Hypermethylation and low expression of FOXM1 predisposes women to unexplained recurrent miscarriage by impairing trophoblast stem cell proliferation.

Recurrent miscarriage (RM) is a distressing pregnancy complication with an unknown etiology. Increasing evidence indicates the relevance of dysregulation of human trophoblast stem cells (hTSCs), which may play a role in the development of RM. However, the potential molecular regulatory mechanism underlying the initiation and maintenance of hTSCs is yet to be fully elucidated. In this study, we performed data analysis and identified Forkhead box M1 (FOXM1) as a potential factor associated with RM. FOXM1 is a typical transcription factor known for its involvement in various pathophysiological processes, while the precise function of FOXM1 functions in hTSCs and RM remains incompletely understood. Utilizing RNA-seq, CUT&Tag, ChIP-qPCR, and sodium bisulfite conversion methods for methylation analysis, we elucidate the underlying regulatory mechanisms of FOXM1 in hTSCs and its implications in RM. Our findings demonstrate the relative high expression of FOXM1 in proliferating cytotrophoblasts (CTBs) compared to differentiated extravillous cytotrophoblasts (EVTs) and syncytiotrophoblasts (STBs). Besides, we provide evidence supporting a significant correlation between FOXM1 downregulation and the incidence of RM. Furthermore, we demonstrate the significant role of FOXM1 in regulating hTSCs proliferation and cell cycle through the transcriptional regulation of CDKN3, CCNB2, CCNA2, MAD2L1 and CDC25C. Notably, we observed a correlation between the downregulation of FOXM1 in RM and hypermethylation in its promoter region. Collectively, these results provide insights into the impact of FOXM1 on trophoblast regulation and offer a novel perspective on RM.

New Analogues of Amides and Quinolinones Produced by Streptomyces sp. YIM S01983.

Streptomide (1), a new amide analogue, streptomynone (2), a new quinolinone, and ten known compounds including three aliphatic acids (3-5), two amides (6-7), four cyclic dipeptides (8-11), and an adenosine (12) were isolated from the fermentation broth of Streptomyces sp. YIM S01983 isolated from a sediment sample collected in Bendong Village, Huadong Town, Chuxiong, China. Their structures were determined by analysis of the 1D/2D-NMR and HR-ESI-MS spectra. Compound 12 presented weak antimicrobial activities against Candida albicans and Aligenes faecalis (MIC=64 µg/mL). Compounds 7 and 12 showed weak cytotoxic activity against MHCC97H.

The impact of gut microbial signals on hematopoietic stem cells and the bone marrow microenvironment.

Hematopoietic stem cells (HSCs) undergo self-renewal and differentiation in the bone marrow, which is tightly regulated by cues from the microenvironment. The gut microbiota, a dynamic community residing on the mucosal surface of vertebrates, plays a crucial role in maintaining host health. Recent evidence suggests that the gut microbiota influences HSCs differentiation by modulating the bone marrow microenvironment through microbial products. This paper comprehensively analyzes the impact of the gut microbiota on hematopoiesis and its effect on HSCs fate and differentiation by modifying the bone marrow microenvironment, including mechanical properties, inflammatory signals, bone marrow stromal cells, and metabolites. Furthermore, we discuss the involvement of the gut microbiota in the development of hematologic malignancies, such as leukemia, multiple myeloma, and lymphoma.

Extreme environments and human health: From the immune microenvironments to immune cells.

Exposure to extreme environments causes specific acute and chronic physiological responses in humans. The adaptation and the physiological processes under extreme environments predominantly affect multiple functional systems of the organism, in particular, the immune system. Dysfunction of the immune system affected by several extreme environments (including hyperbaric environment, hypoxia, blast shock, microgravity, hypergravity, radiation exposure, and magnetic environment) has been observed from clinical macroscopic symptoms to intracorporal immune microenvironments. Therefore, simulated extreme conditions are engineered for verifying the main influenced characteristics and factors in the immune microenvironments. This review summarizes the responses of immune microenvironments to these extreme environments during in vivo or in vitro exposure, and the approaches of engineering simulated extreme environments in recent decades. The related microenvironment engineering, signaling pathways, molecular mechanisms, clinical therapy, and prevention strategies are also discussed.

