Maternal Phlorizin Intake Protects Offspring from Maternal Obesity-Induced Metabolic Disorders in Mice via Targeting Gut Microbiota to Activate the SCFA-GPR43 Pathway.

Maternal obesity increases the risk of obesity and metabolic disorders (MDs) in offspring, which can be mediated by the gut microbiota. Phlorizin (PHZ) can improve gut dysbiosis and positively affect host health; however, its transgenerational metabolic benefits remain largely unclear. This study aimed to investigate the potential of maternal PHZ intake in attenuating the adverse impacts of a maternal high-fat diet on obesity-related MDs in dams and offspring. The results showed that maternal PHZ reduced HFD-induced body weight gain and fat accumulation and improved glucose intolerance and abnormal lipid profiles in both dams and offspring. PHZ improved gut dysbiosis by promoting expansion of SCFA-producing bacteria, Akkermansia and Blautia, while inhibiting LPS-producing and pro-inflammatory bacteria, resulting in significantly increased fecal SCFAs, especially butyric acid, and reduced serum lipopolysaccharide levels and intestinal inflammation. PHZ also promoted intestinal GLP-1/2 secretion and intestinal development and enhanced gut barrier function by activating G protein-coupled receptor 43 (GPR43) in the offspring. Antibiotic-treated mice receiving FMT from PHZ-regulated offspring could attenuate MDs induced by receiving FMT from HFD offspring through the gut microbiota to activate the GPR43 pathway. It can be regarded as a promising functional food ingredient for preventing intergenerational transmission of MDs and breaking the obesity cycle.

Extramedullary hematopoiesis contributes to enhanced erythropoiesis during pregnancy via TGF-ß signaling.

Red blood cells are the predominant cellular component in human body, and their numbers increase significantly during pregnancy due to heightened erythropoiesis. CD71+ erythroid cells (CECs) are immature red blood cells, encompassing erythroblasts and reticulocytes, constitute a rare cell population primarily found in the bone marrow, although they are physiologically enriched in the neonatal mouse spleen and human cord blood. Presently, the mechanisms underlying the CECs expansion during pregnancy remain largely unexplored. Additionally, the mechanisms and roles associated with extramedullary hematopoiesis (EMH) of erythroid cells during pregnancy have yet to be fully elucidated. In this study, our objective was to examine the underlying mechanisms of erythroid-biased hematopoiesis during pregnancy. Our findings revealed heightened erythropoiesis and elevated CECs in both human and mouse pregnancies. The increased presence of transforming growth factor (TGF)-ß during pregnancy facilitated the differentiation of CD34+ hematopoietic stem and progenitor cells (HSPCs) into CECs, without impacting HSPCs proliferation, ultimately leading to enhanced erythropoiesis. The observed increase in CECs during pregnancy was primarily attributed to EMH occurring in the spleen. During mouse pregnancy, splenic stromal cells were found to have a significant impact on splenic erythropoiesis through the activation of TGF-ß signaling. Conversely, splenic macrophages were observed to contribute to extramedullary erythropoiesis in a TGF-ß-independent manner. Our results suggest that splenic stromal cells play a crucial role in promoting extramedullary erythropoiesis and the production of CECs during pregnancy, primarily through TGF-ß-dependent mechanisms.

The role of thymus- and extrathymus-derived regulatory T cells in maternal-fetal tolerance.

