MicroRNAs: key regulators of the trophoblast function in pregnancy disorders.

The placenta is essential for a successful pregnancy and healthy intrauterine development in mammals. During human pregnancy, the growth and development of the placenta are inseparable from the rapid proliferation, invasion, and migration of trophoblast cells. Previous reports have shown that the occurrence of many pregnancy disorders may be closely related to the dysfunction of trophoblasts. However, the function regulation of human trophoblast cells in the placenta is poorly understood. Therefore, studying the factors that regulate the function of trophoblast cells is necessary. MicroRNAs (miRNAs) are small, non-coding, single-stranded RNA molecules. Increasing evidence suggests that miRNAs play a crucial role in regulating trophoblast functions. This review outlines the role of miRNAs in regulating the function of trophoblast cells and several common signaling pathways related to miRNA regulation in pregnancy disorders.

Epigenetic Control of Vascular Smooth Muscle Cell Function in Atherosclerosis: A Role for DNA Methylation.

Atherosclerosis is a complex vascular inflammatory disease in which multiple cell types are involved, including vascular smooth muscle cells (VSMCs). In response to vascular injury and inflammatory stimuli, VSMCs undergo a "phenotypic switching" characterized by extracellular matrix secretion, loss of contractility, and abnormal proliferation and migration, which play a key role in the progression of atherosclerosis. DNA methylation modification is an important epigenetic mechanism that plays an important role in atherosclerosis. Studies investigating abnormal DNA methylation in patients with atherosclerosis have determined a specific DNA methylation profile, and proposed multiple pathways and genes involved in the etiopathogenesis of atherosclerosis. Recent studies have also revealed that DNA methylation modification controls VSMC function by regulating gene expression involved in atherosclerosis. In this review, we summarize the recent advances regarding the epigenetic control of VSMC function by DNA methylation in atherosclerosis and provide insights into the development of VSMC-centered therapeutic strategies.

Factors Affecting the Re-Endothelialization of Endothelial Progenitor Cell.

The vascular endothelium, which plays an essential role in maintaining the normal shape and function of blood vessels, is a natural barrier between the circulating blood and the vascular wall tissue. The endothelial damage can cause vascular lesions, such as atherosclerosis and restenosis. After the vascular intima injury, the body starts the endothelial repair (re-endothelialization) to inhibit the neointimal hyperplasia. Endothelial progenitor cell is the precursor of endothelial cells and plays an important role in the vascular re-endothelialization. However, re-endothelialization is inevitably affected in vivo and in vitro by factors, which can be divided into two types, namely, promotion and inhibition, and act on different links of the vascular re-endothelialization. This article reviews these factors and related mechanisms.

Melatonin inhibits vascular endothelial cell pyroptosis by improving mitochondrial function via up-regulation and demethylation of UQCRC1.

Atherosclerosis (AS) is a chronic inflammatory disease that involves cell death and endothelial dysfunction. Melatonin is an endocrine hormone with anti-inflammatory and anti-AS effects. However, the underlying molecular mechanisms for the anti-AS effects of melatonin are unknown. A previous study has shown that pyroptosis plays a detrimental role in the development of AS, therefore, this study was designed to investigate the anti-pyroptotic effects and potential mechanisms of melatonin in atherosclerotic endothelium. Our results show that melatonin attenuated the expression of genes related to pyroptosis, including NLRP3, caspase-1, and IL-1ß, in human umbilical vein endothelial cells treated with oxidized low-density lipoprotein. Furthermore, melatonin up-regulated the expression of ten-eleven translocation 2 (TET2), inhibited the methylation of ubiquinol-cytochrome c reductase core protein 1 (UQCRC1), and reduced pyroptosis. The up-regulation of UQCRC1 by melatonin improved mitochondrial function, thereby inhibiting oxidative stress and endothelial cell pyroptosis. Collectively, our results indicate that melatonin prevents endothelial cell pyroptosis by up-regulating TET2 to inhibit the methylation of UQCRC1 and improving mitochondrial function.

Interaction Between microRNA and DNA Methylation in Atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory disease accompanied by complex pathological changes, such as endothelial dysfunction, foam cell formation, and vascular smooth muscle cell proliferation. Many approaches, including regulating AS-related gene expression in the transcriptional or post-transcriptional level, contribute to alleviating AS development. The DNA methylation is a crucial epigenetic modification in regulating cell function by silencing the relative gene expression. The microRNA (miRNA) is a type of noncoding RNA that plays an important role in gene post-transcriptional regulation and disease development. The DNA methylation and the miRNA are important epigenetic factors in AS. However, recent studies have found a mutual regulation between these two factors in AS development. In this study, recent insights into the roles of miRNA and DNA methylation and their interaction in the AS progression are reviewed.

