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Xinxin Zhu,1,* Shiyun Huang,1,* Yuxuan Tang,1,* Zhonglan Wu,2,* Yue Sun,1 Huiyan Ren,1 Hongmei Lu,1 Tingting Yin,1 Qing Zuo,1,* Zhiping Ge,1,* Ziyan Jiang1,* 1Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Obstetrics and Gynecology, Women’s Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ziyan Jiang, Department of Obstetrics, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People’s Republic of China, Tel +86-13512534017, Email zyjiangchm@163.comBackground: Grade III meconium stained amniotic fluid (MSAF) is a common obstetric disease, and has the greatest impact on poor maternal and neonatal outcomes.Question or Hypothesis or Aim: There is no consensus on treatment, especially on the timing of delivery.Methods: We collected the medical records of 345 women who gave birth with grade III MSAF and analyzed the difference in baseline characteristics and maternal and neonatal outcomes relative to different labor stage, observation times in the first stage of labor, and the presence or absence of abnormal fetal heart rate (FHR) or thick amniotic fluid.Findings: Higher rate of cesarean section was observed when grade III MSAF was found in active labor. Intervention occurred at an observation time of 90– 120 min, but there were no significant differences in maternal or neonatal outcomes shown when the observation time was greater than 3 or 4 hours. However, a higher rate of admission to the neonatal intensive care unit was demonstrated in cases with grade III MSAF with abnormal FHR either in the first or second stage of labor or in cases with thick MSAF in the second stage of labor.Discussion: Higher rate of composite adverse neonatal outcomes was found when secondary MSAF (a transition from clear AF to MSAF) was diagnosed > 3 h before delivery.Conclusion: In the first stage of labor, an observation time of greater than 4 hours might be possible after grade III MSAF is found if the labor has progressed and is without abnormal FHR.Keywords: MSAF, grade III MSAF, observation time, abnormal FHR, thick AF

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies and requires new therapeutic strategies to improve clinical outcomes. EOC metastasizes in the abdominal cavity through dissemination in the peritoneal fluid and ascites, efficiently adapt to the nutrient-deprived microenvironment, and resist current chemotherapeutic agents. Accumulating evidence suggests that mitochondrial oxidative phosphorylation is critical for the adaptation of EOC cells to this otherwise hostile microenvironment. Although chemical mitochondrial uncouplers can impair mitochondrial functions and thereby target multiple, essential pathways for cancer cell proliferation, traditional mitochondria uncouplers often cause toxicity that precludes their clinical application. In this study, we demonstrated that a mitochondrial uncoupler, specifically 2,5-dichloro-N-(4-nitronaphthalen-1-yl)benzenesulfonamide, hereinafter named Y3, was an antineoplastic agent in ovarian cancer models. Y3 treatment activated AMP-activated protein kinase and resulted in the activation of endoplasmic reticulum stress sensors as well as growth inhibition and apoptosis in ovarian cancer cells in vitro. Y3 was well tolerated in vivo and effectively suppressed tumor progression in three mouse models of EOC, and Y3 also induced immunogenic cell death of cancer cells that involved the release of damage-associated molecular patterns and the activation of antitumor adaptive immune responses. These findings suggest that mitochondrial uncouplers hold promise in developing new anticancer therapies that delay tumor progression and protect patients with ovarian cancer against relapse.

Supplementary Information

Zhu X, Huang S, Tang Y, et al. Int J Womens Health. 2023;15:7–23. The authors have advised that the Funding statement was missed from page 22 of the published paper. The funding statement should read as follows. Funding The work was supported by Project of Jiangsu Health Commission (H2019008), National Natural Science Foundation of China (81971407), Natural Science Foundation of Jiangsu Province (BK20191070) and Postdoctoral Research Foundation of China (2021M691332). The authors apologize for this error.

