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Uterine corpus endometrial carcinoma (UCEC) is one of the most common types of cancer in women, and the incidence is rapidly increasing. Studies have shown that various signaling pathways serve crucial roles in the tumorigenesis of UCEC, amongst which the Wnt/β-catenin pathway is of great interest due to its crucial role in cell proliferation and the huge potential as a therapeutic target. In the present study, it was shown that FBXO17, which is a member of the F-box family, is abnormally downregulated in UCEC tissues compared with non-tumor endometrial tissues, and this was significantly associated with the clinical histological grade, as well as the abnormal proliferation of the UCEC cell line, Ishikawa, both

Deficiency of decidual NK (dNK) cell number and function has been widely regarded as an important cause of spontaneous abortion. However, the metabolic mechanism underlying the crosstalk between dNK cells and embryonic trophoblasts during early pregnancy remains largely unknown. Here, we observed that enriched glutamine and activated glutaminolysis in dNK cells contribute to trophoblast invasion and embryo growth by insulin-like growth factor-1 (IGF-1) and growth differentiation factor-15 (GDF-15) secretion. Mechanistically, these processes are dependent on the downregulation of EGLN1-HIF-1α mediated by α-ketoglutarate (α-KG). Blocking glutaminolysis with the GLS inhibitor BPTES or the glutamate dehydrogenase inhibitor EGCG leads to early embryo implantation failure, spontaneous abortion and/or fetal growth restriction in pregnant mice with impaired trophoblast invasion. Additionally, α-KG supplementation significantly alleviated pregnancy loss mediated by defective glutaminolysis in vivo, suggesting that inactivated glutamine/α-ketoglutarate metabolism in dNK cells impaired trophoblast invasion and induced pregnancy loss.

Background: Patients with endometriosis (EMs) have high risks of infertility and spontaneous abortion. How to remodel the fertility of patients with EMs has always been the hot spot and difficulty in the field of reproductive medicine. As an aglycone of ginsenosides, protopanaxadiol (PPD) possesses pleiotropic biological functions and has high medicinal values. We aimed to investigate the effect and potential mechanism of PPD in the treatment of EMs-associated infertility and spontaneous abortion. Methods: The EMs mice models were constructed by allotransplantation. The pregnancy rates, embryo implantation numbers and embryo resorption rates of control and EMs were counted. RNA sequencing, qRT-PCR, enzyme linked immunosorbent assay (ELISA) and FCM analysis were performed to screen and confirm the expression of endometrial receptivity/decidualization-related molecules, inflammation cytokines and NK cell function-related molecules in vitro and/or in vivo. The SWISS Target Prediction, STRING and Cytoscape were carried out to predict the potential cellular sensory proteins, the protein-protein interaction (PPI) network between sensory proteins and fertility-related molecules, respectively. Micro-CT detection, liver and kidney function tests were used to evaluate the safety. Results: Here, we observe that PPD significantly up-regulates endometrial receptivity-related molecules (e.g., Lif, Igfbp1, Mmps, collagens) and restricts pelvic inflammatory response (low levels of IL-12 and IFN-γ) of macrophage, and further remodel and improve the fertility of EMs mice. Additionally, PPD increases the expression of decidualization-related genes and Collagens, and promotes the proliferation, residence, immune tolerance and anagogic functions of decidual NK cells (low levels of CD16 and NKp30, high levels of Ki67, VEGF, TGF-β) in pregnant EMs mice, and further triggers decidualization, decidual NK cell-mediated maternal-fetal immune tolerance and angiogenesis, preventing pregnant EMs mice from miscarriage. Mechanically, these effects should be dependent on ESRs, PGR and other sensory proteins (e.g., AR). Compared with GnRHa (the clinic first-line drug for EMs), PPD does not lead to the decline of serum estrogen and bone loss. Conclusion: These data suggest that PPD prevents EMs-associated infertility and miscarriage in sex hormones receptors-dependent and independent manners possibly, and provides a potential therapeutic strategy with high efficiency and low side effects to remodels the fertility of patients with EMs.

