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.

SCM-198 protects endometrial stromal cells from oxidative damage through Bax/Bcl-2 and ERK signaling pathways

2019 ◽  
Vol 51 (6) ◽  
pp. 580-587 ◽  
Author(s):  
Yunyun Li ◽  
Yikong Lin ◽  
Xixi Huang ◽  
Chunfang Xu ◽  
Xinhua Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stromal Cells ◽  
Caspase 3 ◽  
Oxidative Injury ◽  
Pathological Process ◽  
Ros Generation ◽  
Endometrial Stromal Cells ◽  
Chain Reactions ◽  
Induced Apoptosis ◽  
Inflammation Cytokines

Abstract Increasing amounts of evidence demonstrated that accumulative reactive oxygen species (ROS) and apoptosis of human endometrial stromal cells (ESCs) are closely associated with endometrial dysfunction induced by oxidative stress, which plays an important role in the pathological process of multiple gynecological and reproduction-related diseases. SCM-198, an alkaloid active component of Leonurus japonicas Houtt, has been reported to have anti-oxidative activity. However, the specific mechanisms of SCM-198 in the prevention of endometrial damage remain unknown. In the present study, we assessed the effect of SCM-198 on hydrogen peroxide (H2O2)-induced oxidative injury in ESCs. ESCs were pretreated with SCM-198 for 4 h and then challenged with H2O2. Morphology changes, apoptosis rate, and intracellular ROS production were measured to assess the level of oxidative injury. Flow cytometry and western blot analysis were performed to detect the expression levels of Bax, Bcl-2, active-caspase-3, and mitogen-activated protein kinases pathways. Classic inflammation cytokines were measured by real-time polymerase chain reactions. Our results showed that SCM-198 attenuated apoptosis and ROS generation of ESCs induced by H2O2. H2O2 induced the apparent apoptotic characteristics, including fragmentation of DNA, upregulation of Bax/Bcl2, activation of caspase-3, and secretion of inflammation cytokines, which were all ameliorated by SCM-198. Furthermore, H2O2-induced apoptosis-related ERK1/2 pathway activation was restrained by SCM-198 pretreatment. These findings suggested that SCM-198 could protect ESCs from oxidative injury, mainly by inhibiting oxidative stress and reducing apoptosis.

Heparin prevents oxidative stress-induced apoptosis in human decidualized endometrial stromal cells

2019 ◽  
Vol 52 (4) ◽  
pp. 209-216
Author(s):  
Shunsuke Tamaru ◽  
Takeshi Kajihara ◽  
Yumi Mizuno ◽  
Natsuko Takano ◽  
Hideno Tochigi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stromal Cells ◽  
Endometrial Stromal Cells ◽  
Induced Apoptosis

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 Hypoxia-inducible factor-1α promotes endometrial stromal cells migration and invasion by upregulating autophagy in endometriosis

Reproduction ◽  
2017 ◽  
Vol 153 (6) ◽  
pp. 809-820 ◽  
Author(s):  
Hengwei Liu ◽  
Zhibing Zhang ◽  
Wenqian Xiong ◽  
Ling Zhang ◽  
Yao Xiong ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Hypoxia Inducible Factor ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Ovarian Endometriosis ◽  
Endometrial Stromal Cells ◽  
Hypoxia Inducible Factor 1Α ◽  
Gynecological Disease ◽  
Benign Gynecological Disease ◽  
Ectopic Endometrium

