Recent studies have shown that a carbohydrate-binding protein, galectin-3, is a novel pro-angiogenic molecule. The mechanism by which galectin-3 promotes angiogenesis remains unknown. We demonstrate here that galectin-3 is a mediator of vascular endothelial growth factor (VEGF)- and basic fibroblast growth factor (bFGF)-mediated angiogenic response. Angiogenesis assays revealed that galectin-3 inhibitors, β-lactose and dominant-negative galectin-3, reduce VEGF- and bFGF-mediated angiogenesis in vitro and that VEGF- and bFGF-mediated angiogenic response is reduced in galectin-3 knockdown cells and Gal3−/− animals. Integrin αvβ3 was identified as the major galectin-3–binding protein and anti-αv, -β3, and -αvβ3 integrin function-blocking antibodies significantly inhibited the galectin-3–induced angiogenesis. Furthermore, galectin-3 promoted the clustering of integrin αvβ3 and activated focal adhesion kinase. Knockdown of GnTV, an enzyme that synthesizes high-affinity glycan ligands for galectin-3, substantially reduced: (a) complex N-glycans on αvβ3 integrins and (b) VEGF- and bFGF-mediated angiogenesis. Collectively, these data suggest that galectin-3 modulates VEGF- and bFGF-mediated angiogenesis by binding via its carbohydrate recognition domain, to the GnTV synthesized N-glycans of integrin αvβ3, and subsequently activating the signaling pathways that promote the growth of new blood vessels. These findings have broad implications for developing novel, carbohydrate-based therapeutic agents for inhibition of angiogenesis.

Galectin-3 Is an Important Mediator of VEGF- and bFGF-Mediated Angiogenic Response

Purpose
To investigate the effects of (−)-epigallocatechin-3-gallate (EGCG) on human papillomavirus (HPV)-16 oncoprotein-induced angiogenesis in non-small cell lung cancer (NSCLC) cells and the underlying mechanisms.

(-)-Epigallocatechin-3-gallate inhibits human papillomavirus (HPV)-16 oncoprotein-induced angiogenesis in non-small cell lung cancer cells by targeting HIF-1α.

Background：The risk of spontaneous abortion in patients with polycystic ovary syndrome (PCOS) undergoing assisted reproductive treatment (ART) is higher than that in patients without PCOS, however, no definitive risk factors have been confirmed to associate with the high spontaneous abortion rate in PCOS patients undergoing ART. This study was performed to assess the impact of relevant risk factors on spontaneous abortion in patients with PCOS. Clinical questions were formulated and organized according to the PICOS principle. Methods: A systematic review and meta-analysis were conducted on all published studies on PCOS and spontaneous abortion in Embase, PubMed, Web of Science and Cochrane Library. Related risk factors included body mass index (BMI), age, insulin resistance (IR), hyperandrogenism, and chromosome aberrations. All patients were diagnosed as PCOS using the Rotterdam criteria. The primary endpoint was miscarriage and live birth rate. Fixed-effect models were used to analyze homogeneous data, and subgroup and sensitivity analyses were performed on heterogeneous data. The source of heterogeneity was evaluated, and the random effect model was used to summarize the heterogeneity. Results: Among 1836 retrieved articles, 22 were eligible and included in the analysis with 11182 patients. High BMI (OR = 1.48, 95% CI [1.32, 1.67], MD = 1.35, 95% CI [0.58,2.12]) and insulin resistance (MD = 0.32, 95% CI [0.15, 0.49]) were associated with an increased risk of spontaneous abortion in PCOS patients undergoing ART. Older age (OR = 0.29, 95% CI [ 0.29, 0.44]，MD = 2.01, 95% CI [0.04, 4.18]), embryonic chromosomal aberrations (OR=0.75, 95%CI [0.31,1.77]), and hyperandrogenism (MD = 0.10, 95% CI [- 0.02, 0.22]) were not associated with the high spontaneous abortion rate in patients with PCOS. A subgroup analysis of BMI showed that there was no statistically significant difference in the effect between overweight and obesity on spontaneous abortion in PCOS patients undergoing ART (OR = 1.34, 95% [0.97, 1.85]). Conclusion: High BMI and insulin resistance are two risk factors for an increased risk of spontaneous abortion in PCOS patients undergoing ART, and losing weight and mitigating insulin resistance may decrease the spontaneous abortion rate in these patients undergoing ART.

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High BMI and Insulin Resistance Are Risk Factors for Spontaneous Abortion in Patients With Polycystic Ovary Syndrome Undergoing Assisted Reproductive Treatment: A Systematic Review and Meta-Analysis.

