Linoleic acid induces human ovarian granulosa cell inflammation and apoptosis through the ER-FOXO1-ROS-NFκB pathway.

Polycystic ovary syndrome (PCOS) is a complex reproductive endocrinological disorder influenced by a combination of genetic and environmental factors. Linoleic acid (LA) is a widely consumed ω-6 polyunsaturated fatty acid, accounting for approximately 80% of daily fatty acid intake. Building upon the prior investigations of our team, which established a connection between LA levels in the follicular fluid and PCOS, this study deeply examined the specific impact of LA using a granulosa cell line. Our findings revealed that LA exerts its influence on granulosa cells (GCs) by binding to the estrogen receptor (ER). Activated ER triggers the transcription of the FOXO1 gene. Reactive oxygen species (ROS)-related oxidative stress (OS) and inflammation occur downstream of LA-induced FOXO1 activation. Increased OS and inflammation ultimately culminate in GC apoptosis. In summary, LA modulates the apoptosis and inflammation phenotypes of GCs through the ER-FOXO1-ROS-NF-κB pathway. Our study provides additional experimental evidence to comprehend the pathophysiology of PCOS and provides novel insights into the dietary management of individuals with PCOS.

Effects of adverse fertility-related factors on mitochondrial DNA in the oocyte: a comprehensive review.

The decline of oocyte quality has profound impacts on fertilization, implantation, embryonic development, and the genetic quality of future generations. One factor that is often ignored but is involved in the decline of oocyte quality is mitochondrial DNA (mtDNA) abnormalities. Abnormalities in mtDNA affect the energy production of mitochondria, the dynamic balance of the mitochondrial network, and the pathogenesis of mtDNA diseases in offspring. In this review, we have detailed the characteristics of mtDNA in oocytes and the maternal inheritance of mtDNA. Next, we summarized the mtDNA abnormalities in oocytes derived from aging, diabetes, obesity, and assisted reproductive technology (ART) in an attempt to further elucidate the possible mechanisms underlying the decline in oocyte health. Because multiple infertility factors are often involved when an individual is infertile, a comprehensive understanding of the individual effects of each infertility-related factor on mtDNA is necessary. Herein, we consider the influence of infertility-related factors on the mtDNA of the oocyte as a collective perspective for the first time, providing a supplementary angle and reference for multi-directional improvement strategies of oocyte quality in the future. In addition, we highlight the importance of studying ART-derived mitochondrial abnormalities during every ART procedure.

Health-Related Quality of Life Among Chinese Pregnant Women in the Third Trimester Based on Theory of Unpleasant Symptoms: A Complex Network Analysis.

Health-related quality of life (HRQOL) is the result of complex interactions between many different factors. But few studies to date have explored the structure of HRQOL. This study aimed to investigate the complex inter-relationship between HRQOL and influencing factors using network analysis. In all, 624 Chinese pregnant women in third trimester were recruited through recruiting sampling. We used regularized network analysis to create a complex network. The relationship with mother-in-law was the most central node followed by relationship with partner. We found the comorbidity of anxiety and depressive symptoms using network analysis. Physical- and mental-related quality of life were a "bridge node" connecting psychological factors with physiologic factors. The present network analysis highlights the strong link between relationship with mother-in-law or partner and HRQOL, which is also a unique phenomenon under Chinese culture. This analysis provides key variables for future intervention or improvement of pregnant women' HRQOL.

The associations of urinary DEHP metabolite levels, serum thyroid hormones, and thyroid-related genes among the adolescent students from China: a cross-sectional study.

Our study aimed to investigate the associations between DEHP exposure and serum thyroid hormone levels in 347 adolescents and young adults. We measured DEHP metabolites including mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), and mono(2-carboxymethyl)hexyl phthalate (MCMHP) in their urine. Total thyroxine (TT4), total triiodothyronine, free triiodothyronine, free thyroxine (FT4), thyroid-stimulating hormone and the mRNA levels of thyroid peroxidase (TPO), thyroglobulin (TG), sodium iodide symporter (NIS), thyroid transcription factor 1 (TTF-1), and paired box gene 8 (PAX-8) in serum were measured. The results of statistical analysis showed that urinary DEHP metabolites were generally negatively associated with TT4 levels in serum. In the males, the FT4 levels showed positive associations with urinary MEHP, MECPP, MCMHP, and ∑DEHP. The mRNA level of TG was significantly positively correlated with the levels of MECPP, MCMHP, and ∑DEHP, while the levels of TTF-1 and PAX-8 mRNA were significantly positively correlated with the levels of DEHP metabolites. Taken together, DEHP may affect the synthesis of TG by altering the normal transcription of TTF-1 and PAX-8, leading to decreased TT4 levels in Chinese adolescents.

