Low STING expression promotes endometrial stromal cell invasion and migration via the STING/IRF-3/IFN-ß1 pathway in eutopic endometrium of women with endometriosis.

Aims: The primary aim of the current study was to elucidate the function of the stimulator of interferon genes (STING) in the eutopic endometrium of women with endometriosis. Materials and Methods: STING expression and signaling pathways were verified by western blot analysis and immunohistochemistry after si-STING treatment. Cell proliferation and invasion and migration were assessed using 5-ethynyl-2'-deoxyuridine and transwell assays, respectively. Results: Within endometriosis tissues, STING was primarily expressed in the stroma of the eutopic endometrium and glandular epithelium of the ectopic endometrium. However, STING expression was significantly lower in the eutopic endometrium of patients with endometriosis compared to controls (p < 0.05). Additionally, cell proliferation (0.2866 ± 0.01470 vs. 0.6911 ± 0.01796, ****p < 0.0001), invasion (130.0 ± 6.296 vs. 424.1 ± 22.31, ****p < 0.0001), and migration (82.93 ± 6.940 vs. 82.93 ± 6.940, ****p < 0.0001) were significantly increased in the si-STING groups. Moreover, following si-STING transfection, the expression of phosphorylated IRF-3 and TBK1 that are involved in STING/IRF3/IFNb1 signaling pathway decreased. The addition of exogenous IFN-ß1 effectively increased stromal cell invasion (IFN-ß1-NC vs. IFN-ß1-si-STING 274.7 ± 7.767 vs. 135.7 ± 12.63, ***p < 0.0001) and migration (IFN-ß1-NC and IFN-ß1-si-STING 28.53 ± 3.625 vs. 28.53 ± 3.625, ***p < 0.0001) without significantly impacting cell proliferation (si-STING vs. IFN-1ß-si-STING 0.6874 ± 0.02081 vs. 0.7187 ± 0.02638, p = 0.795). Conclusions: The STING signaling pathway plays an important role in endometrial stromal cell proliferation, invasion and migration associated with endometriosis.

NeiyiKangfu tablets control the progression of endometriosis through inhibiting RAF/MEK/ERK signal pathway by targeting RKIP.

BACKGROUND: NeiyiKangfu tablets (NYKF) are widely used clinically for the treatment of endometriosis (EMS), whose mechanism of action has been extensively studied. Researchers have found that NYKF may control the development of ectopic lesions by inhibiting angiogenesis and inflammatory cytokine secretion. Nevertheless, NYKF's mechanism of action remains unclear. METHODS: In the present study, the function of NYKF in the progression of EMS and the associated underlying mechanism was investigated by in vivo and in vitro experiments. EMS model mice were treated with NYKF and the pro-inflammatory factors and apoptosis of ectopic endometrium as well as RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling activation were assessed. In addition, human endometriosis-derived immortalized entopic stromal (hEM15A) cells transfected with or without RAF kinase inhibitor protein (RKIP)-small-interfering RNA (siRNA) were also treated with NYKF and the proliferation, migration, apoptosis, and RAF/MEK/ERK signaling activation were measured by Cell Counting Kit-8 (CCK-8), flow cytometry, Transwell, and western blot, respectively. RESULTS: Results showed that NYKF increased the expression of RKIP, inhibited RAF/MEK/ERK signaling activation, and induced apoptosis while inhibiting proliferation and migration both in EMS mice and hEM15A cells. RKIP knockdown could inhibit the effect of NYKF treatment, leading to the activation of RAF/MEK/ERK signaling and the proliferation and migration of hEM15A cells. CONCLUSIONS: In conclusion, these results suggest that NYKF treatment promotes apoptosis and inhibits proliferation and migration in EMS by inhibiting the RAF/MEK/ERK signaling pathway by targeting RKIP.

The role of cytokeratin 19 levels in the determination of endometriosis stages.

