Design,Synthesis and Evaluation of 2,4-Diaminoquinazoline Derivatives as Potential Tubulin Polymerization Inhibitors

Microtubules are highly dynamic polymers composed of α- and β-tubulin proteins that have been shown to be potential therapeutic targets for the development of anticancer drugs. Currently, a wide variety of chemically diverse agents that bind to β-tubulin have been reported. Nocodazole (NZ) and colchicine (COL) are well-known tubulin-depolymerizing agents that have close binding sites in the β-tubulin. In this study, we designed and synthesized a set of nine 2,4-diaminoquinazoline derivatives that could occupy both NZ and COL binding sites. The synthesized compounds were evaluated for their antiproliferative activities against five cancer cell lines (PC-3, HCT-15, MCF-7, MDA-MB-231, and SK-LU-1), a noncancerous one (COS-7), and peripheral blood mononuclear cells (PBMC). The effect of compounds 4 e and 4 i on tubulin organization and polymerization was analyzed on the SK-LU-1 cell line by indirect immunofluorescence, western blotting, and tubulin polymerization assays. Our results demonstrated that both compounds exert their antiproliferative activity by inhibiting tubulin polymerization. Finally, a possible binding pose of 4 i in the NZ/COL binding site was determined by using molecular docking and molecular dynamics (MD) approaches. To our knowledge, this is the first report of non-N-substituted 2,4-diaminoquinazoline derivatives with the ability to inhibit tubulin polymerization.     

Synthesis and Anticancer Properties of Oxazepines Related to Azaisoerianin and IsoCoQuines

In this article, we report the synthesis and biological properties of a series of novel oxazepines related to isoCA-4 having significant antitumor properties. Among them, three oxazepin-9-ol derivatives display a nanomolar or a sub-nanomolar cytotoxicity level against five human cancer cell lines (HCT116, U87, A549, MCF7, and K562). It was demonstrated that the lead compound in this series inhibits tubulin assembly with an IC₅₀ value of 1 μM and totally arrests the cellular cycle in the G2/M phase at the low concentration of 5 nM in HCT116 and K562 cells. Molecular modeling studies perfectly corroborates these promising results.     

Involvement of GPx-3 in the Reciprocal Control of Redox Metabolism in the Leukemic Niche

The bone marrow (BM) microenvironment plays a crucial role in the development and progression of leukemia (AML). Intracellular reactive oxygen species (ROS) are involved in the regulation of the biology of leukemia-initiating cells, where the antioxidant enzyme GPx-3 could be involved as a determinant of cellular self-renewal. Little is known however about the role of the microenvironment in the control of the oxidative metabolism of AML cells. In the present study, a coculture model of BM mesenchymal stromal cells (MSCs) and AML cells (KG1a cell-line and primary BM blasts) was used to explore this metabolic pathway. MSC-contact, rather than culture with MSC-conditioned medium, decreases ROS levels and inhibits the Nrf-2 pathway through overexpression of GPx3 in AML cells. The decrease of ROS levels also inactivates p38MAPK and reduces the proliferation of AML cells. Conversely, contact with AML cells modifies MSCs in that they display an increased oxidative stress and Nrf-2 activation, together with a concomitant lowered expression of GPx-3. Altogether, these experiments suggest that a reciprocal control of oxidative metabolism is initiated by direct cell–cell contact between MSCs and AML cells. GPx-3 expression appears to play a crucial role in this cross-talk and could be involved in the regulation of leukemogenesis.     

