Cushing's Syndrome in Pregnancy Secondary to Adrenocortical Adenoma: A Case Series and Review.

PURPOSE: To present a case series of Cushing's syndrome (CS) during pregnancy caused by adrenocortical adenomas, highlighting clinical features, hormonal assessments and outcomes. METHODS: We describe five pregnant women with CS, detailing clinical presentations and laboratory findings. RESULTS: Common clinical features included a full moon face, buffalo back and severe hypertension. Elevated blood cortisol levels with circadian rhythm disruption and suppressed adrenocorticotrophic hormone (ACTH) levels were observed. Imaging revealed unilateral adrenal tumours. Two cases underwent laparoscopic adrenalectomies during the second trimester, while three had postpartum surgery. All required hormone replacement therapy, with postoperative pathological confirmation of adrenocortical adenomas. CONCLUSION: Diagnosis of CS during pregnancy is challenging due to overlapping features with normal pregnancy: elevated blood cortisol levels and abnormal diurnal rhythm of blood cortisol, suppressed aid diagnosis. Treatment should be individualised due to a lack of explicit optimum therapeutic approaches. Laparoscopic adrenalectomy may be an optimal choice, along with multidisciplinary management including hormone replacement therapy.

Downregulation of miR-92a in Decidual Stromal Cells Suppresses Migration Ability of Trophoblasts by Promoting Macrophage Polarization.

Preeclampsia (PE) is a severe pregnancy complication that accounts for about 14% of maternal deaths. Its clinical manifestations commonly include hypertension and proteinuria. However, it is largely limited in understanding its pathogenetic mechanism. In this study, we used bioinformatics to compare differential gene expressions in decidual stromal cells from PE patients and healthy donors. The result indicated that higher levels of CCL5 and CXCL2 were expressed in decidual stromal cells of PE patients compared with healthy pregnancy. The bioinformatics analysis confirmed that decidual stromal cells derived from PE patients expressed significantly lower miR-92a compared with those derived from healthy donors. Transfection of miR-92a inhibitors upregulated IL-6, CXCL2, CXCL3, CCL5, and CXCL8 expressions in decidual stromal cells. Luciferase activity assay confirmed that miR-92a directly targeted the mRNA of IRF3 whose overexpression could promote the secretion of cytokines. The flow cytometric analysis demonstrated that M1 macrophage infiltration was higher in the placentas of PE patients than in those of healthy donors. We also observed that after transfection of miR-92a inhibitor, condition medium (CM) derived from decidual stromal cells significantly promoted M1 polarization of macrophages. In addition, the transwell migration assay and flow cytometric analysis together showed that decidual stromal cell-derived CM induced macrophages to suppress the trophoblast migration and proliferation. Taken together, our result indicates that downregulation of miR-92a in decidual stromal cells promotes the macrophage polarization and suppresses the trophoblast migration and proliferation.

Co-culture with chorionic villous mesenchymal stem cells promotes endothelial cell proliferation and angiogenesis via ABCA9-AKT pathway.

Human chorionic villous mesenchymal stem cells (CV-MSCs) are a promising and effective therapeutic option for tissue injury. Vascular dysfunction during pregnancies is significantly involved in the pathogenesis of preeclampsia (PE). This work aims to investigate how CV-MSCs regulate the function of vascular endothelial cells. In this study, RNA-seq analysis was used to examine the changes in HUVECs treated with CV-MSC conditioned medium (CM). We examined the levels of ABCA9 and AKT signaling in human umbilical vein endothelial cells (HUVECs) by immunohistochemistry, western blotting, and qRT-PCR assays. CCK-8, colony formation, and tube formation assays were used to understand the role of ABCA9 in HUVEC proliferation and angiogenesis mediated by CV-MSCs. The CV-MSC treatment significantly enhanced the HUVEC proliferation and angiogenesis. Furthermore, a significant increase in the ABCA9 expression and AKT pathway activation was observed in CV-MSCs -treated HUVECs. Consistent with these findings, ABCA9 overexpression exhibited the same proliferation-and angiogenesis-promoting effect in HUVECs as induced by CV-MSC CM, also accompanied the AKT signaling activation. In addition, inhibition of ABCA9 inactivated the AKT signaling in HUVECs and reduced the HUVEC proliferation and angiogenesis. Importantly, the elevation of proliferation and angiogenesis induced by ABCA9 overexpression in HUVECs could be reversed by AKT pathway inhibition. Our results suggest that ABCA9-dependent AKT signaling activation mediated by CV-MSCs could promote HUVEC proliferation and angiogenesis.