[Effects of electroacupuncture on pregnancy outcome in poor ovarian response patients of kidney essence deficiency and undergoing in vitro fertilization-embryo transfer].

OBJECTIVE: To observe the effects of electroacupuncture (EA) on ovarian reaction, egg and embryo quality, as well as pregnancy rate in poor ovarian response (POR) patients of kidney essence deficiency and undergoing in vitro fertilization-embryo transfer (IVF-ET). METHODS: Ninety-six patients who met the inclusion criteria were randomly divided into an EA group and a control group, with 48 cases in each group. Before IVF-ET, the patients in the EA group received EA, once daily, 2 or 3 treatments a week for 12 weeks. Before and after the treatment, traditional Chinese medicine (TCM) syndrome score and clinical pregnancy rate were assessed in two groups. The concentrations of serum follicle-stimulating hormone (FSH), luteinsing hormone, estradiol, progesterone and anti-mullerian hormone were detected by chemiluminescence; the contents of serum insulin-like growth factor-1, serum inhibin B (INHB) and Kisspeptin in follicular fluid were determined by enzyme linked immunosorbent assay (ELISA); the antral follicle counting (AFC) was detected by color Doppler ultrasonography; and the egg and embryo conditions were observed under microscope. Fourteen days after embryo transfer, the positive rate of serum hemchoriconic gonadotropin (HCG) and clinical pregnancy rate were calculated. RESULTS: After the treatment, the TCM syndrome score and level of serum FSH were reduced (P<0.05); the INHB in serum and AFC were increased (P<0.05) when compared with those before the treatment in the EA group. After the treatment, in comparison with the control group, the TCM syndrome score and level of serum FSH were lower (P<0.05); and the contents of serum INHB, AFC, the numbers of MⅡ eggs and high-quality embryos, as well as serum HCG positive rate were all increased (P<0.05) in the EA group. CONCLUSION: EA can relieve the clinical symptoms of TCM in POR patients of kidney essence deficiency and undergoing IVF-ET, increase the ovarian reserve, reduce the serum FSH level, and improve the content of serum INHB, and the quality of eggs and embryos. This therapy tends to improve the clinical pregnancy rate and clinical pregnancy outcome.

Intrauterine Infusion of Leukocyte-Poor Platelet-Rich Plasma Is an Effective Therapeutic Protocol for Patients with Recurrent Implantation Failure: A Retrospective Cohort Study.

BACKGROUND: The clinical application of autologous leukocyte-poor platelet-rich plasma (LP-PRP) in patients with recurrent implantation failure (RIF) is rare. This retrospective observational cohort study aimed to evaluate the efficacy of LP-PRP intrauterine infusion in patients with RIF. METHODS: Patients with RIF undergoing frozen embryo transfer (FET) from January 2019 to December 2021 (n = 118) were enrolled, with those undergoing LP-PRP intrauterine infusion as the PRP group (n = 64), and those receiving no LP-PRP treatment as the control group (n = 54). The beta-human chorionic gonadotropin (ß-hCG)-positive rate, clinical pregnancy rate (CPR), live birth rate (LBR), and miscarriage rate (MR) per ET cycle were compared. RESULTS: The ß-hCG-positive rate (57.8% vs. 38.9%, p = 0.041), CPR (45.3% vs. 24.5%, p = 0.022), and LBR per ET cycle (42.2% vs. 18.5%, p = 0.009) were higher in the PRP group than in the control group, and the three variables (62.5% vs. 41.2%, p = 0.040, 47.5% vs. 23.5%, p = 0.033, and 47.5% vs. 20.6%, p = 0.027) in the PRP group transferred with the blastocyst-stage embryos were also higher than those in the control group. The MR was similar in all groups. CONCLUSIONS: The LP-PRP treatment could improve the ß-hCG-positive rate, CPR, and LBR in RIF patients undergoing FET cycles.

Electroacupuncture for motor dysfunction and constipation in patients with Parkinson's disease: a randomised controlled multi-centre trial.