Changes in the female genital tract microbiome are consistently correlated to gynecological and obstetrical pathologies, and tract dysbiosis can impact reproductive outcomes during fertility treatment. Nonetheless, a consensus regarding the physiological microbiome core inside the uterine cavity has not been reached due to a myriad of study limitations, such as sample size and experimental design variations, and the influence of endometrial bacterial communities on human reproduction remains debated. Understanding the healthy endometrial microbiota and how changes in its composition affect fertility would potentially allow personalized treatment through microbiome management during assisted reproductive therapies, ultimately leading to improvement of clinical outcomes. Here, we review current knowledge regarding the uterine microbiota and how it relates to human conception.

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The Endometrial Microbiome and Its Impact on Human Conception

Oocyte quality is one of the most important factors involving in female reproduction. The number of compromised oocytes will increase with maternal age, while mitochondrial dysfunction has implicated in age-related poor oocyte. Together with the successful application of ooplasmic transfer (OT) and the critical role of mitochondria in the oocyte, functional mitochondria transfer may be a feasible strategy to improve oocyte quality. However, limitation on ethics and laws are strictly and optimal condition or methods to exert transferring need to be further explored. Therefore, the role of oocyte mitochondria and the effective molecular involving in oocyte quality will be hot topics in next few years. In this review, we summarize the potential mechanism of mitochondria in oocyte and embryo development and discuss the next step for mitochondrial transfer therapy.

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Mitochondria: the panacea to improve oocyte quality?

Objective To investigate the Interaction between chronic endometritis (CE) caused endometrial microbiota disorder and endometrial immune environment change in recurrent implantation failure (RIF). Method Transcriptome sequencing analysis of the endometrial of 112 patients was preform by using High-Throughput Sequencing. The endometrial microbiota of 43 patients was analyzed by using 16s rRNA sequencing technology. Result In host endometrium, CD4 T cell and macrophage exhibited significant differences abundance between CE and non-CE patients. The enrichment analysis indicated differentially expressed genes mainly enriched in immune-related functional terms. Phyllobacterium and Sphingomonas were significantly high infiltration in CE patients, and active in pathways related to carbohydrate metabolism and/or fat metabolism. The increased synthesis of lipopolysaccharide, an important immunomodulator, was the result of microbial disorders in the endometrium. Conclusion The composition of endometrial microorganisms in CE and non-CE patients were significantly different. Phyllobacterium and Sphingomonas mainly regulated immune cells by interfering with the process of carbohydrate metabolism and/or fat metabolism in the endometrium. CE endometrial microorganisms might regulate Th17 response and the ratio of Th1 to Th17 through lipopolysaccharide (LPS).

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Interaction Between Chronic Endometritis Caused Endometrial Microbiota Disorder and Endometrial Immune Environment Change in Recurrent Implantation Failure.

Human spermatozoa can fertilize an oocyte only after post-testicular maturation and capacitation. These processes involve dynamic modification and reorganization of the sperm plasma membrane, which allow them to bind to the zona pellucida (ZP) of the oocyte. Defective sperm-ZP binding is one of the major causes of male subfertility. Galectin-3 is a secretory lectin in human seminal plasma well known for its action on cell adhesion. The aim of this study was to determine the role of galectin-3 in spermatozoa-ZP interaction and its association with fertilization rate in clinical assisted reproduction. Our studies revealed that the acrosomal region of ejaculated and capacitated spermatozoa possess strong galectin-3 immunoreactivity, which is much stronger than that of epididymal spermatozoa. Expression of galectin-3 can also be detected on seminal plasma-derived extracellular vesicles (EVs) and can be transferred to the sperm surface. Blocking of sperm surface galectin-3 function by antibody or carbohydrate substrate reduced the ZP-binding capacity of spermatozoa. Purified galectin-3 is capable of binding to ZP, indicating that galectin-3 may serve as a cross-linking bridge between ZP glycans and sperm surface glycoproteins. Galectin-3 levels in seminal plasma-derived EVs were positively associated with fertilization rates. These results suggest that galectin-3 in EVs is transferred to the sperm surface during post-testicular maturation and plays a crucial role in spermatozoa-ZP binding after capacitation. Reduced galectin-3 expression in seminal plasma-derived EVs may be a cause behind a low fertilization rate. Further studies with more clinical samples are required to confirm the relationship between galectin-3 levels and IVF outcomes.

The role of galectin-3 in spermatozoa-zona pellucida binding and its association with fertilization in vitro.

