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.

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.

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.

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.

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.

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.

[Expression and significance of SATB1 and wnt/ß-catenin signaling molecule in the placenta of preeclampsia].

OBJECTIVE: To explore the role of specific AT rich sequence binding protein 1(SATB1) and wnt/ß-catenin signaling pathways in the regulation of trophoblast invasion and its effect in the pathogenesis of preeclampsia. METHODS: From March 2013 to March 2014, 20 cases of human villous tissues (early pregnancy group) from women of 8-10 gestational weeks who received artificial abortion at the First Affiliated Hospital of Chongqing Medical University, 18 cases of placental tissues (mid-pregnancy group) from women of 18-20 gestational weeks who had labor induction by water bag, 20 cases of placental tissues (normal full-term group) from healthy full-term pregnancy women and 20 cases of placental tissues (preeclamptic group) from women with preeclampsia who received elective c-section in were collected. Immunohistochemical SP method was utilized to determine the position of SATB1 and beta-catenin in villous tissues or placental tissues. Western blot was performed to analyze the expression level of SATB1 and beta-catenin in villous tissues or placental tissues. Immunofluorescence assay was used to determine the location of SATB1 and ß-catenin in HTR8/SVneo cells. Western blot was performed to detect the expression level of SATB1 and beta-catenin in HTR8/SVneo cells cultured in normoxia and hypoxia reoxygenation (H/R) condition. Co-Immunoprecipitation detection was used to evaluate the interaction between SATB1 and ß-catenin in placental tissues in preeclamptic group and HTR8/SVneo cells in H/R group. Gelatin zymography analysis was used to measure the activity of matrix metalloproteinases (MMP)-2 and 9 in placental tissues from preeclamptic group and HTR8/SVneo cells in H/R group. RESULTS: (1) In the normal full-term group, rare syncytiotrophoblastic nodule, less fibrinoid necrosis and abundant numbers of capillary could be observed in placental tissues. In comparison, there were obvious vacuolation in the cytoblast of syncytiotrophoblast, rich fibrinoid necrosis and poor numbers of villous capillary in placental tissues from preeclamptic group. (2) SATB1 could be found by immunochemical staining in placenta or villous tissues from all the groups. The staining intensity of SATB1 were more weakening in preeclamptic group than in the normal full-term group. (3) ß-catenin could be found by immunochemical staining in placenta or villous tissues from all the groups. The staining intensity of ß-catenin were more weakening in preeclamptic group than in the normal full-term group. (4) The protein expression levels of SATB1 in early pregnancy group, mid-pregnancy group, normal full-term group and preeclamptic group were 0.300 ± 0.009, 0.271±0.015, 0.238±0.018 and 0.153±0.007, respectively. The protein levels of ß-catenin among the above groups were 0.743±0.041, 0.648±0.021, 0.549±0.069 and 0.269±0.047, respectively. Both the expression of SATB1 and ß-catenin protein were significant decreased in placental tissues from preeclamptic group compared with the other three groups. (5) The SATB1 and ß-catenin protein was located in nucleus of trophoblast and a small amount was in the cytoplasm. The fluorescence intensity of both SATB1 and ß-catenin in the H/R group were significantly decreasing when compared to the normoxia group. (6) HTR8/SVneo cells in H/R group showed a significant decrease in both SATB1 and ß-catenin protein levels when compared to the normoxia group. The protein level of SATB1 in the normoxia group was 0.213±0.005, while was 0.083±0.021 in the H/R group. The protein level of ß-catenin in the normoxia group was 0.797±0.081, and was 0.543±0.131 in the H/R group. (7) There was an interaction between SATB1 and ß-catenin in placental tissues from the preeclamptic group and HTR8/SVneo cells exposed by H/R. (8) The enzymatic activity of MMP-2 and MMP-9 protein were decreased significantly in placental tissues from the preeclamptic group (2.251±0.310, 1.447±0.102, respectively) when compared to the normal full-term group (7.098±0.451, 5.502±0.197, respectively). MMP-2 and MMP-9 were significantly decreased in the H/R group (0.471±0.104, 0.297±0.103, respectively) when compared to the normoxia group (0.842±0.209, 0.595±0.100, respectively). CONCLUSION: The expression of SATB1 decreased in the placenta of preeclampsia. This may influence the activity of MMP-2 and 9 by regulating Wnt/ß-catenin signaling pathways, affect trophoblast invasion and eventually result in preeclampsia.

