International Journal of Molecular Sciences

Saccharomyces boulardii (Sb) is a probiotic yeast amenable to genetic manipulation, making it a promising platform for delivery of recombinant biotherapeutics to the intestinal lumen. In this study, we engineered a recombinant Sb strain to display an anti-CD3 single-chain variable fragment (scFv) on its surface and evaluated its potential as an oral antibody delivery system. To improve antibody accessibility, we tested different stalk lengths between the scFv and the SED1 anchoring domain. The strain with the longer stalk domain (Sb649) showed more stable surface display over time and was subsequently evaluated in a dextran sulfate sodium (DSS)-induced colitis model. Sb649-treated mice showed body weight values and disease activity profiles closer to those of healthy controls. Sb649 administration was also associated with transcriptional changes, including increased Foxp3 expression and no increase in Il6 in mesenteric lymph nodes, unlike DSS and DSS+SbWT-treated mice, along with increased Muc3 expression in the colon compared to DSS-treated mice. Together, these findings show that engineered Sb can stably display antibody fragments and support its potential as a platform for oral delivery of antibody-based immunotherapies to the gastrointestinal tract.

Acute myeloid leukemia (AML) is an increasingly recognized malignancy sustained by a dysregulated inflammatory niche, in which genetic alterations and microenvironmental signaling converge to drive pathogenesis. This review synthesizes emerging evidence linking genetic mutations and immune dysregulation in AML, proposing an integrated mutation-macrophage-signal transducer and activator of transcription 3 (STAT3) axis as a conceptual framework of disease progression. It proposes that mutations in CCAAT/enhancer-binding protein alpha (CEBPA) and Runt-related transcription factor 1 (RUNX1), despite conferring divergent genetic risk, converge on a common pathway of inflammatory cytokine overproduction, including interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10), as well as C-C motif chemokine ligand 2 (CCL2)-mediated recruitment of tumor-associated macrophages. These educated macrophages are proposed to undergo M2-like polarization, releasing oncostatin M (OSM) and IL-6, which are positioned to activate the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) survival pathway in leukemic blasts. Concurrently, IL-10 produced by regulatory T cells, stromal cells, and M2-like polarized macrophages within the leukemic niche signals through its cognate receptor to potently activate STAT3, suppressing antigen-presenting cell function, downregulating major histocompatibility complex class II (MHC class II) expression, and impairing effective anti-tumor T-cell immunity, thereby potentially reinforcing the immunosuppressive architecture that shields leukemic blasts from immune surveillance. This proposed feed-forward loop is associated with transcriptional upregulation of the anti-apoptotic factor BCL2-like 1 (BCL2L1) and the negative-feedback regulator suppressor of cytokine signaling 3 (SOCS3), a pattern consistent with chemoresistance and impaired negative-feedback control of STAT3 signaling. Translational biomarkers, including OSM, IL-6, IL-10, and SOCS3/BCL2L1 transcripts, may quantify this axis, offering a dynamic, functional complement to static genetic risk stratification. Ultimately, this proposed triad suggests that aberrant inflammation may represent a shared therapeutic vulnerability; targeting the IL-6/oncostatin M receptor (OSMR)/STAT3 signaling nodes or reprogramming macrophage polarization could, if validated, disrupt this circuit in selected mutational subtypes.

Placental dysfunction is a major component of several pregnancy complications, particularly preeclampsia and fetal growth restriction (FGR). These disorders could be presented with different phenotypes based on abnormal placentation and inadequate maternal vascular adaptation, which are baseline mechanisms in affected pregnancies. Defective trophoblast invasion and incomplete transformation of the maternal spiral arteries may produce a high-resistance uteroplacental circulation, resulting in placental hypo-perfusion, ischemia–reperfusion injury, oxidative stress and subsequent release of factors that affect maternal endothelial function. The aim of this review is to summarize the current understanding of pro-angiogenic and anti-angiogenic factors in early placental dysfunction, with special emphasis in their biological function and molecular roles, relationship with abnormal placentation and clinical significance during pregnancy. The development of placental dysfunction is generally understood as a multifactorial and multistep process. The literature evidence most often supports the three-step process of placenta dysfunction. The angiogenic imbalance may precede the clinical presentation of preeclampsia and may also be associated with fetal growth restriction. Among currently available biomarkers, the sFlt-1/PlGF ratio has the strongest clinical evidence for risk stratification in women with suspected preeclampsia. Nevertheless, the role of angiogenic factors in the earliest stages of placental dysfunction remains incompletely defined. The major challenge is to determine whether angiogenic abnormalities can identify clinically meaningful placental dysfunction early enough to permit effective intervention. This suggests that pro-angiogenic therapeutics could be a possible option for the treatment of pre-eclampsia, but also a more specific and sensitive predictive and diagnostic tool in modern obstetrics.