scholarly journals Autophagy as a Therapeutic Target of Natural Products Enhancing Embryo Implantation

2021 ◽  
Vol 15 (1) ◽  
pp. 53
Author(s):  
Hyerin Park ◽  
Minkyoung Cho ◽  
Yoonju Do ◽  
Jang-Kyung Park ◽  
Sung-Jin Bae ◽  
...  
Keyword(s):  
Natural Products ◽  
Embryo Quality ◽  
Embryo Implantation ◽  
Prenatal Development ◽  
Endometrial Receptivity ◽  
Female Infertility ◽  
Implantation Failure ◽  
Comprehensive Understanding ◽  
New Treatment ◽  
The Relationship

Infertility is an emerging health issue worldwide, and female infertility is intimately associated with embryo implantation failure. Embryo implantation is an essential process during the initiation of prenatal development. Recent studies have strongly suggested that autophagy in the endometrium is the most important factor for successful embryo implantation. In addition, several studies have reported the effects of various natural products on infertility improvement via the regulation of embryo implantation, embryo quality, and endometrial receptivity. However, it is unclear whether natural products can improve embryo implantation ability by regulating endometrial autophagy. Therefore, we performed a literature review of studies on endometrial autophagy, embryo implantation, natural products, and female infertility. Based on the information from these studies, this review suggests a new treatment strategy for female infertility by proposing natural products that have been proven to be safe and effective as endometrial autophagy regulators; additionally, we provide a comprehensive understanding of the relationship between the regulation of endometrial autophagy by natural products and female infertility, with an emphasis on embryo implantation.

scholarly journals Increased METTL3-mediated m6A methylation inhibits embryo implantation by repressing HOXA10 expression in recurrent implantation failure

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Pingping Xue ◽  
Wenbo Zhou ◽  
Wenqiang Fan ◽  
Jianya Jiang ◽  
Chengcai Kong ◽  
...  
Keyword(s):  
Real Time ◽  
Real Time Pcr ◽  
Embryo Implantation ◽  
Endometrial Receptivity ◽  
Mrna Levels ◽  
Implantation Failure ◽  
Quantitative Real Time Pcr ◽  
Recurrent Implantation Failure ◽  
Ishikawa Cells ◽  
Embryo Attachment

Abstract Background Recurrent implantation failure (RIF) is a major limitation of assisted reproductive technology, which is associated with impaired endometrial receptivity. Although N6-methyladenosine (m6A) has been demonstrated to be involved in various biological processes, its potential role in the endometrium of women with RIF has been poorly studied. Methods Global m6A levels and major m6A methyltransferases/demethylases mRNA levels in mid-secretory endometrium from normal and RIF women were examined by colorimetric m6A quantification strategy and quantitative real-time PCR, respectively. The effects of METTL3-mediated m6A modification on embryo attachment were evaluated by an vitro model of a confluent monolayer of Ishikawa cells co-cultured with BeWo spheroids, and the expression levels of homeo box A10 (HOXA10, a well-characterized marker of endometrial receptivity) and its downstream targets were evaluated by quantitative real-time PCR and Western blotting in METTL3-overexpressing Ishikawa cells. The molecular mechanism for METTL3 regulating HOXA10 expression was determined by methylated RNA immunoprecipitation assay and transcription inhibition assay. Results Global m6A methylation and METTL3 expression were significantly increased in the endometrial tissues from women with RIF compared with the controls. Overexpression of METTL3 in Ishikawa cells significantly decreased the ration of BeWo spheroid attachment, and inhibited HOXA10 expression with downstream decreased β3-integrin and increased empty spiracles homeobox 2 expression. METTL3 catalyzed the m6A methylation of HOXA10 mRNA and contributed to its decay with shortened half-life. Enforced expression of HOXA10 in Ishikawa cells effectively rescued the impairment of METTL3 on the embryo attachment in vitro. Conclusion Increased METTL3-mediated m6A modification represents an adverse impact on embryo implantation by inhibiting HOXA10 expression, contributing to the pathogenesis of RIF.

scholarly journals The Role of Transcriptomic Biomarkers of Endometrial Receptivity in Personalized Embryo Transfer for Patients with Repeated Implantation Failure