OBJECTIVE/AIM: Endometrisosis, one of the most common gynecological disease, is characterized by the presence of endometriotic tissue outside of uterine cavity. The development and the validation of a simple blood biomarker specific and sensitive for endometriosis may facilitate the rapid and the accurate diagnosis of the disease and thus early treatment. Cytokeratin expression changes during epithelial differentiation and this expression is important for the modulation and the control of cell cycle regulation, tumor cell motility and apoptosis. Cytokeratin 19 (CK-19) is expressed in most simple epithelial cells and their malignant counterparts. The aim of this study is to investigate serum CK-19 expression levels in patients with endometriosis and to determine the diagnostic role of CK-19 levels in differentiating various stage of endometriosis. METHODS: Ctytokeratin-19 expression and level were studied in 70 endometriosis patients and 50 volunteers by ELISA and RT-PCR. ROC analysis was performed by comparing all stages with each other and with the control group. RESULTS: The CK-19 levels were significantly higher in the endometriosis groups than that of the control group by ELISA and RT-PCR. A significant (p < .05) difference was observed in endometriosis patients according to the stages. CONCLUSION: Based on our data, it suggests that Cytokeratin-19 may have a potential role in the development of endometriosis.

State of the art, new treatment strategies, and emerging drugs for non-hormonal treatment of endometriosis: a systematic review of randomized control trials.

Objective: The aim of this systematic review is to recap the data obtained from randomized controlled trials looking at new pharmacologic treatments for endometriosis published over the last decade with a focus on non-hormonal therapeutic options alleviating endometriosis-associated pelvic pain.Methods: We identified relevant original studies in the English language through a search of the MEDLINE, Scopus, and EMBASE (2012 to present) databases using the appropriate MeSH terms and applying the article type filter 'randomized controlled trials'. A total of 179 records were found during the electronic search. After a detailed evaluation and review of the manuscripts, seven primary articles met the inclusion criteria. A systematic review of the data was conducted.Results: This review included several, non-hormonal emerging drug therapies for endometriosis-associated pelvic pain. Based on our results, we divided well-founded studies into three subgroups: antiangiogenic agents, immunomodulators, and natural components. Randomized control trials showed promising results with dopamine agonists (cabergoline, quinagolide, and bromocriptine), and the immunomodulatory JNK inhibitor bentamapimod. Agents that have not been represented in randomized control trials or have failed to demonstrate efficacy include statins and TNF-α inhibitors.Conclusion: Although there are substantial improvements in non-hormonal therapy options, majority of the currently available treatment options are supressive rather than curative and do not present a final solution for patients. Future research priorities should be to identify novel target therapies and to evalute the effects of available drugs through different routes of administration.

Impact on ovarian reserve and fertility using carbon dioxide laser for endometriosis treatment: a systematic review.

BackgroundThe application of carbon dioxide (CO2) laser for laparoscopic gynecologic surgery was introduced in 1979 and spread after improving instrumentation, due to the versatility of the CO2 laser technology and the parallel increase of laparoscopic use. In a gynecologic setting, laser laparoscopy has been demonstrated to be effective in treating infertility and pain associated with mild to severe endometriosis.Aim and methods: This document aims at conducting a systematic review to provide a comprehensive literature overview regarding the rationale, indications, safety, and efficacy of CO2 laser treatment of endometriosis and related outcomes on ovarian reserve and fertility.ResultsCO2 laser seems to lead to lower heat damage in the ovarian tissue than bipolar energy during endometriomas treatment. Moreover, several reports have pointed out that laser vaporization allows to selectively destroy the endometrioma wall's internal surface, preserving the pericystic fibrotic capsule or the adjacent healthy ovarian cortex. Despite this, robust data we have so far indicates that the most effective laparoscopic approach for managing endometriomas is the traditional excisional technique providing better postoperative outcomes than drainage and electrocoagulation, and laser treatment. Data about fertility after treatment of deep infiltrating endometriosis (DIE) using dioxide laser are emerging but very poor.ConclusionsCurrent scientific evidence in this field is inconclusive, and the debate about the safety and efficacy of the CO2 laser on fertility outcomes is still ongoing. Further randomized case-control studies are mandatory to attain more consistent evidence.

