METTL3 regulates glucose transporter expression in placenta exposed to hyperglycemia through the mTOR signaling pathway.

BACKGROUND: Alterations in the placental expression of glucose transporters (GLUTs), the crucial maternal-fetal nutrient transporters, have been found in women with hyperglycemia in pregnancy (HIP). However, there is still uncertainty about the underlying effect of the high-glucose environment on placental GLUTs expression in HIP. METHODS: We quantitatively evaluated the activity of mammalian target of rapamycin (mTOR) and expression of GLUTs (GLUT1, GLUT3, and GLUT4) in the placenta of women with normal pregnancies (CTRL, n = 12) and pregnant women complicated with poorly controlled type 2 diabetes mellitus (T2DM, n = 12) by immunohistochemistry. In addition, BeWo cells were treated with different glucose concentrations to verify the regulation of hyperglycemia. Then, changes in the expression of GLUTs following the activation or suppression of the mTOR pathway were also assessed using MHY1485/rapamycin (RAPA) treatment or small interfering RNA (siRNA)-mediated silencing approaches. Moreover, we further explored the alteration and potential upstream regulatory role of methyltransferase-like 3 (METTL3) when exposed to hyperglycemia. RESULTS: mTOR, phosphorylated mTOR (p-mTOR), and GLUT1 protein levels were upregulated in the placenta of women with T2DM compared with those CTRL. In BeWo cells, mTOR activity increased with increasing glucose concentration, and the expression of GLUT1, GLUT3, and GLUT4 as well as GLUT1 cell membrane translocation were upregulated by hyperglycemia to varying degrees. Both the drug-mediated and genetic depletion of mTOR signaling in BeWo cells suppressed GLUTs expression, whereas MHY1485-induced mTOR activation upregulated GLUTs expression. Additionally, high glucose levels upregulated METTL3 expression and nuclear translocation, and decreasing METTL3 levels suppressed GLUTs expression and mTOR activity and vice versa. Furthermore, in METTL3 knockdown BeWo cells, the inhibitory effect on GLUTs expression was eliminated by activating the mTOR signaling pathway using MHY1485. CONCLUSION: High-glucose environment-induced upregulation of METTL3 in trophoblasts regulates the expression of GLUTs through mTOR signaling, contributing to disordered nutrient transport in women with HIP.

Elevated galectin-3 levels detected in women with hyperglycemia during early and mid-pregnancy antagonizes high glucose - induced trophoblast cells apoptosis via galectin-3/foxc1 pathway.

OBJECTIVE: This study was to evaluate plasma galectin-3 levels from early pregnancy to delivery and explore the effects of galectin-3 on the function of trophoblast cells under high glucose exposure. METHODS: The plasma galectin-3 levels were quantified by enzyme-linked immunosorbent assay (ELISA) in the China National Birth Cohort (CNBC) at Peking University First Hospital, and the underlying signaling pathway was identified by protein-protein interaction (PPI) analysis, gene set enrichment analysis (GSEA), quantitative PCR (qPCR), western blotting, small interfering RNA (siRNA) transfections, and flow cytometry. RESULTS: Significantly higher galectin-3 levels were found in patients with gestational diabetes mellitus (GDM group; n = 77) during the first and second trimesters than that in healthy pregnant women (HP group; n = 113) (P < 0.05). No significant differences in plasma galectin-3 levels were detected between GDM and HP groups in maternal third-trimester blood and cord blood. PPI analysis suggested potential interactions between galectin-3 and foxc1. The findings of GSEA showed that galectin-3 was involved in the cytochrome P450-related and complement-related pathways, and foxc1 was associated with type I diabetes mellitus. Additionally, high glucose (25 mM) significantly increased the expression levels of galectin-3 and foxc1 and induced apoptosis in HTR-8/SVneo cells. Further in vitro experiments showed that galectin-3/foxc1 pathway could protect HTR-8/SVneo cells against high glucose - induced apoptosis. CONCLUSION: Future studies were required to validate whether plasma galectin-3 might become a potential biomarker for hyperglycemia during pregnancy. Elevated galectin-3 levels might be a vital protective mechanism among those exposed to hyperglycemia during pregnancy.