Let-7a inhibits Bcl-xl and YAP1 expression to induce apoptosis of trophoblast cells in early-onset severe preeclampsia.

Dysregulation of the MicroRNA (miR) Let-7 family has been implicated in preeclampsia (PE). Abnormal trophoblast cell proliferation and apoptosis associate with the pathogenesis of PE. The present study was designed to test the hypothesis whether let-7a could regulate the biological functions of trophoblasts and explore the mechanism how it works in the development of early-onset severe PE. The putative target genes Bcl-xl and YAP1 of let-7a were verified by luciferase assay. The roles of let-7a, Bcl-xl and YAP1 in regulating JEG-3 cell functions were examined by altering their expression with mimic, overexpression plasmids or siRNAs. The methylation status of let-7a-3 in PE was assessed by methylation-specific and bisulfite sequencing PCR assays. JEG-3 cells were treated with DNA methyltransferase inhibitor to analyze whether let-7a-3 demethylation functioned in PE. Tumor growth and cell apoptosis were measured from nude mice inoculated with JEG-3 cells overexpressing let-7a. The results revealed let-7a was highly expressed in early-onset severe PE and let-7a-3 presented a low methylation level. Functionally, let-7a upregulation could inhibit the viability and cell cycle progression but induce the apoptosis of JEG-3 cells. Bcl-xl and YAP1, target genes of let-7a, could rescue cell apoptosis induced by let-7a. The demethylation of let-7a-3 was also observed to elevate the expression of let-7a and enhance JEG-3 cell apoptosis. Let-7a inhibited tumorigenic ability of JEG-3 cells and enhanced cell apoptosis in vivo. Altogether, let-7a could enhance cell apoptosis in trophoblasts through downregulation of Bcl-xl and YAP1, which suggests that let-7a might be a key regulator in the progression of PE.

Simultaneous detection of the Ca and Ca+ layers by a dual-wavelength tunable lidar system.

A dual-wavelength tunable lidar system that simultaneously detects the Ca and Ca+ layers has been established in Yanqing Station (40.41°N, 116.01°E). The lidar system implements a pulsed Nd:YAG laser that simultaneously pumps two dye lasers, which reduces the hardware configuration of the lidar system. The two dye lasers use infrared laser dyes with high conversion efficiency suitable for long-term observation. The resonance wavelengths of Ca and Ca+ are generated by frequency doubling of the two infrared laser beams. We compared the dual-wavelength tunable lidar system to previous dye-based systems and performed experiments to determine resonance frequencies to within 0.4 pm and to test the dual optical fiber receiving system and found it does not cause cross talk. Three nights of preliminary simultaneous observations of Ca and Ca+ layers are reported; the diversity of these observations begs for more systematic observations and challenging interpretations in terms of Ca processes in the ionosphere and illustrates the effectiveness of this system for aeronomy and space physics studies.

MSC-Secreted Exosomal H19 Promotes Trophoblast Cell Invasion and Migration by Downregulating let-7b and Upregulating FOXO1.

Exosomes perform important functions for intercellular communication through extracellular signaling pathways, leading to the regulation of important biological processes, including cell proliferation, but also systemic dysfunctions such as preeclampsia (PE). However, the inhibitory effects of mesenchymal stem cell (MSCs)-derived exosomes in PE remain largely unknown. Thus, we assessed the possibility that exosomes could transport long non-coding RNA H19 and the correlation between H19 and the apoptosis of trophoblast cells. The expression of microRNA let-7b and forkhead box protein O1 (FOXO1) was characterized in placental tissues of PE patients. Gain- and loss-of-function experiments were performed to examine the roles of FOXO1 and let-7b in trophoblast cells. Interactions between let-7b and H19 as well as between let-7b and FOXO1 were confirmed by a dual-luciferase reporter assay, RNA pull-down, and RNA immunoprecipitation. HTR-8/SVneo cells were co-cultured with exosomes derived from MSCs overexpressing H19, followed by invasion, migration, and apoptosis assessments of trophoblast cells. We found that let-7b was highly expressed and FOXO1 was poorly expressed in placental tissues of PE patients. Furthermore, H19 acts as a competitive endogenous RNA against let-7b, and let-7b directly targeted FOXO1. Moreover, H19 could be transferred to trophoblast cells via MSC-secreted exosomes. MSC-derived exosomes overexpressing H19 decreased let-7b, increased FOXO1, and activated the protein kinase B (AKT) signaling pathway, thus increasing invasion and migration and inhibiting apoptosis of trophoblast cells. These results suggest that MSC-derived exosomes overexpressing H19 may be a novel direction for therapeutic strategies against PE.