Decreased expression of Wiskott-Aldrich syndrome protein family verprolin-homologous protein 2 may be involved in the development of pre-eclampsia.

Wiskott­Aldrich syndrome protein family verprolin-homologous protein 2 (WAVE2) is a protein that mediates actin cytoskeletal reorganization and lamellipodia protrusion formation, which are required for cell migration and invasion. The primary purpose of this study was to determine whether there is an association between reactive oxygen species (ROS) and WAVE2 in pre-eclampsia, and whether WAVE2 expression in trophoblast cells is vulnerable to oxidative stress. This study observed excessive generation of ROS and decreased expression of WAVE2 in pre-eclamptic placentas compared with normotensive controls. Moreover, there was a significant negative correlation between ROS and WAVE2 protein in pre-eclamptic placenta (P < 0.001). An in-vitro model of hypoxia­reoxygenation (H/R) was used to imitate oxidative stress in placental trophoblasts, and it was found that the expression of WAVE2 protein in trophoblasts was decreased after H/R treatment. Additionally, compared with normoxia, decreased cell proliferation, higher cell apoptosis and attenuated cell migration and invasion were detected in trophoblasts exposed to H/R. In conclusion, the findings strongly suggest that excessive oxidative stress can decrease WAVE2 expression in trophoblasts and that the decreased expression of WAVE2 in trophoblast cells may be involved in the development of pre-eclampsia.

Timing of human chorionic gonadotropin (hCG) hormone administration in IVF/ICSI protocols using GnRH agonist or antagonists: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of altering the timing of human chorionic gonadotropin (hCG) administration on the clinical outcome of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) using gonadotropic hormone releasing hormone (GnRH) agonist or antagonist. METHODS: We systematically searched six databases. Randomized controlled trials (RCTs) of the effects of altering the timing of hCG administration on the clinical outcome of IVF and ICSI using GnRH agonist or antagonist were included. A meta-analysis was conducted following a quality evaluation performed with Cochrane Collaboration's Review Manager (RevMan) 5.0.2. RESULTS: Seven RCTs and a total of 1295 participants were included. Significant difference was observed regarding estradiol and progesterone levels on the day of hCG administration and oocyte retrieval between early hCG and late hCG administration group and in favor of the latter. The fertilization rate was not statistically different between early and 24-h late hCG groups, but it is significantly higher in the 48-h late hCG group. The pooled results showed no significant differences in the ongoing pregnancy rate per oocyte pick-up, the miscarriage rate and the live birth rate. CONCLUSION: The prolongation of follicular phase by delaying hCG administration could increase estradiol, progesterone levels and oocyte retrieval, which will not influence ongoing pregnancy rate per oocyte pick-up, miscarriage rate and live birth rate. Postponing hCG may enable increased flexibility of cycle scheduling to avoid weekend procedures.

IL-27 activates human trophoblasts to express IP-10 and IL-6: implications in the immunopathophysiology of preeclampsia.

