Inhibition of the endoplasmic reticulum stress-associated IRE-1 pathway alleviates preterm birth.

BACKGROUND: Premature birth (PTB) remains a major global health concern due to its association with neonatal morbidity and mortality. The unfolded protein response (UPR) within the endoplasmic reticulum (ER) is tightly regulated by Inositol-requiring enzyme type 1 (IRE-1), a pivotal cellular modulator. This study seeks to elucidate the role of the ER stress (ERS)-related IRE-1 pathway in PTB. METHODS: Human placental trophoblast cells HTR8/Svneo were exposed to the ER-stress inducer tunicamycin (TM). The expression of IRE-1 and ERS-associated proteins ATF6, GRP78, and XBP-1 was assessed in placental tissues and TM-treated cells. Cellular viability, migration, invasion, and apoptosis were evaluated through a series of experimental assays. Additionally, various methods were employed to assess and verify the activation of autophagy, using the autophagy marker, microtubule-associated protein 1A/1B-light chain 3 (LC3). Additionally, TUDCA (an ERS inhibitor) was used to assess its potential to counteract the TM-induced cell effects. RESULTS: Elevated levels of ATF6, GRP78, and XBP-1 were observed in PTB tissues and cells. TM treatment substantially reduced cell viability, migration, and invasion while promoting apoptosis. Treatment with TUDCA (an ERS inhibitor) counteracted the effects of TM on the cells. Furthermore, we identified an overexpression of IRE-1 in PTB tissues and cells and its knockdown enhanced cell viability, migration, and invasion while suppressed apoptosis and autophagy under TM stimulation. Notably, IRE-1 was found to modulate the activity of the IRE-1/XBP1/CHOP signaling pathway in TM-treated cells. CONCLUSION: The upregulation of IRE-1 in PTB placental tissues is implicated in the pathogenesis of PTB. Importantly, inhibiting the ERS-associated IRE-1/XBP1/CHOP pathway may be a good strategy in mitigating PTB.

LncRNA PSMA3-AS1 promotes preterm delivery by inducing ferroptosis via miR-224-3p/Nrf2 axis.

Long non-coding RNAs (lncRNAs) have a vital potential in premature delivery. This research was intended to explore PSMA3-AS1's role in premature delivery as well as its possible molecular mechanism. We enrolled 100 premature delivery patients and 100 term patients. Fetal membranes were collected. RT-qPCR was adopted for evaluating PSMA3-AS1, miRNA-224-3p, along with Nrf2 expression. Cell function experiments were implemented to clarify PSMA3-AS1 functions in human trophoblast HTR-8/SVneo cells. Rescue together with mechanistic experiments were implemented for assessing the regulatory function and interaction between miR-224-3p and PSMA3-AS1 or Nrf2 axis in human trophoblast cells. The results uncovered that PSMA3-AS1 level presented downregulation in the fetal membrane tissues and human trophoblast cells. Overexpressed PSMA3-AS1 enhanced cell proliferation but suppressed ferroptosis in human trophoblast cells. Besides, PSMA3-AS1 elevation also attenuated the LPS-induced inflammatory response and restored the LPS-induced upregulation of 20α-HSD and downregulation of progesterone (P4). Mechanistically, miR-224-3p could bind to PSMA3-AS1 and present upregulation in fetal membranes and human trophoblast cells. Notably, overexpressed miR-224-3p offset the influences of PSMA3-AS1 on human trophoblast cell proliferation and ferroptosis. Furthermore, Nrf2 was targeted by miR-224-3p. Downregulated Nrf2 offset the influences of the miR-224-3p inhibitor and induced HTR-8/SVneo dysfunction. Additionally, Nrf2 transcriptionally activated PSMA3-AS1 and GPX4. In conclusion, PSMA3-AS1 expression is low during premature delivery and overexpressing PSMA3-AS1 promotes proliferation and suppresses ferroptosis of human trophoblast cells by interacting with miR-224-3p to downregulate Nrf2. Therefore, enhancing PSMA3-AS1 expression may be a promising therapeutic strategy to prevent premature delivery.

Maternal peripheral blood platelet-to-white blood cell ratio and platelet count as potential diagnostic markers of histological chorioamnionitis-related spontaneous preterm birth.

BACKGROUND: Histological chorioamnionitis (HCA) is one of the leading causes of spontaneous preterm birth, thus, to identify novel biomarkers for the early diagnosis of HCA is in a great need. OBJECTIVE: To investigate the diagnostic value of maternal peripheral blood platelet-to-white blood cell ratio (PLT/WBC) and platelet (PLT) counts in HCA-related preterm birth. METHODS: A total of 400 patients with preterm birth were enrolled in this study: non-HCA group (n = 193) and HCA group (n = 207), and 87 full-term pregnancies were enrolled as the control. The peripheral blood of the participators was collected, and the neutrophil count, WBC count, platelet count, and levels of C-reactive protein (CRP) and procalcitonin were recorded, and the platelet-to-white blood cell ratio (PLT/WBC) of the participators was calculated. Receiver operating characteristic (ROC) curve has been drawn to show the sensitivity and specificity of PLT/WBC and PLT count for the diagnosis of HCA-related spontaneous preterm birth patients. RESULTS: The neutrophil count, WBC count, and procalcitonin show no significant differences among the three groups, and the PLT count, PLT/WBC, and CRP (P < 0.05) were significantly increased in HCA group compared with non-HCA group; moreover, the area under the curve (AUC) of PLT/WBC, PLT, and CRP was 0.744 (95% confidence interval [CI], 0.6966-0.7922), 0.8095 (95% CI, 0.7676-0.8514), and 0.5730 (95% CI, 0.5173-0.6287), respectively. CONCLUSION: Platelet count and PLT/WBC may become a potential biomarker of HCA-related spontaneous preterm birth.