Objective: The maternal–fetal interface undergoes dynamic changes to allow the fetus to grow and develop in the uterus. The interaction between decidual γδ Τ cells and trophoblasts plays a pivotal role during successful pregnancy; however, their physiological functions in early-term human pregnancy are still not completely illustrated. This study was undertaken to illustrate the functional roles of CXCL16/CXCR6 to prevent pregnancy loss via the crosstalk between decidual γδ T cells and HTR8/SVneo trophoblast cells. Methods: The percentile of CXCR6+ γδ T cells in the peripheral blood from normal female and recurrent spontaneous abortion (RSA) patients was analyzed by flow cytometry. The expression of CXCR6 was detected in decidual immune cells via flow cytometry, and the expression of CXCL16 was analyzed in HTR8/SVneo trophoblast cells and lentivirus (LV)-HTR8/SVneo trophoblast cells via enzyme-linked immunosorbent assay. Reverse transcriptase-polymerase chain reaction was used to verify the expression of the CXCL16 gene in LV-HTR8/SVneo trophoblast cells. Expression of granzyme B and cytokines and proliferation of decidual γδ T cocultured with HTR8/SVneo trophoblast cells were analyzed by flow cytometry. Invasion of HTR8/SVneo trophoblast cells was assessed via Matrigel transwell assay. Adoptive transfer was induced in vivo further to illustrate that the normal expression of CXCL16/CXCR6 could prevent pregnancy loss. Results: The percentile of CXCR6+ γδ T cells in the peripheral blood from RSA patients was lower than normal pregnancies. The expression of CXCR6 was highest in the decidual γδ T cells among decidual immune cells, and the expression of CXCL16 increased as the amount of HTR8/SVneo trophoblast cells increased. Expression of granzyme B in the decidual γδ T cells was downregulated by cocultured with HTR8/SVneo cells dependent of CXCL16, and HTR8/SVneo trophoblast cells induced the Th2 cytokines production in the decidual γδ T cells. Both the expression of CXCR6 in the decidual γδ T cells and proliferation of the decidual γδ T cells were promoted by HTR8/SVneo trophoblast cells. On the other hand, decidual γδ T cells enhanced the invasion of HTR8/SVneo trophoblast cells and thus promoted embryo implantation. In vivo study was taken further and shown that low expression of CXCL16/CXCR6 results in pregnancy loss because of dialog disorder between decidual γδ Τ cells and trophoblasts. Conclusions: Low expression of CXCL16/CXCR6 results in pregnancy loss because of the dialog disorder between decidual γδ Τ cells and trophoblasts, and it showed a light on the effective strategy of adoptive transfer of CXCR6+ γδ T cells on the treatment of RSA. This observation provides a scientific basis on which a potential strategy can be applied to the early-detect and treatment of RSA.

Menstruation occurs in few species and involves a cyclic process of proliferation, breakdown and regeneration under the control of ovarian hormones. Knowledge of normal endometrial physiology, as it pertains to the regulation of menstruation, is essential to understand disorders of menstruation. Accumulating evidence indicates that autophagy in the endometrium, under the regulation of ovarian hormones, can result in the infiltration of immune cells, which plays an indispensable role in the endometrium shedding, tissue repair and prevention of infections during menstruation. In addition, abnormal autophagy levels, together with resulting dysregulated immune system function, are associated with the pathogenesis and progression of endometriosis. Considering its potential value of autophagy as a target for the treatment of menstrual-related and endometrium-related disorders, we review the activity and function of autophagy during menstrual cycles. The role of the estrogen/progesterone-autophagy-immunity axis in endometriosis are also discussed.

Aspirin, one of the most widely applied medicines, not only possesses the effects on reducing fever, anti-vascular hyperplasia, and anti-inflammation, but also has the capacity of preventing platelet aggregation. So far, it is acceptable to adopt aspirin, especially low-dose aspirin (LDA), to prevent pregnancy-related complications, such as pregnancy complicated by antiphospholipid syndrome, systemic lupus erythematosus, or preeclampsia; unexplained recurrent spontaneous abortion; fetal growth restriction; and preterm birth. In this article, we reviewed the possible mechanism of action and applications of aspirin in these pregnancy-related complications.

The survival and development of a semi-allogenic fetus during pregnancy require special immune tolerance microenvironment at the maternal fetal interface. During the establishment of a successful pregnancy, the endometrium undergoes a series of changes, and the extracellular matrix (ECM) breaks down and remodels. Collagen is one of the most abundant ECM. Emerging evidence has shown that collagen and its fragment are expressed at the maternal fetal interface. The regulation of expression of collagen is quite complex, and this process involves a multitude of factors. Collagen exerts a critical role during the successful pregnancy. In addition, the abnormal expressions of collagen and its fragments are associated with certain pathological states associated with pregnancy, including recurrent miscarriage, diabetes mellitus with pregnancy, preeclampsia and so on. In this review, the expression and potential roles of collagen under conditions of physiological and pathological pregnancy are systematically discussed.

Immune cells and cytokines have important roles in the pathogenesis of endometriosis. However, the production and role of cytokines of T helper type 1 (Th1) and Th2 cells in the progress of endometriosis have remained to be fully elucidated. The present study reported that the interferon (IFN)-γ levels and the percentage of IFN-γ+CD4+ cells were significantly increased in the peritoneal fluid (PF) at the early stage and maintained at a higher level at the advanced stage of endometriosis; furthermore, interleukin (IL)-10 and IL-10+CD4+ cells were elevated in the advanced stage of endometriosis. In addition, IL-2 levels in the PF at the advanced stage of endometriosis were elevated and negatively associated with IFN-γ expression. In a co-culture system of ectopic endometrial stromal cells (ESCs) and macrophages, elevated IL-2 was observed, and treatment with cytokines IL-2 and transforming growth factor-β led to upregulation of the ratio of IL-2+ macrophages. IL-27-overexpressing ESCs and macrophages were able to induce a higher ratio of IL-10+CD4+ T cells. Blocking of IL-2 with anti-IL-2 neutralizing antibody led to upregulation of the ratio of IFN-γ+CD4+ T cells in the co-culture system in vitro. Recombinant human IL-10 and IFN-γ promoted the viability, invasiveness and transcription levels of matrix metalloproteinase (MMP)2, MMP9, and prostaglandin-endoperoxide synthase 2 of ESCs, particularly combined treatment with IL-10 and IFN-γ. These results suggest that IL-2 and IL-27 synergistically promote the growth and invasion of ESCs by modulating the balance of IFN-γ and IL-10 and contribute to the progress of endometriosis.

