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Acute lymphoblastic leukemia (ALL) is a hematopoietic disorder that mainly affects the child population, and it is characterized by the presence of lymphoid progenitor or precursor cells with different genetic alterations. The origin of this disease is controversial, since some authors assumed that leukemic transformation occurs in a lymphoid progenitor, and there is also evidence that suggests the existence of leukemic initiating cells (LIC). PTL, DMAPT, and PU-H71 are agents that have been shown to eliminate bulk and stem cells from myeloid leukemias, but this effect has not been analyzed in lymphoblastic leukemias. In this study, we evaluated the effect of these compounds in different populations from pediatric B-ALL. For this, bone marrow samples from pediatric patients without treatment were obtained and cultured in the presence or absence of PTL, DMAPT, and PU-H71. The viability and apoptosis index were analyzed by flow cytometry in different hematopoietic subpopulations. These observations indicate that PTL and DMAPT are able to reduce B-ALL cells with a minimum effect in normal hematopoietic and non-hematopoietic cells. In contrast, PU-H71 was able to reduce the leukemic population and had a minimal effect in normal cells. These results present evidence that PTL and DMAPT are able to abrogate in vitro different populations of B-ALL and could represent a possibility of treatment, as well as prevent disease progression or relapse. [ABSTRACT FROM AUTHOR]

Placentas from gestational diabetes mellitus (GDM) patients undergo significant metabolic and immunologic adaptations due to hyperglycemia, which results in an exacerbated synthesis of proinflammatory cytokines and an increased risk for infections. Insulin or metformin are clinically indicated for the treatment of GDM; however, there is limited information about the immunomodulatory activity of these drugs in the human placenta, especially in the context of maternal infections. Our objective was to study the role of insulin and metformin in the placental inflammatory response and innate defense against common etiopathological agents of pregnancy bacterial infections, such as E. coli and S. agalactiae, in a hyperglycemic environment. Term placental explants were cultivated with glucose (10 and 50 mM), insulin (50–500 nM) or metformin (125–500 µM) for 48 h, and then they were challenged with live bacteria (1 × 105 CFU/mL). We evaluated the inflammatory cytokine secretion, beta defensins production, bacterial count and bacterial tissue invasiveness after 4–8 h of infection. Our results showed that a GDM-associated hyperglycemic environment induced an inflammatory response and a decreased beta defensins synthesis unable to restrain bacterial infection. Notably, both insulin and metformin exerted anti-inflammatory effects under hyperglycemic infectious and non-infectious scenarios. Moreover, both drugs fortified placental barrier defenses, resulting in reduced E. coli counts, as well as decreased S. agalactiae and E. coli invasiveness of placental villous trees. Remarkably, the double challenge of high glucose and infection provoked a pathogen-specific attenuated placental inflammatory response in the hyperglycemic condition, mainly denoted by reduced TNF-α and IL-6 secretion after S. agalactiae infection and by IL-1β after E. coli infection. Altogether, these results suggest that metabolically uncontrolled GDM mothers develop diverse immune placental alterations, which may help to explain their increased vulnerability to bacterial pathogens. [ABSTRACT FROM AUTHOR]

Obesity is associated with inflammatory changes and accumulation and phenotype polarization of adipose tissue macrophages (ATMs). Obese pregnant women have alterations in adipose tissue composition, but a detailed description of macrophage population is not available. In this study, we characterized macrophage populations in visceral adipose tissue (VAT) from pregnant women with normal, overweight, and obese pregestational weight. Immunophenotyping of macrophages from VAT biopsies was performed by flow cytometry using CD45 and CD14 as markers of hematopoietic and monocyte linage, respectively, while HLA-DR, CD11c, CD163, and CD206 were used as pro- and anti-inflammatory markers. Adipocyte number and size were evaluated by light microscopy. The results show that pregnant women that were overweight and obese during the pregestational period had adipocyte hypertrophy. Two different macrophage populations in VAT were identified: recruited macrophages (CD45+CD14+), and a novel population lacking CD45, which was considered to be a resident macrophages subset (CD45-CD14+). The number of resident HLA-DRlow/- macrophages showed a negative correlation with body mass index (BMI). Both resident and recruited macrophages from obese women expressed higher CD206 levels. CD11c expression was higher in resident HLA-DR+ macrophages from obese women. A strong correlation between CD206 and CD11c markers and BMI was observed. Our findings show that being overweight and obese in the pregestational period is associated with adipocyte hypertrophy and specific ATMs populations in VAT. [ABSTRACT FROM AUTHOR]

During pregnancy, the placenta, the mother and the fetus exploit several mechanisms in order to avoid fetal rejection and to maintain an immunotolerant environment throughout nine months. During this time, immune cells from the fetal and maternal compartments interact to provide an adequate defense in case of an infection and to promote a tolerogenic milieu for the fetus to develop peacefully. Trophoblasts and decidual cells, together with resident natural killer cells, dendritic cells, Hofbauer cells and other macrophages, among other cell types, contribute to the modulation of the uterine environment to sustain a successful pregnancy. In this review, the authors outlined some of the various roles that the innate immune system plays at the maternal–fetal interface. First, the cell populations that are recruited into gestational tissues and their immune mechanisms were examined. In the second part, the Toll–like receptor (TLR)–dependent immune responses at the maternal–fetal interface was summarized, in terms of their specific cytokine/chemokine/antimicrobial peptide expression profiles throughout pregnancy. [ABSTRACT FROM AUTHOR]