2020 ◽  
Author(s):  
Aihua He ◽  
Yangyun Zou ◽  
Cheng Wan ◽  
Jing Zhao ◽  
Qiong Zhang ◽  
...  
Keyword(s):  
Embryo Transfer ◽  
Controlled Trial ◽  
Embryo Implantation ◽  
Endometrial Receptivity ◽  
Training Dataset ◽  
Control Group ◽  
Second Phase ◽  
Implantation Failure ◽  
Repeated Implantation Failure ◽  
Experimental Group

Abstract Background: Window of implantation (WOI) displacement was known as one of endometrial origin leading to embryo implantation failure, especially for repeated implantation failure (RIF). A accurately prediction tool of endometrial receptivity (ER) is extraordinary needed to precisely guide the successful embryo implantation. We aimed to establish an RNA-seq based endometrial receptivity test tool (rsERT) using transcriptomic biomarkers, and to evaluate the benefit of personalized embryo transfer (pET) guided by this tool in patients with repeated implantation failure (RIF).Methods: Two-phase strategy including tool establishment with retrospective data and benefit evaluation with prospective, nonrandomized controlled trial. In the first phase, the rsERT was established by sequencing and analyzing the RNA of endometrial tissues from 50 infertile patients with normal window of implantation (WOI) timing. In the second phase, 142 patients with RIF were recruited and grouped by patient self-selection (experimental group, n=56; control group, n=86). pET guided by rsERT in the experimental group, and conventional ET in the control group. Results: The rsERT, comprising 175 biomarker genes, showed an average accuracy of 98.4% by using 10-fold cross-validation. IPR of experimental group (50.0%) was significantly improved compared to that (23.7%) of control group (RR, 2.107; 95% CI, 1.159 to 3.830; P = 0.017) when transferring day 3 embryos. Although not statistically different, IPR of experimental group (63.6%) was still 20 percentage points higher than that (40.7%) of control group (RR, 1.562; 95% CI, 0.898 to 2.718; P = 0.111) when transferring blastocyst. Regression analysis can precisely predict the optimal WOI time by using all samples as training dataset (R2= 0.92).Conclusions: The rsERT was developed to accurately predict WOI period and significantly improve pregnancy outcomes of patients with RIF, indicating the clinical potential of rsERT-guided pET. Optimization of the model made it possible to predict the optimal WOI by one-point sampling.Trial registration: Chinese Clinical Trial Registry: ChiCTR-DDD-17013375. Registered 14 November 2017, http://www.chictr.org.cn/index.aspx

scholarly journals hsa_circ_001946 elevates HOXA10 expression and promotes the development of endometrial receptivity via sponging miR-135b

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Fang Zhao ◽  
Yihong Guo ◽  
Zhanrong Shi ◽  
Menglan Wu ◽  
Yuzhen Lv ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Western Blotting ◽  
Embryo Implantation ◽  
Endometrial Receptivity ◽  
Luciferase Reporter ◽  
Implantation Failure ◽  
Recurrent Implantation Failure ◽  
Tissue Samples ◽  
Qrt Pcr

