Targeting gut microbial nitrogen recycling and cellular uptake of ammonium to improve bortezomib resistance in multiple myeloma.

The gut microbiome has been found to play a crucial role in the treatment of multiple myeloma (MM), which is still considered incurable due to drug resistance. In previous studies, we demonstrated that intestinal nitrogen-recycling bacteria are enriched in patients with MM. However, their role in MM relapse remains unclear. This study highlights the specific enrichment of Citrobacter freundii (C. freundii) in patients with relapsed MM. Through fecal microbial transplantation experiments, we demonstrate that C. freundii plays a critical role in inducing drug resistance in MM by increasing levels of circulating ammonium. The ammonium enters MM cells through the transmembrane channel protein SLC12A2, promoting chromosomal instability and drug resistance by stabilizing the NEK2 protein. We show that furosemide sodium, a loop diuretic, downregulates SLC12A2, thereby inhibiting ammonium uptake by MM cells and improving progression-free survival and curative effect scores. These findings provide new therapeutic targets and strategies for the intervention of MM progression and drug resistance.

[Latest Findings on the Mechanism of the Interaction Between Multiple Myeloma Cells and Bone Marrow Microenvironment].

Multiple myeloma (MM) is a hematologic malignancy of terminally differentiated plasma cells. The mechanisms of the pathogenesis and progression of MM include genetic abnormalities of the MM cells and the interaction between MM cells and bone marrow microenvironment (BMME). MM cells start malignant proliferation in BMME and contribute to the pathogenesis and progression of MM through direct or indirect interactions between cells and the extracellular matrix. Exploring the mechanism of interaction between MM cells and the microenvironment is crucial to improving our understanding of the pathogenesis and progression of MM and early diagnosis and treatment. In addition, the metabolic reprogramming of tumors is one of the key issues of oncology research. Herein, we summarized published findings on the the altered metabolic reprogramming of MM and the characteristics of MM metabolic-microbial interactions in order to gain an in-depth understanding of MM pathogenesis and progression and drug resistance mechanisms, and ultimately to explore for new strategies for MM treatment.

Identifying and tailoring C-N coupling site for efficient urea synthesis over diatomic Fe-Ni catalyst.

Electrocatalytic urea synthesis emerged as the promising alternative of Haber-Bosch process and industrial urea synthetic protocol. Here, we report that a diatomic catalyst with bonded Fe-Ni pairs can significantly improve the efficiency of electrochemical urea synthesis. Compared with isolated diatomic and single-atom catalysts, the bonded Fe-Ni pairs act as the efficient sites for coordinated adsorption and activation of multiple reactants, enhancing the crucial C-N coupling thermodynamically and kinetically. The performance for urea synthesis up to an order of magnitude higher than those of single-atom and isolated diatomic electrocatalysts, a high urea yield rate of 20.2 mmol h-1 g-1 with corresponding Faradaic efficiency of 17.8% has been successfully achieved. A total Faradaic efficiency of about 100% for the formation of value-added urea, CO, and NH3 was realized. This work presents an insight into synergistic catalysis towards sustainable urea synthesis via identifying and tailoring the atomic site configurations.

Oxygen Vacancy-Mediated Selective C-N Coupling toward Electrocatalytic Urea Synthesis.

The electrocatalytic C-N coupling for one-step urea synthesis under ambient conditions serves as the promising alternative to the traditional urea synthetic protocol. However, the hydrogenation of intermediate species hinders the efficient urea synthesis. Herein, the oxygen vacancy-enriched CeO2 was demonstrated as the efficient electrocatalyst with the stabilization of the crucial intermediate of *NO via inserting into vacant sites, which is conducive to the subsequent C-N coupling process rather than protonation, whereas the poor selectivity of C-N coupling with protonation was observed on the vacancy-deficient catalyst. The oxygen vacancy-mediated selective C-N coupling was distinguished and validated by the in situ sum frequency generation spectroscopy. The introduction of oxygen vacancies tailors the common catalyst carrier into an efficient electrocatalyst with a high urea yield rate of 943.6 mg h-1 g-1, superior than that of partial noble-metal-based electrocatalysts. This work provides novel insights into the catalyst design and developments of coupling systems.

Genetic Aberrations and Interaction of NEK2 and TP53 Accelerate Aggressiveness of Multiple Myeloma.

It has been previously shown that (never in mitosis gene A)-related kinase 2 (NEK2) is upregulated in multiple myeloma (MM) and contributes to drug resistance. However, the mechanisms behind this upregulation remain poorly understood. In this study, it is found that amplification of NEK2 and hypermethylation of distal CpG islands in its promoter correlate strongly with increased NEK2 expression. Patients with NEK2 amplification have a poor rate of survival and often exhibit TP53 deletion, which is an independent prognostic factor in MM. This combination of TP53 knockout and NEK2 overexpression induces asymmetric mitosis, proliferation, drug resistance, and tumorigenic behaviors in MM in vitro and in vivo. In contrast, delivery of wild type p53 and suppression of NEK2 in TP53-/- MM cell lines inhibit tumor formation and enhance the effect of Bortezomib against MM. It is also discovered that inactivating p53 elevates NEK2 expression genetically by inducing NEK2 amplification, transcriptionally by increased activity of cell cycle-related genes like E2F8 and epigenetically by upregulating DNA methyltransferases. Dual defects of TP53 and NEK2 may define patients with the poorest outcomes in MM with p53 inactivation, and NEK2 may serve as a novel therapeutic target in aggressive MM with p53 abnormalities.

Coupling Electrocatalytic Nitric Oxide Oxidation over Carbon Cloth with Hydrogen Evolution Reaction for Nitrate Synthesis.

NO is a harmful pollutant to the environment. The traditional removal of NO is hindered by the harsh operating conditions and sacrifice of value-added chemicals. Efficient electrocatalytic oxidation of NO was achieved over plasma-treated commercial carbon cloth, serving as a promising anode substitution reaction to couple with the hydrogen evolution reaction without consumption of hydrogen-containing resources. The introduction of carboxyl groups onto the carbon cloth boosted the electrocatalytic activity via the enhancement of NO chemisorption. Only potentials of 1.39 V and 1.07 V were applied to reach the current density of 10 mA cm-2 in neutral and acidic conditions, respectively, which is superior to the state-of-the-art electrocatalysts for oxygen evolution. Energy and environmental concerns on fossil-fuel-derived hydrogen production, ammonia manufacture and nitrate synthesis, are greatly alleviated. This work provides an original strategy to realize the resource utilization of NO, the sustainable nitrate synthesis and hydrogen production in a green and economical way.

Identifying the Geometric Site Dependence of Spinel Oxides for the Electrooxidation of 5-Hydroxymethylfurfural.

Co-based spinel oxides, which are of mixing valences with the presence of both Co2+ and Co3+ at different atom locations, are considered as promising catalysts for the electrochemical oxidation of 5-hydroxymethylfurfural (HMF). Identifying the role of each atom site in the electroxidation of HMF is critical to design the advanced electrocatalysts. In this work, we found that Co2+Td in Co3 O4 is capable of chemical adsorption for acidic organic molecules, and Co3+Oh play a decisive role in HMF oxidation. Thereafter, the Cu2+ was introduced in spinel oxides to enhance the exposure degree of Co3+ and to boost acidic adsorption and thus to enhance the electrocatalytic activity for HMF electrooxidation significantly.