scholarly journals Lipidomic Alterations and PPARα Activation Induced by Resveratrol Lead to Reduction in Lesion Size in Endometriosis Models

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Zhengyun Chen ◽  
Chunyan Wang ◽  
Cuicui Lin ◽  
Lifeng Zhang ◽  
Huimei Zheng ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Therapeutic Potential ◽  
Lesion Size ◽  
Chronic Inflammatory Disease ◽  
Reproductive Age ◽  
Valuable Insight ◽  
Endometrial Stromal Cells ◽  
Proliferation Capacity ◽  
Significant Efficacy ◽  
Insight Into

Endometriosis is an estrogen-dependent chronic inflammatory disease that affects approximately 10% of women of reproductive age and up to 50% of women with infertility. The heterogeneity of the disease makes accurate diagnosis and treatment a clinical challenge. In this study, we generated two models of endometriosis: the first in rats and the second using human ectopic endometrial stromal cells (HEcESCs) derived from the lesion tissues of endometriosis patients. We then applied resveratrol to assess its therapeutic potential. Resveratrol intervention had significant efficacy to attenuate lesion size and to rectify aberrant lipid profiles of model rats. Lipidomic analysis revealed significant lipidomic alterations, including notable increases of sphingolipids and decreases of both glycerolipids and most phospholipids. Upon resveratrol application, both proliferation capacity and invasiveness parameters decreased, and the early apoptosis proportion increased for HEcESCs. The activation of PPARα was also noted as a factor potentially contributing to recovery from endometriosis in both models. Our study provides valuable insight into the mechanisms of resveratrol in endometriosis and therefore strengthens the potential for optimizing resveratrol treatment for this disease.

scholarly journals Down-Regulating Hexokinase 2 Inhibits Proliferation of Endometrial Stromal Cells Through a Noncanonical Pathway Involving Phosphorylated-STAT1 in Endometriosis

2021 ◽  
Author(s):  
Shuhui Hou ◽  
Shating Lei ◽  
Haiyan Peng ◽  
Lichun Weng ◽  
Siji Lv ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Cell Function ◽  
Malignant Tumors ◽  
Reproductive Age ◽  
Endometrial Stromal Cells ◽  
Hexokinase 2 ◽  
Proliferation Capacity ◽  
Glycolysis Pathway ◽  
Elevated Expression

Abstract Background: Endometriosis is a benign gynecologic disease that causes chronic pelvic pain, dysmenorrhea and infertility and shares several characteristics with malignant tumors, afflicting women of reproductive age. Hexokinase 2 (HK2) plays a pivotal role as the first rate-limiting enzyme in the metabolic glycolysis pathway, and its abnormal elevation in tumors is associated with tumor genesis and metastasis. However, the expression and role of HK2 in endometriosis remain unclear.Methods: We sequenced the primary endometrial stromal cells from patients with endometrioma and adopted immunohistochemistry, quantitative real-time PCR and western blot to determine the expression of HK2. Then wound healing assays, cell invasion assays, cell proliferation assays were performed to explore the functions of HK2 in endometrial stromal cells. Furthermore, mice models of endometriosis were recruited to observe the effects of HK2 inhibitors in vivo. Lastly, glycolysis metabolism detection and transcriptome sequencing were carried out in HK2-knockdown endometrial stromal cells to analyze the mechanism of HK2 affecting cell function.Results: Endometriotic stromal cells displayed active glycolysis metabolism and elevated expression of HK2. Downregulating HK2 reduced the migration, invasion and proliferation capacity of endometrial stromal cells. Knockdown of HK2 induced upregulation of signal transducer and activator of transcription 1 (STAT1) and their phosphorylation to attenuate the proliferation of endometrial stromal cells.Conclusions: HK2 was associated with the migration, invasion and proliferation of endometrial stromal cells, which might provide new insights into the pathogenesis and treatment of endometriosis.

Pyrvinium pamoate induces in-vitro suppression of IL-6 and IL-8 produced by human endometriotic stromal cells

2020 ◽  
pp. 096032712096454
Author(s):  
Amin Karamian ◽  
Shahrokh Paktinat ◽  
Sahar Esfandyari ◽  
Hamid Nazarian ◽  
Seyed Ali Ziai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stromal Cells ◽  
Chronic Inflammatory Disease ◽  
Reproductive Age ◽  
Endometrial Stromal Cells ◽  
Mrna Gene ◽  
And Control ◽  
Mrna Gene Expression ◽  
Pyrvinium Pamoate

