Phase separation of Nur77 mediates XS561-induced apoptosis by promoting the formation of Nur77/Bcl-2 condensates.

The orphan nuclear receptor Nur77 is a critical regulator of the survival and death of tumor cells. The pro-death effect of Nur77 can be regulated by its interaction with Bcl-2, resulting in conversion of Bcl-2 from a survival to killer. As Bcl-2 is overexpressed in various cancers preventing them from apoptosis and promoting their resistance to chemotherapy, targeting the apoptotic pathway of Nur77/Bcl-2 may lead to new cancer therapeutics. Here, we report our identification of XS561 as a novel Nur77 ligand that induces apoptosis of tumor cells by activating the Nur77/Bcl-2 pathway. In vitro and animal studies revealed an apoptotic effect of XS561 in a range of tumor cell lines including MDA-MB-231 triple-negative breast cancer (TNBC) and MCF-7/LCC2 tamoxifen-resistant breast cancer (TAMR) in a Nur77-dependent manner. Mechanistic studies showed XS561 potently induced the translocation of Nur77 from the nucleus to mitochondria, resulting in mitochondria-related apoptosis. Interestingly, XS561-induced accumulation of Nur77 at mitochondria was associated with XS561 induction of Nur77 phase separation and the formation of Nur77/Bcl-2 condensates. Together, our studies identify XS561 as a new activator of the Nur77/Bcl-2 apoptotic pathway and reveal a role of phase separation in mediating the apoptotic effect of Nur77 at mitochondria.

Nuclear TIGAR mediates an epigenetic and metabolic autoregulatory loop via NRF2 in cancer therapeutic resistance.

Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance. However, their interplays are poorly understood. We report here that elevated TIGAR (TP53-induced glycolysis and apoptosis regulator), an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2 (nuclear receptor binding SET domain protein 2), is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark. Mechanistically, TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2, H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new (NSD2) and established (NQO1/2, PRDX1 and GSTM4) targets of NRF2, independent of its enzymatic activity. Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis. In addition, nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival. These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.

LncRNA ATXN8OS enhances tamoxifen resistance in breast cancer.

BACKGROUND: Tamoxifen (TAMR) resistance remains a massive obstacle for breast cancer (BC) management. The precise parts of long non-coding RNA ataxin 8 opposite strand (ATXN8OS) in BC TAMR resistance have not been defined. METHODS: The levels of ATXN8OS, vasodilator-stimulated phosphoprotein (VASP), and miR-16-5p were assessed by quantitative real-time polymerase chain reaction or western blot. Colony formation and cell viability were analyzed by MTT and colony formation assays, respectively. Targeted interactions among miR-16-5p, ATXN8OS, and VASP were confirmed by dual-luciferase reporter assay. Animal studies were performed to observe the role of ATXN8OS in TAMR sensitivity in vivo. RESULTS: ATXN8OS expression was increased in BC tissues and cells. ATXN8OS depletion promoted BC cell sensitivity to TAMR. ATXN8OS sequestered miR-16-5p by directly binding to miR-16-5p. The promotional effect of ATXN8OS knockdown on BC cell TAMR sensitivity was mediated by miR-16-5p. VASP was a direct target of miR-16-5p, and miR-16-5p overexpression enhanced TAMR sensitivity by VASP. Moreover, ATXN8OS regulated VASP expression by acting as a miR-16-5p sponge. In addition, ATXN8OS knockdown augmented BC TAMR sensitivity in vivo. CONCLUSION: ATXN8OS knockdown enhanced BC TAMR sensitivity partially through the miR-16-5p/VASP axis, highlighting a potential therapeutic target for improving the clinical benefits of TAMR treatment in BC patients.

A Bottom-Up Synthesis Approach to Silver Nanoparticles Induces Anti-Proliferative and Apoptotic Activities Against MCF-7, MCF-7/TAMR-1 and MCF-10A Human Breast Cell Lines.

