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Abstract Abnormal granulosa cell (GC) death contributes to cyclophosphamide (CTX) induced primary ovarian insufficiency (POI). To investigate the contribution of GCs to POI, gene profiles of GCs exposed to CTX were assessed using RNA-Seq and bioinformatics analysis. The results showed the differentially expressed genes (DEGs) were enriched in the ferroptosis-related pathway, which is correlated with upregulated heme oxygenase 1 (HO-1) and downregulated glutathione peroxidase-4 (GPX4). Using CTX-induced cell culture (COV434 and KGN cells), the levels of iron, reactive oxygen species (ROS), lipid peroxide, mitochondrial superoxide, mitochondrial morphology and mitochondrial membrane potential (MMP) were detected by DCFDA, MitoSOX, C11-BODIPY, MitoTracker, Nonylacridine Orange (NAO), JC-1 and transmission electron microscopy respectively. The results showed iron overload and disrupted ROS, including cytoROS, mtROS and lipROS homeostasis, were associated with upregulation of HO-1 and could induce ferroptosis via mitochondrial dysfunction in CTX-induced GCs. Moreover, HO-1 inhibition could suppress ferroptosis induced GPX4 depletion. This implies a role for ROS in CTX-induced ferroptosis and highlights the effect of HO-1 modulators in improving CTX-induced ovarian damage, which may provide a theoretical basis for preventing or restoring GC and ovarian function in patients with POI.

Abstract Background Heat shock protein 60 (HSP60) is essential for the folding and assembly of newly imported proteins to the mitochondria. HSP60 is overexpressed in most types of cancer, but its association with ovarian cancer is still in dispute. SKOV3 and OVCAR3 were used as experimental models after comparing the expression level of mitochondrial HSP60 in a normal human ovarian epithelial cell line and four ovarian cancer cell lines. Results Low HSPD1 (Heat Shock Protein Family D (HSP60) Member 1) expression was associated with unfavorable prognosis in ovarian cancer patients. Knockdown of HSPD1 significantly promoted the proliferation and migration of ovarian cancer cells. The differentially expressed proteins after HSPD1 knockdown were enriched in the lipoic acid (LA) biosynthesis and metabolism pathway, in which mitochondrial 3-oxoacyl-ACP synthase (OXSM) was the most downregulated protein and responsible for lipoic acid synthesis. HSP60 interacted with OXSM and overexpression of OXSM or LA treatment could reverse proliferation promotion mediated by HSPD1 knockdown. Conclusions HSP60 interacted with OXSM and maintained its stability. Knockdown of HSPD1 could promote the proliferation and migration of SKOV3 and OVCAR3 via lowering the protein level of OXSM and LA synthesis.

Microbial dysbiosis has an increasingly appreciated impact on carcinogenesis, and the cervicovaginal microbiome plays a critical role in microenvironmental inflammation. Here, we investigated the involvement of the female genital tract Peptostreptococcus species in gynecological cancer via indoleacrylic acid (IAA). IAA production from Peptostreptococcus species and the effect of bacterial culture on tumor growth in vivo were examined. The impact of IAA on cytokine production and indoleamine-2,3-dioxygenase 1 (IDO1) expression in an endometrial cancer (EC) cell line, as well as their effect on Treg and Teff cells, and M1 and M2 macrophage populations were examined in EC patients and tumor-grafted mice. Clinically, Peptostreptococcus species abundance, IAA, and IDO1 expression were verified in EC patients. The results showed that IAA production was induced in the uteri of BALB/c nude mice by Peptostreptococcus species transplantation, and the intratumoral injection of a conditioned medium from Peptostreptococcus cultures into tumor-grafted mice promoted tumor growth. IL-10 expression was upregulated by IAA; IFN-γ expression was increased by IL-10. IFN-γ induced IDO1 expression in the EC cell line. The co-culture of IDO1-expressing EC cells with peripheral blood mononuclear cells upregulated the Treg proportion and decreased the M1/M2 ratio. Clinically, P. anaerobius was more abundant amongst the uterine microbiota of EC patients than the control. The IAA, IDO1, and kynurenine/tryptophan ratios were all higher in EC tissue, and the M1/M2 ratio was lower. Our study sheds light on the link between IDO1 induction and uterine Peptostreptococcus dysbiosis and provides a potential rationale for the role of Peptostreptococcus species in immune tolerance induction in type I endometrial cancer.