Abstract Background Impaired endometrial receptivity is a major reason for embryo implantation failure. There’s a paucity of information regarding the role of circRNAs on endometrial receptivity. Here, we investigated the function of hsa_circ_001946 on endometrial receptivity and its mechanisms. Methods A total of 50 women composing 25 with recurrent implantation failure and 25 who conceived after their implantation were recruited in this study. Expression of hsa_circ_001946, miR-135b, and HOXA10 was evaluated by quantitative RT-PCR (qRT-PCR) in biopsied endometrial tissue samples. The levels of HOXA10, and cell cycle markers (CCNB1, CDK1, and CCND1) were determined by IHC and western blotting assays. Binding relationship among miR-135b, hsa_circ_001946 and HOXA10 were confirmed by dual luciferase reporter assays and western blotting. MTT assays and cell cycle assays by FACS were employed to evaluate the proliferation and cell cycle of cells. T-HESCs were cultured with 1 µM medroxyprogesterone acetate (MPA) and 0.5 mM 8-bromoadenosine 3’:5’-cyclic monophosphate (8-Br-cAMP) to induce decidualization. The mechanisms and functions of hsa_circ_001946 on decidualization were further assessed by qRT-PCR evaluating the expression of hsa_circ_001946, miR-135b, HOXA10 and decidual markers (PRL and IGFBP1) in T-HESCs. Results Endometrial tissues from patients with recurrent implantation failure had lower hsa_circ_001946 expression, higher miR-135b expression, and lower HOXA10 expression. Hsa_circ_001946 promoted HOXA10 expression by sponging miR-135b in T-HESCs. Overexpression of hsa_circ_001946 restored cell proliferation and cell cycle that were disrupted by miR-135b overexpression in T-HESCs. Decidualized T-HESCs had higher hsa_circ_001946 expression, lower miR-135b expression, and higher HOXA10 expression. Overexpression of hsa_circ_001946 reversed the expression of decidual markers (PRL and IGFBP1) that were suppressed by miR-135b overexpression in T-HESCs. Conclusions In conclusion, our findings suggest that hsa_circ_001946 promotes cell proliferation and cell cycle process and increases expression of decidualization markers to enhance endometrial receptivity progression via sponging miR-135b and elevating HOXA10.

scholarly journals Transcriptomic Analysis of Porcine Endometrium during Implantation after In Vitro Stimulation by Adiponectin

2019 ◽  
Vol 20 (6) ◽  
pp. 1335 ◽  
Author(s):  
Nina Smolinska ◽  
Karol Szeszko ◽  
Kamil Dobrzyn ◽  
Marta Kiezun ◽  
Edyta Rytelewska ◽  
...  
Keyword(s):  
Reproductive Success ◽  
Cytokine Production ◽  
Regulatory Mechanism ◽  
Embryo Implantation ◽  
Prostaglandin Synthesis ◽  
Comprehensive Understanding ◽  
Implantation Process ◽  
The Relationship ◽  
Pathway Networks

Comprehensive understanding of the regulatory mechanism of the implantation process in pigs is crucial for reproductive success. The endometrium plays an important role in regulating the establishment and maintenance of gestation. The goal of the current study was to determine the effect of adiponectin on the global expression pattern of genes and relationships among differentially expressed genes (DE-genes) in the porcine endometrium during implantation using microarrays. Diverse transcriptome analyses including gene ontology (GO), biological pathway, networks, and DE-gene analyses were performed. Adiponectin altered the expression of 1286 genes with fold-change (FC) values greater than 1.2 (p < 0.05). The expression of 560 genes were upregulated and 726 downregulated in the endometrium treated with adiponectin. Thirteen genes were selected for real-time PCR validation of differential expression based on a known role in metabolism, steroid and prostaglandin synthesis, interleukin and growth factor action, and embryo implantation. Functional analysis of the relationship between DE-genes indicated that adiponectin interacts with genes that are involved in the processes of cell proliferation, programmed cell death, steroid and prostaglandin synthesis/metabolism, cytokine production, and cell adhesion that are critical for reproductive success. The presented results suggest that adiponectin signalling may play a key role in the implantation of pig.

scholarly journals The role of transcriptomic biomarkers of endometrial receptivity in personalized embryo transfer for patients with repeated implantation failure

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Aihua He ◽  
Yangyun Zou ◽  
Cheng Wan ◽  
Jing Zhao ◽  
Qiong Zhang ◽  
...  
Keyword(s):  
Embryo Transfer ◽  
Controlled Trial ◽  
Embryo Implantation ◽  
Endometrial Receptivity ◽  
Control Group ◽  
Second Phase ◽  
Implantation Failure ◽  
Clinical Trial Registry ◽  
Repeated Implantation Failure ◽  
Experimental Group