Endometriosis, a chronic inflammatory disease, is identified by the presence of endometrial tissue outside the uterus. The prevalence of this disease among reproductive-age women is almost 10–15%. High levels of IL-6 and IL-8 have been found in the peritoneal fluid (PF) of women with endometriosis and are involved in its pathogenesis. Isolated stromal cells from 12 ectopic and eutopic endometrial biopsies of women with ovarian endometrioma and also 12 endometrial biopsies of nonendometriotic controls were treated with 1.1 µM pyrvinium pamoate, a Wnt/β-catenin signaling pathway inhibitor, for 72 hrs. Before treatment, mRNA gene expression and secretion of IL-6 and IL-8 were significantly higher in ectopic (EESCs) than eutopic (EuESCs) and control (CESCs) endometrial stromal cells. After treatment, mRNA gene expression and also secretion of IL-6 and IL-8 were significantly reduced. Our Findings showed that pyrvinium pamoate suppresses the mRNA gene expression and secretion of IL-6 and IL-8 in human endometriotic stromal cells. Additional investigations on this compound are required before clinical application.

scholarly journals PPARγ Activation Inhibits Growth and Survival of Human Endometriotic Cells by Suppressing Estrogen Biosynthesis and PGE2 Signaling.

Endocrinology ◽  
2013 ◽  
Vol 154 (12) ◽  
pp. 4803-4813 ◽  
Author(s):  
Dan I. Lebovic ◽  
Shahryar K. Kavoussi ◽  
JeHoon Lee ◽  
Sakhila K. Banu ◽  
Joe A. Arosh
Keyword(s):  
Cell Cycle ◽  
Stromal Cells ◽  
Cell Cycle Regulation ◽  
Chronic Inflammatory Disease ◽  
Reproductive Age ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Growth And Survival ◽  
Cycle Regulation ◽  
Estrogen Biosynthesis

Endometriosis is a chronic inflammatory disease of reproductive age women leading to chronic pelvic pain and infertility. Current antiestrogen therapies are temporizing measures, and endometriosis often recurs. Potential nonestrogenic or nonsteroidal targets are needed for treating endometriosis. Peroxisome proliferator-activated receptor (PPAR)γ, a nuclear receptor, is activated by thiazolidinediones (TZDs). In experimental endometriosis, TZDs inhibit growth of endometriosis. Clinical data suggest potential use of TZDs for treating pain and fertility concurrently in endometriosis patients. Study objectives were to 1) determine the effects of PPARγ action on growth and survival of human endometriotic epithelial and stromal cells and 2) identify the underlying molecular links between PPARγ activation and cell cycle regulation, apoptosis, estrogen biosynthesis, and prostaglandin E2 biosynthesis and signaling in human endometriotic epithelial and stromal cells. Results indicate that activation of PPARγ by TZD ciglitazone 1) inhibits growth of endometriotic epithelial cells 12Z up to 35% and growth of endometriotic stromal cells 22B up to 70% through altered cell cycle regulation and intrinsic apoptosis, 2) decreases expression of PGE2 receptors (EP)2 and EP4 mRNAs in 12Z and 22B cells, and 3) inhibits expression and function of P450 aromatase mRNA and protein and estrone production in 12Z and 22B cells through EP2 and EP4 in a stromal-epithelial cell-specific manner. Collectively, these results indicate that PGE2 receptors EP2 and EP4 mediate actions of PPARγ by incorporating multiple cell signaling pathways. Activation of PPARγ combined with inhibition of EP2 and EP4 may emerge as novel nonsteroidal therapeutic targets for endometriosis-associated pain and infertility, if clinically proven safe and efficacious.

scholarly journals Estrogen Receptors and Endometriosis

2020 ◽  
Vol 21 (8) ◽  
pp. 2815 ◽  
Author(s):  
Elodie Chantalat ◽  
Marie-Cécile Valera ◽  
Charlotte Vaysse ◽  
Emmanuelle Noirrit ◽  
Mariam Rusidze ◽  
...  
Keyword(s):  
Estrogen Receptors ◽  
Stromal Cells ◽  
Large Body ◽  
Treatment Strategies ◽  
Chronic Inflammatory Disease ◽  
Cellular Mechanisms ◽  
Endometrial Stromal Cells ◽  
Protein Levels ◽  
Estrogen Production

