Metformin promotes anti-tumor immunity in STK11 mutant NSCLC through AXIN1-dependent upregulation of multiple nucleotide metabolites

Background:Metformin has pleiotropic effects beyond glucose reduction,including tumor inhibition and immune regulation.It enhanced the anti-tumor effects of programmed cell death protein 1(PD-1)inhibitors in serine/threonine kinase 11(STK11)mutant non-small cell lung cancer(NSCLC)through an axis inhibition protein 1(AXIN1)-dependent manner.However,the alterations of tumor metabolism and metabolites upon metformin administration remain unclear.Methods:We performed untargeted metabolomics using liquid chromatography(LC)-mass spectrometry(MS)/MS system and conducted cell experiments to verify the results of bioinformatics analysis.Results:According to the Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway database,most metabolites were annotated into metabolism,including nucleotide metabolism.Next,the differentially expressed metabolites in H460(refers to H460 cells),H460_met(refers to metformin-treated H460 cells),and H460_KO_met(refers to metformin-treated Axin1-/-H460 cells)were distributed into six clusters based on expression patterns.The clusters with a reversed expression pattern upon metformin treatment were selected for further analysis.We screened out metabolic pathways through KEGG pathway enrichment analysis and found that multiple nucleotide metabolites enriched in this pathway were upregulated.Furthermore,these metabolites enhanced the cytotoxicity of activated T cells on H460 cells in vitro and can activate the stimulator of the interferon genes(STING)pathway independently of AXIN1.Conclusion:Relying on AXIN1,metformin upregulated multiple nucleotide metabolites which promoted STING signaling and the killing of activated T cells in STK11 mutant NSCLC,indicating a potential immunotherapeutic strategy for STK11 mutant NSCLC.

Surface characterization of metal oxides-supported activated carbon fiber catalysts for simultaneous catalytic hydrolysis of carbonyl sulfide and carbon disulfide

The sol–gel method was used to synthesize a series of metal oxides-supported activated carbon fiber (ACF) and the simultaneous catalytic hydrolysis activity of carbonyl sulfide (COS)and carbon disulfide (CS2) at relatively low temperatures of 60°C was tested.The effects of preparation conditions on the catalyst properties were investigated,including the kinds and amount of metal oxides and calcination temperatures.The activity tests indicated that catalysts with 5 wt.%Ni after calcining at 400°C (Ni(5)/ACF(400)) had the best performance for the simultaneous catalytic hydrolysis of COS and CS2.The surface and structure properties of prepared ACF were characterized by scanning electron microscope-energy disperse spectroscopy (SEM-EDS),Brunauer–Emmett–Teller (BET),X-ray diffraction (XRD),carbon dioxidetemperature programmed desorption (CO2-TPD) and diffuse reflectance Fourier transform infrared reflection (DRFTIR).And the metal cation defects were researched by electron paramagnetic resonance (EPR) method.The characterization results showed that the supporting of Ni on the ACF made the ACF catalyst show alkaline and increased the specific surface area and the number of micropores,then improved catalytic hydrolysis activity.The DRFTIR results revealed that-OH species could facilitate the hydrolysis of COS and CS2;-COO and-C–O species could facilitate the oxidation of catalytic hydrolysate H2S.And the EPR results showed that high calcination temperature conditions provide more active reaction center for the COS and CS2 adsorption.