Endometriosis is a benign gynecological disease that shares some characteristics with malignancy like migration and invasion. It has been reported that both hypoxia-inducible factor-1α (HIF-1α) and autophagy were upregulated in ectopic endometrium of patients with ovarian endometriosis. However, the crosstalk between HIF-1α and autophagy in the pathogenesis of endometriosis remains to be clarified. Accordingly, we investigated whether autophagy was regulated by HIF-1α, as well as whether the effect of HIF-1α on cell migration and invasion is mediated through autophagy upregulation. Here, we found that ectopic endometrium from patients with endometriosis highly expressed HIF-1α and autophagy-related protein LC3. In cultured human endometrial stromal cells (HESCs), autophagy was induced by hypoxia in a time-dependent manner and autophagy activation was dependent on HIF-1α. In addition, migration and invasion ability of HESCs were enhanced by hypoxia treatment, whereas knockdown of HIF-1α attenuated this effect. Furthermore, inhibiting autophagy with specific inhibitors and Beclin1 siRNA attenuated hypoxia triggered migration and invasion of HESCs. Taken together, these results suggest that HIF-1α promotes HESCs invasion and metastasis by upregulating autophagy. Thus, autophagy may be involved in the pathogenesis of endometriosis and inhibition of autophagy might be a novel therapeutic approach to the treatment of endometriosis.

scholarly journals Reduced connexin 43 in eutopic endometrium and cultured endometrial stromal cells from subjects with endometriosis

2013 ◽  
Vol 20 (3) ◽  
pp. 260-270 ◽  
Author(s):  
Jie Yu ◽  
Anisoara Boicea ◽  
Kara L. Barrett ◽  
Christopher O. James ◽  
Indrani C. Bagchi ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Connexin 43 ◽  
Endometrial Stromal Cells ◽  
Eutopic Endometrium

scholarly journals A cellular and molecular portrait of endometriosis subtypes

2021 ◽  
Author(s):  
Marcos A. S. Fonseca ◽  
Kelly N. Wright ◽  
Xianzhi Lin ◽  
Forough Abbasi ◽  
Marcela Haro ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Stromal Cells ◽  
Disease Process ◽  
Angiogenic Factor ◽  
Deep Infiltrating Endometriosis ◽  
Cell Compartment ◽  
Ovarian Endometriosis ◽  
Eutopic Endometrium ◽  
Benign Condition ◽  
Transcriptional Reprogramming

Endometriosis is a common, benign condition characterized by extensive heterogeneity in lesion appearance and patient symptoms. We profiled transcriptomes of 207,949 individual cells from endometriomata (n=7), extra-ovarian endometriosis (n=19), eutopic endometrium (n=4), unaffected ovary (n=1) and endometriosis-free peritoneum (n=4) to create a cellular atlas of endometrial-type epithelial cells, endometrial-type stromal cells and microenvironmental cell populations across tissue sites. Signatures of endometrial-type epithelium and stroma differed markedly across eutopic endometrium, endometrioma, superficial extra-ovarian disease and deep infiltrating endometriosis, suggesting that extensive transcriptional reprogramming is a core component of the disease process. Endometriomas were notable for the dysregulation of pro-inflammatory pathways and upregulation of complement proteins C3 and C7. Somatic ARID1A mutation in epithelial cells was associated with upregulation of pro-angiogenic factor SOX17 and remodeling of the endothelial cell compartment. Finally, signatures of endometriosis-associated endometrial-type epithelial clusters were enriched in ovarian cancers, reinforcing the epidemiologic associations between these two diseases.

scholarly journals FKBP4 is regulated by HOXA10 during decidualization and in endometriosis

Reproduction ◽  
2012 ◽  
Vol 143 (4) ◽  
pp. 531-538 ◽  
Author(s):  
Huan Yang ◽  
Yuping Zhou ◽  
Benjiamin Edelshain ◽  
Frederick Schatz ◽  
Charles J Lockwood ◽  
...  
Keyword(s):  
Menstrual Cycle ◽  
Stromal Cells ◽  
Secretory Phase ◽  
Endometrial Stromal Cells ◽  
Eutopic Endometrium ◽  
Protein Levels ◽  
Proliferative Phase ◽  
Progestin Receptor ◽  
Fertile Women