Endometriosis is a frequent and chronic inflammatory disease with impacts on reproduction, health and quality of life. This disorder is highly estrogen-dependent and the purpose of hormonal treatments is to decrease the endogenous ovarian production of estrogens. High estrogen production is a consistently observed endocrine feature of endometriosis. mRNA and protein levels of estrogen receptors (ER) are different between a normal healthy endometrium and ectopic/eutopic endometrial lesions: endometriotic stromal cells express extraordinarily higher ERβ and significantly lower ERα levels compared with endometrial stromal cells. Aberrant epigenetic regulation such as DNA methylation in endometriotic cells is associated with the pathogenesis and development of endometriosis. Although there is a large body of data regarding ERs in endometriosis, our understanding of the roles of ERα and ERβ in the pathogenesis of endometriosis remains incomplete. The goal of this review is to provide an overview of the links between endometriosis, ERs and the recent advances of treatment strategies based on ERs modulation. We will also attempt to summarize the current understanding of the molecular and cellular mechanisms of action of ERs and how this could pave the way to new therapeutic strategies.

scholarly journals Dehydroepiandrosterone Inhibits Glucose Flux Through the Pentose Phosphate Pathway in Human and Mouse Endometrial Stromal Cells, Preventing Decidualization and Implantation

2011 ◽  
Vol 25 (8) ◽  
pp. 1444-1455 ◽  
Author(s):  
Antonina I. Frolova ◽  
Kathleen O'Neill ◽  
Kelle H. Moley
Keyword(s):  
Stromal Cells ◽  
Pentose Phosphate Pathway ◽  
Glucose Transporter ◽  
Polycystic Ovary ◽  
Pentose Phosphate ◽  
Reproductive Age ◽  
Endometrial Stromal Cells ◽  
Glucose Transporter 1 ◽  
Decidual Cells

Endometrial stromal cells (ESC) must undergo a hormone-driven differentiation to form decidual cells as a requirement of proper embryo implantation. Recent studies from our laboratory have demonstrated that decidualizing cells require glucose transporter 1 expression and an increase in glucose use to complete this step. The present study focuses on the glucose-dependent molecular and metabolic pathways, which are required by ESC for decidualization. Inhibition of glycolysis had no effect on decidualization. However, blockade of the pentose phosphate pathway (PPP) with pharmacologic inhibitors 6-aminonicotinamide or dehydroepiandrosterone (DHEA), and short hairpin RNA-mediated knockdown of glucose-6-phosphate dehydrogenase, the rate-limiting step in the PPP, both led to strong decreases in decidual marker expression in vitro and decreased decidualization in vivo. Additionally, the studies demonstrate that inhibition is due, at least in part, to ribose-5-phosphate depletion, because exogenous nucleoside administration restored decidualization in these cells. The finding that PPP inhibition prevents decidualization of ESC is novel and clinically important, because DHEA is an endogenous hormone produced by the adrenal glands and elevated in a high proportion of women who have polycystic ovary syndrome, the most common endocrinopathy in reproductive age women. Together, this data suggest a mechanistic link between increased DHEA levels, use of glucose via the PPP, and pregnancy loss.

Effectiveness of NLRP3 Inhibitor as a Non-Hormonal Treatment for Ovarian Endometriosis

2021 ◽  
Author(s):  
Mayuko Murakami ◽  
Satoko Osuka ◽  
Ayako Muraoka ◽  
Shotaro Hayashi ◽  
Bayasula Bayasula ◽  
...  
Keyword(s):  
Murine Model ◽  
Stromal Cells ◽  
Ovarian Function ◽  
Interleukin 1 ◽  
Hormonal Treatment ◽  
Reproductive Age ◽  
Ovarian Endometriosis ◽  
Endometrial Stromal Cells ◽  
Nlrp3 Gene ◽  
Gene And Protein Expression

Abstract Background Endometriosis is a complex syndrome characterized by an estrogen-dependent chronic inflammatory process that affects 10% of women of reproductive age. Ovarian endometriosis (OE) is the most common lesion in endometriosis and may cause infertility in addition to dysmenorrhea. Hormonal treatments for endometriosis suppress ovulation; hence, they are not compatible with fertility. The inflammasome is a complex that includes Nod-like receptor (NLR) family proteins that sense pathogen-/danger‐associated molecular patterns and homeostasis-altering molecular processes. It has been reported that the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing (NLRP) 3 inflammasome, which contributes to the activation of interleukin-1 beta (IL-1β), might be related to the progression of endometriosis. Therefore, the aim of the present study was to evaluate non-hormonal therapies for OE, such as the inhibitors of the NLRP3 inflammasome. Methods The expression of NLRP3 was measured in the eutopic endometrium (EM) of patients with/without endometriosis and OE and stromal cells derived from the endometrium of patients with endometriosis and OE (endometrial stromal cells [ESCs] and cyst-derived stromal cells [CSCs]). The effect of an NLRP3 inhibitor (MCC950) on ESC and CSC survival and IL-1β production was evaluated. We then administered MCC950 to a murine model of OE to evaluate its effects on OE lesions and ovarian function. Results NLRP3 gene and protein expression levels were higher in OE and CSCs than in EM and ESCs, respectively. MCC950 treatment significantly reduced the survival of CSCs but not that of ESCs. Moreover, MCC950 treatment reduced the co-localization of NLRP3 and IL-1β in CSCs and IL-1β concentrations in CSC supernatants. In the murine model, MCC950 treatment reduced OE lesion size compared to phosphate-buffered saline treatment (89 ± 15 vs. 49 ± 9.3 mm3 per ovary; P < 0.05). In addition, IL-1β and Ki67 levels in the OE-associated epithelia and oxidative stress markers of granulosa cells were reduced in the MCC950-treated group. Conclusions These results indicate that NLRP3/IL-1β is involved in the pathogenesis of endometriosis and that NLRP3 inhibitors may be useful for suppressing OE and improving the function of ovaries with endometriosis.

