2-Hydroxyestradiol Overcomes Mesenchymal Stem Cells-Mediated Platinum Chemoresistance in Ovarian Cancer Cells in an ERK-Independent Fashion

Ovarian cancer (OC) is the second most common type of gynecological malignancy. Platinum (Pt)-based chemotherapy is the standard of care for OC, but toxicity and acquired chemoresistance has proven challenging. Recently, we reported that sensitivity to platinum was significantly reduced in a co-culture of OC cells with MSC. To discover compounds capable of restoring platinum sensitivity, we screened a number of candidates and monitored ability to induce PARP cleavage. Moreover, we monitored platinum uptake and expression of ABC transporters in OC cells. Our results showed that 2-hydroxyestradiol (2HE2), a metabolite of estradiol, and dasatinib, an Abl/Src kinase inhibitor, were significantly effective in overcoming MSC-mediated platinum drug resistance. Dasatinib activity was dependent on ERK1/2 activation, whereas 2HE2 was independent of the activation of ERK1/2. MSC-mediated platinum drug resistance was accompanied by reduced intracellular platinum concentrations in OC cells. Moreover, MSC co-cultured with OC cells resulted in downregulation of the expression of cellular transporters required for platinum uptake and efflux. Exposure to 2HE2 and other modulators resulted in an increase in intracellular platinum concentrations. Thus, 2HE2 and dasatinib might act as sensitizers to restore platinum drug sensitivity to OC cells and thus to limit TME-mediated chemoresistance in OC.     

A Novel Docetaxel-Biotin Chemical Conjugate for Prostate Cancer Treatment

A novel conjugate of docetaxel and biotin (designated as IDD-1010) was designed and chemically synthesized via an ester linkage at position 2’ carbon in docetaxel. The synthesized pure IDD-1010 exhibits a potent anti-cancer activity in in vitro and in vivo studies. At 10 nM, IDD-1010 has induced increased apoptosis and mitotic arrest of PC3-Luc prostate cancer cells, causing aneuploidy and cell death at higher concentrations. Toxicology studies indicate that the maximal tolerated dose (MTD) of IDD-1010 is 150 mg/kg in mice; equivalent to about 12.2 mg/kg of body weight, or to about an 850 mg dose for a patient weighing 70 kg. The MTD-treated mice exhibited weight gain similar to that of the control group, with no gross pathological signs at 14 days post-dosing. At a lower dose, IDD-1010 treatment did not lead to any significant weight loss in mice, although decreased the tumor volume stemming from injecting cancer cells into the dorsal loop of mouse prostate, and it was found to be more potent than Paclitaxel (reference drug). Similarly, IDD-1010 treatment significantly reduced tumor weight and thereby increased the percentage of mice survival as compared to reference drug-treated and control groups. To summarize, the described experiments using IDD-1010, as compared to the reference drug, strongly suggest a potential treatment utility with a wider therapeutic window for prostate cancer. Henceforth, clinical research on such a novel drug candidate would be greatly worthwhile.     

Dielectric Properties of Colossal-Dielectric-Constant Na1/2La1/2Cu3Ti4O12 Ceramics Prepared by Spark Plasma Sintering

In the current study, we report on the dielectric behavior of colossal-dielectric-constant Na_1/2La_1/2Cu₃Ti₄O₁₂ (NLCTO) ceramics prepared by mechanochemical synthesis and spark plasma sintering (SPS) at 850 °C, 900 °C, and 925 °C for 10 min. X-ray powder diffraction analysis showed that all the ceramics have a cubic phase. Scanning electron microscope observations revealed an increase in the average grain size from 175 to 300 nm with an increase in the sintering temperature. SPS NLCTO ceramics showed a room-temperature colossal dielectric constant (>10³) and a comparatively high dielectric loss (>0.1) over most of the studied frequency range (1 Hz–40 MHz). Two relaxation peaks were observed in the spectra of the electrical modulus and attributed to the response of grain and grain boundary. According to the Nyquist plots of complex impedance, the SPS NLCTO ceramics have semiconductor grains surrounded by electrically resistive grain boundaries. The colossal dielectric constant of SPS NLCTO ceramics was attributed to the internal barrier layer capacitance (IBLC) effect. The high dielectric loss is thought to be due to the low resistivity of the grain boundary of SPS NLCTO.     

Antimicrobial and Antioxidant Properties of Total Polyphenols of Anchusa italica Retz

