ABSTRACT
Acute myeloid leukemia (AML) is an aggressive, often fatal hematopoietic malignancy. All-trans retinoic acid (atRA), one of the first molecularly targeted drugs in oncology, has greatly improved the outcome of a subtype of AML, acute promyelocytic leukemia (APL). In contrast, atRA has so far provided little therapeutic benefit in the much larger group of patients with non-APL AML. Attempts to identify genetically or molecularly defined subgroups of patients that may respond to atRA have not yielded consistent results. Since AML is a stem cell-driven disease, understanding the effectiveness of atRA may require an appreciation of its impact on AML stem cells. Recent studies reported that atRA decreased stemness of AML with an FLT3-ITD mutation, yet increased it in AML1-ETO driven or EVI1-overexpressing AML. This review summarizes the role of atRA in normal hematopoiesis and in AML, focusing on its impact on AML stem cells.
Subject(s)
Leukemia, Myeloid, Acute/drug therapy , Leukemia, Promyelocytic, Acute/drug therapy , Neoplastic Stem Cells/drug effects , Tretinoin/pharmacology , Animals , Apoptosis/drug effects , Hematopoiesis/drug effects , HumansABSTRACT
The semiconductor manufacturing sector plans to introduce III/V film structures (eg, gallium arsenide (GaAs), indium arsenide (InAs) onto silicon wafers due to their high electron mobility and low power consumption. Aqueous solutions generated during chemical and mechanical planarization of silicon wafers can contain a mixture of metal oxide nanoparticles (NPs) and soluble indium, gallium, and arsenic. In this work, the cytotoxicity induced by Ga- and In-based NPs (GaAs, InAs, Ga2O3, In2O3) and soluble III-V salts on human bronchial epithelial cells (16HBE14o-) was evaluated using a cell impedance real-time cell analysis (RTCA) system. The RTCA system provided inhibition data at different concentrations for multiple time points, for example, GaAs (25 mg/L) caused 60% inhibition after 8 hours of exposure and 100% growth inhibition after 24 hours. Direct testing of As(III) and As(V) demonstrated significant cytotoxicity with 50% growth inhibition concentrations after 16-hour exposure (IC50) of 2.4 and 4.5 mg/L, respectively. Cell signaling with rapid rise and decrease in signal was unique to arsenic cytotoxicity, a precursor of strong cytotoxicity over the longer term. In contrast with arsenic, soluble gallium(III) and indium(III) were less toxic. Whereas the oxide NPs caused low cytotoxicity, the arsenide compounds were highly inhibitory (IC50 of GaAs and InAs = 6.2 and 68 mg/L, respectively). Dissolution experiments over 7 days revealed that arsenic was fully leached from GaAs NPs, whereas only 10% of the arsenic was leached out of InAs NPs. These results indicate that the cytotoxicity of GaAs and InAs NPs is largely due to the dissolution of toxic arsenic species.
Subject(s)
Epithelial Cells/drug effects , Gallium/toxicity , Indium/toxicity , Metal Nanoparticles/toxicity , Oxides/toxicity , Arsenicals/chemistry , Bronchi/cytology , Cell Line , Cell Survival/drug effects , Drug Liberation , Electric Impedance , Endocytosis , Epithelial Cells/metabolism , Epithelial Cells/ultrastructure , Gallium/chemistry , Humans , Indium/chemistry , Metal Nanoparticles/chemistry , Microscopy, Electron, TransmissionABSTRACT
This study describes the effects of graphene oxide (GO) and reduced graphene oxide (rGO) on the acetoclastic, hydrogenotrophic and methylotrophic pathways of methanogenesis by an anaerobic consortium. The results showed that GO negatively affected the hydrogenotrophic and acetoclastic pathways at a concentration of 300 mg/L, causing a decrease of ~ 38% on the maximum specific methanogenic activity (MMA) with respect to the controls lacking GO. However, the presence of rGO (300 mg/L) promoted an improvement of the MMA (> 45%) achieved with all substrates, except for the hydrogenotrophic pathway, which was relatively insensitive to rGO. The presence of either rGO or GO enhanced the methylotrophic pathway and resulted in an increase of the MMA of up to 55%. X-ray photoelectron spectroscopy (XPS) analysis revealed that GO underwent microbial reduction during the incubation period. Electrons derived from substrates oxidation were deviated from methanogenesis towards the reduction of GO, which may explain the MMA decreased observed in the presence of GO. Furthermore, XPS evidence indicated that the extent of GO reduction depended on the metabolic pathway triggered by a given substrate.
Subject(s)
Graphite , Biodegradation, Environmental , Oxidation-Reduction , Photoelectron SpectroscopyABSTRACT
III-V semiconductor materials such as gallium arsenide (GaAs) and indium arsenide (InAs) are increasingly used in the fabrication of electronic devices. There is a growing concern about the potential release of these materials into the environment leading to effects on public and environmental health. The waste effluents from the chemical mechanical planarization process could impact microorganisms in biological wastewater treatment systems. Currently, there is only limited information about the inhibition of gallium- and indium-based nanoparticles (NPs) on microorganisms. This study evaluated the acute toxicity of GaAs, InAs, gallium oxide (Ga2O3), and indium oxide (In2O3) particulates using two microbial inhibition assays targeting methanogenic archaea and the marine bacterium, Aliivibrio fischeri. GaAs and InAs NPs were acutely toxic towards these microorganisms; Ga2O3 and In2O3 NPs were not. The toxic effect was mainly due to the release of soluble arsenic species and it increased with decreasing particle size and with increasing time due to the progressive corrosion of the NPs in the aqueous bioassay medium. Collectively, the results indicate that the toxicity exerted by the arsenide NPs under environmental conditions will vary depending on intrinsic properties of the material such as particle size as well as on the dissolution time and aqueous chemistry.