During gestation, excess palmitate (PA) is enriched in decidua. Both excess PA and decidual dysfunctions are associated with numerous adverse pregnancy outcomes such as gestational diabetes, preeclampsia and preterm birth and intrauterine growth restriction. Here, mRNA data about the effects of PA were collected from multiple databases and analyzed. Human decidual tissues were obtained from clinically normal pregnancies, terminated for non-medical reasons, during the first trimester, and decidual stromal cells (DSCs) were isolated and exposed to PA, alone or together with the inhibitors of Toll-like receptor 4 (TLR4), Jun N-terminal kinase (JNK), nuclear factor-kappa-gene binding (NF-kB) or glutamine (GLN) oxidation. Furthermore, DSCs were transfected with lentiviral particles overexpressing human TLR4. We demonstrate that excess PA interacting with its receptor TLR4 disturbs DSC hemostasis during the first trimester. Specifically, high PA signal induced DSC apoptosis and formed an inflammatory program (elevated interleukin-1 beta and decreased interleukin-10) via the activation of TLR4/JNK/NF-kB pathways. A complexed cross-talk was found between TLR4/JNK/NF-kB signals and PA deposition in DSCs. Besides, under an excess PA environment, GLN oxidation was significantly enhanced in DSCs and the suppression of GLN oxidation further augmented PA-mediated DSC apoptosis and inflammatory responses. In conclusion, excess PA induces apoptosis and inflammation in DSCs via the TLR4/JNK/NF-kB pathways, which can be augmented by the suppression of GLN oxidation.

Massive infiltrated and enriched decidual macrophages (dMφ) have been widely regarded as important regulators of maternal-fetal immune tolerance and trophoblast invasion, contributing to normal pregnancy. However, the characteristics of metabolic profile and the underlying mechanism of dMφ residence remain largely unknown. Here, we observe that dMφ display an active glycerophospholipid metabolism. The activation of ENPP2-lysophosphatidic acid (LPA) facilitates the adhesion and retention, and M2 differentiation of dMφ during normal pregnancy. Mechanistically, this process is mediated through activation of the LPA receptors (LPAR1 and PPARG/PPARγ)-DDIT4-macroautophagy/autophagy axis, and further upregulation of multiple adhesion factors (e.g., cadherins and selectins) in a CLDN7 (claudin 7)-dependent manner. Additionally, poor trophoblast invasion and placenta development, and a high ratio of embryo loss are observed in Enpp2(±), lpar1(−/−) or PPARG-blocked pregnant mice. Patients with unexplained spontaneous abortion display insufficient autophagy and cell residence of dMφ. In therapeutic studies, supplementation with LPA or the autophagy inducer rapamycin significantly promotes dMφ autophagy and cell residence, and improves embryo resorption in Enpp2(±) and spontaneous abortion mouse models, which should be dependent on the activation of DDIT4-autophagy-CLDN7-adhesion molecules axis. This observation reveals that inactivation of ENPP2-LPA metabolism and insufficient autophagy of dMφ result in resident obstacle of dMφ and further increase the risk of spontaneous abortion, and provides potential therapeutic strategies to prevent spontaneous abortion. Abbreviations: ACTB: actin beta; ADGRE1/F4/80: adhesion G protein-coupled receptor E1; Atg5: autophagy related 5; ATG13: autophagy related 13; BECN1: beclin 1; CDH1/E-cadherin: cadherin 1; CDH5/VE-cadherin: cadherin 5; CFSE: carboxyfluorescein succinimidyl ester; CLDN7: claudin 7; CSF1/M-CSF: colony stimulating factor 1; CSF2/GM-CSF: colony stimulating factor 2; Ctrl: control; CXCL10/IP-10: chemokine (C-X-C) ligand 10; DDIT4: DNA damage inducible transcript 4; dMφ: decidual macrophage; DSC: decidual stromal cells; ENPP2/ATX: ectonucleotide pyrophosphatase/phosphodiesterase 2; Enpp2(±): Enpp2 heterozygous knockout mouse; ENPP2i/PF-8380: ENPP2 inhibitor; EPCAM: epithelial cell adhesion molecule; ESC: endometrial stromal cells; FGF2/b-FGF: fibroblast growth factor 2; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GPCPD1: glycerophosphocholine phosphodiesterase 1; HE: heterozygote; HIF1A: hypoxia inducible factor 1 subunit alpha; HNF4A: hepatocyte nuclear factor 4 alpha; HO: homozygote; ICAM2: intercellular adhesion molecule 2; IL: interleukin; ITGAV/CD51: integrin subunit alpha V; ITGAM/CD11b: integrin subunit alpha M; ITGAX/CD11b: integrin subunit alpha X; ITGB3/CD61: integrin subunit beta 3; KLRB1/NK1.1: killer cell lectin like receptor B1; KRT7/cytokeratin 7: keratin 7; LPA: lysophosphatidic acid; LPAR: lysophosphatidic acid receptor; lpar1(−/−): lpar1 homozygous knockout mouse; LPAR1i/AM966: LPAR1 inhibitor; LY6C: lymphocyte antigen 6 complex, locus C1; LYPLA1: lysophospholipase 1; LYPLA2: lysophospholipase 2; Lyz2: lysozyme 2; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MARVELD2: MARVEL domain containing 2; 3-MA: 3-methyladenine; MBOAT2: membrane bound O-acyltransferase domain containing 2; MGLL: monoglyceride lipase; MRC1/CD206: mannose receptor C-type 1; MTOR: mechanistic target of rapamycin kinase; NP: normal pregnancy; PDGF: platelet derived growth factor; PLA1A: phospholipase A1 member A; PLA2G4A: phospholipase A2 group IVA; PLPP1: phospholipid phosphatase 1; pMo: peripheral blood monocytes; p-MTOR: phosphorylated MTOR; PPAR: peroxisome proliferator activated receptor; PPARG/PPARγ: peroxisome proliferator activated receptor gamma; PPARGi/GW9662: PPARG inhibitor; PTPRC/CD45: protein tyrosine phosphatase receptor type, C; Rapa: rapamycin; RHEB: Ras homolog, mTORC1 binding; SA: spontaneous abortion; SELE: selectin E; SELL: selectin L; siCLDN7: CLDN7-silenced; STAT: signal transducer and activator of transcription; SQSTM1: sequestosome 1; TJP1: tight junction protein 1; VCAM1: vascular cell adhesion molecule 1; WT: wild type.