Background: Motor disturbances and non-motor disturbances such as constipation are the main factors affecting the quality of life in patients with Parkinson's disease (PD). We investigated the efficacy and safety of electroacupuncture combined with conventional pharmacological treatment on motor dysfunction and constipation in PD. Methods: In this multi-centre randomised controlled trial, we enrolled 166 eligible participants between September 19, 2018 and September 25, 2019 in four hospitals in China. Participants were randomly assigned (1:1) to the electroacupuncture (EA) group and the waitlist control group. Each participant in both groups received the conventional pharmacological treatment, EA group received 3 sessions of electroacupuncture per week for 12 weeks. The primary outcome was the change in the Unified Parkinson's Disease Rating Scale (UPDRS) score from baseline to week 12. The secondary outcomes included the evaluation of functional disability in motor symptoms and constipation, the adherence and adverse events were also recorded. Registered with Chictr.org.cn, ChiCTR1800019517. Findings: At week 12, the change in the UPDRS score of the EA group was significantly higher than that of the control group, with a difference of -9.1 points (95% CI, -11.8 to -6.4), and this difference continued into weeks 16 and 24. From baseline to week 12, the 39-item Parkinson Disease Question (PDQ-39) decreased by 10 points (interquartile range, IQR -26.0 to 0.0) in the EA group and 2.5 points (IQR: -11.0 to 4.0) in the control group, the difference was statistically significant. The time and steps for the 20-m walk at week 12, as well as the changes from baseline in the EA group, were comparable with that in the control group. But the EA group had a greater decrease than the control group from baseline in the times for 20-m walks at weeks 16 and 24. From week 4 to week 24, the median values of spontaneous bowel movements (SBMs) per week in the EA group were higher than that in the control group, the differences were all statistically significant. The incidence of EA-related adverse events during treatment was low, and they are mild and transient. Interpretation: The findings of our study suggested that compared with conventional pharmacological treatment, conventional pharmacological treatment combined with electroacupuncture significantly enhances motor function and increased bowel movements in patients with PD, electroacupuncture is a safe and effective treatment for PD. Funding: Shanghai "Science and Technology Innovation Action Plan" Clinical Medicine Field Project (18401970700), Shanghai Special Project on Aging and Women's and Children's Health Research (020YJZX0134), Shanghai Clinical Research Centre for Acupuncture and Moxibustion (20MC1920500).

Baicalein-functionalized collagen scaffolds direct neuronal differentiation toward enhancing spinal cord injury repair.

Spinal cord injury (SCI) repair remains a major challenge in clinics. Though neural stem cells (NSCs) have shown great potentials in SCI treatment, their applications were hampered since they primarily differentiate into astrocytes rather than neurons in the injured area, indicating a high demand for effective strategies to direct neuronal differentiation. Baicalein is a clinical drug with multiple pharmacological activities, while its effects on NSCs have rarely been reported. In the current work, inspired by a similarity of the metabolic reprogramming required in neuronal differentiation and that involved in chemoresistance reversal of cancer cells induced by baicalein, we studied the role of baicalein in NSC differentiation and discovered its promotion effects on neuronal differentiation. Based on this observation, baicalein-functionalized collagen scaffolds (BFCSs) were developed and applied for SCI treatment. The BFCSs released the payload in a sustained way and possessed comparable physical properties to the commonly used collagen. Both in vitro studies with primary NSCs and in vivo studies in SCI rats showed that the BFCSs containing a low amount of baicalein can facilitate not only neurogenesis and axon extension, but also reduce astrocyte production and glial scar formation. More importantly, the BFCS implantation led to improvement in the motor functional recovery of SCI rats. Thus, the BFCSs provided a potential strategy to induce neuronal differentiation towards facilitating SCI repair, as well as for the treatment of other central nervous system injuries.

Deciphering the Efficacy and Mechanism of Astragalus membranaceus on High Altitude Polycythemia by Integrating Network Pharmacology and In Vivo Experiments.