Objective We compared maternal and foetal outcomes between termination gestational age at 40 0/7-40 6/7 and 41 0/7-41 6/7 weeks. Design Retrospective cohort, observational, single-centre study. Setting Jiangsu Province Hospital, China: January 2020-December 2020 Population 1569 low-risk pregnancies. Methods Maternal medical records and neonatal delivery data were analysed retrospectively. Main outcome measures Difference in adverse outcomes of mothers and babies between termination gestational age at 40 0/7-40 6/7 and 41 0/7-41 6/7 weeks. Results The study included 1569 pregnancies, with 1107 (70.6%) delivered at 40 0/7-40 6/7 weeks and 462 (29.4%) delivered at 41 0/7-41 6/7 weeks. Intrapartum caesarean section (8% versus 16%, P

Objective To explore the effect of antepartum bleeding caused by PP on pregnancy outcomes. Study design We retrospectively analyzed 493 pregnant women complicated with PP. Patients were divided into antepartum repeated bleeding and non-bleeding groups. Maternal characteristics and pregnancy outcomes were compared. Results The risk of antepartum hemorrhage was 2.038 times higher when gravidity was 5 (95% CI 1.104-3.760, p = .023). Pregnant women with a history of more than three intrauterine procedures had a 1.968 times higher risk of antepartum hemorrhage (95% CI 1.135-3,412, p = .016) compared to pregnant women without any intrauterine procedures. The risk of antepartum bleeding was found to be decreasing with the pregnancy advancing; When the placenta edge was noted to be over cervical os, the risk of antepartum bleeding was 4.385-fold than the low-lying plcaenta cases (95%CI2.454-8.372, p = .000). In the respect of maternal outcomes, the repeated bleeding group, the risk of emergency surgery was 7.213 times higher than elective surgery (95% CI 4.402-11.817, p = .000). As for the neonatal outcomes, the risk of asphyxia was 2.970 times and the risk of neonatal intensive care unit (NICU) admission was 2.542-fold higher in repeated bleeding group compared to non-bleeding group, respectively. Conclusions Obstetricians should be aware of the increased risk of antepartum bleeding especially for ≤34 weeks and placenta edge over cervical os PP patients, they have a higher risk of antepartum bleeding. These women have higher possibility of emergency C-section and need preterm newborn resuscitation.

Preeclampsia is a hypertensive disorder of pregnancy that can lead to multiorgan complications in the mother and fetus. Our study aims to uncover the underlying mechanisms and hub genes between genomic subgroups of preeclampsia. A total of 180 preeclampsia cases from 4 gene profiles were classified into 3 subgroups. Weighted gene coexpression analysis was performed to uncover the genomic characteristics associated with different clinical features. Functional annotation was executed within the significant modules and hub genes were predicted using Cytoscape software. Subsequently, miRNet analysis was performed to identify potential miRNA-mRNA networks. Three key subgroup-specific modules were identified. Patients in subgroup II were found to develop more severe preeclampsia symptoms. Subgroup II, characterized by classical markers, was considered representative of typical preeclampsia patients. Subgroup I was considered as an early stage of preeclampsia with normal-like gene expression patterns. Moreover, subgroup III was a proinflammatory subgroup, which presented immune-related genomic characteristics. Subsequently, miR-34a-5p and miR-106a-5p were found to be correlated with all 3 significant gene modules. This study revealed the transcriptome classification of preeclampsia cases with unique gene expression patterns. Potential hub genes and miRNAs may facilitate the identification of therapeutic targets for preeclampsia in future.

Preeclampsia (PE) is a hypertensive disorder that occurs during pregnancy. Low-dose aspirin is used to reduce the occurrence of early-onset PE; however, the mechanisms are not clear. The aim of this study was to reveal the underlying mechanism of aspirin in reducing sFlt-1-mediated apoptosis of trophoblast cells in PE. Serum sFlt-1 and sEng profiles and placental oxidative stress levels were significantly decreased in PE patients treated with aspirin compared with untreated patients without it, whereas serum PLGF and placental SOD profiles were increased in PE patients with aspirin. Aspirin attenuated the role of sFlt-1 in oxidative stress and endothelial dysfunction and reduced apoptosis of trophoblasts by inactivating the NF-κB signalling pathway in HTR-8/SVneo trophoblast cells. Blood pressure, urine protein, swelling of the villous vessels and mitochondrial parameters were noted to be much better after aspirin administrated to sFlt-1 treated pregnant mice. In conclusion, aspirin reverses the endothelial dysfunction and oxidative stress caused by sFlt-1 and thus reduces apoptosis of preeclamptic trophoblasts by inactivating NF-κB signalling pathway.