MiR-124-3p promotes trophoblast cell HTR-8/SVneo pyroptosis by targeting placental growth factor.

INTRODUCTION: MiR-124-3p is one of the aberrantly expressed miRNAs in the placentas of patients with preeclampsia (PE), a severe obstetric complication characterised by hypertension and proteinuria. This study aimed to investigate the role of miR-124-3p in the invasion, migration and death of trophoblast cells and explore the potential mechanisms. METHODS: MiR-124-3p expression in placental tissues was compared with that in normal placenta. HTR8/SVneo cells were then transfected with miR-124-3p mimics to examine cellular apoptosis, migration and invasion. Furthermore, the expression of pyroptosis-related molecular NLRP3, Pro-caspase1, caspase1, IL-1ß and GSDMD was examined with Western blot. Dual luciferase reporter assay was performed to confirm that placental growth factor (PLGF) is a direct target of miR-124-3p, and HTR-8/SVneo cells were transfected with small interfering RNA PLGF (siPLGF) to determine whether PLGF knockdown promotes HTR-8/SVneo pyroptosis. Finally, intracellular ROS was diminished with N-acetyl-l-cysteine (NAC) to observe whether the pro-pyroptosis effect of PLGF knockdown is alleviated. RESULTS: Results in this study showed that miR-124-3p expression was remarkably increased in the placenta of patients with PE. Moreover, the transfection of miR-124-3p mimics in trophoblastic cells significantly decreased cell migration and invasion but increased cell apoptosis and the expression of NLRP3, pro-caspase1, caspase1, IL-1ß and GSDMD. Therefore, PLGF was confirmed as a direct target of miR-124-3p. Finally, siPLGF transfection can mimic the effects of miR-124-3p, and NAC can inhibit this effect. CONCLUSION: In summary, miR-124-3p is upregulated in PE, and in vitro functional analysis revealed that this mRNA inhibits trophoblast invasion and migration but promotes cell pyroptosis partly via the PLGF-ROS pathway.

High glucose condition inhibits trophoblast proliferation, migration and invasion by downregulating placental growth factor expression.

AIM: This study aimed to investigate the effect of high glucose (HG) level on the proliferation, migration and invasion of trophoblasts and determine the role of placental growth factor (PLGF) in the process. METHODS: HTR8-S/Vneo was treated with different concentrations of d-glucose (0, 10, 15, 20, 25 and 30 µM) at different times (0, 6, 12 and 24 h). qRT-PCR and Western blot analyses were used to measure PLGF expression. The protein level of PLGF was measured by immunofluorescence. Cell proliferation was assessed with CCK-8 analysis. Wound healing and transwell assays were used to evaluate cell migration and invasion. Intercellular ROS was detected with DCFH-DA. RESULTS: After d-glucose treatment, the viability decreased in 25 and 30 µM groups. The HG group (25 µM) showed inhibited cell migration and invasion ability. The mRNA and protein levels of PLGF decreased under HG condition. Elevated ROS production was also detected in the HG group. Knocked-down PLGF expression enhanced increased ROS production and decreased cell migration and invasion, which reverted to the original levels after PLGF was overexpressed. CONCLUSION: High glucose treatment inhibited HTR8-S/Vneo viability, migration and invasion by downregulating PLGF expression.

Inhibition of the ox-LDL-Induced Pyroptosis by FGF21 of Human Umbilical Vein Endothelial Cells Through the TET2-UQCRC1-ROS Pathway.

Fibroblast growth factor 21 (FGF21) is a hormone-like member of the FGF family that is associated with cell death in atherosclerosis. However, its underlying mechanisms remain unclear. In this study, the effect of FGF21 on endothelial cell pyroptosis and its potential mechanisms were investigated. Results showed that FGF21 inhibits oxidized low-density lipoprotein (ox-LDL)-induced pyroptosis and related molecular expression in human umbilical vein endothelial cells (HUVECs). Mitochondrial function was damaged by ox-LDL and restored by FGF21. A mechanism proved that ubiquinol cytochrome c reductase core protein I (UQCRC1) was downregulated by ox-LDL and upregulated by FGF21. Further, the silencing of UQCRC1 aggravated HUVEC pyroptosis and impaired mitochondrial function and reactive oxygen species (ROS) production. Moreover, Tet methylcytosine dioxygenase (TET2) was involved in the regulation of UQCRC1 expression and pyroptosis. In summary, FGF21 inhibited ox-LDL-induced HUVEC pyroptosis through the TET2-UQCRC1-ROS pathway.