LncRNA HAND2-AS1 exerts anti-oncogenic effects on ovarian cancer via restoration of BCL2L11 as a sponge of microRNA-340-5p.

In the early stage of ovarian cancer (OC), molecular biomarkers are critical for its diagnosis and treatment. Nevertheless, there is little research on the mechanism underlying tumorigenesis in OC. Herein, we aimed to explore whether long noncoding RNA (lncRNA) HAND2-AS1 participated in the regulation of the cell proliferation, migration, and apoptosis of OC by regulating B-cell lymphoma 2 like 11 (BCL2L11) and microRNA-340-5p (miR-340-5p). Differentially expressed lncRNAs in OC were screened by microarray-based analysis. HAND2-AS1, BCL2L11, and miR-340-5p expression was assessed in normal ovarian and OC tissues and human OC cell lines. Then, the relationships among HAND2-AS1, BCL2L11, and miR-340-5p were explored. Ectopic expression and depletion experiments were applied to analyze the effects of HAND2-AS1, miR-340-5p and BCL2L11 on migration, invasion, and proliferation of OC cells, as well as apoptosis. Lastly, the tumor xenograft in nude mice was conducted to test the tumorigenesis in vivo. In silico analysis displayed poor expression of HAND2-AS1 in OC. HAND2-AS1 specifically sponged with miR-340-5p which was found to directly target BCL2L11. Importantly, HAND2-AS1 or BCL2L11 overexpression or miR-340-5p downregulation resulted in reduction of cell invasion and migration, together with decrease of cell proliferation and increase of cell apoptosis in OC. Besides, high-expressed HAND2-AS1 inhibited the tumorigenesis in nude mice. To sum up, these data suggests HAND2-AS1 as an anti-oncogene in OC through upregulation of BCL2L11 by competitively binding to miR-340-5p, which demonstrates that there are potential diagnosis and therapy values of HAND2-AS1 in OC.

Expression profile of Let-7s in peripheral blood mononuclear cells of normal and severe preeclampsia pregnant women.

HEADINGS AIM: We aimed to investigate if the let-7 s expression level in the serum of peripheral blood from pregnant women with severe pre-eclampsia and normal pregnant women is related to the incidence of severe pre-eclampsia. METHODS: Total RNA was extracted from collected peripheral blood mononuclear cells from 20 or over weeks pregnant women diagnosed with severe pre-eclampsia (age: 31.57 ±â€¯4.94) and normal pregnant women (age: 29.75 ±â€¯4.6) respectively, followed by real-time PCR to examine the expression of let-7 s. Correlation between let-7 s expression level and maternal age or body mass index of the normal pregnant women were also analyzed using SPSS21.0 software. RESULTS: Let-7a and let-7 g were significantly increased in pregnant women with severe pre-eclampsia by 4.67 fold and 2.37 fold respectively compared to the normal pregnant women, whereas there was no significant difference in let-7b and let-7i. Moreover, there was no correlation between maternal age or body mass index and the expression level of let-7a, let-7b, let-7 g, and let-7i. CONCLUSIONS: In conclusion, let-7a and let-7 g were significantly increased in the PBMCs of severe pre-eclampsia women compared to normal controls. Moreover, their expression level was not correlated to the maternal age or body mass of patients. Our data indicated that let-7a and let-7 g may be considered as predictive markers for SPE.

Analysis of 62 placental abruption cases: Risk factors and clinical outcomes.