Background Placenta previa (PP) is a serious complication of late pregnancy. Exploring the effect of antepartum bleeding caused by PP on pregnancy outcomes is very important.Methods We retrospectively analyzed 493 women complicated with PP. Patients were divided into antepartum repeated bleeding and non-bleeding groups. Maternal characteristics and pregnancy outcomes were compared.Results The risk of antepartum hemorrhage was 2.038 times higher when gravidity was 5 (95% CI 1.104 ~ 3.760, P = 0.023). Pregnant women with a history of more than three intrauterine procedures had a 1.968 times higher risk of antepartum hemorrhage (95% CI 1.135 ~ 3,412, P = 0.016) compared to pregnant women without any intrauterine procedures. The risk of antepartum bleeding was found to be decreasing with the pregnancy advancing; When the placenta edge was noted to be over cervival os, the risk of antepartum bleeding was 4.385-fold than the low-lying plcaenta cases (95%CI2.454ཞ8.372,P = 0.000). In the respect of maternal outcomes, the repeated bleeding group, the risk of emergency surgery was 7.213 times higher than elective surgery (95% CI 4.402ཞ11.817, P = 0.000). As for the neonatal outcomes, the risk of asphyxia was 2.970 times and the risk of NICU admission was 2.542-fold higher in repeated bleeding group compared to non-bleeding group, respectively.Conclusions Obstetricians should be aware of the increased risk of antepartum bleeding especially for ≤ 34 weeks and placenta edge over cervical os PP patients, they have a higher risk of antepartum bleeding. These women have higher possibility of emergency c-section and need preterm newborn resuscitation.

Ethnopharmacological relevance Typhae Pollen (TP) is a well-known Traditional Chinese Medicine (TCM) to remove blood stasis. Carbonized Typhae Pollen (CTP), a processed product of TP after being stir-fried, has been widely applied to clinical practice with its capability of hemostasis. However, the underlying mechanism of TP and CTP are still not fully elucidated and discrimination against TP and CTP remains a challenge. Aim of study The aim of this study is to investigate whether TP could remove blood stasis by promoting angiogenesis and the process of carbonizing it could enhance hemostatic effect. Meanwhile, some chemical markers for quality control of CTP had better to be found. Material and methods The changes of constituents between TP and CTP were analyzed by UPLC-QTOF-MS/MS. We investigated pro-angiogenic and hemostatic effects of TP and CTP in two zebrafish models: VRI-induced ISV insufficiency model and Ator-induced cerebral hemorrhage model. Subsequently, quantitative real-time PCR (qRT-PCR) was applied to investigate the mechanism of pharmacological effects. Finally, chemometric method was applied to find chemical markers. Results A total of 19 compounds were identified in qualitative analysis. The loss rate of each compound was calculated and compared. Two compounds (huaicarbon A/B) could only be detected in CTP and the content of flavonoid glycosides in CTP was significantly decreased compared with TP. The average content of the three identified flavonoid aglycones (quercetin, isorhamnetin and kaempferol) was increased about 30 percent in CTP. TP promoted pro-angiogenesis by up-regulating the expression of VEGFA, flt1 and kdr. After heating process, the pro-angiogenic activity was reduced and hemostatic activity was enhanced in CTP. Then qRT-PCR analysis found that CTP could significantly up-regulate the expression of VEGFA and vWF. In the discovery of markers, 6 chemical markers for discrimination of TP and CTP were obtained by chemometric method. Conclusion Our research indicated that the pro-angiogenic activity of TP was involved in VEGF signaling pathway. After processing, hemostatic activity of CTP has been enhanced by up-regulating the expression of VEGFA and vWF. A chemical marker database was established to provide a scientific evidence for quality control, mechanism and the clinical application of TP and CTP.

