Preeclampsia (PE) is a major cause of perinatal and maternal mortality and morbidity, which affects 2% to 8% of pregnancies in the world. The aberrant maternal inflammation and angiogenic imbalance have been demonstrated to contribute to the pathogenesis of PE. This research aimed to investigate the effect of Astragaloside IV (AsIV) in the treatment of PE and the underlying mechanisms. A rat PE‐like model was established by tail vein injection of lipopolysaccharide (LPS) and different doses of AsIV (40 and 80 mg/kg) were treated at the same time. Systolic blood pressure, total urine protein and urine volume were observed. Serum and placenta inflammatory cytokines were measured by ELISA kit. The mRNA and protein expression of relative genes were analyzed by qRT‐PCR and Western blotting. In PE‐like rats, there were obvious increases in systolic blood pressure, total urine protein and urine volume, which were obviously alleviated by treatment with AsIV. Serum levels of interleukin (IL)‐1β, tumor necrosis factor alpha (TNF‐α), IL‐6 and IL‐18, as well as IL‐4, IL‐10, PIGF, VEGF and sFlt‐1, were all reversed by treatment with AsIV. Meanwhile, AsIV treatment improved abnormal pregnancy outcomes, such as low litter size and low fetal weight. In addition, AsIV treatment downregulated the mRNA expression of inflammatory gene IL‐1β and IL‐6 in PE rats model, and AsIV treatment inhibited the activation of TLR‐4, NF‐κB, and sFlt‐1 in the placenta of PE rats. Our findings indicated the first evidence that AsIV alleviated PE‐like signs, and this improvement effect is possibly through inhibition of inflammation response via the TLR4/NF‐κB signaling pathway.
Disruption in homeostatic feedback loops between inflammatory mediators and the hypothalamic‐pituitary‐adrenal (HPA) axis is a key mechanism linking chronic stress to inflammation and adverse health outcomes, including those occurring during pregnancy. In particular, alterations in glucocorticoid sensitivity may occur as a result of chronic stress, including that due to racial discrimination, and may be implicated in the persistent adverse maternal and infant health outcomes experienced by African Americans. While there are a few large‐scale studies in human pregnancy that measure both cytokines and HPA axis hormones, to our knowledge, none directly measure glucocorticoid sensitivity at the cellular level, especially in an African American population.
We measured the full range of the dexamethasone (DEX) dose‐response suppression of TNF‐α in first‐trimester blood samples from 408 African American women and estimated leukocyte cell type contribution to the production of TNF‐α.
The mean (SD) DEX level needed to inhibit TNF‐α production by 50% (ie, DEX IC50) was 9.8 (5.8) nmol/L. Monocytes appeared to be the main driver of Uninhibited TNF‐α production, but monocyte counts explained only 14% of the variation. Monocyte counts were only weakly correlated with the DEX IC50(
These findings challenge some prior assumptions and position this comprehensive study of glucocorticoid sensitivity as an important anchor point in the growing recognition of interindividual variation in maternal HPA axis regulation and inflammatory responses.
- NSF-PAR ID:
- 10376556
- Publisher / Repository:
- Wiley-Blackwell
- Date Published:
- Journal Name:
- American Journal of Reproductive Immunology
- Volume:
- 84
- Issue:
- 1
- ISSN:
- 1046-7408
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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NR3C1 in whole blood at age 7 years, including the main predictor variable of the first principal component score of observed maternal–infant interaction quality (derived from the Thorpe Interaction Measure at 12 months of age) and covariates of cell‐type proportion, maternal financial difficulties and marital status at 8 months postnatal, child birthweight, and sex.Results CpG site cg27122725 methylation was negatively associated with warmer, more positive maternal interaction with her infant (
β = 0.19,p = .02,q = 0.13). In sensitivity analyses, the second highest quartile of maternal behavior (neutral, hesitant behavior) was positively associated with cg12466613 methylation. The other five CpG sites were not significantly associated with maternal–infant interaction quality.Conclusions Narrow individual variation of maternal interaction with her infant is associated with childhood methylation of two CpG sites on
NR3C1 that may be particularly sensitive to environmental influences. Infancy may be a sensitive period for even small influences from the social–emotional environment on the epigenetic determinants of HPA‐axis function.