OBJECTIVE: This study aimed to explore the clinical characteristics and outcomes of placental abruption. MATERIALS AND METHODS: A total of 62 placental abruption cases were collected from the Second Hospital of Jilin University between January 2007 and December 2012. A retrospective study was conducted to explore the risk factors for placental abruption, clinical characteristics, and maternal and fetal outcomes. RESULTS: Risk factors for placental abruption mainly include preeclampsia (39%) and premature rupture of membrane (10%). Abdominal pain (68%) and bleeding (35%) comprise the classical symptoms of placental abruption but the clinical picture varies from asymptomatic, in which the diagnosis is made by inspection of the placenta at delivery, to massive abruption leading to fetal death and severe maternal morbidity. Emergency cesarean section was performed in 45 cases (73%) of placental abruption. Sixty-two placental abruption cases were divided into 2 groups according to whether uteroplacental apoplexy occurred. The incidence of preeclampsia and the duration (time between on-set of clinical symptom and placenta delivery) in the observational group were significantly higher than that of the control group, showing statistical significance (P < 0.01). CONCLUSION: The diagnosis of placental abruption should consider risk factors, symptoms, physical signs, dynamic ultrasound monitoring, and cardiac care. Early diagnosis and treatment can improve maternal and infant prognosis.

Upregulation of DAPK2 ameliorates oxidative damage and apoptosis of placental cells in hypertensive disorder complicating pregnancy by suppressing human placental microvascular endothelial cell autophagy through the mTOR signaling pathway.

Death-associated protein kinase 2 (DAPK2) has indicated functional roles in cellular processes, including survival, apoptosis, and autophagy. This study is aimed to identify the effect of DAPK2 on oxidative damage and apoptosis of placental cells in hypertensive disorder complicating pregnancy (HDCP) through mTOR pathway. Microarray-based gene expression analysis was performed to predict the differentially expressed genes related to HDCP. To investigate the specific mechanism of DAPK2 in HDCP cells, placental microvascular endothelial cells were treated with mimic or siRNA of DAPK2 and mTOR to detect the expression of related genes, cell autophagy and apoptosis and oxidative damage. Finally, rats were modeled with HDCP to verify the cell experiment results. DAPK2 was downregulated in HDCP, and could activate mTOR. Besides, DAPK2 overexpression led to decreases in autophagy in HPVECs as well as apoptosis and oxidative damage in placental cells indicated by a substantial decrease in Beclin-1, LC3 II/LC3 I and Bax along with an increase in Bcl-2, 4EBP1 and p70S6K. It also ameliorates blood pressure elevation in HDCP rats. The study defined remission effect of DAPK2 on placental cell oxidative damage and apoptosis in HDCP via mTOR activation. Together, DAPK2 regulating mTOR pathway presents a promising therapy for HDCP treatment.

TPX2 gene silencing inhibits cell proliferation and promotes apoptosis through negative regulation of AKT signaling pathway in ovarian cancer.

Ovarian cancer (OC) is the leading cause of death from gynecological malignancy. Accumulated studies have revealed that targeting protein for Xklp2 (TPX2) was tightly associated with the development and progression of OC. The present study further determined a novel mechanism of TPX2 in OC via the AKT signaling pathway. The differentially expressed genes were screened in GEO database for gene expression microarray of OC. Bioinformatics was used to analyze the key differentially expressed genes in OC. We prepared CD133/1+ OC stem cells. Then cells were treated with TPX2-1 siRNA and perifcsine to explore the correlation of TPX2 and the AKT signaling pathway. We determined the expression of TPX2, AKT, Pl3 K, PTEN, caspase-3, Bax and Bcl-2 in OC cells. Cell proliferation, migration, invasion, and apoptosis rate were respectively measured using MTT and EdU assays, Transwell assay, Scratch test, and flow cytometry. Xenograft tumor in nude mice was used to determine the effect of TPX2 in OC cells in vitro. Initially, TPX2 overexpression was observed in OC, and TPX2 mediated the effect of the AKT signaling pathway in OC. TPX2 knockdown decreased expression of AKT, Pl3 K, and Bcl-2, and the extent of AKT phosphorylation, but increased expression of PTEN, Caspase-3, and Bax. Furthermore, TPX2 knockdown suppressed OC cell proliferation, migration and invasion, but promoted OC cell apoptosis. Taken together, TPX2 silencing negatively regulates the AKT signaling pathway by which OC cell proliferation was inhibited yet cell apoptosis was accelerated, suggesting a potential therapeutic approach to OC.

GPIbα reflects the development and progress of the patients with severe preeclampsia.