Objectives Despite improvements in diagnosis and treatment, preeclampsia (PE) continues to pose a significant risk of maternal and foetal morbidity and mortality if not addressed promptly. An increasing number of studies have suggested that tissue factor pathway inhibitor 2 (TFPI2) acts as a suppressor gene, possibly inhibiting multiple serine proteases affecting cell proliferation and migration. It plays an essential role in the occurrence and development of PE, but the pathogenesis remains unclear. Materials and methods In our research, we performed western blotting, immunohistochemistry and qPCR assays to investigate TFPI2 and miR-616-3p expression in preeclamptic placental tissues. Cell assays were performed in HTR-8/SVneo and JEG3 cell lines. Cell proliferation and migration events were investigated by MTT, EdU and transwell assays. In conjunction with bioinformatics analysis, luciferase reporter assays were performed to elucidate the mechanism by which miR-616-3p binds to TFPI2 mRNA. Results We established that TFPI2 protein levels were significantly upregulated in PE placental tissues. In addition, we found that miR-616-3p binds specifically to the 3'-UTR region of TFPI2 mRNA. Furthermore, miR-616-3p knockdown or TFPI2 overexpression substantially impaired cell growth and migration, whereas miR-616-3p upregulation or TFPI2 knockdown stimulated cell proliferation and migration. This miR-616-3p/TFPI2 axis was also found to affect the epithelial-mesenchymal transition process in PE. Conclusions Our results demonstrated that TFPI2 plays a vital role in the progression of PE and might provide a prospective therapeutic strategy to mitigate the severity of the disorder.

To investigate a possible association between miR-101 and apoptosis of human trophoblast cells mediated by endoplasmic reticulum protein 44 (ERp44) in preeclampsia (PE), we explored the expression of miR-101 in PE placentas (n=30) compared with normotensive pregnant placentas (n=30) and the correlation between miR-101 and ERp44 was also analyzed. Furthermore, both the apoptotic rate of trophoblast cells and the ER stress-induced apoptotic proteins were assayed when the HTR-8/SVneo cells were treated with miR-101 mimics or inhibitors in vitro. We found a lower expression of miR-101 and an inverse correlation between miR-101 and ERp44 protein in PE placentas. Upregulation of miR-101 expression could inhibit trophoblast HTR-8/SVneo cell apoptosis and repress ER stress-induced apoptotic proteins by targeting ERp44 in vitro, whereas inhibition of miR-101 could induce HTR-8/SVneo cell apoptosis. Our findings indicated that overexpression of miR-101 could downregulate ERp44 and suppress apoptosis in trophoblast cells during PE. Therefore, loss of miR-101 expression could contribute to ER stress-induced trophoblast cell apoptosis by targeting ERp44.

The effect of angiotensin-converting enzyme inhibitors on hypertension patients regarding endothelial progenitor cell (EPC) functions is poorly understood. The aim of this study was to investigate the effects of benazepril on the proliferation, adhesion and migration capacity of EPCs and its possible mechanism. The functions of EPCs from hypertension patients were obviously reduced compared with control group, and this could be improved by benazepril in a dose-dependent manner, whereas this improvement were obviously blocked when AMD3100 were used together. Therefore, benazepril could obviously improve functions of EPCs from hypertension patients, and the potential mechanism may be related to SDF-1/CXCR4 axis.

