Iron-based metal-organic framework co-loaded with buthionine sulfoximine and oxaliplatin for enhanced cancer chemo-ferrotherapy via sustainable glutathione elimination.

BACKGROUND: Emerging ferroptosis-driven therapies based on nanotechnology function either by increasing intracellular iron level or suppressing glutathione peroxidase 4 (GPX4) activity. Nevertheless, the therapeutic strategy of simultaneous iron delivery and GPX4 inhibition remains challenging and has significant scope for improvement. Moreover, current nanomedicine studies mainly use disulfide-thiol exchange to deplete glutathione (GSH) for GPX4 inactivation, which is unsatisfactory because of the compensatory effect of continuous GSH synthesis. METHODS: In this study, we design a two-in-one ferroptosis-inducing nanoplatform using iron-based metal-organic framework (MOF) that combines iron supply and GPX4 deactivation by loading the small molecule buthionine sulfoxide amine (BSO) to block de novo GSH biosynthesis, which can achieve sustainable GSH elimination and dual ferroptosis amplification. A coated lipid bilayer (L) can increase the stability of the nanoparticles and a modified tumor-homing peptide comprising arginine-glycine-aspartic acid (RGD/R) can achieve tumor-specific therapies. Moreover, as a decrease in GSH can alleviate resistance of cancer cells to chemotherapy drugs, oxaliplatin (OXA) was also loaded to obtain BSO&OXA@MOF-LR for enhanced cancer chemo-ferrotherapy in vivo. RESULTS: BSO&OXA@MOF-LR shows a robust tumor suppression effect and significantly improved the survival rate in 4T1 tumor xenograft mice, indicating a combined effect of dual amplified ferroptosis and GSH elimination sensitized apoptosis. CONCLUSION: BSO&OXA@MOF-LR is proven to be an efficient ferroptosis/apoptosis hybrid anti-cancer agent. This study is of great significance for the clinical development of novel drugs based on ferroptosis and apoptosis for enhanced cancer chemo-ferrotherapy.

Integrated microbiological and metabolomics analyses to understand the mechanism that allows modified biochar to affect the alkalinity of saline soil and winter wheat growth.

In order to understand the mechanism that allows modified biochar (BC) to enhance the salt tolerance and growth of crops in saline-alkali soil, we tested the effects of ordinary BC, nanoparticle-size BC, acidified BC (HBC), and acidified nanoparticle-size BC on winter wheat growth and the soil properties by combining microbiological and metabolomics analyses. The results showed that compared with the control with no BC, the plant height increased by 17.33 % under HBC and the proportion of large soil aggregates increased by 1.25-2.83 times. HBC increased the relative abundances of some dominant genera of bacteria (e.g., Streptococcus) and fungi (e.g., Mycothermus), as well as functions such as bacterial metabolic genetic information processing and cellular processes, and reduced the abundance of pathotrophic fungi. Metabolomics analysis showed that HBC upregulated various metabolites (including amino acids and their derivatives, lipids, flavonoids, and organic acids) and five main metabolic pathways. Among the KEGG pathways, the pyrimidine metabolism pathway was significantly upregulated, as well as crop leaf metabolism, ß-alanine metabolism, and valine, leucine, and isoleucine metabolism, and the antioxidant levels and resistance to salt-alkali stress were enhanced in winter wheat leaves. Partial least squares-path modeling suggested that HBC affected the growth of winter wheat by significantly changing the soil physicochemical properties and microbial structure (path coefficients of 0.566 and 0.512, respectively).

Bioorthogonally activatable cyanine dye with torsion-induced disaggregation for in vivo tumor imaging.

Advancement of bioorthogonal chemistry in molecular optical imaging lies in expanding the repertoire of fluorophores that can undergo fluorescence signal changes upon bioorthogonal ligation. However, most available bioorthogonally activatable fluorophores only emit shallow tissue-penetrating visible light via an intramolecular charge transfer mechanism. Herein, we report a serendipitous "torsion-induced disaggregation (TIDA)" phenomenon in the design of near-infrared (NIR) tetrazine (Tz)-based cyanine probe. The TIDA of the cyanine is triggered upon Tz-transcyclooctene ligation, converting its heptamethine chain from S-trans to S-cis conformation. Thus, after bioorthogonal reaction, the tendency of the resulting cyanine towards aggregation is reduced, leading to TIDA-induced fluorescence enhancement response. This Tz-cyanine probe sensitively delineates the tumor in living mice as early as 5 min post intravenous injection. As such, this work discovers a design mechanism for the construction of bioorthogonally activatable NIR fluorophores and opens up opportunities to further exploit bioorthogonal chemistry in in vivo imaging.

Changes in antibiotic resistance genes and mobile genetic elements during cattle manure composting after inoculation with Bacillus subtilis.

This study explored the effects of Bacillus subtilis at four levels (0, 0.5%, 1%, and 2% w/w compost) on the variations in ARGs, mobile genetic elements (MGEs), and the bacterial community during composting. The composting process had a greater impact on ARGs than Bacillus subtilis. The main ARG detected was sul1. The addition of Bacillus subtilis at 0.5% reduced the relative abundances of ARGs, MGEs, and human pathogenic bacteria (by 2-3 logs) in the mature products. Network and redundancy analyses suggested that intI1, Firmicutes, and pH were mainly responsible for the changes in ARGs, thus controlling these factors might help to inhibit the spread of ARGs.