UNLABELLED: Preeclampsia (PE) is a pregnancy-specific syndrome that occurs in a previously normotensive woman. Some data suggested that the activation parameters of platelets in preeclampsia. The aim of this study is to determine whether the levels of GPIbα and GPIIb for patients with preeclampsia were enhanced after cesarean section. In this study, detecting levels of GPIbα and GPIIb by flow cytometry (FCM). The venous blood of 48 severe preeclampsia women, 16 mild preeclampsia and 22 normotensive women, were collected before operation and 72 hours after the operation. Blood samples were obtained also from 20 non-pregnant women. RESULTS: The level of GPIbα of the normotensive pregnancy was lower than the control group, but there was no significance (P > 0.05). The level of GPIbα of the severe preeclampsia group was much lower than other groups (P < 0.01). In the severe preeclampsia group, the level of GPIbα of postoperative patients was higher than preoperative patients (P < 0.01). There was no significance of GPIIb levels between each group (P > 0.05). In conclusion, GPIbα was an important index of reflecting the change of severe preeclampsia. Detecting the levels of GPIbα plays an important role in observing the development of this disease and guiding clinical treatment.

KIR2DL4 expression rather than its single nucleotide polymorphisms correlates with pre-eclampsia.

OBJECTIVE: To evaluate the single nucleotide polymorphisms and expression of KIR2DL4 (killer cell immunoglobulin-like receptors) gene in pre-eclampsia patients. METHODS: KIR2DL4 gene polymorphisms were detected in 100 patients with pre-eclampsia and 100 healthy pregnant women, respectively, by using PCR-SS. Then, the expression of KIR2DL4 was measured in 5 cases of placentas tissues with pre-eclampsia and normal pregnancies by using qRT-PCR. RESULTS: Compared with healthy controls, 16 loci of single nucleotide polymorphisms (SNP) were identified in pre-eclampsia patients, including 7 new polymorphisms loci. But, no significant difference was found in genotype distributions and allele frequencies in pre-eclampsia and controls (P>0.05). However, qRT-PCR results showed that KIR2DL4 mRNA in placenta tissues with pre-eclampsia was significantly lower than those with normal pregnancy, and the difference was statistically significant. CONCLUSION: Decreased level of KIR2DL4 rather than its SNP is correlated with the susceptibility of pre-eclampsia.

The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells.

The H19 lncRNA has been implicated in development and growth control and is associated with human genetic disorders and cancer. Acting as a molecular sponge, H19 inhibits microRNA (miRNA) let-7. Here we report that H19 is significantly decreased in muscle of human subjects with type-2 diabetes and insulin resistant rodents. This decrease leads to increased bioavailability of let-7, causing diminished expression of let-7 targets, which is recapitulated in vitro where H19 depletion results in impaired insulin signaling and decreased glucose uptake. Furthermore, acute hyperinsulinemia downregulates H19, a phenomenon that occurs through PI3K/AKT-dependent phosphorylation of the miRNA processing factor KSRP, which promotes biogenesis of let-7 and its mediated H19 destabilization. Our results reveal a previously undescribed double-negative feedback loop between sponge lncRNA and target miRNA that contributes to glucose regulation in muscle cells.

PreImplantation factor promotes neuroprotection by targeting microRNA let-7.

Dysfunction and loss of neurons are the major characteristics of CNS disorders that include stroke, multiple sclerosis, and Alzheimer's disease. Activation of the Toll-like receptor 7 by extracellular microRNA let-7, a highly expressed microRNA in the CNS, induces neuronal cell death. Let-7 released from injured neurons and immune cells acts on neighboring cells, exacerbating CNS damage. Here we show that a synthetic peptide analogous to the mammalian PreImplantation factor (PIF) secreted by developing embryos and which is present in the maternal circulation during pregnancy inhibits the biogenesis of let-7 in both neuronal and immune cells of the mouse. The synthetic peptide, sPIF, destabilizes KH-type splicing regulatory protein (KSRP), a key microRNA-processing protein, in a Toll-like receptor 4 (TLR4)-dependent manner, leading to decreased production of let-7. Furthermore, s.c. administration of sPIF into neonatal rats following hypoxic-ischemic brain injury robustly rescued cortical volume and number of neurons and decreased the detrimental glial response, as is consistent with diminished levels of KSRP and let-7 in sPIF-treated brains. Our results reveal a previously unexpected mechanism of action of PIF and underscore the potential clinical utility of sPIF in treating hypoxic-ischemic brain damage. The newly identified PIF/TLR4/KSRP/let-7 regulatory axis also may operate during embryo implantation and development.