Ordered macro–mesoporous titania (TiO2) film with a mesoporous anatase nanocrystalline wall was synthesized by simultaneous application of polystyrene (PS) array colloidal crystal and triblock copolymer P123 as templates, and tetrabutyl orthotitanate as titanium source. Mesoporous structure was optimized through solvent species, amount of P123, and the addition of hydrochloric acid. Permeation of mesoporous TiO2 precursors into PS array template was examined by altering the sol concentration. The results show that the mesoporous anatase nanocrystalline titania (nc-TiO2) formed has a Brunauer–Emmett–Teller surface area of 89.55 m2/g typically and an average mesoporous size of 5.67 nm. Sol concentration, characterized by viscosity, surface tension, and contact angle between the sol and PS template, dominates the perfection of macro–mesoporous structure. Optical transmittance for the mesoporous film keeps a high level (above 70%) beyond the wavelength of 400 nm, ∼10% higher than that of the macro–mesoporous film. The band gap of macro–mesostructure TiO2 film is 3.00 eV, which is not only lower than the 3.25 eV of the mesoporous film, but is also lower than the 3.18 eV of P25 TiO2, because of the defect level from the surface state of macroporous structure.

Pre-eclampsia (PE) is a hypertensive disorder that occurs during pregnancy, and is a multifactorial disease. The antiangiogenic factor, soluble fms-like tyrosine kinase 1 (sFlt-1), has been reported to be important in the pathogenesis of PE, but the mechanism of its involvement remains unknown. To test the effects of sFlt-1 on pregnancy, we injected pregnant mice with exogenous mouse sFlt-1. After 18 days of gestation, higher blood pressure, proteinuria, and histological differences were observed compared with controls. Mitochondrial swelling inside the trophoblast cells in the placenta of sFlt-1-treated pregnant mice was observed by electron microscopy, which suggested a role of sFlt-1 in oxidative stress in trophoblasts in PE. Furthermore, apoptosis markers were upregulated in sFlt-1-treated mice. In conclusion, sFlt-1 appears to play a role in oxidative stress, which promotes apoptosis of trophoblasts. This may be an important mechanism in the development of PE.

Due to limited treatment options, pre-eclampsia (PE) is associated with fetal perinatal and maternal morbidity and mortality. During the causes of PE, failure of uterine spiral artery remodeling which might be related to functioning abnormally of trophoblast cells, result in the occurrence and progression of PE. Recently, abnormal expression of long non-coding RNAs (lncRNAs), as imperative regulators involved in human diseases progression (included PE), which has been indicated by increasing evidence. In this research, we found that TUG1, a lncRNA, was markedly reduced in placental samples from patients with PE. Loss-function assays indicated that knockdown TUG1 significantly affected cell proliferation, apoptosis, migration and network formation in vitro. RNA-seq revealed that TUG1 could affect abundant genes, and then explore the function and regulatory mechanism of TUG1 in trophoblast cells. Furthermore, RNA immunoprecipitation and chromatin immunoprecipitation assays validated that TUG1 can epigenetically inhibit the level of RND3 through binding to EZH2, thus promoting PE development. Therefore, via illuminating the TUG1 mechanisms underlying PE development and progression, our findings might furnish a prospective therapeutic strategy for PE intervention.

Pre-eclampsia (PE) is a hypertensive disorder that occurs during pregnancy, and is a multifactorial disease. The antiangiogenic factor, soluble fms-like tyrosine kinase 1 (sFlt-1), has been reported to be important in the pathogenesis of PE, but the mechanism of its involvement remains unknown. To test the effects of sFlt-1 on pregnancy, we injected pregnant mice with exogenous mouse sFlt-1. After 18 days of gestation, higher blood pressure, proteinuria, and histological differences were observed compared with controls. Mitochondrial swelling inside the trophoblast cells in the placenta of sFlt-1-treated pregnant mice was observed by electron microscopy, which suggested a role of sFlt-1 in oxidative stress in trophoblasts in PE. Furthermore, apoptosis markers were upregulated in sFlt-1-treated mice. In conclusion, sFlt-1 appears to play a role in oxidative stress, which promotes apoptosis of trophoblasts. This may be an important mechanism in the development of PE.

