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De Souza, A.

Publications and source records attributed to De Souza, A..

2 recordsLinked to original sources

Untargeted metabolomics reveals key metabolites and genes underlying salinity tolerance mechanisms in maize

Understanding the physiological, metabolic, and genetic mechanisms underlying salt tolerance is essential for improving crop resilience and productivity, yet their complex interactions remain poorly defined. We compared physiological and metabolic responses to salinity between two contrasting maize inbred lines: the salt-sensitive C68 and the salt-tolerant NC326. The senstitivity of C68 was characterized by reduced shoot and root dry weights and plant height, high tissue accumulation of Na and Cl, but low K, and lower leaf proline accumulation compared to the salt-tolerant NC326. Untargeted metabolomics identified 56 metabolites categorized as constitutively upregulated or salt-responsive. In NC326, constitutive accumulation of flavonoids, including schaftoside, tricin, and kaempferol-related compounds in leaves suggests adaptive priming against oxidative stress, while constitutively higher lipids and fatty acids in roots may enhance membrane stability. Salt-responsive metabolites, notably antioxidants and lanosterol, highlighted inducible oxidative-stress mitigation and membrane-stabilization strategies. By integrating metabolomic and genetic analyses, we identified 10 candidate genes involved in the biosynthesis of key metabolites. These findings establish a comprehensive platform for functional validation of metabolites and candidate genes for developing maize varieties with improved resilience to soil salinity through targeted breeding or biotechnological strategies. Plane Language SummarySalinity, or high salt content in soil, is a major challenge to crop growth worldwide, reducing food production. Maize, an important crop globally, struggles to grow under salty conditions. This study compared two maize types--one that grows well in salty soil and one that struggles--to understand how maize plants adapt to salt stress. Using advanced techniques, we measured hundreds of compounds (metabolites) in plant tissues to identify protective substances. We discovered that plants resistant to salt stress naturally produce higher amounts of protective substances, helping them avoid damage from salt. Additionally, we found specific metabolites that plants produce when exposed to salty conditions to protect their cells. We also identified genes that control the production of these important metabolites. This research provides new insights into how maize plants manage salt stress and highlights potential targets for developing crops that grow better in saline soils. Core IdeasO_LIMaize genotypes differ in growth, ion balance, and proline under salt stress. C_LIO_LIMetabolomics reveals pre-stress buildup of protective flavonoids and fatty acids. C_LIO_LISalt triggers metabolic changes like sterol increase to protect membranes. C_LIO_LIGenetic analysis links genes to key metabolites controlling salt tolerance. C_LIO_LIMetabolite-gene insights guide breeding of maize for salt resilience C_LI

plant biology↗

Androgen receptor signaling blockade enhances NK cell-mediated killing of prostate cancer cells and sensitivity to NK cell checkpoint blockade

BackgroundThe blockade of the androgen receptor (AR) pathway is an effective treatment for prostate cancer (PCa), but many patients progress to metastatic castration-resistant prostate cancer (mCRPC). Treatments for mCRPC include AR inhibitors (ARi), chemotherapy, PARP inhibitors, and radioligands. Checkpoint inhibitor activity is limited to a small subset of MSI-H mCRPC. AR signaling modulates CD8+ T cell function, but its impact on natural killer (NK) cell cytotoxicity is unknown. We investigated the effect of ARi on NK cell activation, cytokine secretion, NKG2A expression, and NK cell-mediated killing of PCa cells in vitro. MethodsPCa cell lines (LNCaP, 22Rv1, DU145, PC3) were co-cultured with NK-92 and treated with ARi (enzalutamide [enza], darolutamide [daro]) alone or in combination with anti-NKG2A antibody monalizumab. Immune cell-mediated tumor cell killing and cytokine secretion were quantified. NK cell expression of NKG2A and PCa cell expression of HLA-E were investigated by flow cytometry. The AR-negative cell lines PC3 and DU145 were stably transduced with an AR expression vector to evaluate the AR modulation of HLA-E. To assess the in vivo combination of NKG2A blockade and ARi therapy in vivo, Cas9 was used to genetically ablate the murine HLA-E ortholog, H2-T23, from RM-1 murine PCa cells. H2-T23 knockout and control cells were grown subcutaneously in castrated C57BL/6 mice and treated with daro or control. The activation status of peripheral blood NK cell isolated from patients with PCa before and after initiation of androgen deprivation therapy (ADT) was evaluated by flow cytometry. ResultsARi activated NK cells and significantly increased immune-mediated NK-92 cell killing of PCa cells. IFN-{gamma} and TRAIL mediated ARi-induced NK cell activation. ARi increased expression of the inhibitory receptor NKG2A on NK cells, and immune killing of PCa cells was enhanced with the combination of ARi and monalizumab. ARi also increased the expression of HLA-E, the ligand of NKG2A, on PCa cell lines. By transducing AR into AR-negative PC3 and DU145, we demonstrated that androgen signaling regulates HLA-E expression. In a mouse model of PCa, HLA-E knockout synergized with darolutamide to increase NK cell activation. NK cells derived from patients with metastatic PCa exhibited increased expression of Granzyme B and Perforin following ARi treatment. ConclusionsARi activates NK cells via IFN-{gamma} and TRAIL and promotes the killing of PCa cells. ARi also upregulates expression of HLA-E on PCa which may suppress the innate immune response against PCa. ARi-mediated NK cell killing of PCa cells was enhanced by NKG2A blockade. These results support novel immunotherapeutic strategies for PCa targeting NK activation through the combination of ARi and monalizumab. Graphical AbstractAndrogen receptor inhibitors (ARi) enhance NK cell-mediated killing of prostate cancer cells and sensitivity to NK cell checkpoint NKG2A blockade. ARi upregulate the NK cell inhibitor ligand (HLA-E) mediating suppression NK cell killing of PCa. This regulation is dependent on a functional AR signal on tumor cell lines. Adding an anti-NKG2a-HLA-E mAb with ARi further enhances the NK cell-mediated killing of PCa. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/567201v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@ba35e6org.highwire.dtl.DTLVardef@128a2e7org.highwire.dtl.DTLVardef@def16aorg.highwire.dtl.DTLVardef@bb72e7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