Potential genetic biomarkers predict adverse pregnancy outcome during early and mid-pregnancy in women with systemic lupus erythematosus.

Background: Effectively predicting the risk of adverse pregnancy outcome (APO) in women with systemic lupus erythematosus (SLE) during early and mid-pregnancy is a challenge. This study was aimed to identify potential markers for early prediction of APO risk in women with SLE. Methods: The GSE108497 gene expression dataset containing 120 samples (36 patients, 84 controls) was downloaded from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA) was performed, and differentially expressed genes (DEGs) were screened to define candidate APO marker genes. Next, three individual machine learning methods, random forest, support vector machine-recursive feature elimination, and least absolute shrinkage and selection operator, were combined to identify feature genes from the APO candidate set. The predictive performance of feature genes for APO risk was assessed using area under the receiver operating characteristic curve (AUC) and calibration curves. The potential functions of these feature genes were finally analyzed by conventional gene set enrichment analysis and CIBERSORT algorithm analysis. Results: We identified 321 significantly up-regulated genes and 307 down-regulated genes between patients and controls, along with 181 potential functionally associated genes in the WGCNA analysis. By integrating these results, we revealed 70 APO candidate genes. Three feature genes, SEZ6, NRAD1, and LPAR4, were identified by machine learning methods. Of these, SEZ6 (AUC = 0.753) showed the highest in-sample predictive performance for APO risk in pregnant women with SLE, followed by NRAD1 (AUC = 0.694) and LPAR4 (AUC = 0.654). After performing leave-one-out cross validation, corresponding AUCs for SEZ6, NRAD1, and LPAR4 were 0.731, 0.668, and 0.626, respectively. Moreover, CIBERSORT analysis showed a positive correlation between regulatory T cell levels and SEZ6 expression (P < 0.01), along with a negative correlation between M2 macrophages levels and LPAR4 expression (P < 0.01). Conclusions: Our preliminary findings suggested that SEZ6, NRAD1, and LPAR4 might represent the useful genetic biomarkers for predicting APO risk during early and mid-pregnancy in women with SLE, and enhanced our understanding of the origins of pregnancy complications in pregnant women with SLE. However, further validation was required.

The pathologic changes of human placental macrophages in women with hyperglycemia in pregnancy.

As the most common complication of pregnancy, hyperglycemia has a profound impact on maternal and fetal health and the long-term development of the offspring. Placental macrophages, including fetal-derived macrophages also known as Hofbauer cells (HBCs) and placenta-associated maternal monocyte/macrophages (PAMMs), are thought to play a crucial role in regulating pregnancy and maintaining the internal environment, and are critical for fetal development. This review aims to profile existing knowledge on HBCs and PAMMs across gestation, and consider how hyperglycemia may impact their phenotype and function in pregnancy.

Perspectives from metabolomics in the early diagnosis and prognosis of gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is one of the most common metabolic disorders in pregnant women. The early detection of GDM provides an opportunity for the effective treatment of hyperglycemia in pregnancy, thus decreasing the risk of adverse perinatal outcomes for mothers and newborns. Metabolomics, an emerging technique, offers a novel point of view in understanding the onset and development of diseases and has been repeatedly used in various gestational periods in recent studies of GDM. Moreover, metabolomics provides varied opportunities in the different diagnoses of GDM from prediabetes or predisposition to diabetes, the diagnosis of GDM at a gestational age several weeks earlier than that used in the traditional method, and the assessment of prognosis considering the physiologic subtypes of GDM and clinical indexes. Longitudinal metabolomics truly facilitates the dynamic monitoring of metabolic alterations over the course of pregnancy. Herein, we review recent advancements in metabolomics and summarize evidence from studies on the application of metabolomics in GDM, highlighting the aspects of the diagnosis and differential diagnoses of GDM in an early stage. We also discuss future study directions concerning the physiologic subtypes, prognosis, and limitations of metabolomics.