FKBP4 (FKBP52) and FKBP5 (FKBP51) are progestin receptor (PR) co-chaperone proteins that enhance and inhibit, respectively, progestin-mediated transcription by PR. Here, we examinedFKBP4andFKBP5expression in the eutopic endometrium of fertile women with endometriosis and effects of FKBP4 and FKBP5 on the decidualization of human endometrial stromal cells (HESCs), and assessed HOXA10 regulation of FKBP4. Expression ofFKBP4mRNA was increased in the late proliferative phase and remained elevated throughout the secretory phase.FKBP5expression was low and remained constant throughout the menstrual cycle. Compared with controls,FKBP4mRNA expression was decreased in the endometrium of women with endometriosis, whereas no significant endometriosis-related change was seen forFKBP5. Cultured HESCs were treated with eitherFKBP4orFKBP5siRNA and then decidualized by incubation with progesterone (P4) and 8-bromoadenosine cAMP. Treatment of HESCs withFKBP4siRNA resulted in 60% lowerIGFBP1expression. In contrast, incubation withFKBP5siRNA did not significantly decreaseIGFBP1expression duringin vitrodecidualization.HOXA10andFKBP4expression increased in parallel duringin vitrodecidualization. In HESCs, overexpressed HOXA10 enhanced FKBP4 mRNA and protein levels, whereas HOXA10 knockdown decreased FKBP4 mRNA and protein levels compared with controls. Similarly, duringin vitrodecidualization,FKBP4expression was decreased in HOXA10-silenced cells. EnhancedHOXA10expression in HESCs elicits a decidualization mediating increase inFKBP4expression. The findings are consistent with the observation that women with endometriosis have diminishedFKBP4expression leading to impaired decidualization and infertility. The P4resistance seen in endometriosis may be mediated through HOXA10-regulatedFKBP4expression.

scholarly journals Evaluation of apoptosis and angiogenesis in ectopic and eutopic stromal cells of patients with endometriosis compared to non-endometriotic controls

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Ali-Akbar Delbandi ◽  
Mahmoud Mahmoudi ◽  
Adel Shervin ◽  
Sahel Heidari ◽  
Roya Kolahdouz-Mohammadi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Stromal Cells ◽  
Caspase 3 ◽  
Cultured Cells ◽  
Enzymatic Digestion ◽  
Immunofluorescent Staining ◽  
Endometrial Stromal Cells ◽  
Expression Of Genes ◽  
Uterine Growth

Abstract Background Endometriosis is a chronic, painful, and inflammatory disease characterized by extra-uterine growth of endometrial tissues. Increased angiogenesis and resistance to apoptosis have been suggested to be involved in pathogenesis and development of endometriosis. The objective of this study was to examine apoptosis potential and angiogenesis contribution of eutopic (EuESCs) and ectopic (EESCs) endometrial stromal cells in patients with endometriosis compared to endometrial stromal cells from non-endometriotic controls (CESCs). Methods Stromal cells were isolated by enzymatic digestion of ectopic (n = 11) and eutopic (n = 17) endometrial tissues from laparoscopically-confirmed endometriotic patients. Endometrial stromal cells of 15 non-endometriotic patients served as control. Following cell characterization by immunofluorescent staining and flow cytometry using a panel of antibodies, the total RNA was isolated from the cultured cells, and analyzed for the expression of genes involved in apoptosis (Bcl-2, Bcl-xL, Bax, and caspase-3) and angiogenesis [vascular endothelial growth factor-A (VEGF-A) and hepatocyte growth factor (HGF)] by Real-time PCR. Results Significantly higher gene expression levels of Bcl-2 and Bcl-xL were found in EESCs compared with EuESCs and CESCs (p < 0.01). The gene expression of Bax in EESCs, EuESCs, and CESCs was not statistically significant. Furthermore, EuESCs exhibited a significantly lower caspase-3 gene expression compared with CESCs (p < 0.01) or EESCs (p < 0.05). Regarding angiogenesis, VEGF-A gene expression in EESCs (p < 0.001) and EuESCs (p < 0.05) were significantly higher compared with those of CESCs. EESCs exhibited a significantly higher HGF gene expression compared with EuESCs (p < 0.05). Conclusions These findings suggest reduced propensity to apoptosis and increased angiogenesis potential of EESCs, which may be involved in pathogenesis of endometriosis.

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