Chorionic villus-derived mesenchymal stem cell-mediated autophagy promotes the proliferation and invasiveness of trophoblasts under hypoxia by activating the JAK2/STAT3 signalling pathway.

BACKGROUND: Trophoblast dysfunction during pregnancy is fundamentally involved in preeclampsia. Several studies have revealed that human chorionic villous mesenchymal stem cells (CV-MSCs) could regulate trophoblasts function. RESULTS: To understand how human chorionic villous mesenchymal stem cells (CV-MSCs) regulate trophoblast function, we treated trophoblasts with CV-MSC supernatant under hypoxic conditions. Treatment markedly enhanced proliferation and invasion and augmented autophagy. Transcriptome and pathway analyses of trophoblasts before and after treatment revealed JAK2/STAT3 signalling as an upstream regulator. In addition, STAT3 mRNA and protein levels increased during CV-MSC treatment. Consistent with these findings, JAK2/STAT3 signalling inhibition reduced the autophagy, survival and invasion of trophoblasts, even in the presence of CV-MSCs, and blocking autophagy did not affect STAT3 activation in trophoblasts treated with CV-MSCs. Importantly, STAT3 overexpression increased autophagy levels in trophoblasts; thus, it positively regulated autophagy in hypoxic trophoblasts. Human placental explants also proved our findings by showing that STAT3 was activated and that LC3B-II levels were increased by CV-MSC treatment. CONCLUSION: In summary, our data suggest that CV-MSC-dependent JAK2/STAT3 signalling activation is a prerequisite for autophagy upregulation in trophoblasts.

Effect of Yiqi Buxue Decoction on Hemodynamic Changes of the Uterine Artery and Fetal Umbilical Artery and Pregnancy Outcomes in Pregnant Patients with Pulmonary Arterial Hypertension.

OBJECTIVE: To explore the effect of Yiqi Buxue decoction on hemodynamic changes of the uterine artery and fetal umbilical artery and pregnancy outcomes in pregnant patients with pulmonary arterial hypertension (PAH). METHODS: 120 pregnant patients with PAH treated in our hospital (January 2019-January 2020) were chosen as the research objects, and randomly split into group A (n = 60) and group B (n = 60). Both groups received routine treatment, and group B was treated with sildenafil citrate, while group A was treated with Yiqi Buxue decoction combined with sildenafil citrate. Both groups received 6 weeks of treatment to analyze the hemodynamic changes of the uterine artery and fetal umbilical artery and compare the cardiopulmonary function indexes and pregnancy outcomes between the two groups. RESULTS: The hemodynamic indexes of the uterine artery and fetal umbilical artery, cardiopulmonary function indexes, and pregnancy outcomes in group A after treatment were notably better compared with group B (P < 0.01). CONCLUSION: Yiqi Buxue decoction can stabilize the hemodynamics of pregnant patients with PAH, improve their cardiopulmonary function, alleviate hypotension, and thus, reduce the possibility of adverse pregnancy outcomes, which should be popularized in practice.

Adipose-derived mesenchymal stem cells induced PAX8 promotes ovarian cancer cell growth by stabilizing TAZ protein.