A recyclable and light-triggered nanofibrous membrane against the emerging fungal pathogen Candida auris.

The emerging "super fungus" Candida auris has become an important threat to human health due to its pandrug resistance and high lethality. Therefore, the development of novel antimicrobial strategy is essential. Antimicrobial photodynamic therapy (aPDT) has excellent performance in clinical applications. However, the relevant study on antifungal activity and the mechanism involved against C. auris remains scarce. Herein, a recyclable and biodegradable polylactic acid-hypocrellin A (PLA-HA) nanofibrous membrane is newly developed. In vitro PLA-HA-aPDT could significantly reduce the survival rate of C. auris plankton and its biofilms, and the fungicidal effect of the membrane is still significant after four repeated uses. Simultaneously, PLA-HA exhibits good biocompatibility and low hemolysis. In vivo experiments show that PLA-HA-aPDT can promote C. auris-infected wound healing, reduce inflammatory response, and without obvious toxic side-effects. Further results reveal that PLA-HA-aPDT could increase endogenous reactive oxygen species (ROS) levels, leading to mitochondrial dysfunction, release of cytochrome C, activation of metacaspase, and nuclear fragmentation, thereby triggering apoptosis of C. auris. Compared with HA, PLA-HA shows stronger controllability and reusability, which can greatly improve the utilization efficiency of HA alone. Taken together, the efficacy, safety and antifungal activity make PLA-HA-aPDT a highly promising antifungal candidate for skin or mucous membrane C. auris infection.

The Distributional Characteristics of M2 Macrophages in the Placental Chorionic Villi are Altered Among the Term Pregnant Women With Uncontrolled Type 2 Diabetes Mellitus.

Aim: No definite conclusions have been drawn regarding how prolonged exposure to hyperglycemia affects the distribution of macrophages in the placenta, especially in pregnant women with uncontrolled type 2 diabetes mellitus (T2DM). Herein, we explored the distributional characteristics of placental M2 macrophages, including hofbauer cells (HBCs) in the chorionic villi and decidual macrophages, in pregnant women with uncontrolled T2DM. Methods: Six healthy singleton pregnancies and five uncontrolled T2DM singleton pregnancies were collected. Multicolor immunofluorescence and immunohistochemistry were performed to record M1 macrophages by CD80 and CD86, the general M2 macrophages by CD163, M2a macrophages by CD163 and DG-SIGN, M2b macrophages by CD163 and CD86, and M2c macrophages by CD163 and CD206. Meanwhile, the monocyte marker of CD14 and the general macrophage marker of CD68 were also documented on placenta. Results: In the chorionic villi and decidua, the most common infiltrated macrophages was the general M2. There were only few M1 and M2b macrophages distributed in the placenta of both the healthy and uncontrolled T2DM groups. The infiltrated degree of M2c macrophages was moderate in chorionic villi and decidua. The uncontrolled T2DM and healthy pregnant women had a comparable amount of M2c macrophages infiltration in the chorionic villi (p = 0.158). Notedly, in both of the healthy and uncontrolled T2DM pregnant women, the predominant subtype of M2 macrophages in the chorionic villi was M2a, where it mainly infiltrated around vessels and syncytiotrophoblasts. The uncontrolled T2DM pregnant women had more M2a macrophage infiltration than the healthy pregnant women (p = 0.016). The M2a macrophages in the decidua of the uncontrolled T2DM group were similar to those of the normal group (p = 0.800). Meanwhile, it was in the chorionic villi but not the decidua, that the CD68+ macrophages and CD14+ M2a macrophages were also elevated in the uncontrolled T2DM group (p = 0.035 and 0.044, respectively). Conclusion: These results confirmed that the M2 macrophages exhibited increased in the chorionic villi of pregnant women with uncontrolled T2DM. The subsets of M2 macrophages in the placental decidua were similar between uncontrolled T2DM pregnant women and normal groups. It may provide a basis for exploring the functions of different subsets of macrophages in the placental chorionic villi.

