. Zeolite and Pozzolana represent potential adsorbents of chloride.     

Effect of phosphorus on activity of hydrotreating catalyst of Maya heavy crude

The effect of phosphorus on physical properties of the catalyst and on activity of hydrotreating of Maya crude was studied in this work. Catalysts were prepared by the co-impregnation method. Alumina-titania binary oxide was used as a support material. The presence of phosphorus in the catalyst decreases the percentage of micropores, and it results in a decrease of specific surface area. Temperature program reduction (TPR) shows that phosphates reduce metal support interaction. It leads to the formation of polymolybdate phases in expense of strongly bonded tetrahedral molybdates. At higher P loading, polymolybdates may be present with quasi crystalline MoO₃. However, the TPR experiment is not sufficiently sensitive to distinguish several phases present on the catalysts used by the authors. A slight increment of HDM activity is observed, but HDS activity is lower in the P containing catalyst compared with the P free catalyst. The changes of physical properties of the spent catalysts are mainly due to the coke formation on the catalyst. The presence of phosphorus on hydrotreating catalysts inhibits coke formation during the hydrotreating reaction.     

Maya crude hydrodemetallization and hydrodesulfurization catalysts: An effect of TiO2 incorporation in Al2O3

Hydrotreating of Maya heavy crude oil over high specific surface area CoMo/TiO₂–Al₂O₃ oxide supported catalysts was studied in an integral reactor close to industrial practice. Activity studies were carried out with Maya crude hydrodesulfurization (HDS), hydrodemetallization (HDM), hydrodenitrogenation (HDN), and hydrodeasphaltenization (HDAs) reactions. The effect of support composition, the method of TiO₂ incorporation, and the catalyst deactivation are examined. Supported catalysts are characterized by BET specific surface area (SSA), pore volume (PV), pore size distribution (PSD), and atomic absorption. It has been found that sulfided catalysts showed a wide range of activity variation with TiO₂ incorporation into the alumina, which confirmed that molybdenum sulfided active phases strongly depend on the nature of support. The pore diameter and nature of the active site for HDS, HDM, HDN, and HDAs account for the influence of the large reactant molecules restricted diffusion into the pore, and/or the decrease in the number of active sites due to the MoS₂ phases buried with time-on-stream. The textural properties and hysteresis loop area of supported and spent catalysts indicated that catalysts were deactivated at the pore mouth due to the metal and carbon depositions. The atomic absorption results agreed well regarding the textural properties of spent catalysts. Thus, incorporation of TiO₂ with γ-Al₂O₃ alters the nature of active metal interaction with support, which may facilitate the dispersion of active phases on the support surface. Therefore, the TiO₂ counterpart plays a promoting role to HDS activity due to the favorable morphology of MoS₂ phases and metal support interaction.