Decidualization is an intricate biological process in which extensive remodeling of the endometrium occurs to support the development of an implanting blastocyst. However, the immunometabolic mechanisms underlying this process are still largely unknown. We found that the decidualization process is accompanied by the accumulation of fructose-1,6-bisphosphate (FBP). The combination of FBP with pyruvate kinase M stimulated IL-27 secretion by endometrial stromal cells in an ERK/c-FOS–dependent manner. IL-27 induced decidual COX-2 + M2-like macrophage differentiation, which promotes decidualization, trophoblast invasion, and maternal-fetal tolerance. Transfer of Ptgs2 + /COX-2 + macrophages prevented fetal loss in Il27ra -deleted pregnant mice. FBP levels were low in plasma and decidual tissues of patients with unexplained recurrent spontaneous abortion. In therapeutic studies, FBP supplementation significantly improved embryo loss by up-regulation of IL-27–induced COX-2 + macrophage differentiation in a mouse model of spontaneous abortion. These findings collectively provide a scientific basis for a potential therapeutic strategy to prevent pregnancy loss.

Endometriosis (EMS) is the most common gynecological disease in women of reproductive age, and it is associated with chronic pelvic pain, dyspareunia and infertility. As a consequence of genetic, immune and environmental factors, endometriotic lesions have high cyclooxygenase (COX)-2 and COX-2-derived prostaglandin E2 (PGE2) biosynthesis compared with the normal endometrium. The transcription of the PTGS2 gene for COX-2 is associated with multiple intracellular signals, which converge to cause the activation of mitogen-activated protein kinases (MAPKs). COX-2 expression can be regulated by several factors, such as estrogen, hypoxia, proinflammatory cytokines, environmental pollutants, metabolites and metabolic enzymes, and platelets. High concentrations of COX-2 lead to high cell proliferation, a low level of apoptosis, high invasion, angiogenesis, EMS-related pain and infertility. COX-2-derived PGE2 performs a crucial function in EMS development by binding to EP2 and EP4 receptors. These basic findings have contributed to COX-2-targeted treatment in EMS, including COX-2 inhibitors, hormone drugs and glycyrrhizin. In this review, we summarize the most recent basic research in detail and provide a short summary of COX-2-targeted treatment.

Excessive estrogen exposure is an important pathogenic factor in uterine endometrial cancer (UEC). Recent studies have reported the metabolic properties can influence the progression of UEC. However, the underlying mechanisms have not been fully elucidated. Glutaminase (GLS), MYC and autophagy levels were detected. The biological functions of estrogen-MYC-GLS in UEC cells (UECC) were investigated both in vivo and in vitro. Our study showed that estrogen remarkably increased GLS level through up-regulating c-Myc, and enhanced glutamine (Gln) metabolism in estrogen-sensitive UEC cell (UECC), whereas fulvestrant (an ER inhibitor antagonist) could reverse these effects. Estrogen remarkably promoted cell viability and inhibited autophagy of estrogen sensitive UECC. However, CB-839, a potent selective oral bioavailable inhibitor of both splice variants of GLS, negatively regulated Gln metabolism, and inhibited the effects of Gln and estrogen on UECC’s growth and autophagy in vitro and / or in vivo. CB-839 triggers autophagy and restricts growth of UEC by suppressing ER/Gln metabolism, which provides new insights into the potential value of CB-839 in clinical treatment of estrogen-related UEC.

Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in arachidonic acid (AA) metabolism. COX-2 and its products (prostanoids) serve versatile biological functions during pregnancy. Numerous evidences demonstrate special reprogramming of COX-2-catalyzing AA metabolism in decidual immune cells (DICs), particularly in decidual macrophages, corresponding to special gestational phases. This review summarizes the reprogramming of COX-2-catalyzing AA metabolism in DICs as well as the immunoregulation of diverse COX-2-generating prostanoids in DICs during the different phases of gestation.

Recent studies on natural and experimental seismic faults have revealed that frictional heating plays an important role in earthquake dynamics. We report changes in the optically stimulated luminescence (OSL)/thermo-luminescence (TL) and electron spin resonance (ESR) signals in quartz fault gouge (grain size 90–250 μm, given dose 40 ± 5 Gy) after frictional experiments. Our results indicate that high-rate (2.0 m/s) frictional heating during seismic events can reset the 'geologic clocks' of fault rocks. Thus, the OSL/TL/ESR signal in quartz from natural fault zones has the potential to directly constrain the age of seismic events. Whereas low-rate (2.0 mm/s) frictional slip, even over long times (1000 s), does not reset the OSL/TL signals in quartz. However, low-rate slip can reset the Al center ESR signal, but not the E’ center signal.

Endometriosis (EMS) is a chronic inflammatory and estrogen-dependent gynecological disease characterized by the presence of endometrial tissue outside the uterine cavity. Although it is a benign disease, EMS is tumor-like in several aspects, which include unrestrained growth, decreased apoptosis, and aggressive invasion. EMS involves endocrine disorders and immunological factors. Indoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme that catalyzes the initial and rate-limiting step of the metabolism of tryptophan. IDO is a potential candidate facilitating EMS development. Increased IDO expression in both eutopic and ectopic endometria of women with EMS is biologically important in aspects, which include regulation of endometrial stromal cell function and modulation of adjacent local immunocytes to generate a supportive microenvironment. In turn, the expression of IDO can be regulated by the complex endocrine-immune microenvironment networks in endometrial lesions. Here, we systematically review the roles of IDO in EMS to explore its pathological implications and treatment potential.

Angiogenesis is an essential process involved in various physiological, including placentation, and pathological, including cancer and endometriosis, processes. Melatonin (MLT), a well‑known natural hormone secreted primarily in the pineal gland, is involved in regulating neoangiogenesis and inhibiting the development of a variety of cancer types, including lung and breast cancer. However, the specific mechanism of its anti‑angiogenesis activity has not been systematically elucidated. In the present study, the effect of MLT on viability and angiogenesis of human umbilical vein endothelial cells (HUVECs), and the production of vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS), under normoxia or hypoxia was analyzed using Cell Counting kit 8, tube formation, flow cytometry, ELISA and western blot assays. It was determined that the secretion of VEGF by HUVECs was significantly increased under hypoxia, while MLT selectively obstructed VEGF release as well as the production of ROS under hypoxia. Furthermore, MLT inhibited the viability of HUVECs in a dose‑dependent manner and reversed the increase in cell viability and tube formation that was induced by hypoxia/VEGF/H2O2. Additionally, treatment with an inhibitor of hypoxia inducible factor (HIF)‑1α (KC7F2) and MLT synergistically reduced the release of ROS and VEGF, and inhibited cell viability and tube formation of HUVECs. These observations demonstrate that MLT may serve dual roles in the inhibition of angiogenesis, as an antioxidant and a free radical scavenging agent. MLT suppresses the viability and angiogenesis of HUVECs through the downregulation of HIF‑1α/ROS/VEGF. In summary, the present data indicate that MLT may be a potential anticancer agent in solid tumors with abundant blood vessels, particularly combined with KC7F2.

Indoleamine 2, 3-dioxygenase (IDO), a tryptophan-catabolizing enzyme, is essential in physiological immunoregulation. The present research was conducted to elucidate the expression and roles of IDO in decidual macrophages (dMφ) during early pregnancy. Here, we observed a remarkable decrease of IDO

The survival and development of a semi-allogeneic fetus during pregnancy require the involvement of decidual stromal cells (DSCs), a series of cytokines and immune cells. Insulin-like growth factor 1 (IGF1) is a low molecular weight peptide hormone with similar metabolic activity and structural characteristics of proinsulin, which exerts its biological effects by binding with its receptor. Emerging evidence has shown that IGF1 is expressed at the maternal–fetal interface, but its special role in establishment and maintenance of pregnancy is largely unknown. Here, we found that the expression of IGF1 in the decidua was significantly higher than that in the endometrium. Additionally, decidua from women with normal pregnancy had high levels of IGF1 compared with that from women with unexplained recurrent spontaneous miscarriage. Estrogen and progesterone led to the increase of IGF1 in DSCs through upregulating the expression of WISP2. Recombinant IGF1 or DSCs-derived IGF1 increased the survival, reduced the apoptosis of DSCs, and downregulated the cytotoxicity of decidual NK cells (dNK) through interaction with IGF1R. These data suggest that estrogen and progesterone stimulate the growth of DSCs and impair the cytotoxicity of dNK possibly by the WISP2/IGF1 signaling pathway.