Regulatory T (Treg) cells could be divided into thymus-derived Treg (tTreg) cells and peripherally derived Treg (pTreg) cells, and in vitro induced Treg (iTreg) cells. To date, the functions of tTreg versus pTreg and their relative contributions to maternal-fetal immune tolerance remain insufficiently defined due to a lack of a specific marker to distinguish tTreg cells from pTreg cells. In this study, we investigated the role of thymus- and extrathymus-derived Treg cells in pregnancy tolerance using transgenic ACT-mOVA, Foxp3DTR and Foxp3GFP mice, and Treg cell adoptive transfer, etc. We found that the frequencies of Treg cells in the thymus, spleen and lymph nodes (LNs) in either syngeneically- or allogeneically-mated pregnant mice were not different from non-pregnant mice. However, percentages of blood Treg cells in pregnant mice increased at mid-gestation, and percentages of decidua Treg cells in pregnant mice increased as the pregnancy progressed compared with non-pregnant mice, and were significantly higher in allogeneic mice than those in syngeneic group. Compared with syngeneic mice, levels of CCR2 and CCR6 on blood and decidua Treg cells and CCL12 in the decidua significantly increased in allogeneic mice. A surrogate fetal antigen mOVA that was recognized by naïve T cells from OT-IIFoxp3GFP mice induced the generation of pTreg cells in vivo. Transfusion of thymus and spleen Treg cells significantly decreased diphtheria toxin (DT)-increased embryo resorption rates (ERRs) and IFN-γ levels in the blood and decidua. iTreg cells also decreased ERRs and IFN-γ levels in the blood and decidua to an extent lower than thymus and spleen Treg cells. In conclusion, increased blood and decidua Treg cells in pregnancy and increased ERRs in DT-treated Foxp3DTR mice suggest an important immunosuppressive role of Treg cells in pregnancy. Elevated decidua Treg cells in pregnancy could be derived from the recruitment of tTreg cells to the decidua, or from the transformation of naïve T cells in the decidua to pTreg cells. While the immune-suppression effects of thymus and spleen Treg cells are comparable, iTreg cells might play a weaker role in maternal-fetal tolerance.

Advanced Oxidative Protein Products Drive Trophoblast Cells Into Senescence by Inhibiting the Autophagy: The Potential Implication of Preeclampsia.

Introduction: Advanced oxidation protein products (AOPPs), the novel marker of oxidative stress, have been found to be elevated in preeclampsia (PE). To date, the effect of AOPPs on the senescence of trophoblast cells is still unclear. In this study, we investigated whether AOPPs promoted the senescence of trophoblast cells and explored the underlying mechanisms of AOPPs-induced aging process which may facilitate the progression of PE. Methods: The trophoblast cell line HTR-8/SV neo cells were cultured in the presence of PBS, AOPPs, AOPPs plus an anti-oxidant N-acetyl-L-cysteine (NAC). In some experiments, cells were pre-treated with rapamycin (an activator of autophagy), 3-MA (an inhibitor of autophagy), or cyclic pifithrin-α (PFT-α, an antagonist of p53), and then treated with AOPPs. Cellular senescence was analyzed by measuring the levels of senescence-associated ß-galactosidase (SA ß-Gal), senescence-associated heterochromatin foci (SAHF), mitochondrial membrane potential (ΔΨm), and cell cycle. Cell autophagic flux was analyzed by measuring tandem fluorescence-tagged LC3 reporter (mCherry-EGFP-LC3). Levels of p53, phosphorylated p53 (p-p53), p21, BECN1, p62, p-mTOR and p-p70S6K were measured by western blot. Results: Treatment with AOPPs significantly increased the levels of SA ß-Gal and SAHF, the percentage of cells in the G0/G1 phase, and decreased cell ΔΨm compared with the control group. Co-treatment with NAC and AOPPs significantly reversed AOPPs-induced senescence. Pre-treatment with rapamycin or 3-MA significantly inhibited or promoted AOPPs-induced senescence, respectively. In addition, administration of AOPPs significantly decreased the numbers of mCherry+EGFP+ autophagosomes and mCherry+EGFP- autolysosomes in cells compared with cells treated with PBS. Furthermore, AOPPs significantly increased the levels of proteins p-p53, p21, p-mTOR and p-p70S6K compared with the control group. Pre-treatment with rapamycin or PFT-α significantly down-regulated the levels of SA ß-Gal, SAHF, p-p53, p21, autophagy related protein p62, the percentage of cells in the G0/G1 phase, and significantly up-regulated ΔΨm, autophagy related protein BECN1, autophagosomes and autolysosomes compared with cells only treated with AOPPs. Conclusion: AOPPs may induce trophoblast cell senescence by inhibiting the autophagy process in a p53/mTOR/p70S6K-dependent pathway.