Targeted single‐cell RNA sequencing analysis reveals metabolic reprogramming and the ferroptosis‐resistant state in hematologic malignancies

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Abstract

Hematologic malignancies are the most common hematopoietic diseases and a major public health concern. However, the mechanisms underlying myeloid tumors remain unknown owing to the intricate interplay between mutations and diverse clonal evolution patterns, as evidenced by the analysis of bulk cell-derived omics data. Several single-cell omics techniques have been used to characterize the hierarchies and altered immune microenvironments of hematologic malignancies. The comprehensive single-cell atlas of hematologic malignancies provides novel opportunities for personalized combinatorial targeted treatments, avoiding unwanted chemo-toxicity. In the present study, we performed transcriptome sequencing by combining single-cell RNA sequencing (scRNA-seq) with a targeted oncogenic gene panel for acute myeloid leukemia, overcoming the limitations of scRNA-seq in detecting oncogenic mutations. The distribution of oncogenic IDH1, IDH2, and KRAS mutations in each cell type was identified in the bone marrow (BM) samples of each patient. Our findings suggest that ferroptosis and metabolic reprogramming are involved in the tumorigenesis and chemotherapy resistance of oncogenic mutation-carrying cells. Biological progression via IDH1, IDH2, and KRAS mutations arrests hematopoietic maturation. Our study findings provide a rationale for using primary BM cells for personalized treatment in clinical settings.

Cold Plasma for Green Advanced Reduction/Oxidation Processes (AROPs) of Organic Pollutants in Water

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Cold Plasma for Green Advanced Reduction/Oxidation Processes (AROPs) of Organic Pollutants in Water**

Plasma activation: These extremely reactive milieux attack any organic compound, including the most refractory environmental pollutants, leading to their mineralization. Depending on the specific target, suitable plasma sources can be developed for best performance. Cold plasmas offer the promise of novel technologies for PFAS degradation in water under ambient conditions using only (green) energy.


Abstract

Cold plasma is gaining increasing attention as a novel tool to activate energy demanding chemical processes, including advanced reduction/oxidation processes (AROPs) of organic pollutants in water. The very complex milieu generated by discharges at the water/plasma interface comprises photons, strong oxidants and strong reductants which can be exploited for achieving the degradation of most any kind of pollutants. Despite the complexity of these systems, the powerful arsenal of mechanistic tools and chemical probes of physical organic chemists can be usefully applied to understand and develop plasma chemistry. Specifically, the added value of air plasma generated by in situ discharge with respect to ozonation (ex situ discharge) is demonstrated using phenol and various phenol derivatives and mechanistic evidence for the prevailing role of hydroxyl radicals in the initial attack is presented. On the reduction front, the impressive performance of cold plasma in inducing the degradation of recalcitrant perfluoroalkyl substances, which do not react with OH radicals but are attacked by electrons, is reported and discussed. The widely different reactivities of perfluorooctanoic acid (PFOA) and of perfluorobutanoic acid (PFBA) underline the crucial role played in these processes by the interface between plasma and solution and the surfactant properties of the treated pollutants.

Zn‐Based Metal–Organic Frameworks Using Triptycene Hexacarboxylate Ligands: Synthesis, Structure, and Gas‐Sorption Properties

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Zn-Based Metal–Organic Frameworks Using Triptycene Hexacarboxylate Ligands: Synthesis, Structure, and Gas-Sorption Properties

Two types of zinc MOF, Zn-X2Trp and Zn-X2PET (X=H, F, Cl, Br, I, Me, Et, Pr), with difunctionalized triptycene-hexacarboxylate ligands H6X2Trp and H6X2PET that differ in size have been synthesized. All of these Zn-MOFs show high thermal stability as well as H2- and CO2-adsorption capacities. Moreover, MOFs with smaller pore size showed higher H2 and CO2 adsorption. Thus, the introduction of methyl, chloro, and bromo substituents at the bridgehead positions of the triptycene ligands enhances the H2- and CO2-adsorption capacities.


Abstract

A series of metal–organic frameworks (MOFs) based on zinc ions and two triptycene ligands of different size have been synthesized under solvothermal conditions. Structural analyses revealed that they are isostructural 3D-network MOFs. The high porosity and thermal stability of these MOFs can be attributed to the highly rigid triptycene-based ligands. Their BET specific surface areas depend on the size of the triptycene ligands. In contrast to these surface-area data, the H2 and CO2 adsorption of these MOFs is larger for MOFs with small pores. Consequently, we introduced functional groups to the bridge-head position of the triptycene ligands and investigated their effect on the gas-sorption properties. The results unveiled the role of the functional groups in the specific CO2 binding via an induced interaction between adsorbates and the functional groups. Excellent H2 and CO2 properties in these MOFs were achieved in the absence of open metal sites.