Objective: To explore the recent influences of pacemaker with automatic search function of atrial hysteresis on atrial arrhythmias, and to evaluate it clinical efficacy and safety. Methods: Indentify ADx DDD 5286 implanted dual chamber pacemaker for sick sinus syndrome in 43 cases. Automatic search of atrial lag was not opened with after pacemaker implantation, and the pacemaker settings were kept. Follow-up program after 3 months, DDD mode with automatic search of atrial lag was opened, and this mode was followed up for 6 months, comparing the atrial pacing percentage and DCG atrial tachyarrhythmias of pacemaker implantation to opening atrium lag mode. Results: Compared with the preoperative and operative 3 months later, dynamic electrocardiogram (DCG) 24 h showed that the number of atrial premature beats (APB) and atrial tachycardia, atrial fibrillation (AF) array increased ( p < .05); the cases of APB, atrial tachycardia and AF episodes were also increased ( p < .05). Compared with the automatic search function in atrial hysteresis model opened with and not opened: atrial pacing percentage decreased [0.54 (0.41, 0.71) vs. 0.82 (0.65, 0.93), p

Lung adenocarcinoma is the most frequently histologic subtype and the most histologically heterogeneous form of lung cancer. De-regulation of Wnt/β-catenin signaling pathway is implicated in lung carcinogenesis. SOX7, as a member of high mobility group (HMG) transcription factor family, plays a role in the modulation of the Wnt/β-catenin signaling pathway. However, the expression pattern and clinicopathological significance of SOX7 in patients with lung adenocarcinoma is still unclear. To address this problem, the SOX7 mRNA expression was detected by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Immunohistochemical studies were performed on 288 pairs of adjacent normal lung and lung adenocarcinoma tissues with complete follow-up records. Association of SOX7 protein expression with clinical outcomes was evaluated using the Kaplan-Meier method and a multivariate Cox proportional hazards regression model. SOX7 mRNA expression was significantly down-regulated in lung adenocarcinoma compared with matched adjacent normal tissues (P < 0.001). SOX7 protein was expressed in the cytoplasm of lung adenocarcinoma cells in 106/288 (36.8 %) of cases, whereas its immunoreactivities were predominantly located in the cytoplasm of the adjacent normal tissues. The reduced SOX7 expression was correlated with poor differentiation (P = 0.002), lymph node metastasis (P = 0.011) and advanced TNM stage (P = 0.006). Regarding patient survival, the overall survival and the disease-free survival rates were both significantly lower in patients with SOX7-negative tumors than in those with SOX7-positive tumors (P = 0.018 and 0.013, respectively). Multivariate analysis using a Cox proportional-hazards model demonstrated that SOX7 expression status was an independent prognostic factor predicting the overall survival and the disease-free survival of patients with lung adenocarcinoma (P = 0.021 and 0.016, respectively).Our data suggest that the decreased expression of SOX7 is an important feature of lung adenocarcinoma. The expression level of SOX protein may be a useful prognostic marker for patients with lung adenocarcinoma.

SPRY4-IT1 has been reported to have extremely high expression in normal placenta tissues. It is a Long noncoding RNA (lncRNA), which is associated with cell growth, migration, invasion, and apoptosis in melanoma. A 2.8-fold increase of SPRY4-IT1 expression was validated by Real-time reverse transcription-polymerase chain reaction (qRT-PCR) in severe preeclamptic placenta as compared with that of the normal ones (n=25) in this study. Furthermore, the role of SPRY4-IT1 in proliferation, migration, apoptosis, and network formation ability of trophoblast cells HTR-8/SVneo was assessed. Suppression of SPRY4-IT1 using siRNA treatment and its overexpression using plasmid targeting SPRY4-IT1 were performed in order to explore the biological function of SPRY4-IT1 in the development and progression of trophoblast cells HTR-8/SVneo, in vitro. The results showed that SPRY4-IT1 knockdown enhanced the cell migration and proliferation, and reduced the response of cells to apoptosis. However, exogenous SPRY4-IT1 overexpression significantly decreased the cell migration and proliferation, while increased cell apoptosis. Our study showed for the first time that aberrant expression of lncRNA SPRY4-IT1 might contribute to the abnormal condition of trophoblast cells HTR-8/SVneo. Therefore, we proposed SPRY4-IT1 as a novel lncRNA molecule, which might be associated with the pathogenesis of preeclampsia and might provide a new target for its early diagnosis and treatment.