PURPOSE: To investigate the effects of IL-27 on human trophoblasts and the underlying regulatory signaling mechanisms in preeclampsia. METHODS: The expression of IL-27 and IL-27 receptor (WSX-1) was studied in the placenta or sera from patients with preeclampsia. In vitro, we investigated the effects of IL-27 alone or in combination with inflammatory cytokine tumor necrosis factor (TNF-α) on the proinflammatory activation of human trophoblast cells (HTR-8/SVneo) and the underlying intracellular signaling molecules. RESULTS: The expression of IL-27 and IL-27 receptor α (WSX-1) was significantly elevated in the trophoblastic cells from the placenta of patients with preeclampsia compared with control specimens. In vitro, IL-27 could induce the expression of inflammatory factors IFN-γ-inducible protein 10 (CXCL10/IP-10) and IL-6 in trophoblasts, and a synergistic effect was observed in the combined treatment of IL-27 and TNF-α on the release of IP-10 and IL-6. Furthermore, the production of IP-10 and IL-6 stimulated by IL-27 was differentially regulated by intracellular activation of phosphatidylinositol 3-OH kinase-AKT, p38MAPK, and JAK/STAT pathways. CONCLUSIONS: These results provide a new insight into the IL-27-activated immunopathological effects mediated by distinct intracellular signal transduction molecules in preeclampsia.

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.

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.

Heterogeneous stiffness of the bone marrow microenvironment regulates the fate decision of haematopoietic stem and progenitor cells.

The bone marrow (BM) niches are the complex microenvironments that surround cells, providing various external stimuli to regulate a range of haematopoietic stem cell (HSC) behaviours. Recently, it has been proposed that the fate decision of HSCs is often correlated with significantly altered biophysical signals of BM niches. To thoroughly elucidate the effect of mechanical microenvironments on cell fates, we constructed 2D and 3D cell culture hydrogels using polyacrylamide to replicate the mechanical properties of heterogeneous sub-niches, including the inherent rigidity of marrow adipose tissue (2 kPa), perivascular tissue (8 kPa) and endosteum region (35 kPa) in BM. Our observations suggest that HSCs can respond to the mechanical heterogeneity of the BM microenvironment, exhibiting diversity in cell mechanics, haematopoietic pool maintenance and differentiated lineages. Hydrogels with higher stiffness promote the preservation of long-term repopulating HSCs (LT-HSCs), while those with lower stiffness support multi-potent progenitors (MPPs) viability in vitro. Furthermore, we established a comprehensive transcriptional profile of haematopoietic subpopulations to reflect the multipotency of haematopoietic stem and progenitor cells (HSPCs) that are modulated by niche-like stiffness. Our findings demonstrate that HSPCs exhibit completely distinct downstream differentiated preferences within hydrogel systems of varying stiffness. This highlights the crucial role of tissue-specific mechanical properties in HSC lineage decisions, which may provide innovative solutions to clinical challenges.

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.

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.

[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.

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).

The optimal duration of progesterone supplementation in pregnant women after IVF/ICSI: a meta-analysis.

UNLABELLED: can improve the rates of clinical pregnancy and live birth, but the optimal duration of treatment remains controversial. The objective of this meta-analysis was to investigate the effects of early progesterone cessation on pregnancy outcomes in women undergoing IVF/ICSI. METHODS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), the Chinese biomedicine (CBM) literature database, and the Wanfang database. The final search was performed in July 2012. All available randomised trials that compared the effects of early progesterone cessation with progesterone continuation during early pregnancy after IVF/ICSI were included. The main outcome measures were live birth rate, miscarriage rate and ongoing pregnancy rate. Fixed or random-effects models were chosen to calculate the risk ratio (RR). RESULTS: Six eligible studies with a total of 1,201 randomised participants were included in the final analysis. No statistically significant differences were detected between patients who underwent early progesterone cessation and those who received progesterone continuation for luteal phase support in terms of live birth rate (RR: 0.95, 95% CI: 0.86-1.05), miscarriage rate (RR: 1.01, 95% CI: 0.74-1.38) or ongoing pregnancy rate (RR: 0.97, 95% CI: 0.90-1.05). These results did not change after a sensitivity analysis. CONCLUSIONS: The currently available evidence suggests that progesterone supplementation beyond the first positive hCG test after IVF/ICSI might generally be unnecessary, although large-scale randomised controlled trials are needed to strengthen this conclusion.

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.

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.