Abstract Background Window of implantation (WOI) displacement is one of the endometrial origins of embryo implantation failure, especially repeated implantation failure (RIF). An accurate prediction tool for endometrial receptivity (ER) is extraordinarily needed to precisely guide successful embryo implantation. We aimed to establish an RNA-Seq-based endometrial receptivity test (rsERT) tool using transcriptomic biomarkers and to evaluate the benefit of personalized embryo transfer (pET) guided by this tool in patients with RIF. Methods This was a two-phase strategy comprising tool establishment with retrospective data and benefit evaluation with a prospective, nonrandomized controlled trial. In the first phase, rsERT was established by sequencing and analyzing the RNA of endometrial tissues from 50 IVF patients with normal WOI timing. In the second phase, 142 patients with RIF were recruited and grouped by patient self-selection (experimental group, n = 56; control group, n = 86). pET guided by rsERT was performed in the experimental group and conventional ET in the control group. Results The rsERT, comprising 175 biomarker genes, showed an average accuracy of 98.4% by using tenfold cross-validation. The intrauterine pregnancy rate (IPR) of the experimental group (50.0%) was significantly improved compared to that (23.7%) of the control group (RR, 2.107; 95% CI 1.159 to 3.830; P = 0.017) when transferring day-3 embryos. Although not significantly different, the IPR of the experimental group (63.6%) was still 20 percentage points higher than that (40.7%) of the control group (RR, 1.562; 95% CI 0.898 to 2.718; P = 0.111) when transferring blastocysts. Conclusions The rsERT was developed to accurately predict the WOI period and significantly improve the pregnancy outcomes of patients with RIF, indicating the clinical potential of rsERT-guided pET. Trial registration Chinese Clinical Trial Registry: ChiCTR-DDD-17013375. Registered 14 November 2017, http://www.chictr.org.cn/index.aspx

scholarly journals Non-invasive intra-uterine administration of Botulinum Toxin A enhances endometrial angiogenesis and improves the rates of embryo implantation

2020 ◽  
Author(s):  
Hwa Seon Koo ◽  
Min-Ji Yoon ◽  
Seon-Hwa Hong ◽  
Jungho Ahn ◽  
Hwijae Cha ◽  
...  
Keyword(s):  
Botulinum Toxin ◽  
Botulinum Toxin A ◽  
Embryo Implantation ◽  
Endometrial Receptivity ◽  
Marker Genes ◽  
Implantation Failure ◽  
Toxin A ◽  
Major Barrier ◽  
Repeated Implantation Failure ◽  
Non Invasive

Abstract Background. Endometrial angiogenesis plays crucial roles in determining the endometrial receptivity. Defects in endometrial receptivity often cause repeated implantation failure, which is one of the major unmet needs for infertility and contributes a major barrier to the assisted reproductive technology. Despite the numerous extensive research work, there are currently no effective evidence-based treatments to prevent or cure this condition.Method. As a non-invasive treatment strategy, Botulinum toxin A (BoTA) was administered into one side of mouse uterine horns and saline was infused into the other side of horns for the control. Impact of BoTA was assessed in the endometrium at 3 or 8 days after infusion.Results. We demonstrated that BoTA administration enhances the capacity of endothelial cell tube formation and sprouting. The intrauterine BoTA administration significantly induced endometrial angiogenesis displaying increased numbers of vessel formation and expression levels of related-marker genes. Moreover, BoTA intrauterine application promoted the endometrial receptivity and the rates of embryo implantation were improved with BoTA treatment with no morphologically retarded embryos. Conclusion. Intrauterine BoTA treatment has a beneficial effect on vascular reconstruction of functional endometrium prior to embryo implantation by increasing endometrial blood flow near the uterine cavity suggesting BoTA treatment as a potential therapeutic strategy for patients who are suffering from repeated implantation failure with the problems with endometrial receptivity.

scholarly journals Correlative analyze of predictable factors of successful implantation in assisted reproduction programme

2003 ◽  
Vol 131 (7-8) ◽  
pp. 311-313 ◽  
Author(s):  
Milena Papic-Obradovic ◽  
Svetlana Dragojevic-Dikic ◽  
Ana Mitrovic ◽  
Dusan Papic
Keyword(s):  
Assisted Reproduction ◽  
Embryo Quality ◽  
Mutual Influence ◽  
Endometrial Thickness ◽  
Statistical Tests ◽  
Embryo Implantation ◽  
Endometrial Receptivity ◽  
Ovarian Activity ◽  
Pulsatile Index ◽  
Relevant Factors