scholarly journals Gene Expression Profile of Human Mesenchymal Stromal Cells Exposed to Hypoxic and Pseudohypoxic Preconditioning—An Analysis by RNA Sequencing

2021 ◽  
Vol 22 (15) ◽  
pp. 8160
Author(s):  
Katarzyna Zielniok ◽  
Anna Burdzinska ◽  
Victor Murcia Pienkowski ◽  
Agnieszka Koppolu ◽  
Malgorzata Rydzanicz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Sequencing ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Therapeutic Potential ◽  
Phospholipid Metabolism ◽  
Functional Enrichment ◽  
Valuable Insight ◽  
Illumina Platform ◽  
Insight Into

Mesenchymal stromal cell (MSC) therapy is making its way into clinical practice, accompanied by research into strategies improving their therapeutic potential. Preconditioning MSCs with hypoxia-inducible factors-α (HIFα) stabilizers is an alternative to hypoxic priming, but there remains insufficient data evaluating its transcriptomic effect. Herein, we determined the gene expression profile of 6 human bone marrow-derived MSCs preconditioned for 6 h in 2% O2 (hypoxia) or with 40 μM Vadadustat, compared to control cells and each other. RNA-Sequencing was performed using the Illumina platform, quality control with FastQC and adapter-trimming with BBDUK2. Transcripts were mapped to the Homo_sapiens. GRCh37 genome and converted to relative expression using Salmon. Differentially expressed genes (DEGs) were generated using DESeq2 while functional enrichment was performed in GSEA and g:Profiler. Comparison of hypoxia versus control resulted in 250 DEGs, Vadadustat versus control 1071, and Vadadustat versus hypoxia 1770. The terms enriched in both phenotypes referred mainly to metabolism, in Vadadustat additionally to vesicular transport, chromatin modifications and interaction with extracellular matrix. Compared with hypoxia, Vadadustat upregulated autophagic, phospholipid metabolism, and TLR cascade genes, downregulated those of cytoskeleton and GG-NER pathway and regulated 74 secretory factor genes. Our results provide valuable insight into the transcriptomic effects of these two methods of MSCs preconditioning.

scholarly journals Molecular Predictors of Effective Implantation and Live Birth in IVF Programs

2021 ◽  
Vol 11 (4) ◽  
pp. 532-537
Author(s):  
Elena Chukhnina ◽  
Evgeny Kazachkov ◽  
Ekaterina Voropaeva ◽  
Ella Kazachkova ◽  
Miroslava Polina ◽  
...  
Keyword(s):  
Live Birth ◽  
Stromal Cells ◽  
Reproductive Age ◽  
Prognostic Models ◽  
Immunohistochemical Method ◽  
Morphological Examination ◽  
Endometrial Stromal Cells ◽  
Art Programs ◽  
Vitamin D Receptors ◽  
Blastocyst Implantation

The aim of the study was to improve the possibilities of predicting blastocyst implantation and live birth of ART programs in women of late reproductive age with tubal-peritoneal infertility based on immunohistochemical markers of the endometrium. Methods and Results: The results of IVF and IVF/ICSI programs were analyzed in 68 patients of late reproductive age (36-44 years of age) with tubal-peritoneal factor of infertility. Morphological examination of the endometrium was performed on Day 7 after confirmed ovulation in the cycle preceding ART. The expression of vitamin D receptors (VDR) and HOXA11 in endometrial stromal cells was assessed by immunohistochemical method. The effectiveness of using the endometrial markers VDR and HOXA11 as potential predictors of ART programs efficiency was confirmed by prognostic models. The levels of the stromal expression of VDR<8.7% and HOXA11<6.1% (probability >0.27) were determined to be favorable for successful blastocyst implantation. The expression levels of VDR<8.3% and HOXA11<6.1% in endometrial stromal cells are prognostically favorable for live birth (probability >0.19) in women of late reproductive age with tubal-peritoneal infertility who undergoing ART treatment with their own oocytes.