Deficiency in decidualization has been widely regarded as an important cause of spontaneous abortion. Generalized decidualization also includes massive infiltration and enrichment of NK cells. However, the underlying mechanism of decidual NK (dNK) cell residence remains largely unknown. Here, we observe that the increased macroautophagy/autophagy of decidual stromal cells (DSCs) during decidualization, facilitates the adhesion and retention of dNK cells during normal pregnancy. Mechanistically, this process is mediated through activation of the MITF-TNFRSF14/HVEM signaling, and further upregulation of multiple adhesion adhesions (e.g. Selectins and ICAMs) in a MMP9-dependent manner. Patients with unexplained spontaneous abortion display insufficient DSC autophagy and dNK cell residence. In addition, poor vascular remodeling of placenta, low implantation number and high ratio of embryo loss are observed in NK cell depletion mice. In therapeutic studies, low doses of rapamycin, a known autophagy inducer that significantly promotes endometrium autophagy and NK cell residence, and improves embryo absorption in spontaneous abortion mice models, which should be dependent on the activation of MITF-TNFRSF14/HVEM-MMP9-adhension molecules axis. This observation reveals novel molecular mechanisms underlying DSCs autophagy-driven dNK cell residence, and provides a potential therapeutic strategy to prevent spontaneous abortion. Abbreviations: ACTA2/αSMA: actin alpha 2, smooth muscle; ATG: autophagy-related; ATG5(over) ESC: ATG5-overexpressed ESCs; BTLA: B and T lymphocyte associated; CDH1: cadherin 1; CDH5: cadherin 5; CXCL12: C-X-C motif chemokine ligand 12; dNK: decidual NK; DIC: decidual immune cell; DSC: decidual stromal cell; EOMES: eomesodermin; ESC: endometrial stromal cell; FCGR3A/CD16: Fc fragment of IgG receptor IIIa; HUVEC: human umbilical vein endothelial cell; ICAM: intercellular cell adhesion molecule; ILC: innate lymphoid cell; ITGB1: integrin subunit beta 1; ITGA2: integrin subunit alpha 2; IPA: Ingenuity Pathway Analysis; KIR2DL1: killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1; KLRD1/CD94: killer cell lectin like receptor D1; KLRK1/NKG2D: killer cell lectin like receptor K1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; 3-MA: 3-methyladenine; MITF: melanocyte inducing transcription factor; MiT-TFE: microphthalmia family of bHLH-LZ transcription factors; MMP9: matrix metalloproteinase 9; MTOR: mechanistic target of rapamycin kinase; NCAM1/CD56: neural cell adhesion molecule 1; NCR2/NKp44: natural cytotoxicity triggering receptor 2; NK: natural killer; KLRB1/NK1.1: killer cell lectin like receptor B1; NP: normal pregnancy; PBMC: peripheral blood mononuclear cell; PECAM1/CD31: platelet and endothelial cell adhesion molecule 1; pNK: peripheral blood NK; PRF1/Perforin: Perforin 1; PTPRC/CD45: protein tyrosine phosphatase receptor type C; Rapa: rapamycin; rh-TNFSF14/LIGHT: recombinant human TNFSF14/LIGHT; SA: spontaneous abortion; SELE: selectin E; SELP: selectin P; SELL: selectin L; siATG5 DSCs: ATG5-silenced DSCs; siTNFRSF14/HVEM DSCs: TNFRSF14/HVEM-silenced DSCs; TBX21/T-bet: T-box transcription factor 21; SQSTM1/p62: sequestosome 1; TNFRSF14/HVEM: TNF receptor superfamily member 14; TNFSF14/LIGHT: TNF superfamily member 14; uNK: uterine NK; UIC: uterine immune cell; USC: uterine stromal cell; VCAM1: vascular cell adhesion molecule 1; VIM: vimentin.

The results of previously published meta-analyses showed that dietary fiber could reduce the levels of p-cresyl sulfate, blood urea nitrogen, and creatinine in patients with chronic kidney disease (CKD). However, these results were based on some trials with pre-post design and randomized controlled trials of low quality. Additionally, it has been suggested that the dosage and duration of fiber supplementation and patients' characteristics potentially influence the effect of dietary fiber in reducing uremic toxins, but it would appear that no research has provided reliable evidence.We searched PubMed, Web of Science, and Cochrane Library. Data were pooled by the generic inverse variance method using random effects models and expressed as standardized mean difference (SMD) with 95% confidence interval (CI). Heterogeneity was quantified by ITen randomized controlled trials involving 292 patients with CKD were identified. Dietary fiber supplementation can significantly reduce the levels of indoxyl sulfate (SMD = -0.55, 95% CI = -1.04, -0.07, P = .03), p-cresyl sulfate (SMD = -0.47, 95% CI = -0.82, -0.13, P .01), blood urea nitrogen (SMD = -0.31, 95% CI = -0.58, -0.03, P = .03), and uric acid (SMD = -0.60, 95% CI = -1.02, -0.18, P .01), but not on reducing creatinine (SMD = -0.31, 95% CI = -0.73, 0.11, P = .14). In subgroup analyses, the reduction of indoxyl sulfate was more obvious among patients on dialysis than patients not on dialysis (P for interaction = .03); the reduction of creatinine was more obvious among patients without diabetes than those with diabetes (P for interaction.01).This meta-analysis indicates that dietary fiber supplementation can significantly reduce the levels of uremic toxins in patients with CKD, with evidence for a more obvious effect of patients on dialysis and without diabetes. These findings inform recommendations for using dietary fiber to reducing the uremic toxin among CKD patients in clinical practice.