INTRODUCTION Endometrial receptivity as isolated predictive factor of successful implantation, with its specifity is determined with numbered factors. PURPOSE Purpose of this study was to evaluate significance and correlation between relevant factors using appropriate statistical analyses on term of embryo implantation. MATERIAL AND METHODS Evaluated group contained 85 women whom according different causes of infertility have been determined for assisted reproduction program. Analysed measurements were endometrial thickness, assessed hyperechogenity in relation with absolute endometrial thickness (HEA relation) and uterine blood flow (pulsatile index - Pi). Simultaneously were analyzed serum estradiol (E2; pg/ml) and progesteron (P; nmol/l) levels. After these evaluations achieved results were processed with standard statistical pack. Beside that were applied parameter and nonparameter tests with aim to test significancy of difference and multiple regressive analyse (Stepwise). RESULTS Resulted measured parameters have been presented in basic analyse as middle value (Xrs) from all measurements +SD (standard deviation) and significance of difference is tested by mentioned statistical tests (Table 1). Application of Stepwise analyse, "step by step", has used parameter by parameter based on value which has decreased variability and based on achieved correlative coefficient between dependent uneven and complex of independent uneven values. This procedure confirmes best correlation between HEA relation and serum progesteron levels and HEA relation in correlation with associated values: P, E2 and endometrial thickness (Table 1). DISCUSSION Investigation provided till now shows that embryo quality and endometrial receptivity with highest probability determine success of applied assisted reproduction, successful embryonal implantation There is assessed influence of endometrial receptivity represented trough HEA relation using manyfolded regressive analyse where qualitative endometryal value has been looked with dependency with other parameters gives picture for high determinancy with hormonal activity and with stimulative ovarian activity. This determinacy could be viewed mostly through serum progesteron levels on day of HCG administration. Correlative relation between qualitative endometrial characteristics on day of HCG administration has highes value related to progesteron levels. CONCLUSION Results presented with this research confirm once again complexity characteristic for factors that play final role in embryo implantation in IVF program. There is presented only one aspect related with this problem with aim to contribute quantification importance and assessment rate of mutual influence these factors known till now as relevant.

scholarly journals Single Cell Proteomics Profiling Revealing that Embryo Secreted TNF-α play Critical Role during Embryo Implantation to Endometrium

2020 ◽  
Author(s):  
Lv Jiao ◽  
Shan Xudong ◽  
Yang Haoxuan ◽  
Wen Yuting ◽  
Zhang Xueguang ◽  
...  
Keyword(s):  
Single Cell ◽  
Embryo Quality ◽  
Embryo Implantation ◽  
Critical Role ◽  
Cell Mass ◽  
Gene Profiling ◽  
Immunofluorescence Staining ◽  
Tunel Staining ◽  
Implantation Failure ◽  
Tnf Α

Abstract Problem: Although it has long been known that endometrium secreted cytokines play critical role during embryo implantation, whether cytokines secreted from embryo is relevant to embryo quality and is actively involved in embryo attachment remain unclear.Method of study: The concentration of cytokines in embryo culture medium were tested by a new developed high-sensitive single cell proteomic platform, compared with embryo quality and clinical outcome. The effect of TNF-α on embryo and endometrium Ishikawa cell was investigated using immunofluorescence staining, CCK- 8 assay, TUNEL staining, and RT-qPCR reaction.Results: Of the 10 cytokines measured, only TNF-α concentration is significantly higher in group of embryo implantation failure. Immunofluorescence staining showed that the expression of TNF-α was unevenly distributed in blastocysts, and the expression level was significantly correlated with blastocysts inner cell mass (ICM) quality score. Adding TNF-α caused significant increase of apoptotic cells, which could be inhibited by TNF-α receptor blocker entanecept (ETA). Gene profiling showed that adding TNF-α lead to increased expression of TNFR1 and apoptosis related genes, as well as ion channel genes, including CFTR, ENaCA, AQP3 and CRISP2, and the increase can be inhibited by ETA. Conclusion: In conclusion, our result showed that higher TNF-α level is associated with implantation failure through activation of TNF-α receptor, and TNF-α maybe an independent predictor for pre-transfer assessment of the embryo development potential in IVF patients.