A bottom-up approach for synthesizing silver nanoparticles (AgNPs-GA) phytomediated by Garcinia atroviridis leaf extract is described. Under optimized conditions, the AgNPs-GA were synthesized at a concentration of 0.1 M silver salt and 10% (w/v) leaf extract, 1:4 mixing ratio of reactants, pH 3, temperature 32 °C and 72 h reaction time. The AgNPs-GA were characterized by various analytical techniques and their size was determined to be 5-30 nm. FTIR spectroscopy indicates the role of phenolic functional groups in the reduction of silver ions into AgNPs-GA and in supporting their subsequent stability. The UV-Visible spectrum showed an absorption peak at 450 nm which reflects the surface plasmon resonance (SPR) of AgNPs-GA and further supports the stability of these biosynthesized nanoparticles. SEM, TEM and XRD diffractogram analyses indicate that AgNPs-GA were spherical and face-centered-cubic in shape. This study also describes the efficacy of biosynthesized AgNPs-GA as anti-proliferative agent against human breast cancer cell lines, MCF-7 and MCF-7/TAMR-1. Our findings indicate that AgNPs-GA possess significant anti-proliferative effects against both the MCF-7 and MCF-7/TAMR-1 cell lines, with inhibitory concentration at 50% (IC50 values) of 2.0 and 34.0 µg/mL, respectively, after 72 h of treatment. An induction of apoptosis was evidenced by flow cytometry using Annexin V-FITC and propidium iodide staining. Therefore, AgNPs-GA exhibited its anti-proliferative activity via apoptosis on MCF-7 and MCF-7/TAMR-1 breast cancer cells in vitro. Taken together, the leaf extract from Garcinia atroviridis was found to be highly capable of producing AgNPs-GA with favourable physicochemical and biological properties.

Drastic reduction of sludge in wastewater treatment plants: co-digestion of sewage sludge and aqueous waste in a thermophilic membrane reactor.

Sewage sludge and aqueous wastes are usually treated in separate facilities. Both may pose specific issues, mainly related to the uncertainty of the recovery/disposal route and costs, for the sludge, and to the extremely variable quantitative and qualitative properties, for the aqueous waste. In the present work, the co-digestion of thickened sludge and aqueous wastes in a Thermophilic Aerobic Membrane Reactor (TAMR) was studied in order to allow the almost complete reduction of sludge directly in wastewater treatment plants (WWTPs). Different conditions (aerobic and alternate aeration) were tested in a pilot plant, at the semi-industrial scale. The TAMR plant was operated at 48°C with constant organic load rate (5 kgCOD m-3 d-1) and hydraulic retention time (5 days). The main results obtained are the following: (I) high overall COD (78-97%) and total phosphorus (>60%) removal rate under both the studied aeration conditions; (II) increase of ammonia concentration due to the effective ammonification of organic nitrogen; (III) low specific sludge production (0.04[Formula: see text]) in the thermophilic reactor.

Treatment of aqueous wastes by means of Thermophilic Aerobic Membrane Reactor (TAMR) and nanofiltration (NF): process auditing of a full-scale plant.

This work focuses on the Thermophilic Aerobic Membrane Reactor (TAMR) process. The research was carried out on a full-scale facility where, all along a 12-year period, daily monitoring and process audit tests were conducted for the process analysis and optimization. The plant treated -light and high-strength aqueous wastes and two different configurations were adopted: (1) thermophilic biological reactor + ultrafiltration (TAMR) and (2) TAMR + nanofiltration (TAMR + NF). In the latter case, the average chemical oxygen demand removal yield was equal to 89% and an effective denitrification (nitrogen oxides removal equal to 96%) was achieved by reducing the dissolved oxygen concentration in the bioreactor. Low specific sludge production was observed. Poor sludge settling properties were measured by a lab-scale settling test; respirometric tests (nitrogen uptake rate and ammonia uptake rate) showed the presence of denitrification and the inhibition of nitrification. Hydrodynamic tests revealed the presence of a significant dead space, thus showing room for improving the overall process performance. Finally, the rheological properties of the sludge were measured as a function of the biomass concentration, pH, temperature, and aeration scheme.

