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.

Synergistic regenerative effects of functionalized endometrial stromal cells with hyaluronic acid hydrogel in a murine model of uterine damage

2019 ◽  
Vol 89 ◽  
pp. 139-151 ◽  
Author(s):  
Yoon Young Kim ◽  
Kyu-Hyung Park ◽  
Yong Jin Kim ◽  
Moon Suk Kim ◽  
Hung Ching Liu ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Murine Model ◽  
Stromal Cells ◽  
Endometrial Stromal Cells ◽  
Hyaluronic Acid Hydrogel

scholarly journals N-Acyl Dopamines Induce Apoptosis in Endometrial Stromal Cells from Patients with Endometriosis

2021 ◽  
Vol 22 (19) ◽  
pp. 10648
Author(s):  
Alina M. Gamisonia ◽  
Marina N. Yushina ◽  
Irina A. Fedorova-Gogolina ◽  
Mikhail G. Akimov ◽  
Chupalav M. Eldarov ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Caspase 3 ◽  
Endocannabinoid System ◽  
Serine Palmitoyltransferase ◽  
Intrinsic Pathway ◽  
Ovarian Endometriosis ◽  
Endometrial Stromal Cells ◽  
Eutopic Endometrium ◽  
Inhibitory Analysis ◽  
Induced Apoptosis

Endometriosis is characterized by the formation and development of endometrial tissues outside the uterus, based on an imbalance between proliferation and cell death, leading to the uncontrolled growth of ectopic foci. The potential target for the regulation of these processes is the endocannabinoid system, which was found to be involved in the migration, proliferation, and survival of tumor cells. In this paper, we investigated the effect of endocannabinoid-like compounds from the N-acyl dopamine (NADA) family on the viability of stromal cells from ectopic and eutopic endometrium of patients with ovarian endometriosis. N-arachidonoyldopamine, N-docosahexaenoyldopamine, and N-oleoyldopamine have been shown to have a five-times-more-selective cytotoxic effect on endometrioid stromal cells. To study the mechanisms of the toxic effect, inhibitory analysis, measurements of caspase-3/9 activity, reactive oxygen species, and the mitochondrial membrane potential were performed. It was found that NADA induced apoptosis via an intrinsic pathway through the CB1 receptor and downstream serine palmitoyltransferase, NO synthase activation, increased ROS production, and mitochondrial dysfunction. The higher selectivity of NADA for endometriotic stromal cells and the current lack of effective drug treatment can be considered positive factors for further research of these compounds as possible therapeutic agents against endometriosis.

Interleukin 1 beta is induced by interleukin 11 during decidualization of human endometrial stromal cells, but is not released in a bioactive form

2007 ◽  
Vol 73 (1) ◽  
pp. 28-38 ◽  
Author(s):  
Christine A. White ◽  
Evdokia Dimitriadis ◽  
Andrew M. Sharkey ◽  
Chelsea J. Stoikos ◽  
Lois A. Salamonsen
Keyword(s):  
Stromal Cells ◽  
Interleukin 1 ◽  
Interleukin 1 Beta ◽  
Endometrial Stromal Cells ◽  
Interleukin 11

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 Analysis of Transcriptomic Changes in Bovine Endometrial Stromal Cells Treated With Lipopolysaccharide

2020 ◽  
Vol 7 ◽  
Author(s):  
Xuefen Ding ◽  
Haimiao Lv ◽  
Lixin Deng ◽  
Wenju Hu ◽  
Zhan Peng ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Stromal Cells ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Interleukin 1 ◽  
Interleukin 12 ◽  
Receptor Interaction ◽  
Control Group ◽  
Toll Like Receptor ◽  
Endometrial Stromal Cells

Endometritis adversely affects the ability of cattle to reproduce and significantly reduces milk production. The is mainly composed of epithelial and stromal cells, and they produce the first immune response to invading pathogens. However, most of the epithelial cells are disrupted, and stromal cells are exposed to an inflammatory environment when endometritis occurs, especially postpartum. Many bacteria and toxins start attacking stromal cell due to loss of epithelium, which stimulates Toll-like receptor (TLRs) on stromal cells and causes upregulated expression of cytokines. Understanding the genome-wide characterization of bovine endometritis will be beneficial for prevention and treatment of endometritis. In this study, whole-transcriptomic gene changes in bovine endometrial stromal cells (BESCs) treated with LPS were compared with those treated with PBS (control group) and were analyzed by RNA sequencing. Compared with the control group, a total of 366 differentially expressed genes (DEGs) were identified in the LPS-induced group (234 upregulated and 132 downregulated genes), with an adjusted P &lt; 0.05 by DESeq. Gene Ontology (GO) enrichment analysis revealed that DEGs were most enriched in interleukin-1 receptor binding, regulation of cell activation, and lymphocyte-activated interleukin-12 production. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed DEGs were most enriched in the TNF signaling pathway, Toll-like receptor signaling pathway, cytokine–cytokine receptor interaction, NF-κB signaling pathway, and chemokine signaling pathway. The results of this study unraveled BESCs affected with LPS transcriptome profile alterations, which may have a significant effect on treatment inflammation by comprehending molecular mechanisms and authenticating unique genes related to endometritis.

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