[Study on the relationship between semen HBV-DNA load and offspring-paternal-vertical- transmission of HBV].

OBJECTIVE: To explore the relationship between HBV-DNA load and the offspring vertical transmission of HBV. METHODS: 138 families who had taken the examination between August 2009 and November 2011 but the HBsAg of the housewife was negative, were chosen as research objects. Blood from the couples and sperms from the husbands during pregnancy were followed and collected for detection on related indicators. Cord blood was sampled after delivery for HBVM and HBV-DNA quantification. Those with HBV-DNA load ≥5×10(2) copies/ml were chosen as cases while those <5 × 10(2) copies/ml were formed as controls, respectively. RESULTS: 1) The positive rates of HBV-DNA was 34.8% (48/138)in the neonatal cord blood while the positive rates of cord blood HBsAg and HBeAg were 28.3% (39/138) and 15.2% (21/138) respectively. 2) The positive rate of semen HBV-DNA was 21.0% (29/138) while the positive rates of paternal serum HBV-DNA and HBeAg were 76.8% (106/138) and 42.8% (59/138). 3) Among the positive ones on paternal serum HBV-DNA, paternal serum HBeAg, semen HBV-DNA, items as measures taken for HBV vertical transmission and prevention on the fathers and the first class family histories on HBV appeared to be the risk factors for HBV paternal transmission (P < 0.05). 4) Data from Multivariate analysis showed that positivities on paternal serum HBV-DNA, paternal serum HBeAg and semen HBV-DNA were risk factors for HBV paternal transmission (OR = 5.7, 95%CI:1.1-29.1; OR = 4.2, 95%CI:1.7-10.0; OR = 6.7, 95% CI:2.4-18.9). 5)Dose-response relationships were seen between levels of paternal serum HBV-DNA load and cord blood HBV-DNA load, between levels of paternal serum HBV-DNA load and semen HBV-DNA load, between levels of semen HBV-DNA load and cord blood HBV-DNA load. 6)Results from the analysis on ROC curve showed that paternal serum HBV-DNA load level (10(5) copies/ml)and semen HBV-DNA load level (10(3) copies/ml) were better demarcation points to forecast the occurrence of paternal transmission of HBV, because of the better sensitivity and specificity they had. CONCLUSION: Items as positives on paternal serum HBV-DNA, paternal serum HBeAg and semen HBV-DNA were risk factors for HBV paternal transmission. When paternal serum HBV-DNA load >10(5) copies/ml and semen HBV-DNA load >10(3) copies/ml appeared, the positive rate of HBV paternal transmission would increase.

[Study on the risk factors related vertical transmission of HBV positive couples to their infant].

OBJECTIVE: To explore the risk factors and the rate of HBV vertical transmission from HBsAg-positive couple to their infant. METHODS: 46 families who had antenatal examination at Fujian Provincial Maternal and Child Health Hospital during August 2010 and November 2011 were chosen as research object. Cord blood was sampled after delivery for HBVM and HBV-DNA quantification. Those with HBV-DNA load ≥ 5 × 10(2) copies/ml were involved in the case group while those having < 5 × 10(2) copies/ml were chosen as controls. RESULTS: The average positive rate of neonatal cord blood HBV-DNA was 45.7% (21/46), while the positive rates of cord blood HBsAg and HBeAg were 34.8% (16/46) and 23.9% (11/46) respectively. The positive rates of maternal serum HBV-DNA and paternal serum HBV-DNA were 52.2% (24/46) and 69.6% (32/46) respectively, with the positive rate of couple serum HBeAg as 39.1% (18/46) and 32.6% (15/46) respectively. Results from univariate analysis showed that hepatitis B surface markers, serum HBeAg-positive, serum HBV-DNA positive, and serum HBV-DNA load of the couples were risk factors to the HBV vertical transmission (χ(2) = 8.731, 8.414, 8.932, 9.663, 10.823, 3.962, 13.638, 36.501; P < 0.05). Data from the multivariate analysis showed that maternal serum HBV-DNA positive and paternal serum HBV-DNA load were risk factors to the HBV vertical transmission[OR = 17.6 (1.3 - 238.4) ; OR = 3.5 (1.6-7.6)]. Serum HBV-DNA loads of the couples were positively correlated with the cord blood HBV-DNA load, while the load levels of the couple's serum HBV-DNA were higher than cord blood HBV-DNA. There appeared dose-response relationship between couple's serum HBV-DNA load level and the cord blood HBV-DNA load level. RESULTS: from the analysis of ROC curve showed that both maternal serum HBV-DNA load level (10(3) copies/ml) and paternal serum HBV-DNA load level (10(4) copies/ml) were demarcation points to better forecast the occurrence of vertical transmission of HBV, because there showed higher sensitivity and specificity for the forecasting process. Neonatal outcomes showed no significant difference between the case group and the control group. The negative conversion rate became 15.0% (3/20) when the HBV-DNA positive infants were followed up for 7 months. CONCLUSION: Both maternal serum HBV-DNA positive and paternal serum HBV-DNA load were risk factors of HBV vertical transmission. When the maternal serum HBV-DNA load appeared > 10(3) copies/ml and paternal serum HBV-DNA load > 10(4) copies/ml, the rate of HBV vertical transmission would increase.