Aluminium and Gallium Silylimides as Nitride Sources

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Aluminium and Gallium Silylimides as Nitride Sources**

Terminal aluminium and gallium silylimides have been accessed for the first time by exploiting the oxidative reactions of anionic aluminium(I)/gallium(I) (‘aluminyl’/’gallyl’) reagent with silylazides. These compounds feature minimal M=N π-bonding and can be shown to act as sources of the nitride ion, [N]3− in reactions with CO or N2O.


Abstract

Terminal aluminium and gallium imides of the type K[(NON)M(NR)], bearing heteroatom substituents at R, have been synthesised via reactions of anionic aluminium(I) and gallium(I) reagents with silyl and boryl azides (NON=4,5-bis(2,6-diisopropyl-anilido)-2,7-di-tert-butyl-9,9-dimethyl-xanthene). These systems vary significantly in their lability in solution: the N(SiiPr3) and N(Boryl) complexes are very labile, on account of the high basicity at nitrogen. Phenylsilylimido derivatives provide greater stabilization through the π-acceptor capabilities of the SiR3 group. K[(NON)AlN(SitBuPh2)] offers a workable compromise between stability and solubility, and has been completely characterized by spectroscopic, analytical and crystallographic methods. The silylimide species examined feature minimal π-bonding between the imide ligand and aluminium/gallium, with the HOMO and HOMO-1 orbitals effectively comprising orthogonal lone pairs centred at N. Reactivity-wise, both aluminium and gallium silylimides can act as viable sources of nitride, [N]3−, with systems derived from either metal reacting with CO to afford cyanide complexes. By contrast, only the gallium system K[(NON)Ga{N(SiPh3)}] is capable of effecting a similar transformation with N2O to yield azide, N3 −, via formal oxide/nitride metathesis. The aluminium systems instead generate RN3 via transfer of the imide fragment [RN]2−.

Beryllium‐Mediated Halide and Aryl Transfer onto Silicon

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Beryllium-Mediated Halide and Aryl Transfer onto Silicon

Ring opening of hexamethylcyclotrisoloxane with BeBr2, BeI2 and BePh2 was observed. These reactions yielded previously unknown diorgano bromo and iodo silanolates, [Be3Br2(OSiMe2Br)4] and [Be3I2(OSiMe2I)4], respectively, as well as [Be3Ph2(OSiMe2Ph)4]. Hydrolysis of these beryllium silanolates revealed that dimethyl bromo and iodo silanol are unstable and react to various cyclic cyclosiloxanes.


Abstract

The reactivity of hexamethylcyclotrisiloxane (D3) towards BeCl2, BeBr2, BeI2 and [Be3Ph6]3 was investigated. While BeCl2 only showed unselective reactivity, BeBr2, BeI2 and [Be3Ph6] cleanly react to the trinuclear complexes [Be3Br2(OSiMe2Br)4], [Be3I2(OSiMe2I)4] and [Be3Ph2(OSiMe2Ph)4]. These unprecedented bromide, iodide and phenyl transfer reactions from a group II metal onto silicon offer a versatile access to previously unknown diorgano bromo and iodo silanolates.

Polyfluoroalkyl Chain‐Based Assemblies for Biomimetic Catalysis

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Amphiphobic fluoroalkyl chains are exploited for creating robust and diverse self-assembled biomimetic catalysts in aqueous solution. Long terminal perfluoroalkyl chains (CnF2n+1 with n = 6, 8, and 10) yoked with a short perhydroalkyl chains (CmH2m with m = 2 and 3) were used to synthesize several 1,4,7-triazacyclononane (TACN) derivatives, CnF2n+1-CmH2m-TACN. In the presence of an equimolar amount of Zn2+ ions that coordinate the TACN moiety and drive the self-assembly into micelle-like aggregates, the critical aggregation concentration of polyfluorinated CnF2n+1-CmH2mTACN·Zn2+ was lowered by ~1 order of magnitude compared to the traditional perhyroalkyl counterpart with identical carbon number of alkyl chain. When 2’-hydroxypropyl-4-nitrophenyl phosphate was used as the model phosphate substrate, polyfluorinated CnF2n+1CmH2m-TACN·Zn2+ assemblies showed higher affinity and catalytic activity, compared to its perhyroalkyl chain-based counterpart. Coarse-grained molecular dynamic simulations have been introduced to explore the supramolecular assembly of polyfluoroalkyl chains in the presence of Zn2+ ions and to better understand their enhanced catalytic activity.