Background Enteral nutrition (EN) therapy is widely used in clinical practice to provide artificial nutrition to patients, while the incidence of adverse events are relatively highly. In the clinical setting, the occurrence of adverse events is associated with the nurse’s risk perception. Thus, using tool to evaluate nurse’s risk perception of enteral nutrition is necessary. Methods The draft questionnaire with 37-items was formed by comprehensive literature reviews and semi-structured in-depth interviews with 11 nurses. Two iterations of expert consultations were used to evaluate the content validity, and 4 items were deleted in this phrase. A 33-items questionnaire was used to survey 352 nurses from five tertiary hospitals in China from May to July 2019 with convenience sampling. Content validity, construct validity and known-groups validity were evaluated by content validity index (CVI), exploratory factor analysis, and the comparisons of the different EN risk perception levels of nurses at different working departments and different educational backgrounds, respectively. Reliability was tested by internal consistency, test-retest reliability, and split-half reliability. Results After the exploratory factor analysis, four items were excluded. Finally, the newly developed questionnaire included 29 items explaining 71.356% of the total variance. It consisted of three factors: Risks of operation (15 items); Risks of EN-related adverse events (11 items), and Risks of EN solution selection (3 items). The CVI of the questionnaire was 0.95 and the CVI of items ranged from 0.875–1.0. The results of known-groups validity showed that the nurses with different educational backgrounds had a statistically significant difference of EN risk perception (z = − 3.024, p = 0.002), whereas there was not significantly different between EN risk perception of nurses working in different departments (z = − 1.644, p = 0.100). The Cronbach’s α, test-retest reliability, and split-half reliability of the questionnaire were 0.967, 0.818, and 0.815, respectively. Conclusions The newly developed questionnaire for assessing nurse’s EN risk perception showed good reliability and validity. It can be used as a tool for nursing managers to assess Chinese nurses’ EN risk perception ability, so as to help to reduce the occurrence of adverse events during EN implementation.

Problem Endometrial hyperplasia (EH) is characterized by an endometrial gland-to-stroma ratio >1 and is one of the most common gynecological diseases in the world. The role of immunocyte subsets in the development of EH remains unknown. Methods Patients who underwent dilatation and curettage due to abnormal uterine bleeding were recruited in the present study. Alterations in the numbers of different types of immune cell subsets in the endometrium of patients were analyzed by flow cytometry. Results The present study included 48 patients who were divided into three groups, based on the pathological results: (a) proliferative period (PP, n = 12); (b) simple EH (SEH, n = 30); and (c) complex EH (CEH, n = 6). The results showed that immune cell subpopulations were significantly different between these three groups. Compared with the PP group, the proportion of CD45+ cells and neutrophils and the subtypes of T cells and macrophages were significantly increased in the SEH patients. Compared with the PP and SEH groups, subsets of immunocytes in the CEH group were significantly decreased, including the population of CD45+ cells and the subtypes of T cells and natural killer cells; in contrast, the proportion of macrophages was significantly increased. There were no significant differences between the other cell subsets in each group. Conclusion The changes in immune cell subsets may be closely associated with the progression of EH. Although the specific role of different immune cell subsets in the development of the diseases requires further study, the changes in the proportions of immune cell subsets should not be ignored.