Subject(s)
Aliivibrio fischeri/drug effects , Gallium/toxicity , Indium/toxicity , Nanoparticles/toxicity , Water Pollutants, Chemical/toxicity , Aliivibrio fischeri/metabolism , Arsenicals/chemistry , Gallium/chemistry , Indium/chemistry , Methane/biosynthesis , Nanoparticles/chemistry , Particle Size , Semiconductors , Sewage/microbiology , Surface Properties , Water Pollutants, Chemical/chemistry , Water Purification/methodsABSTRACT
A detannified methanolic extract of Scrophularia lucida L. attenuated the formation of cancer cell-induced circular chemorepellent induced defects (CCIDs) in the lymph endothelial cell barrier, which resemble entry ports for the intravasating tumor into the vasculature as a prerequisite for lymph node metastasis. Therefore, the composition of this extract was studied in an activity-guided approach. Since no data on the secondary metabolites of this plant were available, first phytochemical data were collected in the course of the fractionation of the extract. The study resulted in the identification of 14 substances, among them very rare iridoids, such as scrovalentinoside or koelzioside, and several flavonoids (e.g., nepitrin and homoplantaginin). One of the latter group, 2â³-O-acetyl-homoplantaginin, is a new natural compound. In the most active fraction, the flavonoid hispidulin was identified as major component and the assay of the pure compound confirmed a contribution of hispidulin to the CCID-inhibitory effects of S. lucida. The activity of the two major iridoids in this assay was less compared to hispidulin.
ABSTRACT
Flavonoids, present in fruits, vegetables and traditional medicinal plants, show anticancer effects in experimental systems and are reportedly non-toxic. This is a favorable property for long term strategies for the attenuation of lymph node metastasis, which may effectively improve the prognostic states in breast cancer. Hence, we studied two flavonoids, apigenin and luteolin exhibiting strong bio-activity in various test systems in cancer research and are readily available on the market. This study has further advanced the mechanistic understanding of breast cancer intravasation through the lymphatic barrier. Apigenin and luteolin were tested in a three-dimensional (3-D) assay consisting of MDA-MB231 breast cancer spheroids and immortalized lymph endothelial cell (LEC) monolayers. The 3-D model faithfully resembles the intravasation of breast cancer emboli through the lymphatic vasculature. Western blot analysis, intracellular Ca2+ determination, EROD assay and siRNA transfection revealed insights into mechanisms of intravasation as well as the anti-intravasative outcome of flavonoid action. Both flavonoids suppressed pro-intravasative trigger factors in MDA-MB231 breast cancer cells, specifically MMP1 expression and CYP1A1 activity. A pro-intravasative contribution of FAK expression in LECs was established as FAK supported the retraction of the LEC monolayer upon contact with cancer cells thereby enabling them to cross the endothelial barrier. As mechanistic basis, MMP1 caused the phosphorylation (activation) of FAK at Tyr397 in LECs. Apigenin and luteolin prevented MMP1-induced FAK activation, but not constitutive FAK phosphorylation. Luteolin, unlike apigenin, inhibited MMP1-induced Ca2+ release. Free intracellular Ca2+ is a central signal amplifier triggering LEC retraction through activation of the mobility protein MLC2, thereby enhancing intravasation. FAK activity and Ca2+ levels did not correlate. This implicates that the pro-intravasative contribution of FAK and of Ca2+ release in LECs was independent of each other and explains the better anti-intravasative effects of luteolin in vitro. In specific formulations, flavonoid concentrations causing significant anti-intravasative effects, can certainly be achieved in vivo. As the therapeutic strategy has to be based on permanent flavonoid treatment both the beneficial and adverse effects have to be investigated in future studies.
ABSTRACT
This research investigated the use of an electrochemical system for regenerating ion-exchange media and for promoting the crystallization of hardness minerals in a fluidized bed crystallization reactor (FBCR). The closed-loop process eliminates the creation of waste brine solutions that are normally produced when regenerating ion-exchange media. A bipolar membrane electrodialysis stack was used to generate acids and bases from 100 mM salt solutions. The acid was used to regenerate weak acid cation (WAC) ion-exchange media used for water softening. The base solutions were used to absorb CO2 gas and to provide a source of alkalinity for removing noncarbonate hardness by WAC media operated in H(+) form. The base solutions were also used to promote the crystallization of CaCO3 and Mg(OH)2 in a FBCR. The overall process removes hardness ions from the water being softened and replaces them with H(+) ions, slightly decreasing the pH value of the softened water. The current utilization efficiency for acid and base production was â¼75% over the operational range of interest, and the energy costs for producing acids and bases were an order of magnitude lower than the costs for purchasing acid and base in bulk quantities. Ion balances indicate that the closed-loop system will accumulate SO4(2-), Cl(-), and alkali metal ions. Acid and base balances indicate that for a typical water, small amounts of base will be accumulated.