Question of CO’s Ability to Induce HO‑1 Expression in Cell Culture: A Comparative Study Using Different CO Sources

With the recognition of the endogenous signaling roles and pharmacological functions of carbon monoxide (CO), there is an increasing need to understand CO’s mechanism of actions. Along this line, chemical donors have been introduced as CO surrogates for ease of delivery, dosage control, and sometimes the ability to target. Among all of the donors, two ruthenium–carbonyl complexes, CORM-2 and -3, are arguably the most commonly used tools for about 20 years in studying the mechanism of actions of CO. Largely based on data using these two CORMs, there has been a widely accepted inference that the upregulation of heme oxygenase-1 (HO-1) expression is one of the key mechanisms for CO’s actions. However, recent years have seen reports of very pronounced chemical reactivities and CO-independent activities of these CORMs. We are interested in examining this question by conducting comparative studies using CO gas, CORM-2/-3, and organic CO donors in RAW264.7, HeLa, and HepG2 cell cultures. CORM-2 and CORM-3 treatment showed significant dose-dependent induction of HO-1 compared to “controls,” while incubation for 6 h with 250–500 ppm CO gas did not increase the HO-1 protein expression and mRNA transcription level. A further increase of the CO concentration to 5% did not lead to HO-1 expression either. Additionally, we demonstrate that CORM-2/-3 releases minimal amounts of CO under the experimental conditions. These results indicate that the HO-1 induction effects of CORM-2/-3 are not attributable to CO. We also assessed two organic CO prodrugs, BW-CO-103 and BW-CO-111. BW-CO-111 but not BW-CO-103 dose-dependently increased HO-1 levels in RAW264.7 and HeLa cells. We subsequently studied the mechanism of induction with an Nrf2-luciferase reporter assay, showing that the HO-1 induction activity is likely due to the activation of Nrf2 by the CO donors. Overall, CO alone is unable to induce HO-1 or activate Nrf2 under various conditions in vitro. As such, there is no evidence to support attributing the HO-1 induction effect of the CO donors such as CORM-2/-3 and BW-CO-111 in cell culture to CO. This comparative study demonstrates the critical need to consider possible CO-independent effects of a chemical CO donor before attributing the observed biological effects to CO. It is also important to note that such in vitro results cannot be directly extrapolated to in vivo studies because of the increased level of complexity and the likelihood of secondary and/or synergistic effects in the latter

Upregulation of p53 through induction of MDM2 degradation: improved potency through the introduction of an alkylketone sidechain on the anthraquinone core

Overexpression of ubiquitin ligase MDM2 causes depletion of the p53 tumour-suppressor and thus leads to cancer progression. In recent years, anthraquinone analogs have received significant attention due to their ability to downregulate MDM2, thereby promoting p53-induced apoptosis. Previously, we have developed potent anthraquinone compounds having the ability to upregulate p53 via inhibition of MDM2 in both cell culture and animal models of acute lymphocytic leukaemia. Earlier work was focussed on mechanistic work, pharmacological validation of this class of compounds in animal models, and mapping out structural space that allows for further modification and optimisation. Herein, we describe our work in optimising the substituents on the two phenol hydroxyl groups. It was found that the introduction of an alkylketone moiety led to a potent series of analogs with BW-AQ-350 being the most potent compound yet (IC50 = 0.19 ± 0.01 µM) which exerts cytotoxicity by inducing MDM2 degradation and p53 upregulation.</p

Additional file 1 of An atlas of cell-type-specific interactome networks across 44 human tumor types

Additional file 1: Table S1. The collection of scRNA-seq data used in this study. Table S2. The scRNA-seq datasets of solid tumor samples used in this study. Table S3. The scRNA-seq datasets of hematologic malignancy samples used in this study. Table S4. Curated marker genes for different cell types. Table S5. Curated marker genes for different immune cell subsets. Table S6. Information of four reference networks used in this study. Table S7. Curated COSMIC somatic mutation data for each solid tumor type. Table S8. Number of nodes and edges of cell-type-specific networks in each tumor type. Table S9. Number of nodes and edges of cell-subset-specific networks in pan-tumor TIMEs. Table S10. DisGeNET disease gene sets used in network performance evaluation. Table S11. Canonical marker genes for 8 cell subsets in myeloid cells of pan-tumor TIMEs. Table S12. The data collection of six ICB therapy cohorts

MOESM1 of Partial nitritation of stored source-separated urine by granular activated sludge in a sequencing batch reactor

Additional file 1. Additional table and figure

Energy-Transfer-Powered Sultine Synthesis

Molecules with precise sultine structures are particularly sought after since the function of a molecule depends on this interesting structure. Despite the positive pivotal significance of the sultines in synthesis, medicine, and materials science, the sultines’ chemistry long remains unexplored due to their inaccessibility; only very limited protocols have been developed. Here, we report an energy-transfer-powered intramolecular radical–radical cross-coupling cyclization for the practical and atom-economical assembly of otherwise challenging-to-access sultines under mild and operationally simple conditions using an inexpensive organic photocatalyst. Importantly, this work presents a practical method of trifluoromethyl radical generation from alkyl trifluoromethanesulfinate, and the obtained sultines were confirmed as promising electrolyte additives for high-voltage lithium batteries employing LiNi0.5Mn1.5O4 cathodes and carbonate electrolytes. Sultines were applied to build highly valuable sultones, mercaptoalkanols, and disulfides. Mechanistic studies and density functional theory calculations supported that the reaction likely proceeds through an energy-transfer-powered radical–radical cross-coupling cyclization process