Problem The state of self-renewal and self-maintain of decidual macrophages would be important for immune homeostasis at the maternal-fetal interface. The roles of interleukin (IL)-24 derived from decidual stromal cells (DSCs) on decidual macrophages have not been explored. Method of study IL-24 expression in DSCs was interfered by lentivirus, and the transcription levels of IL-24 in DSCs were verified by real time (RT)-PCR. The levels of IL-24 receptors were determined by flow cytometry assays. The effect of recombination human IL-24 (rhIL-24) on the differentiation and apoptosis of macrophages was analyzed by flow cytometry in vitro. The viability of macrophages was detected by Cell Counting Kit-8 assays. Results The growth of DSCs was not affected obviously only by IL-24 knockdown while the growth of knockdown DSCs was inhibited significantly after co-cultured with decidual macrophages. The levels of IL-24 receptors (IL-20R1 and IL-22R1) were moderately to highly expressed on decidual macrophages and human macrophage cell line U937. The differentiation of decidual macrophages treated by rhIL-24 or co-cultured with IL-24 knockdown DSCs was not affected. Both apoptosis and viability of U937 cells were promoted by rhIL-24. The ratio of Bcl-2/Bax was down-regulated and Ki-67 was up-regulated by IL-24 treatment. The expression of Bcl-2/Bax was up-regulated while Ki-67 was down-regulated in U937 cells after co-cultured by IL-24 knockdown DSCs. Conclusion IL-24 secreted by DSCs promotes the renewal and homeostasis of decidual macrophages possibly via down-regulating the ratio of Bcl-2/Bax and up-regulating of the expression of Ki-67 in early pregnancy.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid-origin cells which have immunosuppressive activities in several conditions, such as cancer and inflammation. Recent research has also associated MDSCs with numerous obstetrical and gynecological diseases. During pregnancy, MDSCs accumulate to ensure maternal-fetal immune tolerance, whereas they are decreased in patients who suffer from early miscarriage or pre-eclampsia. While the etiology of endometriosis is still unknown, abnormal accumulation of MDSCs in the peripheral blood and peritoneal fluid, alongside an increased level of reactive oxygen species (ROS), has been observed in these patients, which is central to the cellular immune regulations by MDSCs. Additionally, the regulation of MDSCs observed in tumours is also applicable to gynecologic neoplasms, including ovarian cancer and cervical cancer. More recently, emerging evidence has shown that there are high levels of MDSCs in premature ovarian failure (POF) and in vitro fertilization (IVF), but the underlying mechanisms are unknown. In this review, the generation and mechanisms of MDSCs are summarized. In particular, the modulation of these cells in immune-related obstetrical and gynecological diseases is discussed, including potential treatment options targeting MDSCs.

The survival and development of a semi-allogeneic fetus during pregnancy require the involvement of a series of cytokines and immune cells. Chemokines are a type of special cytokine those were originally described as having a role in leukocyte trafficking. CXC chemokine ligand (CXCL) 16 is a member of the chemokine family, and CXC chemokine receptor (CXCR) 6 is its sole receptor. Emerging evidence has shown that CXCL16/CXCR6 is expressed at the maternal-fetal interface, by cell types that include trophoblast cells, decidual stroma cells, and decidual immune cells (eg, monocytes, γδT cells, and natural killer T (NKT) cells). The regulation of expression of CXCL16 is quite complex, and this process involves a multitude of factors. CXCL16 exerts a critical role in the establishment of a successful pregnancy through a series of molecular interactions at the maternal-fetal interface. However, an abnormal expression of CXCL16 is associated with certain pathological states associated with pregnancy, including recurrent miscarriage, pre-eclampsia, and gestational diabetes mellitus (GDM). In the present review, the expression and pleiotropic roles of CXCL16 under conditions of physiological and pathological pregnancy are systematically discussed.

Background/Aims: Uterus endometrial cancer (UEC) is the common malignancy among gynecologic cancers, and most of them are type I estrogen-dependent UEC. Diabetes is well-known risk factor for the development of UEC. However, the underlying link between high glucose (HG) and the estrogen receptor in UEC remains unclear. Epithelial-mesenchymal transition (EMT) has also been shown to occur during the initiation of metastasis in cancer progression. The aim of this study was to determine the relationships and roles of HG, estrogen receptor and EMT in the growth and migration of UEC. Methods: The expression of glucose transport protein 4 (GLUT4) in the control endometrium and UEC tissues was detected by immunohistochemistry (IHC); the cell viability and invasion were analyzed through CCK-8 and Matrigel invasion assays; the transcriptional level of EMT-related genes was evaluated through real-time PCR; and the effect of HG and / or GLUT4 on estrogen receptors, vascular endothelial growth factor (VEGF) and its receptor VEGFR was analyzed through western blotting, ELISA and flow cytometry (FCM) assay, respectively. In addition, Ishikawa-xenografted nude mice were constructed and were used to analyze the effect of estrogen and GLUT4 on the growth of UEC in vivo. Results: Here, we found that exposure to HG led to a high level of viability and invasion of UEC cell lines (UECC, Ishikawa and RL95-2 cells). Compared with the normal endometrium, a higher level of GLUT4 was observed in UEC tissues. Silencing GLUT4 obviously inhibited the HG-promoted viability, invasion and expression of EMT-related genes (TWIST, SNAIL and CTNNB1) of UECC promoted by HG. Further analysis showed that HG and GLUT4 promoted the secretion of VEGF and expression of VEGFR in UECC. Treatment with HG led to the increase of estrogen receptor α (ERα) and β (ERβ) in UECC, blocking ERα or ERβ resulted in the decreases in GLUT4 expression, TWIST, SNAIL and CTNNB1 transcription, and VEGF and VEGFR expression in UECC. Treatment with anti-human VEGF neutralizing antibody restricted the viability and invasion of UECC that was induced by HG and estrogen. Exposure to estrogen accelerated growth, VEGF production, and TWIST and CTNNB1 expression in UEC in Ishikawa-xenografted nude mice, and silencing GLUT4 restricted these effects. Conclusion: These data suggest that HG increases GLUT4 and VEGF/VEGFR expression, further promotes EMT process and accelerates the development of UEC by up-regulating ER