9‐Azahomocubane

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Homocubane, a highly strained cage hydrocarbon, contains two very different positions for the introduction of a nitrogen atom into the skeleton, e.g., a position 1 exchange results in a tertiary amine whereas position 9 yields a secondary amine. Herein reported is the synthesis of 9-azahomocubane along with associated structural characterization, physical property analysis and chemical reactivity. Not only is 9-azahomocubane readily synthesized, and found to be stable as predicted, the basicity of the secondary amine was observed to be significantly lower than the structurally related azabicyclo[2.2.1]heptane, although similar to 1-azahomocubane.

Cross‐Binding of Adenosine by Aptamers Selected Using Theophylline

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Cross-Binding of Adenosine by Aptamers Selected Using Theophylline

The newly selected DNA aptamer for theophylline can also bind adenosine, whereas the classical RNA aptamer cannot. Theophylline and adenosine are related molecules in regulating sleep, suggesting that nucleic acids also have the chemical basis for a similar function.


Abstract

We recently reported that some adenosine binding aptamers can also bind caffeine and theophylline with around 20-fold lower affinities. This discovery led to the current work to examine the cross-binding of adenosine to theophylline aptamers. For the DNA aptamer for theophylline, cross-binding to adenosine was observed, and the affinity was 18 to 38-fold lower for adenosine based on assays using isothermal titration calorimetry and ThT fluorescence spectroscopy. The binding complexes were characterized using NMR spectroscopy, and both adenosine and theophylline showed an overall similar binding structure to the DNA theophylline aptamer, although small differences were also observed. In contrast, the RNA aptamer did not show binding to adenosine, although both aptamers have very similar relative selectivity for various methylxanthines including caffeine. After a negative selection, a few new aptamers with completely different primary sequences for theophylline were obtained and they did not show binding to adenosine. Thus, there are many ways for aptamers to bind theophylline and some can have cross-binding to adenosine. In biology, theophylline, caffeine, and adenosine can bind to the same protein receptors to regulate sleep, and their binding to the same DNA motifs may suggest an early role of nucleic acids in similar regulatory functions.

Covalent Targeting of Glutamate Cysteine Ligase to Inhibit Glutathione Synthesis

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Covalent Targeting of Glutamate Cysteine Ligase to Inhibit Glutathione Synthesis**

We have discovered a covalent inhibitor of glutamate-cysteine ligase (GCL) that targets an allosteric C114 in the regulatory subunit GCLM to inhibit GCL activity, lower GSH levels, and impair cell viability in ARID1A-negative cancer cells.


Abstract

Dysregulated oxidative stress plays a major role in cancer pathogenesis and some types of cancer cells are particularly vulnerable to inhibition of their cellular antioxidant capacity. Glutamate-cysteine ligase (GCL) is the first and rate-limiting step in the synthesis of the major cellular antioxidant glutathione (GSH). Developing a GCL inhibitor may be an attractive therapeutic strategy for certain cancer types that are particularly sensitive to oxidative stress. In this study, we reveal a cysteine-reactive ligand, EN25, that covalently targets an allosteric cysteine C114 on GCLM, the modifier subunit of GCL, and leads to inhibition of GCL activity. This interaction also leads to reduced cellular GSH levels and impaired cell viability in ARID1A-deficient cancer cells, which are particularly vulnerable to glutathione depletion, but not in ARID1A-positive cancer cells. Our studies uncover a novel potential ligandable site within GCLM that can be targeted to inhibit GSH synthesis in vulnerable cancer cell types.

Deriving Novel Quaternary Ammonium Compound Disinfectant Scaffolds from a Natural Product: Mechanistic Insights of the Quaternization of Ianthelliformisamine C

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Deriving Novel Quaternary Ammonium Compound Disinfectant Scaffolds from a Natural Product: Mechanistic Insights of the Quaternization of Ianthelliformisamine C

In the search for polypharmacological quaternary ammonium compound disinfectants, we sought to investigate the quaternization of the ianthelliformisamine C scaffold. We synthesized a small library of quaternary ammonium compounds, finding that the tetramethyl derivative had the best activity. We investigated the mechanism of action of the natural product and methylated derivative, finding that both permeabilized the membrane.


Abstract

In the search for novel quaternary ammonium compound (QAC) disinfectants that can evade bacterial resistance, we turned to natural products as a source of inspiration. Herein we used natural product ianthelliformisamine C as a scaffold to design a small library of QACs. We first synthesized ianthelliformisamine C via an amide coupling that allowed for facile purification without the need for protecting groups. We then alkylated and quaternized the internal amines to yield four novel QACs, but all but one demonstrated no antibacterial activity against the tested strains. Using a combination of membrane depolarization and permeabilization assays, we were able to demonstrate that ianthelliformisamine C and the active QAC analog enact cell death via membrane permeabilization, contrary to prior reports on ianthelliformisamine C's mechanism of action.