Hypoxic exposure makes plateau migrators susceptible to high altitude polycythemia (HAPC). Astragalus membranaceus (AM) is an edible and medicinal plant with remarkable immunomodulatory activities. The purpose of this study was to discover if AM could be a candidate for the prevention of HAPC and its mechanism. Here, network pharmacology was applied to screen active compounds, key targets, and enriched pathways of AM in the treatment of HAPC. Molecular docking evaluated the affinity between compounds and core targets. Subsequently, the mechanisms of AM were further verified using the hypoxia exposure-induced mice model of HAPC. The network pharmacology analysis and molecular docking results identified 14 core targets of AM on HAPC, which were predominantly mainly enriched in the HIF-1 pathway. In the HAPC animal models, we found that AM inhibited the differentiation of hematopoietic stem cells into the erythroid lineage. It also suppressed the production of erythrocytes and hemoglobin in peripheral blood by reducing the expression of HIF-1α, EPO, VEGFA, and Gata-1 mRNA. Furthermore, AM downregulated the expression of IL-6, TNF-α, and IFN-γ mRNA, thereby alleviating organ inflammation. In conclusion, AM supplementation alleviates hypoxia-induced HAPC in mice, and TNF-α, AKT1, HIF-1α, VEGFA, IL-6, and IL-1B may be the key targets.

TOP2A deficiency leads to human recurrent spontaneous abortion and growth retardation of mouse pre-implantation embryos.

BACKGROUND: Recurrent spontaneous abortion (RSA), is a dangerous pregnancy-related condition and is a subject of debate in the gynaecology and obstetrics communities. The objective of this study was to determine the function of DNA Topoisomerase II Alpha (TOP2A) in RSA and elucidate the underlying molecular mechanisms. METHODS: In vitro models of TOP2A-knockdown and -overexpression were generated by transfecting specific sh-RNA lentivirus and overexpression plasmid, respectively. An in vitro TOP2A inhibition model was established by culturing mouse embryos at the two-cell stage in a medium containing PluriSIn2, a TOP2A inhibitor. Immunohistochemical staining was used to analyse expression of TOP2A in villi tissues of patients with RSA. Western blotting and qRT-PCR were used to analyse the expression of TOP2A and proteins involved in trophoblast functions, the FOXO signalling pathway, and the development of pre-implantation embryos. 5-Ethynyl-2'-deoxyuridine staining, TUNEL assay and flow cytometry were used to further evaluate the effect of TOP2A on cell proliferation and apoptosis. Transwell and wound healing assays were used to evaluate migration and invasion. Moreover, the effect of TOP2A inhibitor on embryos was determined by immunofluorescence and mitochondrial-related dyes. RESULTS: Evaluation of clinical samples revealed that the villi tissues of patients that have experienced RSA had lower TOP2A expression compared with that from women who have experienced normal pregnancy (P < 0.01). In vitro, TOP2A knockdown decreased the proliferation, migration, and invasion of trophoblast cell lines, and increased apoptosis and activation of the FOXO signalling pathway (P < 0.05). Conversely, TOP2A overexpression reversed these effects. Moreover, in vivo experiments confirmed that inhibition of TOP2A impairs trophectoderm differentiation, embryonic mitochondrial function as well as the developmental rate; however, no differences were noted in the expression of zygotic genome activation-related genes. CONCLUSIONS: Collectively, our data suggest that lower TOP2A expression is related to RSA as it inhibits trophoblast cell proliferation, migration, and invasion by activation of the FOXO signalling pathway. Additionally, TOP2A inhibition resulted in impaired development of pre-implantation embryos in mice, which could be attributed to excessive oxidative stress.

TOP2A deficit-induced abnormal decidualization leads to recurrent implantation failure via the NF-κB signaling pathway.

