Systemic manifestation of preeclampsia (PE) is associated with circulating factors, including inflammatory cytokines and damage-associated molecular patterns (DAMPs), or alarmins. However, it is unclear whether the placenta directly contributes to the increased levels of these inflammatory triggers. Here, we demonstrate that pyroptosis, a unique inflammatory cell death pathway, occurs in the placenta predominantly from early onset PE, as evidenced by elevated levels of active caspase-1 and its substrate or cleaved products, gasdermin D (GSDMD), IL-1β, and IL-18. Using cellular models mimicking pathophysiological conditions (e.g., autophagy deficiency, hypoxia, and endoplasmic reticulum (ER) stress), we observed that pyroptosis could be induced in autophagy-deficient human trophoblasts treated with sera from PE patients as well as in primary human trophoblasts exposed to hypoxia. Exposure to hypoxia elicits excessive unfolded protein response (UPR) and ER stress and activation of the NOD-like receptor pyrin-containing 3 (NLRP3) inflammasome in primary human trophoblasts. Thioredoxin-interacting protein (TXNIP), a marker for hyperactivated UPR and a crucial signaling molecule linked to NLRP3 inflammasome activation, is significantly increased in hypoxia-treated trophoblasts. No evidence was observed for necroptosis-associated events. Importantly, these molecular events in hypoxia-treated human trophoblasts are significantly observed in placental tissue from women with early onset PE. Taken together, we propose that placental pyroptosis is a key event that induces the release of factors into maternal circulation that possibly contribute to severe sterile inflammation and early onset PE pathology.

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There exists a strong correlation between unscheduled inflammation at the maternal-fetal interface and the continuum of pregnancy complications. In normal pregnancy, immunological tolerance is established to protect the semi-allogeneic fetus. There has been extensive research on how the immunity, endovascular trophoblast migration, and hormonal nexus are orchestrated during pregnancy at the maternal-fetal interface to program a normal pregnancy outcome. It is not clear what contributes to the plasticity of uterine immune tolerance, fetal survial, and long-term post-partum health of the mother and the offspring. Old and new concepts have reemerged and emerged that include cell-free fetal DNA (cffDNA), telomere shortening, microchimerism involving bidirectional migration of maternal and fetal cells, and pregnancy as a stress factor. The question is how these pathways converge in a gestational age-dependent manner to contribute to the health of the mother and the offspring later in life and respond to an array of inflammatory challenges. In this Review, we provide pertinent discussion on maternal-fetal cross talk through cffDNA, telomere shortening, and microchimerism in the context of inflammatory and anti-inflammatory settings, particularly how these pathways lead to normal and adverse pregnancy outcomes.

ABSTRACT. Here, we investigated the effect of uric acid (UA) on hepatocyte mitochondria. Hepatocytes cultured in vitro were treated with varying concentrations of UA. The change in apoptotic activity was detected by flow cytometry. The DNA damage index 8-hydroxy-deoxyguanosine (8-OHdG) and mitochondrial function indices succinate dehydrogenase (SDH), cytochrome C oxidase (CCO), and adenosine triphosphate (ATP) were detected by enzyme assays. Reactive oxygen species (ROS) accumulation was confirmed by a dichloro-dihydrofluorescein diacetate assay. We observed an increase in apoptotic activity, ROS accumulation, and 8-OHdG activity in hepatocytes treated with UA for extended periods, indicating DNA damage; specifically, we observed a significant increase in these activities 48, 72, and 96 h after UA addition, compared to those observed at 24 h (P < 0.05). Cells treated with 30 mg/dL UA for 96 h showed a peak in apoptotic activity. We also observed a significant decrease in ATP, SDH, and CCO activities with the increase in uric acid concentration over time. Cells treated with 30 mg/dL UA for 96 h showed the highest ATP levels, while SDH and CCO activities at 48, 72, and 96 h post-UA treatment were significantly lower than those at 24 h (P < 0.01). Moreover, cells treated with 30 mg/dL UA showed a 0.02 ± 0.02 and 0.15 ± 0.01 mmol/ mg/min decrease in SDH and CCO levels after 72 h. Therefore, we concluded that high concentrations of UA may induce oxidative stress in hepatocyte mitochondria, increasing ROS production and ultimately resulting in mitochondrial damage.

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This study aimed to explore the effects of 1,25(OH) 2 D 3 on lipid droplet (LD) growth in 3T3-L1 adipocytes of hypertrophy model. Cocktail method was used to induce differentiation in 3T3-L1 cells. After 8 days, the cells were modeled by 100, 300, 600, and 900 μM palmitic acid (PA) for 24 hr. The best concentration of modeling was screened by MTT results and triglycerides (TG) content. The model cells were intervened by 1, 10, and 100 nM 1,25(OH) 2 D 3 for 24 hr. Then, the TG content of cells were detected and stained by oil red O. The diameter and quantity of LDs were analyzed. mRNA relative expression levels of genes related to LD (CIDE-a, Fsp27, PLIN-1), upstream response factor (PPAR-α, PPAR-γ, and VDR), and TG metabolism (long chain acyl-CoA synthetase 3, 1-acylglycerol-3-phosphate O-acyltransferase 1, adipose triglyceride lipase, diacylglycerol acyltransferase 1, diacylglycerol acyltransferase 2, glycerol-3-phosphate O-acyltransferase 3, glycerol-3-phosphate O-acyltransferase 4, hormone-sensitive lipase, mannosyl (alpha-1,3-)-glycoprotein beta-1,2-N-acetyl glucosaminyl transferase, phosphatidic acid phosphatase, and uncoupling protein-1) were detected by RT-qPCR. A total of 300 μM PA was selected as the optimum concentration. Compared with model group, 10 and 100 nM 1,25(OH) 2 D 3 decreased the average diameter, increased the quantity of LDs, upregulated PPAR-α and PLIN-1 mRNA expression levels, and downregulated CIDE-a and Fsp27 mRNA expression levels significantly (p < .05). However, 1 nM 1,25(OH) 2 D 3 did not alter LD morphology and TG content. mRNA expression levels of long chain acyl-CoA synthetase 3, 1-acylglycerol-3-phosphate O-acyltransferase 1, diacylglycerol acyltransferase 2, glycerol-3-phosphate O-acyltransferase 3, and glycerol-3-phosphate O-acyltransferase 4 in 10 and 100 nM groups were significantly lower than those in the model group (p < .05); mRNA expression levels of adipose triglyceride lipase, diacylglycerol acyltransferase 1, hormone-sensitive lipase, mannosyl (alpha-1,3-)-glycoprotein beta-1,2-N-acetyl glucosaminyl transferase, phosphatidic acid phosphatase, and uncoupling protein-1 were significantly

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