by Keyword: Sex-differences
Bernabeu, M, Prieto, A, Salguero, D, Miro, L, Cabrera-Rubio, R, Collado, M C, Huttener, M, Perez-Bosque, A, Juarez, A, (2024). Infection of mice by the enteroaggregative E. coli strain 042 and two mutant derivatives overexpressing virulence factors: impact on disease markers, gut microbiota and concentration of SCFAs in feces Scientific Reports 14, 16945 
Several pathogenic Escherichia coli strains cause diarrhea. Enteroaggregative E. coli (EAEC) strains are one of the diarrheagenic pathotypes. EAEC cells form a "stacked-brick" arrangement over the intestinal epithelial cells. EAEC isolates express, among other virulence determinants, the AggR transcriptional activator and the aggregative adherence fimbriae (AAF). Overexpression of the aggR gene results in increased expression of virulence factors such as the aff genes, as well as several genes involved in specific metabolic pathways such as fatty acid degradation (fad) and arginine degradation (ast). To support the hypothesis that induction of the expression of some of these pathways may play a role in EAEC virulence, in this study we used a murine infection model to evaluate the impact of the expression of these pathways on infection parameters. Mice infected with a mutant derivative of the EAEC strain 042, characterized by overexpression of the aggR gene, showed increased disease symptoms compared to those exhibited by mice infected with the wild type (wt) strain 042. Several of these symptoms were not increased when the infecting mutant, which overexpressed aggR, lacked the fad and ast pathways. Therefore, our results support the hypothesis that different metabolic pathways contribute to EAEC virulence.
JTD Keywords: Adherence, Aggr, Burde, Chain fatty-acids, Children, Enteroaggregative e. coli, Escherichia-coli, Etiology, Infection, Mice, Microbiota, Persistent diarrhea, Protein, Scfa, Sex-differences
Pepe, G, Sfogliarini, C, Rizzello, L, Battaglia, G, Pinna, C, Rovati, G, Ciana, P, Brunialti, E, Mornata, F, Maggi, A, Locati, M, Vegeto, E, (2021). ER alpha-independent NRF2-mediated immunoregulatory activity of tamoxifen Biomedicine & Pharmacotherapy 144, 112274
Sex differences in immune-mediated diseases are linked to the activity of estrogens on innate immunity cells, including macrophages. Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) used in estrogen receptor-alpha (ER alpha)-dependent breast cancers and off-target indications such as infections, although the immune activity of TAM and its active metabolite, 4-OH tamoxifen (4HT), is poorly characterized. Here, we aimed at investigating the endocrine and immune activity of these SERMs in macrophages. Using primary cultures of female mouse macrophages, we analyzed the expression of immune mediators and activation of effector functions in competition experiments with SERMs and 17 beta-estradiol (E2) or the bacterial endotoxin LPS. We observed that 4HT and TAM induce estrogen antagonist effects when used at nanomolar concentrations, while pharmacological concentrations that are reached by TAM in clinical settings regulate the expression of VEGF alpha and other immune activation genes by ER alpha- and G protein-coupled receptor 1 (GPER1)-independent mechanisms that involve NRF2 through PI3K/Akt-dependent mechanisms. Importantly, we observed that SERMs potentiate cell phagocytosis and modify the effects of LPS on the expression of inflammatory cytokines, such as TNF alpha and IL1 beta, with an overall increase in cell inflammatory phenotype, further sustained by potentiation of IL1 beta secretion through caspase-1 activation.
JTD Keywords: drug repurposing, inflammation, macrophage, nrf2, Apoptosis, Breast-cancer, Drug repurposing, Expression, Inflammation, Macrophage, Nrf2, Resistance, Sex-differences, Tamoxifen, Tumor-associated macrophages