BACKGROUND: Successful implantation is a complex process that is influenced by embryo quality, endometrial receptivity, immune factors, and the specific type of in vitro fertilization protocol used. DNA topoisomerase IIα (TOP2A) is a well-known protein involved in cell proliferation; however, its expression and effect on the endometrium in recurrent implantation failure (RIF) have not been fully elucidated. METHODS: The human endometrial tissues of healthy controls and patients with RIF were collected. A proteomic analysis was performed to evaluate the differentially expressed proteins between the RIF group and the fertile control group. The expression patterns of TOP2A in the human preimplantation endometrium of the patients with RIF were determined by immunohistochemical staining, Western blotting and qRT-PCR. TOP2A knockdown (sh-TOP2A) T-HESCs were generated using lentiviruses. The expression of TOP2A in T-HESCs was manipulated to investigate its role in decidualization. The TOP2A-related changes in decidualization were screened by mRNA sequencing in decidualized TOP2A knockdown and control T-HESCs and then confirmed by Western blotting and immunofluorescence staining. TOP2A-deficient mice were generated by injection of TOP2A-interfering adenovirus on GD2.5 and GD3.5. RESULTS: We performed a proteomic analysis of endometrial tissues to investigate the potential pathogenesis of RIF by comparing the patients with RIF and the matched controls and found that TOP2A might be a key protein in RIF. TOP2A is ubiquitously expressed in both stromal and glandular epithelial cells of the endometrium. The data indicate that TOP2A expression is significantly lower in the mid-secretory endometrium of women with RIF. TOP2A expression was downregulated under stimulation by 8-bromo-cAMP and MPA. Ablation of TOP2A resulted in upregulated expression of decidual biomarkers and morphological changes in the cells. Mechanistic analysis revealed that TOP2A regulates the NF-κB signaling pathway in decidualized T-HESCs. The TOP2A-deficient mice exhibited lower fetal weights. CONCLUSIONS: Our findings revealed that abnormal expression of TOP2A affects decidualization and changes the "window of implantation", leading to RIF. TOP2A participates in the processes of decidualization and embryo implantation, functioning at least in part through the NF-κB pathway. Regulating the expression of TOP2A in the endometrium may become a new strategy for the prevention and treatment of RIF.

ANKRD37 inhibits trophoblast migration and invasion by regulating the NF-κB pathway in preeclampsia.

BACKGROUND: Inadequate trophoblast invasion is associated with preeclampsia (PE). Ankyrin repeat domain protein 37 (ANKRD37) has been reported to be abnormally expressed in PE placentas. However, the role of ANKRD37 in trophoblasts has not been investigated. We aimed to determine the functions of ANKRD37 in PE and to explore the molecular mechanisms. METHODS: Here, fluorescence in situ hybridization, immunohistochemistry, Western blotting and quantitative real-time polymerase chain reaction were used to detect protein and mRNA expression levels. Cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine assay, flow cytometry, wound healing assay, transwell assay and RNA sequencing were performed to investigate the role of ANKRD37 and the underlying mechanism in HTR8/SVneo and JEG-3 cells, and extravillous explant cultures were used to evaluate the migration and invasion abilities of extravillous cytotrophoblasts. RESULTS: We found that ANKRD37 expression was upregulated in PE placentas compared to normal pregnancy placentas. ANKRD37 knockdown enhanced trophoblast migration and invasion, promoted extravillous explant outgrowth, and regulated the expression of key invasion proteins, whereas ANKRD37 overexpression exerted the opposite effects. RNA sequencing indicated that nuclear factor-kappa B (NF-κB) was the potential downstream pathway of ANKRD37, which was confirmed by the change in p-p65 and p-IκBα expression in JEG-3 and HTR8/SVneo cells. CONCLUSIONS: Our findings suggest that high expression of ANKRD37 inhibits trophoblast cell migration and invasion possibly via the NF-κB pathway, and may be related to the development of PE.

High strength pure chitosan hydrogels via double crosslinking strategy.

Chitosan (CS) hydrogels have been widely used throughout basic tissue engineering and regenerative medicine research and it is very desirable to develop advanced CS materials with superior mechanical and topographical properties for more extensive applications. Herein, we present the design of a double crosslinking pure CS hydrogel material via the synergic effect of the chemical covalent network, hydrophobic interactions, enhanced intermolecular hydrogen bonding and the formation of the CS crystallite. The resultant pure CS hydrogel possesses increases in strength and toughness by two orders of magnitude (fracture energy ∼7.733 J m-2; maximal compression stress ∼10.81 MPa, elastic modulus ∼1.33 MPa). We utilize1H NMR and FT-IR to prove the success of chemical modification. The results of Raman spectra and WXRD have proved the existence of physical interaction between CS hydrogels and microcrystals, thus explaining the enhancement mechanism of mechanical strength of CS hydrogel. The live and death results also show that MSCs can grow well on CS hydrogels, and the results of CCK-8 indicate low cytotoxicity of CS hydrogels. This CS hydrogel shows great potential applications in tissue engineering and regenerative medicine.