BackgroundHearing loss (HL) is one of the main medical complications for Turner Syndrome (TS) patients, with an earlier presentation and higher incidence than normal women. However, the etiology of HL in TS is unclear. The aim of this study was to investigate the hearing status of TS patients in China and the influencing factors, so as to provide a theoretical basis for early intervention treatment for TS patients with HL.MethodsIn total 46 female patients aged 14–32 diagnosed with TS received tympanic membrane and audiological examinations, including pure tone audiometry and tympanometry. In addition, the effects of karyotype, sex hormone levels, thyroid function, insulin, blood lipids, bone mineral density, age and other factors on hearing levels were analyzed, and the possible risk factors associated with HL in TS patients were explored.ResultsIn 9 patients (19.6%) had HL, including 1 (2.2%) with mild conductive hearing loss, 5 (10.9%) with mild sensorineural hearing loss, 3 (6.5%) with moderate sensorineural hearing loss. TS is often associated with age-related mid-frequency and high-frequency HL, and the incidence of HL increases with age. Compared with other karyotypes, patients with 45, X haplotype have an increased risk of mid-frequency HL.ConclusionsTherefore, karyotype may be a predictor of hearing problems in TS.

Decidual leukocytes make up approximately 30% of all decidual stromal cells in early pregnancy, of which 70% are uterine natural killer (uNK) cells. uNK cells are phenotypically distinct from peripheral blood NK cells, being CD56brightCD16−. A recent single-cell sequencing project of the decidua identified three subsets of uNK cells, but we are yet to determine how they differ functionally. Several roles for uNK cells in implantation are starting to emerge including biosensing of poor-quality embryos, killing of bacteria infected trophoblast, spiral artery remodeling, and regulation of trophoblast invasion. Altered numbers of uNK cells have been identified in several pathological conditions, but whether this is causative of the condition is currently unclear.

Background: Turner syndrome (TS) affects approximately one out of 2,500 females. Previous research indicates that girls with TS experience psychosocial impairment in addition to their physical health issues. However, there is no current data demonstrating whether reducing the clinical symptoms of girls or women with TS through hormone replacement therapy (HRT) combined with psychological interventions, referred to as psychosomatic mutual aid treatment (PMAT), improves physical and psychological self-identification, so that psychological problems such as anxiety, depression, low self-esteem, social loneliness, and psychological resilience are improved. Therefore, the objective of this research was to assess the efficacy of PMAT on anxiety and depression in girls and women with TS.Methods: Twenty-six girls and women with TS aged 11–29 years (17.5 ± 4.2 years) were recruited. Anxiety and depression were assessed using Hamilton Anxiety Rating Scale (HAMA) and Zung Self-Rating Depression Scale (SDS) questionnaires, respectively. The 26 TS patients were surveyed for anxiety and depression before the beginning of PMAT and again in January 2020. In addition, 20 healthy volunteer women aged 16–39 years (23.1 ± 5.7 years) were selected as the control group and filled in the questionnaire.Results: Pre-therapy (pre-HRT and Pre-PMAT) there were significant differences between the TS patients (n = 26) and healthy controls (n = 20). In particular, the TS patients had higher anxiety status (P = 0.04) and severity (P = 0.03) (HAMA score), as well as depression status (P = 0.002) and severity (P < 0.001) (SDS score). Post-therapy there was no longer any difference in depression scores, but TS patients still had higher levels of anxiety post-therapy compared with healthy control women (psychic symptoms score, P = 0.03; anxiety status score, P = 0.04; anxiety severity score, P = 0.04). In the TS patients, there was an improvement in depression scores (SDS score P < 0.001; depression severity score, P = 0.005) after therapy but no change in levels of anxiety.Conclusions: PMAT significantly improves depression status, but not anxiety, in girls and women with TS.Clinical Trial Registration:http://www.chictr.org.cn/showproj.aspx?proj=124736, identifier: ChiCTR2100045230.

Appropriate growth and development of the endometrium across the menstrual cycle is key for a woman’s quality of life and reproductive well-being. Recurrent pregnancy loss (RPL) and heavy menstrual bleeding (HMB) affect a significant proportion of the female population worldwide. These endometrial pathologies have a significant impact on a woman’s quality of life as well as placing a high economic burden on a country’s health service. An underlying cause for both conditions is unknown in approximately 50% of cases. Previous research has demonstrated that aberrant endometrial vascular maturation is associated with both RPL and HMB, where it is increased in RPL but reduced in HMB. TGFβ1 is one of the key growth factors that regulate vascular maturation, by inducing phenotypic switching of vascular smooth muscle cells (VSMCs) from a synthetic phenotype to a more contractile one. Our previous data demonstrated an increase in TGFβ1 in the endometrium of RPL, while others have shown a decrease in women with HMB. However, TGFβ1 bioavailability is tightly controlled, and we therefore sought to perform an extensive immunohistochemical analysis of different components in the pathway in the endometrium of normal controls, women with HMB or RPL. In addition, two in vitro models were used to examine the role of TGFβ1 in endometrial vascular maturation and endothelial cell (EC):VSMC association. Taken all together, the immunohistochemical data suggest a decrease in bioavailability, receptor binding capacity, and signaling in the endometrium of women with HMB compared with controls. In contrast, there is an increase in the bioavailability of active TGFβ1 in the endometrium of women with RPL compared with controls. Endometrial explants cultured in TGFβ1 had an increase in the number of vessels associated with contractile VSMC markers, although the total number of vessels did not increase. In addition, TGFβ1 increased EC:VSMC association in an in vitro model. In conclusion, TGFβ1 is a key regulator of endometrial vascular maturation and could be considered as a therapeutic target for women suffering from HMB and/or RPL.