The Gut Microbiota: A Potential Gateway to Improved Health Outcomes in Breast Cancer Treatment and Survivorship

Breast cancer is the most frequently diagnosed cancer in women worldwide. The disease and its treatments exert profound effects on an individual’s physical and mental health. There are many factors that impact an individual’s risk of developing breast cancer, their response to treatments, and their risk of recurrence. The community of microorganisms inhabiting the gastrointestinal tract, the gut microbiota, affects human health through metabolic, neural, and endocrine signaling, and immune activity. It is through these mechanisms that the gut microbiota appears to influence breast cancer risk, response to treatment, and recurrence. A disrupted gut microbiota or state of ‘dysbiosis’ can contribute to a biological environment associated with higher risk for cancer development as well as contribute to negative treatment side-effects. Many cancer treatments have been shown to shift the gut microbiota toward dysbiosis; however, the microbiota can also be positively manipulated through diet, prebiotic and probiotic supplementation, and exercise. The objective of this review is to provide an overview of the current understanding of the relationship between the gut microbiota and breast cancer and to highlight potential strategies for modulation of the gut microbiota that could lead to improved clinical outcomes and overall health in this population.     

Experimental study and modelling of an azo colourant dynamic adsorption onto functional cross-linked chitosan/ceramic particles in a fixed bed column

The use of azo dyes in industrial activities generates a large volume of contaminated wastewater; these pollutants in water bodies affect aquatic biota and human health. A functional biocomposite sorbent material was synthesized using cross-linked chitosan with oxalic acid that forms a coating on alumina ceramic particles (AOCh). The removal of Reactive Red 195, a reactive azo dye, using a fixed-bed adsorption column filled with this material was tested. AOCh was physico-chemically characterized by Fourier transform infrared spectroscopy–total attenuated reflection (FTIR-ATR), scanning electron microscopy–energy dispersion spectrometry X-ray (SEM-EDS), X-ray diffraction (XDR), thermo-gravimetric analysis (TGA), and Z-potential. The dynamic adsorption performance was analyzed from experimental breakthrough curves obtained in fixed-bed columns by modifying different operating conditions (bed depth, volumetric flow rate, and dye inlet concentration). Equilibrium adsorption isotherms were determined under dynamic conditions and compared with batch results. The maximum adsorption capacity of the dynamic equilibrium isotherm obtained from the continuous assays was 331 mg/g; this value was the highest in comparison to other tested materials reported in the literature. Different dynamic adsorption models were applied to fit experimental data, including Thomas, Bohart–Admas, Yoon–Nelson, logistic general model, bed depth surface time (BDST), and modified dose response (Yan) models. A critical analysis of these equations was presented, showing the equivalences and the relationship among the coefficients. The Yan model achieved the highest level of agreement between the experimental and predicted values of the breakthrough curves. The use of this model enables scaling-up the industrial process for dye removal. The present work proposed a novel biosorbent material and contributes to the analysis of industrial dye removal under dynamic conditions.     

Deep learning-based hybrid reconstruction algorithm for fibre instance segmentation from 3D x-ray tomographic images

3D x-ray tomography is a powerful scanning technique used for generating images of complex fibre structures. A novel machine-learning algorithm to identify and separate individual fibres using 3D images is proposed in this article. The developed four-step hybrid 3D fibre segmentation algorithm involves deep-learning aided semantic segmentation that slices 3D images to create 2D images for fibre extraction, elliptical contour estimation combined with the marker-controlled watershed algorithm for separating fibres from the background area, identifying individual fibres through 3D reconstruction, and, lastly, the 3D object refining approach based on outlier object detection and replacement. The proposed methodology is implemented on a real-time sample of nylon fibre bundle under compression and its 3D x-ray image volume to validate the performance. The results show its superior performance compared to off-the-shelf image processing algorithms in terms of precision, that is, with a validation accuracy greater than 90%, and efficiency, that is, preventing the need for a huge data set and reducing the complexity.     