NSCs Migration Promoted and Drug Delivered Exosomes-Collagen Scaffold via a Bio-Specific Peptide for One-Step Spinal Cord Injury Repair.

Spinal cord injury (SCI) is plaguing medical professionals globally due to the complexity of injury progression. Based on tissue engineering technology, there recently emerges a promising way by integrating drugs with suitable scaffold biomaterials to mediate endogenous neural stem cells (NSCs) to achieve one-step SCI repair. Herein, exosomes extracted from human umbilical cord-derived mesenchymal stem cells (MExos) are found to promote the migration of NSCs in vitro/in vivo. Utilizing MExos as drug delivery vehicles, a NSCs migration promoted and paclitaxel (PTX) delivered MExos-collagen scaffold is designed via a novel dual bio-specificity peptide (BSP) to effectively retain MExos within scaffolds. By virtue of the synergy that MExos recruit endogenous NSCs to the injured site, and PTX induce NSCs to give rise to neurons, this multifunctional scaffold has shown superior performance for motor functional recovery after complete SCI in rats by enhancing neural regeneration and reducing scar deposition. Besides, the dual bio-specific peptide demonstrates the capacity of tethering other cells-derived exosomes on collagen scaffold, such as erythrocytes-derived or NSCs-derived exosomes on collagen fibers or membranes. The resulting exosomes-collagen scaffold may serve as a potential multifunctional therapy modality for various disease treatments including SCI.

[Rolling needle pricking-cupping therapy and traditional pricking-cupping therapy for cervical spondylosis of neck type: a randomized controlled trial].

OBJECTIVE: To compare the clinical efficacy between rolling needle pricking-cupping (RNP-C) and traditional pricking-cupping (TP-C) for cervical spondylosis of neck type. METHODS: A total of 96 patients with cervical spondylosis of neck type were randomly divided into an RNP-C group, a TP-C group and an electroacupuncture (EA) group, 32 cases in each group. Each group was treated with EA at Jingbailao (EX-HN 15), Fengchi (GB 20), Dazhui (GV 14), Jianjing (GB 21) and ashi points with continuous wave and 2 Hz of frequency; each EA treatment lasted for 20 min, once every 3 to 5 days, totaling 6 treatments. On the basis of EA treatment, the patients in the TP-C group were treated with bloodletting by seven-star needle, followed by fire cupping; the patients in the RNP-C group were treated with bloodletting by rolling needle, followed by fire cupping. The treatment was given once a week for 4 weeks. The follow-up was 1 month. Before treatment, 2 and 4 weeks into treatment and follow-up, the Northwick Park neck-pain questionnaire (NPQ) and visual analogue scale (VAS) scores were evaluated. The acupuncture pain degree was recorded at the first treatment and 2 and 4 weeks into treatment. The efficacy was evaluated after 4 weeks of treatment. RESULTS: Compared before treatment, the scores of NPQ and VAS in each group were all reduced at 2 and 4 weeks into treatment and follow-up (P<0.05). The scores of NPQ in the TP-C group and the RNP-C group were lower than those in the EA group at 2 and 4 weeks into treatment (P<0.05). The scores of VAS in the TP-C group and the RNP-C group were lower than those in the EA group at 2 and 4 weeks into treatment and follow-up (P<0.05). The differences of NPQ and VAS scores between the TP-C group and the RNP-C group at each time point after treatment were not significant (P>0.05). The acupuncture pain degree in the RNP-C group was lower than that in the TP-C group (P<0.05). The total effective rates were 79.3% (23/29) in the TP-C group and 75.0% (24/32) in the RNP-C group, which was superior to 63.3% (19/30) in the EA group (P<0.05), but there was no statistical significance between the TP-C group and the RNP-C group (P>0.05). CONCLUSION: TP-C and RNP-C could both improve the cervical pain symptoms in patients with cervical spondylosis of neck type, and improve the overall function of the cervical spine, and the curative effect is similar.