The inflammation patterns of different inflammatory cells in histological structures of hyperplasic prostatic tissues.

BACKGROUND: The distribution characteristics of inflammatory cells in hyperplastic prostatic tissue and its influences on disease development remain unknown. We aimed to explore the infiltration characteristics of different inflammatory cells in histological structures of benign prostatic hyperplasia (BPH) in combination with clinical data. METHODS: The present study included 76 cases of BPH patients underwent transurethral resection of prostate (TURP). Hematoxylin-eosin staining was performed to identify the degree of general inflammation in prostatic tissues. The infiltration of T-lymphocytes (CD3), B-lymphocytes (CD20), and macrophages (CD68) were recorded by immunohistochemistry. RESULTS: The present study included 76 BPH patients with the mean age of 69.5 years old (range, 49-83 years) and the mean prostate volume of 91.9 mL (range, 24-218 mL). Periglandular inflammation was the most common pattern, being presented in 94.7% (72/76) patients, followed by stromal inflammation (67/76, 88.2%) and glandular inflammation (57/76, 75.0%). However, the stroma presented the highest rate of severe inflammation (14.6%). And the grades of glandular inflammation and stromal inflammation were independently correlated with prostate volume. T-lymphocytes, B-lymphocytes and macrophages had different infiltrated patterns in histological structures of prostate. And stromal hyperplasia dominated BPH was only significantly correlated with the T-lymphocytes infiltration condition (P=0.001). Meanwhile, overweight patients had more severe glandular inflammation in the prostate (P=0.010). The grade of glandular inflammation could independently increase prostate-specific antigen (PSA). CONCLUSIONS: We characterized infiltrated patterns of different inflammatory cells in histological structures of hyperplasic prostatic tissues from surgically treated BPH specimens. The role of inflammation in BPH development was highlighted by its correlation with the prostate volume, metabolism and PSA level.

Transvaginal management of symptomatic complex urethral diverticula by definite closure of diverticula and robust reconstruction of the urethra.

BACKGROUND: Management of complex urethral diverticula (UDs) is challenging not only for the ostia detection and urethral reconstruction in surgery but also for the high risk of postoperative complications. We aimed to present the experience of surgical management for UDs by transvaginal partial diverticulectomy and urethral reconstruction. METHODS: The database of medical record library was retrospectively searched for patients underwent partial diverticulectomy for symptomatic complex UDs. During the surgical procedure, the cystourethroscopy was firstly performed to locate the diverticular ostium. The surgeon exposed and opened the diverticulum along its maximum axis. The surgeon recorded the location of ostia where saline solution flowed out, when one assistant pressed suprapubic region to increase inner-pressure of bladder and urethra. We focused on definite closure of diverticular ostia and robust urethral reconstruction. RESULTS: The present study included 39 patients with mean age of 45 years. There were 28 patients, 23 patients and 21 patients suffering from recurrent urinary infection, frequency and urgency. Ten patients had stress urinary incontinence. All of the 39 patients had complex UDs because of U-shaped diverticula (24/39) and circumferential diverticula (15/39). Multiloculated UDs were detected in 17 out of 39 patients. During the median follow-up time of 2.0 (1.0-12.0) years, there was no case of de novo urinary incontinence. However, 2 patients still had mild stress urinary incontinence without additional treatment. At postoperative 3 months, five patients had para-urethral cysts with the size ranging from 0.3 to 0.4 cm, which were absorbed in follow-up. CONCLUSIONS: The method of transvaginal partial diverticulectomy, definite closure of diverticular ostium, and layered reconstruction of the urethra is a feasible surgical alternative for UDs.