Anisotropic Magnetoresistance in NiFe-Based Polymer Spin Valves.

Precise evaluation of magnetoresistance (MR) with the identified transport mechanism is one of the key points in organic spin-valve (OSV) devices. To investigate the origin of the spin-valve-like signal in polymer spin valve with a vertical structure of NiFe/P3HT/AlO x/Co, the magnetic response measurements in the rotated magnetization direction were established in different well-designed device configurations. We identified the significant influence of anisotropic MR (AMR) and further induced tunneling AMR in NiFe electrodes contributing to the total MR signal. These findings suggest that the mechanisms responsible for the transport mode in polymer spin-valve devices also strongly depend on the interface between the ferromagnetic electrodes and organic semiconductor layer. Even for the spin-valve-resembled MR response with distinct parallel and antiparallel states, carefully controlled experiments such as temperature-dependent and angle-dependent measurements should always be performed to track down the injected spin-polarized carriers. Our thorough experiments and analyses may shed light on the effective MR signal evaluation in OSVs and spin-related parameters with transport mechanism identification.

Wastewater treatment by means of thermophilic aerobic membrane reactors: respirometric tests and numerical models for the determination of stoichiometric/kinetic parameters.

Existing wastewater/aqueous waste treatment plants often need to be upgraded in order to improve their performance. The satisfactory operation of biological treatment plants requires appropriate monitoring, and respirometric techniques are needed to determine the kinetic parameters that regulate biological processes. Innovative technologies are treating industrial wastewater/aqueous waste, such as thermophilic aerobic treatments. Thermophilic aerobic biological systems operate at temperatures higher than 45°C. Such temperature levels can be reached, at a reasonable cost, using wastewater with a high organic loading and reactors, which are appropriately thermally insulated. This kind of treatment shows high removal kinetics of biodegradable substrates and a very low sludge production. This paper describes the application of respirometric tests in thermophilic conditions on the biomass derived from a thermophilic aerobic membrane reactor in order to model the process, with a particular focus on the rapidly biodegradable chemical oxygen demand (rbCOD). The utility of rbCOD determination is related to the optimal treatment that the aqueous waste should undergo. Calculating the kinetic parameters is critical to the biological modelling used in the management and control of wastewater treatment plants.

Effect of artesunate on apoptosis and autophagy in tamoxifen resistant breast cancer cells (TAM-R).

BACKGROUND: The antitumor effect of artesunate (ART) is well-recognized. To investigate the effect of ART on tamoxifen-resistant breast cancer cells (TAM-R) proliferation, apoptosis, and autophagy with TAM-R cells of breast cancer as objects of study, and to investigate whether ART could re-sensitize TAM-R cells to TAM therapy. METHODS: Experiments were performed using TAM-R cell lines. Cell Death Detection ELISA kit was used to detect the level of apoptosis. Western blot and immunofluorescent staining analysis were conducted to detect autophagy and apoptosis related proteins in TAM-R cells. RESULTS: After treated with ART, the proliferation activity of TAM-R cells was inhibited in a concentration-dependent manner. Increased apoptosis activity was detected in TAM-R cells when treated with ART. Compared with 10-6 M TAM monotherapy group, treatment group with ART and TAM in combination caused significant reduction in the levels of Bcl-2, XIAP, and Survivin proteins, and elevation of caspase-7. However, increased p53 proteins was not detected after ART treatment. No significant change was observed in autophagy proteins LC-3 and Beclin-1 among control, ART, TAM, and ART combined with TAM groups. CONCLUSIONS: The intervention of ART could not inhibit protective autophagy in TAM-R cells, however, possess potential in inducing apoptosis. In addition, as ART inhibit TAM-R cells growth in a dose-dependent manner, co-administration of 1 or 3 µM of ART with 10-6 M TAM might not be enough to re-sensitize TAM-R cells to TAM therapy.

Effect of Goat's Milk Supplementation with Tamr on Free Fatty Acids, Antioxidant Activity, and Probiotic Bacteria of Bio-Rayeb Milk.