Vitamin D deficiency is associated with complications of pregnancy such as pre-eclampsia, fetal growth restriction, and miscarriage, all of which are also associated with incomplete spiral artery (SpA) remodeling. We have previously shown that both uterine natural killer (uNK) cells and extravillous trophoblast cells (EVT) are required for successful SpA remodeling, but whether their activity in this process is modulated by vitamin D is not known. In the current study, we use a previously described chorionic plate artery (CPA) ex vivo model of vascular remodeling to determine the effects of 1,25(OH)2D treated uNK cell, placental explant (PEx), and uNK/PEx conditioned medium (CM) on vascular smooth muscle cell (VSMC) disorganization and phenotypic switching. Significant results were followed up in VSMCs in vitro. We demonstrate that 1,25(OH)2D can enhance the ability of PEx to induce SpA remodeling, via a mechanism associated with increased secretion of granulocyte-colony stimulating factor (G-CSF). G-CSF appears able to increase VSMC disorganization and phenotypic switching in both an ex vivo vascular model and in vitro VSMC cultures. The clinical relevance of these findings are still to be determined. G-CSF may have differential effects depending on dose and vascular bed, and vitamin D may play a role in potentiating these actions. G-CSF may be an interesting potential therapeutic target for facilitating physiological vascular remodeling for the prevention of adverse obstetric outcomes.

Background/Aims: Circular RNAs (circRNAs) are transcribed prevalently in the genome; however, their potential roles in multiple cardiovascular diseases, particularly preeclampsia (PE), are not yet well understood. This study investigated the expression profiles of circRNAs and explored circRNA-mediated pregnancy-associated plasma protein A (PAPP-A) expression as a potential biomarker for PE before 20 weeks of pregnancy. Methods: A nested case-control two-phase screening/validation study was performed in pregnant women before 20 weeks of gestation (before clinical diagnosis) at Guangzhou Women and Children’s Medical Center from 2012 to 2015. In the screening phase, circRNA expression profiles of blood cells were assessed using a human circRNA microarray, which was designed to detect simultaneously 5396 circRNAs, in 5 patients with PE and 5 age- and gestational week-matched controls. In the validation phase, 18 circRNAs in blood cells predicted by bioinformatics tools were validated by quantitative reverse transcription PCR in a cohort of 60 patients (PE and age-, gestational week-, and sample storage time-matched controls). Then, we examined the involvement of circRNAs in PE-related pathways via interactions with miRNAs by multiple bioinformatics approaches. Bioinformatics analysis predicted that hsa_circ_0004904 and hsa_circ_0001855 miRNA sponges directly target PAPP-A. PAPP-A was verified in the serum of the same cohort of patients using an enzyme-linked immunosorbent assay. Finally, we combined PAPP-A with circRNAs to create a novel preclinical diagnostic model for PE with logistic regression and evaluated the efficiency of this model with receiver operating curve analysis. Results: Volcano plot analysis using various parameters showed that circRNAs were differentially expressed among both groups (P < 0.01, fold change > 2). In the screening phase, we found that 2178 circRNAs were differentially expressed between the control and PE groups, in which 884 circRNAs were downregulated and 1294 circRNAs were upregulated in the PE group compared with the control group. In the validation phase, two circRNAs, hsa_circ_0004904 and hsa_circ_0001855, were significantly upregulated in PE patients compared with healthy pregnant women (P < 0.05). PAPP-A expression levels, related to the two circRNAs based on bioinformatics prediction, were increased in the PE group compared with the control group. The area under the curve of the combined model was 0.94 in the predicted PE subjects. Conclusions: This is the first study to report circRNA profiling in patients with PE prior to the onset of symptoms. Our data suggested that hsa_circ_0004904 and hsa_circ_0001855 combined with PAPP-A might be promising biomarkers for the detection of PE. Moreover, circRNAs may provide new insights into the potential mechanisms underlying the pathophysiology of PE.