scholarly journals Controlling Semi-Invasive Activity of Human Endometrial Stromal Cells by Inhibiting NF-kB Signaling Pathway Using Aloe-emodin and Aspirin

2021 ◽  
Author(s):  
Nahid Nasiri ◽  
Sara Babaei ◽  
Ashraf Moini ◽  
Poopak Eftekhari-Yazdi
Keyword(s):  
Stromal Cells ◽  
Single Cells ◽  
Stage Iv ◽  
Underlying Mechanism ◽  
Lesion Size ◽  
Protein Markers ◽  
Endometrial Stromal Cells ◽  
Migratory Activity ◽  
Endometrial Cells ◽  
Aloe Emodin

Background: Inflammation and its master regulator, Nuclear Factor-kB (NF-kB), have been implicated in the development of endometriosis. Inhibition of NF-kB pathway using small molecules ameliorated disease progression and reduced the lesion size; nevertheless, the underlying mechanism is not fully understood. Therefore, this study, is an attempt to assess whether inhibiting NF-kB signaling by aloe-emodin (AE) or aspirin (Asp), as anti-inflammatory compounds, can suppresses the invasive activity of human endometrial stromal cells at stage IV endometriosis. Methods: The eutopic and healthy endometrial biopsies from a total of 8 infertile women with confirmed endometriosis and 8 women without endometriosis were digested and the single cells were cultured. Gene and protein markers of proliferation, migration, adhesion, and invasion of eutopic endometrial stromal cells (EuESCs) with and without treatment with AE or Asp, as well as control endometrial stromal cells (CESCs) was analyzed using q-PCR and immunofluorescence staining, respectively. Comparison between groups was performed using one-way ANOVA and the Bonferroni post hoc and p≤0.5 was considered statistically significant. Results: There was an association between NF-kB overexpression and higher proliferation/adhesion capacity in EuESCs. EuESCs (at stage IV endometriosis) displayed no invasive and migratory behaviors. Pre-treatment of EuESCs with AE or Asp significantly attenuated NF-kB expression and reduced proliferative, adhesive, invasive, and migratory activity of endometrial cells (p≤0.5). Conclusion: Eutopic endometrial stromal cells seem to have a semi-invasive activity which is largely suppressed by AE or Asp. It can be suggested that both Asp and AE (as potent NF-kB inhibitors) can be used as a supplement in conventional endometriosis treatments.

Pyrvinium pamoate inhibits proliferation and invasion of human endometriotic stromal cells

2019 ◽  
Vol 39 (5) ◽  
pp. 662-672
Author(s):  
A Karamian ◽  
H Nazarian ◽  
SA Ziai ◽  
A-H Zarnani ◽  
S Salehpour ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Cultured Cells ◽  
Therapeutic Potential ◽  
Migration And Invasion ◽  
Endometrial Stromal Cells ◽  
Anticancer Effects ◽  
And Control ◽  
Proliferation And Invasion ◽  
Pyrvinium Pamoate

Endometriosis is characterized by the presence of functional endometrial tissue in other pelvic organs. This gynecologic problem occurs in 35–50% of women with pain and infertility. Endometriotic cells share some characteristics such as proliferation, migration, and invasion with tumor cells. Pyrvinium pamoate, an anthelmintic drug approved by the Food and Drug Administration, could inhibit the Wnt/β-catenin signaling pathway and its anticancer effects were examined by several researchers. In this study, 12 ectopic and eutopic endometrial biopsies from females with ovarian endometrioma and 12 endometrial biopsies from nonendometriotic females were obtained. Ectopic (EESCs), eutopic (EuESCs), and control (CESCs) endometrial stromal cells were isolated. Then, the effect of pyrvinium pamoate on the proliferation and invasiveness of in vitro cultured cells was evaluated. The proliferation of CESCs, EuESCs, and EESCs was significantly decreased after treatment with pyrvinium pamoate. In addition, treatment with pyrvinium pamoate significantly inhibited the invasiveness of CESCs, EuESCs, and EESCs compared to nontreated groups. The results of the present research showed that pyrvinium pamoate inhibits the proliferation and invasion of human endometriotic stromal cells in vitro, further investigations on the therapeutic potential of this compound in endometriosis are required.

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