Tamr (dried dates) has a high sugar content, essential vitamins, and high nutrient density. Dairy products still are the most typical carriers of probiotic bacteria. Six treatments of bio-rayeb milk were manufactured from goat's milk fortified with 5%, 10%, 15%, 20%, and 25% Tamr using ABT-5 culture. Rayeb milk containing tamr had lower pH and fat and higher carbohydrate, total solids, dietary fiber, ash, total protein, water-soluble nitrogen, and total volatile fatty acids. Mixing tamr with bio-rayeb milk increased nutritional value by decreasing saturated fatty acids and increasing unsaturated fatty acids, oleic, linoleic, α-linolenic acids, and antioxidant activity values. The greatest counts of probiotic bacteria (L. acidophilus and Bifidobacterium) were detected in tamr rayeb milk, which increased the healthy value. The recommended level of bifidobacteria as a probiotic (107 cfu g-1) was exceeded for treatments of tamr rayeb milk and remained above 107 cfu g-1 until the end of storage. Adding 10% or 15% tamr to goat's milk highly improved the sensory properties of rayeb milk.

Effect of Orbital Hybridization on Spin-Polarized Tunneling across Co/C60 Interfaces.

The interaction between ferromagnetic surfaces and organic semiconductors leads to the formation of hybrid interfacial states. As a consequence, the local magnetic moment is altered, a hybrid interfacial density of states (DOS) is formed, and spin-dependent shifts of energy levels occur. Here, we show that this hybridization affects spin transport across the interface significantly. We report spin-dependent electronic transport measurements for tunnel junctions comprising C60 molecular thin films grown on top of face-centered-cubic (fcc) epitaxial Co electrodes, an AlOx tunnel barrier, and an Al counter electrode. Since only one ferromagnetic electrode (Co) is present, spin-polarized transport is due to tunneling anisotropic magnetoresistance (TAMR). An in-plane TAMR ratio of approximately 0.7% has been measured at 5 K under application of a magnetic field of 800 mT. The magnetic switching behavior shows some remarkable features, which are attributed to the rotation of interfacial magnetic moments. This behavior can be ascribed to the magnetic coupling between the Co thin films and the newly formed Co/C60 hybridized interfacial states. Using the Tedrow-Meservey technique, the tunnel spin polarization of the Co/C60 interface was found to be 43%.

Synthesis of novel 1,8-acridinediones derivatives: Investigation of MDR reversibility on breast cancer cell lines T47D and tamoxifen-resistant T47D.

Multi drug resistance (MDR) is a serious obstacle in the management of breast cancer. Therefore, overcoming MDR using novel anticancer agents is a top priority for medicinal chemists. It was found that dihydropyridines lacking calcium antagonistic activity (e.g acridinediones) possess MDR modifier potency. In this study, the capability of four novel acridine-1,8-diones derivatives 3a-d were evaluated as MDR reversing agents. In addition, the relationship between structural properties and biological effects of synthesized compounds was discussed. In vitro cytotoxicity of acridine-1,8-diones 3a-d derivatives in combination with doxorubicin (DOX) on T47D and tomoxifen-resistant T47D (TAMR-6) breast cancer cell lines were investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. Drug resistant index (DRI), which is equal to the ratio of IC50 in drug-resistant cells over IC50 in drug-sensitive cells, was calculated for each substance. Flowcytometry experiments were also implemented to distinguish cells undergoing apoptosis from those undergoing necrosis. The results from MTT and flowcytometry experiments indicated that 1 nM 3c derivative along with DOX significantly (P<0.05) increased the DOX cytotoxicity in T47D and TAMR-6 breast cancer cell lines. Synthesized compounds 3a and 3b also at concentrations of 1 nM with DOX significantly increased the cytotoxicity of DOX on T47D and TAMR-6 breast cancer cell lines. Meanwhile, 3d derivative with DOX did not exhibit good synergistic effect on cytotoxic activity of DOX, and slightly increased DOX cytotoxicity in both cell lines. Our results proposed that 3c may be an attractive lead compound for further development as a chemotherapeutic agent for MDR breast cancer therapy in combination with routine chemotherapeutic agents such as DOX.