The presence of unusual natural killer cells in human endometrium has been recognized for 30 years, but despite considerable research effort, the in vivo role of uterine natural killer (uNK) cells in both normal and pathological pregnancy remains uncertain. uNK cells may differentiate from precursors present in endometrium, but migration from peripheral blood in response to chemokine stimuli with in situ modification to a uNK cell phenotype is also possible. uNK cells produce a wide range of secretory products with diverse effects on trophoblast and spiral arteries which may play an important role in implantation and early placentation. Interactions with other decidual cell populations are also becoming clear. Recent evidence has demonstrated subpopulations of uNK cells and the presence of other innate lymphoid cell populations in decidua which may refine future approaches to investigation of the role of uNK cells in human pregnancy.

A longitudinal observational study was performed comparing BMD and body composition in Turner syndrome girls before and after 1 year of HRT treatment. Whole body BMD, femur neck BMD, total hip BMD, and lean mass were significantly increased, but there was no difference in fat mass, and lumbar spine BMD.Purpose: Low bone mineral density (BMD) is one of the major health problems in Turner syndrome (TS) patients, and a certain percentage of TS girls are treated with hormone replacement therapy (HRT) to improve their BMD, among other health benefits. While it is generally accepted that HRT improves BMD and body composition in adolescent and young adult TS patients, studies of HRT in Chinese TS patients are limited.Methods: To investigate the effects of HRT in Chinese TS girls, we performed a longitudinal observational study which compared measurement of BMD and body composition by dual energy X-ray absorptiometry (DXA) using a Lunar DXA densitometer in 20 Chinese adolescent and young adult TS patients (average age = 18) before and after 1 year of HRT treatment.Results: Whole body BMD (0.85 vs. 0.87 g/cm2, P < 0.001), femur neck BMD (0.6 vs. 0.62 g/cm2, P = 0.02), total hip BMD (0.68 vs. 0.71 g/cm2, P = 0.003) and whole body lean mass (30.39 vs. 31.66 kg, P = 0.002) were significantly increased in these patients after 1 year HRT treatment, but there was no difference in whole body fat mass, android:gynoid ratio and lumbar spine BMD.Conclusions: In summary, our study found that HRT was an effective way to increase whole body BMD, femur neck BMD, total hip BMD and whole body lean mass in Chinese TS girls, with no effect on whole body fat mass, android:gynoid ratio or lumbar spine BMD.

Gestational trophoblastic disease or neoplasia covers a spectrum of benign and malignant conditions arising from pregnancies with highly abnormal development of trophoblastic tissue. In this brief review, we discuss the different features of these different conditions and their origins and risk factors and introduce some of the more novel and controversial treatment options currently being explored.

Tumour hypoxia is associated with resistance to therapy and with increased invasion and metastatic potential. Recent studies in our laboratory have shown that the hypoxic up-regulation of tumour cell invasiveness and chemoresistance is in part due to reduced nitric oxide (NO) signaling. Using B16F10 murine melanoma cells, we demonstrate here that the increased metastatic potential associated with exposure to hypoxia is mediated by a reduction in cGMP-dependent NO-signaling. Pre-incubation of B16F10 cells in hypoxia (1% vs. 20% O2) for 12 hr increased lung colonization ability by over 4-fold. This effect of hypoxia on metastasis was inhibited by co-incubation with low concentrations of the NO-mimetic drugs glyceryl trinitrate (GTN) and diethylenetriamine NO adduct (DETA/NO). In a manner similar to hypoxia, pharmacological inhibition of NO synthesis resulted in a significant increase in lung nodule formation, an effect that was prevented by co-incubation with GTN. An important NO-signaling pathway involves the activation of soluble guanylyl cyclase and the consequential generation of cGMP. Culture in the presence of a non-hydrolysable cGMP analogue (8-Br-cGMP) abrogated the hypoxia-induced lung nodule formation, suggesting that the effects of NO on metastasis are mediated via a cGMP-dependent pathway. These findings suggest that a novel mechanism whereby hypoxia regulates metastatic potential involves a downstream inhibition of cGMP-dependent NO signaling. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Monocarboxylate transporter 8 (MCT8) is a well-established thyroid hormone (TH) transporter. In humans, MCT8 mutations result in changes in circulating TH concentrations and X-linked severe global neurodevelopmental delay. MCT8 is expressed in the human placenta throughout gestation, with increased expression in trophoblast cells from growth-restricted pregnancies. We postulate that MCT8 plays an important role in placental development and transplacental TH transport. We investigated the effect of altering MCT8 expression in human trophoblast in vitro and in a Mct8 knockout mouse model. Silencing of endogenous MCT8 reduced T3 uptake into human extravillous trophoblast-like cells (SGHPL-4; 40%, P