The influence of different zeolitic supports on hydrogen production and waste degradation

The photocatalyst composition affects the chemical–physical properties and directly impacts photocatalytic activity, both in the hydrogen production and degradation of organic contaminants. In this work, the influence of zeolitic structures NaA, NaY, and ZSM-5 combined with a 10% active phase, TiO₂ catalyst doped with 1% copper, and cobalt cocatalysts was tested to mineralize the reactive blue dye (CI250) and to produce hydrogen by photocatalysis under ultraviolet radiation. The band gap energy was affected mainly by the cocatalyst, while the Brunauer-Emmett-Teller method (BET) area was affected by the zeolite structure as well as the X-ray diffraction (XRD). The most active catalyst was the Cu@TiO₂/NaY, which promoted a hydrogen production rate of 240 μmolH₂gcat⁻¹ using 10% ethanol (v/v) aqueous solution as a sacrificial agent and mineralization of 53% of the organic dye, followed by the catalysts impregnated on ZSM-5 zeolites, which had discolouration up to 50% and hydrogen evolution of 92.6 and 109.7 μmolH₂gcat⁻¹ for the catalyst doped with Cu and Co, respectively.     

Hydrophobization of hair to improve the interfacial adhesion between hair and high-density polyethylene

Concerned about environmental pollution, and aware of the comfort that polyethylene provides for daily human life, this work sought to replace a percentage of high-density polyethylene (HDPE) with human or bovine hair. Hair is natural, abundant, light weight, non-toxic, and disposed of as garbage. The main disadvantage of natural composites is the interfacial adhesion. To increase the interfacial adhesion between hair and HDPE, stearic acid or oleic acid was chemically anchored on the hair surface, which leads to an improved contact angle hysteresis and hydrophobicity. Dynamic-mechanical properties of the composites were investigated focusing on the type of carboxylic acid used (stearic or oleic acid), hair length, hair type (human or bovine) and amount of hair used in the composite. Taking 40°C as a reference, using 15% of hair with a length of 1 ± 0.15 mm, the highest storage modulus value was obtained with HDPE with human hair modified with oleic acid, exceeding the value of the storage modulus of HDPE by 67.64%. Increasing storage modulus on composites indicates of interfacial interaction and chemical affinity improvement between hair and polyethylene.     

Failure by slow crack growth of SiC fibers: Comparing the lifetime scatter for single filaments and multifilament tows

SiC-based fibers are subjected to slow crack growth, a crack growth mechanism activated by stresses and the chemical environment, as identified by static fatigue testing. Such tests can be performed on filaments or bundles. Although both types of specimens show a similar lifetime variation, testing of bundles is often preferred. This work compares the scatter of lifetimes predicted for filaments and for tows using a dedicated Monte Carlo simulation tool relying on the following hypotheses: The stress applied to a single filament can be defined, whereas the size of its most critical flaw cannot; on a bundle, neither the applied stress nor the strength of the critical filament (which triggers the cascade failure and the tow failure) can be defined. Depending on the parallelism of fibers inside the bundle and their strength dispersion, the lifetime scatter can be narrower for filaments compared to tows or vice versa.     

New Biocompatible β-Phosphorylated Linear Nitrones Targeting Mitochondria: Protective Effect in Apoptotic Cells

The mitochondrion, an essential organelle involved in cellular respiration, energy production, and cell death, is the main cellular source of reactive oxygen species (ROS), including superoxide. Mitochondrial diseases resulting from uncontrolled/excess ROS generation are an emerging public health concern and there is current interest in specific mitochondriotropic probes to get information on in-situ ROS production. As such, nitrones vectorized by the triphenylphosphonium (TPP) cation have recently drawn attention despite reported cytotoxicity. Herein, we describe the synthesis of 13 low-toxic derivatives of N-benzylidene-1-diethoxyphosphoryl-1-methylethylamine N-oxide (PPN) alkyl chain-grafted to a pyridinium, triethylammonium or berberinium lipophilic cation. These nitrones showed in-vitro superoxide quenching activity and EPR/spin-trapping efficiency towards biologically relevant free radicals, including superoxide and hydroxyl radicals. Their mitochondrial penetration was confirmed by ³¹P NMR spectroscopy, and their anti-apoptotic properties were assessed in Schwann cells treated with hydrogen peroxide. Two pyridinium-substituted PPNs were identified as potentially better alternatives to TPP nitrones conjugates for studying mitochondrial oxidative damage.