A Clinical Study on Uttar Basti of Bhrihat Shatavari Ghrita and Baladi Churna in the management of Female Infertility w.s.r. to Endometrial Receptivity

2017 ◽  
Vol 2 (1) ◽  
Author(s):  
Anjali Verma ◽  
Kamini Dhiman ◽  
Sarvesh Kumar
Keyword(s):  
Clinical Trial ◽  
Clinical Study ◽  
Randomized Clinical Trial ◽  
Doppler Sonography ◽  
Endometrial Receptivity ◽  
Female Infertility ◽  
Implantation Failure ◽  
Colour Doppler Sonography ◽  
Colour Doppler ◽  
Group A

Introduction: Endometrial factor comes under the umbrella of Kshetra, which is one of the important factor for conception described in Ayurveda i.e Rutu, Kshetra, Ambu , Beej. Decreased endometrial factor is the major cause of implantation failure, Therefore the present study was carried out for the clinical evaluation of efficacy of Uttar Basti of Bhrihat Shatavari Ghrita and Baladi Churna in female infertility w.s.r endometrial factor. Materials and methods: A simple randomized clinical trial was conducted of total 28 registered patients in two groups i.e. First Group with Bhrihat Shatavari Ghrita Uttar Basti combined with Baladi Churna Oral and other Group Baladi Churna Oral. Assessment of results was done on the basis of Appelbaum’s USSR by the tool of Transvaginal colour doppler sonography. Results: Study shows statistically highly significant (p>0.001) effect of therapies in the both groups but clinically Group A (Bhrihat Shatavari Ghrita Uttar Basti combined with Baladi Churna Oral) provided better result in upgrading endometrial receptivity comparatively. Conclusion: It can be concluded that Bhrihat Shatavari Ghrita Uttar Basti combined with Baladi Churna Oral overall can be a better choice in improving endometrial receptivity in cases of female infertility.

scholarly journals Administration of a herbal formulation enhanced blastocyst implantation via IκB activation in mouse endometrium

2020 ◽  
Author(s):  
Songhee Jeon ◽  
Quan Feng Liu ◽  
Hua Cai ◽  
Ha Jin Jeong ◽  
Su-Hyun Kim ◽  
...  
Keyword(s):  
Embryo Implantation ◽  
Water Extract ◽  
Treated Group ◽  
Endometrial Receptivity ◽  
Implantation Failure ◽  
Herbal Formulation ◽  
Blastocyst Implantation ◽  
Implantation Sites

Abstract Background: BaelanChagsangBang (BCB), a herbal formulation consisting of eleven herbs, may be prescribed as a reproductive functional supplement to improve ovulation and implantation during the treatment of infertility and recurrent abortion in Korean Medicine. This study aimed to investigate the effects and action mechanisms of water-extracted BCB on endometrial receptivity and blastocyst implantation under normal conditions and in a mifepristone (RU486)-induced implantation failure murine model.Methods: In vitro, the antioxidant potentials of BCB were evaluated using DPPH and superoxide anion radical scavenging assays and a DCFH-DA assay, and the cytotoxic and cytoprotective effects of BCB were confirmed using an MTT assay. In vivo, C57BL/6 female mice (n = 6 per group) orally received BCB (300 mg/kg/day), a dose similar to that used clinically, from 7 days before pregnancy until the end of the experiment. On day 4 of pregnancy, RU486 (4 mg/kg) was injected subcutaneously to induce implantation failure. The effect of BCB on embryo implantation was evaluated by implantation rate analysis, histological examination, and western blotting of uterus tissues.Results: BCB water extract showed strong anti-oxidative and cytoprotective effects in vitro. In vivo administration of BCB water extract increased the number of newborn pups in BCB-treated mice versus sham-treated mice under normal conditions and improved the number of implantation sites in pregnant mice despite RU486 injection. BCB increased the protein levels of cyclooxygenase-2 and inducible nitric oxide synthase through IκB activation. Moreover, the expression levels of matrix metalloproteinases (MMPs) at uterus implantation sites were up-regulated in the BCB-treated group as compared with those in the RU486-treated group. Conclusion: These results show BCB improved embryo implantation through IκB activation in our mouse model and suggest that BCB has therapeutic potential in the context of poor endometrial receptivity.

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