Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), for which therapeutic options are limited. Strategies to promote intestinal tissue tolerance during aGVHD may improve patient outcomes. Using single-cell RNA sequencing, we identified a lipocalin-2 (LCN2)–expressing neutrophil population in mice with intestinal aGVHD. Transfer of LCN2-overexpressing neutrophils or treatment with recombinant LCN2 reduced aGVHD severity, whereas the lack of epithelial or hematopoietic LCN2 enhanced aGVHD severity and caused microbiome alterations. Mechanistically, LCN2 induced insulin-like growth factor 1 receptor (IGF-1R) signaling in macrophages through the LCN2 receptor SLC22A17, which increased interleukin-10 (IL-10) production and reduced major histocompatibility complex class II (MHCII) expression. Transfer of LCN2-pretreated macrophages reduced aGVHD severity but did not reduce graft-versus-leukemia effects. Furthermore, LCN2 expression correlated with IL-10 expression in intestinal biopsies in multiple cohorts of patients with aGVHD, and LCN2 induced IGF-1R signaling in human macrophages. Collectively, we identified a LCN2-expressing intestinal neutrophil population that reduced aGVHD severity by decreasing MHCII expression and increasing IL-10 production in macrophages. This work provides the foundation for administration of LCN2 as a therapeutic approach for aGVHD.

The cobalt alkyne complex [(prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS) is an auspicious lead, which exhibits its anticancer activity mainly by inhibition of both cyclooxygenases (COX-1 and COX-2). Since COX-2 participates in carcinogenesis, a selective inhibition of that isoenzyme is aimed. To study if fluorination increases the COX-2/COX-1 inhibition ratio of the lead, substitution was respectively performed in the positions 3, 4, 5, and 6 of the aromatic moiety. The complexes 3/4/5F-Co-ASS and to a much lower extent also 6F-Co-ASS showed cytotoxic, antimetabolic, and apoptotic effects in COX-1/2-positive HT-29 and MDA-MB-231 cells and remarkably less activity in the COX-1/2-negative MCF-7 cell line. The metabolic activity in MCF-7 cells was even unaffected up to a concentration of 40 μM. With exception of 6F-Co-ASS, the complexes strongly reduced the PGE₂ synthesis in HT-29 cells and all complexes inhibited COX-2 more effectively than COX-1 in an assay at isolated enzymes. These findings point to an interference in the COX cascade as part of the mode of antitumor action. The limited cellular effects of 6F-Co-ASS are related to its poor uptake as determined by HR CS AAS/MAS. Moreover, the cellular uptake studies confirm fluorination as beneficial tool for bioanalytical labeling. The higher quantification of fluorine by HR CS MAS makes this method about 5-fold more sensitive than HR CS AAS measuring cobalt. As a further positive result, 3/4/5/6-Co-ASS demonstrated high selectivity to tumor cells due to lack of antimetabolic activity against the non-tumorigenic bone marrow stromal cell line HS-5.

In continuation of the structure-activity study about 4-substituted chlorido[N,N′-disalicylidene-1,2-phenylenediamine]iron(III) complexes as necroptosis and ferroptosis inducers, we introduced a 4-COOH group at the 1,2-phenylenediamine moiety of the lead ([Fe(III)salopheneCl]) and derived the resulting complex 15 to the respective ethyl, propyl, or butyl amides (16–18) and esters (19–21). The compounds 16–21 exerted concentration-dependent antiproliferative and antimetabolic effects against HL-60 cells. The esters were more active than the analogous amides. Elongation of the alkyl chain enhanced the activity of the amides, while that of the esters decreased. The complexes 16–21 induced necroptosis and/or ferroptosis but not apoptosis. Studies on protein binding and uptake into HL-60 cells indicated that the complexes mainly accumulated by passive transport. The high binding tendency of all complexes to apo-Transferrin, however, points to participation of a carrier-mediated transport into the cells, too.

Bromido[3-ethyl-4-aryl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2H-imidazol-2-ylidene]gold(I) complexes (8a–h) with methoxy, methyl and fluorine substituents at different positions of the 4-aryl ring were synthesized and characterized. The relevance of the 2-methoxypyridin-5-yl residue and the substituents at the 4-aryl ring with regard to the activity against a series of cell lines was determined. Particularly against the Cisplatin-resistant ovarian cancer cell line A2780cis, the most active bromido[3-ethyl-4-(4-methoxyphenyl)-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2H-imidazol-2-ylidene]gold(I) complex 8c was more active than Auranofin. It also inhibited thioredoxin reductase more effectively and induced high amounts of reactive oxygen species in A2780cis cells. Furthermore, its influence on non-cancerous SV 80 lung fibroblasts was lower than that of Auranofin. This fact, together with a high accumulation rate in tumor cells, determined on the example of MCF-7 cells, makes this complex an interesting candidate for further extensive studies.