The physical microenvironment of hematopoietic stem cells and its emerging roles in engineering applications.

Stem cells are considered the fundamental underpinnings of tissue biology. The stem cell microenvironment provides factors and elements that play significant roles in controlling the cell fate direction. The bone marrow is an important environment for functional hematopoietic stem cells in adults. Remarkable progress has been achieved in the area of hematopoietic stem cell fate modulation based on the recognition of biochemical factors provided by bone marrow niches. In this review, we focus on emerging evidence that hematopoietic stem cell fate is altered in response to a variety of microenvironmental physical cues, such as geometric properties, matrix stiffness, and mechanical forces. Based on knowledge of these biophysical cues, recent developments in harnessing hematopoietic stem cell niches ex vivo are also discussed. A comprehensive understanding of cell microenvironments helps provide mechanistic insights into pathophysiological mechanisms and underlies biomaterial-based hematopoietic stem cell engineering.

Downregulated N-acetylglucosaminyltransferase III is involved in attenuating trophoblast migration and invasion under hypoxia-reoxygenation condition.

OBJECTIVE: Many studies have confirmed that N-acetylglucosaminyltransferase III (GnT-III) is correlated with tumor invasion and metastasis. However, the expression of GnT-III and its role in normal pregnancy and preeclampsia (PE) has not been reached. So the primary objective of this study is to determine GnT-III expression in normal pregnancy and whether its expression is vulnerable to oxidative stress in the trophoblast cells. METHODS: Human first trimester villous tissues from normal pregnancies and third trimester placentas from pregnancies with or without preeclampsia (PE) were used for the detection of GnT-III expression. Human first trimester extravillous trophoblast cell line (HTR8/SVneo) exposed to hypoxia/reoxygenation (H/R) condition was employed as an oxidative stress model in vitro to investigate the expression of GnT-III. RESULTS: GnT-III was strongly expressed in cytotrophoblast (CTBs), syncytiotrophoblast (STBs) and the trophoblast columns (TCs) of human placental villi, and decidual cells in the maternal decidua. The expression of GnT-III was decreased in PE placentas compared with the normal control placentas. In addition, GnT-III was found to have decreased expression in H/R-exposed HTR8/SVneo cells, and the invasive and migratory abilities of HTR8/SVneo cells were attenuated, too. CONCLUSIONS: These findings suggest that GnT-III is an important regulator at the maternal-fetal interface during early pregnancy. Excessive oxidative stress can decrease GnT-III expression in trophoblast and the decreased expression of GnT-III may be involved in the development of preeclampsia.

Expression of N-Acetylglucosaminyltransferase III Promotes Trophoblast Invasion and Migration in Early Human Placenta.

INTRODUCTION: Trophoblast migration and invasion at the maternal-fetal interface are crucial events for normal placentation and successful pregnancy. This progress is well controlled by many placenta-specific factors. Inadequate trophoblast invasion results in poor placenta plantation or even complications such as preeclampsia. It has been shown that N-acetylglucosaminyltransferase III (GnT-III) participates in tumor invasion and metastasis as a suppressor; however, the expression of GnT-III and its role in normal pregnancy is unclear. Our objective was to characterize GnT-III expression and function during placental development and identify the underlying mechanisms. METHODS: The expression of GnT-III in human placental tissue from the first trimester was determined by immunohistochemistry. The HTR8/SVneo cell line was used to investigate the effects of GnT-III on proliferation, apoptosis, migration/invasion, matrix metalloproteinase (MMP) 2/9 activity, and the expression of the tissue inhibitor of metalloproteinase (TIMP) 1/2 using cell 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays, flow cytometric analysis, transwell migration/invasion assays, gelatin zymography, and Western blot, respectively. Moreover, a placental villous explant model was employed to determine its functions in placentation. RESULTS: In the first-trimester placental tissue, GnT-III was localized within the cytotrophoblast, the syncytiotrophoblast and the trophoblast columns of human placental villi, decidual cells, and some extravillous cells in the maternal decidua. GnT-III silencing significantly inhibited HTR8/SVneo cell invasion and migration as well as extravillous explant outgrowth. The application of GnT-III siRNA significantly attenuated MMP2/9 activity and increased TIMP1/2 expression. DISCUSSION AND CONCLUSION: GnT-III is expressed in trophoblasts during normal human pregnancy and is involved in regulating trophoblast function.