As a novel biomarker, there is inconsistent evidence regarding the association between anti-Mullerian hormone (AMH) and live birth rate in freezing-all embryo transfer cycles. We aim to assess the prognostic effect of baseline AMH on clinical outcomes, especially live birth rate in freezing-all embryo transfer cycles. A total of 828 non-polycystic ovary patients that underwent their first frozen-thawed embryo transfers in our center between January 2010 and January 2015 were recruited in this retrospective analysis. Patients were stratified into three groups based on their baseline AMH concentration: low AMH group ( 5.8 ng/mL). The results showed that low AMH level was associated with adverse clinical outcomes. The differences in implantation rate (21.9% vs. 43.2% vs. 58.8%, P<0.001), clinical pregnancy rate (32.0% vs. 55.2% vs. 65.7%, P<0.001), live birth delivery rate (21.8% vs. 43.6% vs. 52.7%, P<0.001) and miscarriage rate (31.8% vs. 17.5% vs. 15.4%, P=0.014) among the three groups were statistically significant. After adjusting confounders (i.e. age, baseline FSH level, AFC, endometrium thickness, endometrium preparation protocols, number of embryos transferred, etiologies of infertility), differences in live birth rate, clinical pregnancy rate and implantation rate between groups remained significant. The further age subgroup analysis demonstrated that low AMH concentration was significantly associated with poor outcomes both in young and advanced patients. The area under the curve for serum AMH, age, AFC and FSH were 0.635, 0.634, 0.615 and 0.543 respectively, for predicting live birth. In conclusion, baseline AMH was an independent prognostic factor of live birth rate of freezing-all embryo transfers, but its predictive value on live birth rate was of limited clinical value.

Basal Serum Anti-Müllerian Hormone Level as a Predictor of Clinical Outcomes in Freezing-all Embryo Transfer Program.

Objective: To analyze spontaneous abortion rate and its associated risk factors in patients with polycystic ovary syndrome (PCOS) after in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET). Methods: This was a retrospective cohort study on 2,231 PCOS patients undergoing IVF/ICSI treatment. For comparison, we enrolled another 2,231 patients with tubular factors in control group. Spontaneous abortion rate and chromosomal abnormality rate were compared between the two groups. Furthermore, clinical data were compared between the patients with spontaneous abortion and those with ongoing pregnancy using univariate and multivariate analysis for risk factors of spontaneous abortion in PCOS patients. Results: Patients in the PCOS group had significantly higher spontaneous abortion rate (24.15%) than that in the control group (12.75%, P Conclusions: Compared with non-PCOS patients, PCOS patients had higher spontaneous abortion rate, but the chromosomal abnormality was not a major factor for the high spontaneous abortion rate in the PCOS patients. Age, BMI, and HOMA-IR were risk factors for spontaneous abortion after IVF/ICSI-ET in PCOS patients.

Logistic Regression Analysis of Risk Factors Associated with Spontaneous Abortion after In Vitro Fertilization/Intracytoplasmic Sperm Injection-Embryo Transfer in Polycystic Ovary Syndrome Patients

Background In-vitro-grow (IVG) of preantral follicles is essential for female fertility preservation, while practical approach for improvement is far from being explored. Studies have indicated that neurotrophin-4 (NT-4) is preferentially expressed in human preantral follicles and may be crucial to preantral follicle growth. Methods We observed the location and expression of Tropomyosin-related kinase B (TRKB) in human and mouse ovaries with immunofluorescence and Western blot, and the relation between oocyte maturation and NT-4 level in follicular fluid (FF). Mice model was applied to investigate the effect of NT-4 on preantral follicle IVG. Single-cell RNA sequencing of oocyte combined with cell-specific network analysis was conducted to uncover the underlying mechanism of effect. Results We reported the dynamic location of TRKB in human and mouse ovaries, and a positive relationship between human oocyte maturation and NT-4 level in FF. Improving effect of NT-4 was observed on mice preantral follicle IVG, including follicle development and oocyte maturation. Transcriptome analysis showed that the reparative effect of NT-4 on oocyte maturation might be mediated by regulation of PI3K-Akt signaling and subsequent organization of F-actin. Suppression of advanced stimulated complement system in granulosa cells might contribute to the improvement. Cell-specific network analysis revealed NT-4 may recover the inflammation damage induced by abnormal lipid metabolism in IVG. Conclusions Our data suggest that NT-4 is involved in ovarian physiology and may improve the efficiency of preantral follicle IVG for fertility preservation.

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C. Fang

Papers

Interaction Between Chronic Endometritis Caused Endometrial Microbiota Disorder and Endometrial Immune Environment Change in Recurrent Implantation Failure.

The role of galectin-3 in spermatozoa-zona pellucida binding and its association with fertilization in vitro.

Basal Serum Anti-Müllerian Hormone Level as a Predictor of Clinical Outcomes in Freezing-all Embryo Transfer Program.

Logistic Regression Analysis of Risk Factors Associated with Spontaneous Abortion after In Vitro Fertilization/Intracytoplasmic Sperm Injection-Embryo Transfer in Polycystic Ovary Syndrome Patients

Single-cell transcriptome and cell-specific network analysis reveal the reparative effect of neurotrophin-4 in preantral follicles grown in vitro.