Our previous studies have shown that the Adipose-derived mesenchymal stem cells (ADSCs) can regulate metastasis and development of ovarian cancer. However, its specific mechanism has yet to be fully revealed. In this study, an RNA-seq approach was adopted to compare the differences in mRNA levels in ovarian cancer cells being given or not given ADSCs. The mRNA level of paired box 8 (PAX8) changed significantly and was confirmed as an important factor in tumour-inducing effect of ADSCs. In comparison with the ovarian cancer cells cultured in the common growth medium, those cultured in the medium supplemented with ADSCs showed a significant increase of the PAX8 level. Moreover, the cancer cell growth could be restricted, even in the ADSC-treated group (P < .05), by inhibiting PAX8. In addition, an overexpression of PAX8 could elevate the proliferation of ovarian cancer cells. Moreover, Co-IP assays in ovarian cancer cells revealed that an interaction existed between endogenous PAX8 and TAZ. And the PAX8 levels regulated the degradation of TAZ. The bioluminescence images captured in vivo manifested that the proliferation and the PAX8 expression level in ovarian cancers increased in the ADMSC-treated group, and the effect of ADSCs in promoting tumours was weakened through inhibiting PAX8. Our findings indicate that the PAX8 expression increment could contribute a role in promoting the ADSC-induced ovarian cancer cell proliferation through TAZ stability regulation.

Amnion-Derived Mesenchymal Stem Cell Exosomes-Mediated Autophagy Promotes the Survival of Trophoblasts Under Hypoxia Through mTOR Pathway by the Downregulation of EZH2.

Human amnion-derived mesenchymal stem cells (AD-MSCs) have been reported as a promising effective treatment to repair tissue. Trophoblast dysfunction during pregnancy is significantly involved in the pathogenesis of preeclampsia (PE). To understand how AD-MSCs regulated trophoblast function, we treated trophoblasts with AD-MSC-derived exosomes under hypoxic conditions. The treatment markedly enhanced the trophoblast proliferation and autophagy. Furthermore, significant decrease of EZH2 levels and inactivation of mTOR signaling were observed in AD-MSC exosomes-treated trophoblasts. Consistent with these findings, overexpression of EZH2 activated the mTOR signaling in trophoblasts, and reduced the autophagy and survival of trophoblasts, even in the presence of AD-MSC-derived exosomes. In addition, EZH2 inhibition exhibited the same trophoblast autophagy-promoting effect as induced by AD-MSC-derived exosomes, also accompanied by the inactivation of mTOR signaling. Importantly, when EZH2 was overexpressed in trophoblasts treated with PQR620, a specific mTOR signaling inhibitor, the autophagy and proliferation in trophoblasts were decreased. Studies on human placental explants also confirmed our findings by showing that the expression levels of EZH2 and mTOR were decreased while the autophagy-associated protein level was increased by AD-MSC-derived exosome treatment. In summary, our results suggest that EZH2-dependent mTOR signaling inactivation mediated by AD-MSC-derived exosomes is a prerequisite for autophagy augmentation in hypoxic trophoblasts.

Adipose-Derived Mesenchymal Stem Cells Enhance Ovarian Cancer Growth and Metastasis by Increasing Thymosin Beta 4X-Linked Expression.

As shown in our previous studies, growth and metastasis of ovarian cancer can be regulated by adipose-derived mesenchymal stem cells (ADSCs). However, the underlying mechanism has not yet been revealed. In this study, a proteomics analysis was performed to compare protein expression treated with and without ADSCs in ovarian cancer cells. Protein levels were altered in ovarian cancer cells due to the treatment of ADSCs. Thymosin beta 4 X-linked (TMSB4X) levels changed dramatically, and this protein was identified as one of the most important candidate molecules contributing to the tumour-promoting effects of ADSCs. Compared with the cells that are cultured in the normal growth medium, the TMSB4X levels cultured in ADSC-conditioned medium increased significantly in ovarian cancer cells. Furthermore, the growth and invasion of cancer cells were decreased, even in the ADSC-conditioned medium treatment group (P < 0.05), by the inhibition of TMSB4X. As shown in the bioluminescence images captured in vivo, increased ovarian cancer's growth and metastasis, along with elevated TMSB4X expression, were observed in the group of ADSC-conditioned medium, and the tumour-promoting effect of ADSCs was attenuated by the inhibition of TMSB4X. Based on our findings, increased TMSB4X expression may play a role in accelerating the ADSC-mediated proliferation, invasion, and migration of ovarian cancers.