Recombinant adiponectin alleviates abortion in mice by regulating Th17/Treg imbalance via p38MAPK-STAT5 pathway.

Recurrent spontaneous abortion is associated with abnormal maternal tolerance to the semi-allogenic fetus, wherein the Th17/Treg axis plays a crucial role. Adiponectin (APN) is an adipocytokine that is shown to be a novel negative T-cell regulator and induce immune tolerance. The CBA/J × DBA/2 mating was used as an abortion-prone model to investigate whether the addition of recombinant adiponectin (rAPN) improves the pregnancy outcome. Recombinant adiponectin therapy reduced the abortion rate in abortion-prone model. It skewed the ability of serum cytokine production toward a Treg bias and induced APN production. Flow cytometry revealed that rAPN administration expanded the splenic CD4+CD25+ regulatory T-cell (Treg) population and reduced the Th17 cell populations in CBA/J × DBA/2 matings. RT-PCR revealed that rAPN administration induced the expression of AdipoR1 and AdipoR2 mRNA at the maternofetal interface. Recombinant adiponectin administration induced FoxP3 and reduced RORγt expressions at the maternofetal interface. In vitro experiment also showed that rAPN treatment enhanced the FoxP3 mRNA and protein expression and decreased the RORγt expression in splenic lymphocytes of abortion-prone mice. Blocking the different signal transduction pathways downstream of APN, p38MAPK inhibitor (SB203580) and STAT5 inhibitor (Pimozide) could abrogate the regulatory effect of rAPN on FoxP3 and RORγt expression, while STAT3 inhibitor (Stattic) and AMPK inhibitor (p5499) did not exert any influence. Thus, the current results demonstrated that rAPN therapy improves pregnancy outcome in a murine model of abortion by expanding the Treg cell population and function and decreasing the Th17 cell population and function via a p38MAPK-STAT5 pathway.

The Impact of Noncavity-Distorting Intramural Fibroids on the Efficacy of In Vitro Fertilization-Embryo Transfer: An Updated Meta-Analysis.

AIM: To address the impact of noncavity-distorting intramural fibroids on the efficacy of in vitro fertilization-embryo transfer (IVF-ET) outcomes. METHODS: The PubMed, Web of Science, Embase, Cochrane Library, and China National Knowledge Infrastructure were searched systematically. A meta-analysis was performed based on comparative or cohort studies that explored the impact of noncavity-distorting intramural fibroids on the efficacy of IVF-ET treatment. The IVE-ET outcomes of study group (women with noncavity-distorting intramural fibroids) and control group (women without fibroids) were compared, including live birth rate (LBR), clinical pregnancy rate (cPR), implantation rate (IR) , miscarriage rate (MR), and ectopic pregnancy rate (ePR). RESULTS: A total of 28 studies involving 9189 IVF cycles were included. Our meta-analysis showed a significant reduction of LBR in the study group compared to control group (RR = 0.82, 95% CI: 0.73-0.92, and P = 0.005). In addition, it indicated that study group had a significant reduction in cPR (RR = 0.86, 95% CI: 0.80-0.93, P = 0.0001) and IR (RR = 0.90, 95% CI: 0813-1.00, P = 0.04) and have a significantly increase in MR (RR = 1.27, 95% CI: 1.08-1.50, and P = 0.004) compared with control group. CONCLUSIONS: The present evidence suggests that noncavity-distorting intramural fibroids would significantly reduce the IR, cRP, and LBR and significantly increase the MR after IVF treatment, but it would not significantly increase the ePR.