Anchusa italica Retz has been used for a long time in phytotherapy. The aim of the present study was to determine the antioxidant and antibacterial activities of extracts from the leaves and roots of Anchusa italica Retz. We first determined the content of phenolic compounds and flavonoids using Folin–Ciocalteu reagents and aluminum chloride (AlCl₃). The antioxidant activity was determined using three methods: reducing power (FRAP), 2.2-diphenyl-1-picrylhydrazyl (DPPH), total antioxidant capacity (TAC). The antimicrobial activity was investigated against four strains of Escherichia coli, two strains of Klebsiella pneumoniae and coagulase-negative Staphylococcus, and one fungal strain of Candida albicans. The results showed that the root extract was rich in polyphenols (43.29 mg GAE/g extract), while the leave extract was rich in flavonoids (28.88 mg QE/g extract). The FRAP assay showed a strong iron reduction capacity for the root extract (IC₅₀ of 0.11 µg/mL) in comparison to ascorbic acid (IC₅₀ of 0.121 µg/mL). The DPPH test determined an IC₅₀ of 0.11 µg/mL for the root extract and an IC₅₀ of 0.14 µg/mL for the leaf extract. These values are low compared to those for ascorbic acid (IC₅₀ of 0.16 µg/mL) and BHT (IC₅₀ 0.20 µg/mL). The TAC values of the leaf and root extracts were 0.51 and 0.98 mg AAE/g extract, respectively. In vitro, the extract showed inhibitory activity against all strains studied, with diameters of zones of inhibition in the range of 11.00–16.00 mm for the root extract and 11.67–14.33 mm for the leaf extract. The minimum inhibitory concentration was recorded for the leaf extract against E. coli (ATB:57), corresponding to 5 mg/mL. Overall, this research indicates that the extracts of Anchusa italica Retz roots and leaves exert significant antioxidant and antibacterial activities, probably because of the high content of flavonoids and polyphenols.     

Synthesis and characterization of water-soluble palladium(II)-functionalized diphosphine complexes

Water-soluble functionalized bis(phosphine) ligands L (a–h) of the general formula CH₂(CH₂PR₂)₂, where for a: R = (CH₂)₆OH; b–g: R = (CH₂)_nP(O)(OEt)₂, n = 2–6 and n = 8; h: R = (CH₂)₃NH₂ ( Scheme 1), have been prepared photochemically by hydrophosphination of the corresponding 1-alkenes with H₂P(CH₂)₃PH₂. Water-soluble palladium complexes cis-[Pd(L)(OAc)₂] (1–8) were obtained by the reaction of Pd(OAc)₂ with the ligands a–h in a 1:1 mixture of dichloromethane:acetonitrile. The water-soluble phosphine ligands and their palladium complexes were characterized by IR, ¹H and ³¹P NMR. A crystallographic study of complex 1 shows that the Pd(II) ion has a square planar coordination sphere in which the acetate ligands and the diphosphine ligand deviate by less than 0.12 Å from ideal planar.     

Macro-Reticular Ion Exchange Resins for Recovery of Direct Dyes from Spent Dyeing and Soaping Liquors

Dyes are a major class of organic pollutants that are well-known for their harmful impact on aquatic life and humans. Several new strategies for removing colours from industrial and residential effluents have recently emerged, with adsorption being the best option. The current study looked at the recovery of direct dyes from aqueous streams for reuse using macro-reticular ion exchange resins (IERs). The investigation includes dyeing single jersey cotton grey textiles with direct dyes from the Isma dye Company in Kafr El Dawar, Egypt. After centrifuging and separating the supernatant liquid, solutions from thirteen different dyes, produced at an average concentration between the wasted and soaping liquor concentrations, were calculated spectrophotometrically from the first dyeing trials. Kinetic data were well fitted with pseudo-second-order rate kinetics. The amounts of dye retained by the anion exchangers increased with a rise in temperature in the case of Strong Base Resin (SBR) and vice versa for Weak Base Resin (WBR). Batch adsorption experiments with SBR and WBR were conducted for each dye, and both Freundlich and Langmuir isotherms were constructed. It was found that adsorption obeyed both isotherms, that monolayer adsorption took place, and that the dye molecular weight, structure, and solubility, as well as the type of anionic resin used, had varying effects on the extent of absorption. The monolayer sorption capacities Q₀ determined from the Langmuir isotherm model for the strongly and weakly basic anion exchangers were found to be 537.6 and 692 mg/g for Direct Yellow RL, respectively. As a result, Yellow RL exhibited the greatest adsorption on both SBR and WBR. Orange GRLL, Blue 3B, and Congo Red, on the other hand, were the poorest colours absorbed by the IERs, whereas Blue RL demonstrated good adsorption by SBR and accelerated adsorption by WBR. Most of the dyes may be recovered and reused in this manner.     

Quantitative analysis of two-dimensional gel-separated proteins using isotopically marked alkylating agents and matrix-assisted laser desorption/ionization mass spectrometry

We describe a simple approach for the relative quantification of individual proteins within a mixture. The method is based on the differential labelling of the mixtures by use of a commercially available acrylamide and deuterium-labelled [2,3,3'-d(3)]-acrylamide to alkylate proteins prior to two-dimensional (2-D) gel electrophoresis. The tryptic digests of the separated proteins were subjected to reflector matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) analysis and the relative peak heights of cysteine-containing peptides were used to quantify their precursor proteins. This approach was tested for the relative quantification of proteins within an artificial mixture of standard proteins and for proteins observed in a 2-D map of rat serum. A good correlation was found between the measured ratios derived from MALDI-TOF data and those theoretically calculated prior to 2-D analysis via known mixing ratios of the two alkylating reagents. The described procedure has proved to be effective for comparative measurements of protein abundances within the investigated mixtures.