Influence of the local atom configuration on a hexagonal skyrmion lattice.

Spin-resolved scanning tunneling microscopy is used to reveal a commensurate hexagonal nanoskyrmion lattice in the hcp stacked Fe monolayer on Ir(111). The exact nature of the spin configuration is due to magnetic interactions between the Fe atoms and the Ir substrate, either originating from polarization effects, or due to a three-site hopping mechanism of the Dzyaloshinsky-Moriya interaction leading to a canting of the Dzyaloshinsky-Moriya vector with respect to the interface.

Why use a thermophilic aerobic membrane reactor for the treatment of industrial wastewater/liquid waste?

This paper describes the advantages of thermophilic aerobic membrane reactor (TAMR) for the treatment of high strength wastewaters. The results were obtained from the monitoring of an industrial and a pilot scale plant. The average chemical oxygen demand (COD) removal yield was equal to 78% with an organic loading rate (OLR) up to 8-10 kgCOD m(-3) d(-1) despite significant scattering of the influent wastewater composition. Total phosphorus (TP) was removed with a rate of 90%, the most important removal mechanism being chemical precipitation (as hydroxyapatite, especially), which is improved by the continuous aeration that promotes phosphorus crystallization. Moreover, surfactants were removed with efficiency between 93% and 97%. Finally, the experimental work showed that thermophilic processes (TPPs) are complementary with respect to mesophilic treatments.

Treatment of high strength pharmaceutical wastewaters in a Thermophilic Aerobic Membrane Reactor (TAMR).

In the present work we studied the thermophilic biological treatability of high strength liquid wastes from a pharmaceutical industry (rich in organic matter - COD: Chemical Oxygen Demand, nutrients and salinity). Different mixtures (with concentrations of COD, phosphorus and chloride up to 57,000 mg L(-1), 2000 mg L(-1) and 9000 mg L(-1), respectively) were tested. The pilot plant used in this work was designed and built with dimensions comparable to a semi-industrial unit. The results are therefore representative for full-scale applications. During four months of experimentation, the pilot plant (TAMR - Thermophilic Aerobic Membrane Reactor) was operated at 49 ± 1 °C and the organic loading rate was 1.5-5.5 kgCOD m(-3) d(-1) with a hydraulic retention time of 5-10 days. Main results are the following: a) extremely high COD removal rate (up to 98%); b) very low sludge production (∼0.016 kgVSS produced kgCOD removed(-1)); c) suitability as a pre-treatment to a conventional (e.g. activated sludge) biological treatment (the studied pharmaceutical industrial wastewaters are discharged into the sewer system for final polishing in a centralized municipal wastewater treatment plant) and d) high phosphorus removal (up to 99%).

Determination of heavy metals in the fruit of date palm growing at different locations of Riyadh.

Exposure of heavy metals to human beings has risen dramatically in the last 50 years. In today's urban and industrial society, there is no escaping from exposure to toxic chemicals and heavy metals. Humans are more likely to be exposed to heavy metal contamination from the dust that adheres to edible plants than from bioaccumulation. This is because it is very difficult to wash off all the dust particles from the plant material before ingesting them. The objectives of this experiment were to determine the concentrations of lead (Pb) and cadmium (Cd) in washing residues and in the tissues of fruits of date palm growing in 14 sites of Riyadh and also to assess whether the fruits were safe for human consumption. The washing residues and tissue of date palm fruits collected from different sites showed the presence of significant amounts of the Pb and Cd. The concentration of Pb in the dust and fruit tissue increased with increasing anthropogenic sources. Therefore, fruits of date palm might be used as a pollution indicator; it might be recommend that fruits of date palm could be safe for human consumption after washing. The mean concentration of Pb and Cd in all the samples collected from different sites is within the safe limits recommended by FAO/WHO.