Current status and challenges of drug development for hormonal treatment of endometriosis: a systematic review of randomized control trials.

OBJECTIVE: The aim of this systematic review is to summarize the data obtained from randomized controlled trials looking at new pharmacologic treatments for endometriosis published over the last decade with a focus on hormonal therapeutic options for endometriosis-associated pelvic pain (EAPP), excluding studies focusing on fertility. METHODS: We identified relevant original studies in the English language through a search of the MEDLINE, Scopus, and EMBASE (2012 to present) databases using the appropriate MeSH terms and applying the article type filter 'randomized controlled trials'. A total of 219 records were found during the electronic search. After a detailed evaluation and review of the manuscripts, 11 primary articles met the inclusion criteria. A systematic review of the data was conducted. RESULTS: This review included several emerging drug therapies for EAPP. Randomized control trials showed promising results with several oral gonadotropin-releasing hormone antagonists (elagolix, relugolix, ASP1707, linzagolix). However, studies of other hormonal agents such as aromatase inhibitors and selective progesterone receptor modulators have not yielded significant or new advantages. Selective estrogen receptor modulators have not been represented in randomized control trials and have failed to demonstrate clinical efficacy. CONCLUSION: Although numerous novel agents are being investigated for the treatment of endometriosis, there is still no significant progress in the development of curative rather than suppressive drugs. Therefore, further efforts are needed to develop an effective and hopefully curative treatment for this chronic, costly, and overwhelming disease.

Endometriosis has no negative impact on outcomes of in vitro fertilisation in women with poor ovarian response.

OBJECTIVE: To compare the in vitro fertilisation (IVF) outcomes of poor ovarian responders among women with laparoscopically diagnosed minimal-mild endometriosis (Group A), moderate-severe endometriosis (Group B) and those without endometriosis (Group C). The comparisons were made separately for age groups younger than 35 years and 35 years or older. DESIGN: Retrospective study. SETTING: A university-affiliated hospital in Guangzhou, China. POPULATION: 495 women younger than 35 years old and 543 women aged 35 or older who had poor ovarian response with or without laparoscopically diagnosed endometriosis. METHODS: Poor ovarian response (POR) was diagnosed using the Bologna criteria. First cycle parameters were analysed over the same period of time from January 2011 to October 2014. MAIN OUTCOME MEASURES: The primary endpoint was the live birth rate per embryo transfer cycle. Secondary outcome measures were clinical pregnancy rate, cycle cancellation rate and miscarriage rate. RESULTS: In women aged 35 or older no differences were found among the three subgroups in terms of live birth rate, clinical pregnancy rate, cycle cancellation rate or miscarriage rate; in women aged younger than 35 years, the clinical pregnancy rates were 62.96, 45.45 and 43.27% for Groups A, B and C, respectively (P = 0.028). The live birth rate, cycle cancellation rate and miscarriage rate were not significantly different. Compared with the older group of women, the younger women had a significantly higher live birth rate (P < 0.001). CONCLUSIONS: A woman's age is the most important factor governing the live birth rate with IVF. Endometriosis has no consistent impact on IVF outcomes in women with POR. TWEETABLE ABSTRACT: Endometriosis has no negative impact on IVF outcomes in women with poor ovarian response.

Label-free based quantitative proteomics analysis to explore the molecular mechanism of gynecological cold coagulation and blood stasis syndrome.

Cold coagulation and blood stasis (CCBS) syndrome is one of the common traditional Chinese medicine (TCM) syndromes of gynecological diseases. However, the molecular mechanism of CCBS syndrome is still unclear. Thus, there is a need to reveal the occurrence and regulation mechanism of CCBS syndrome, in order to provide a theoretical basis for the treatment of CCBS syndrome in gynecological diseases. The plasma proteins in primary dysmenorrhea (PD) patients with CCBS syndrome, endometriosis (EMS) patients with CCBS syndrome, and healthy women were screened using Label-free quantitative proteomics. Based on the TCM theory of "same TCM syndrome in different diseases," the differentially expressed proteins (DEPs) identified in each group were subjected to intersection mapping to obtain common DEPs in CCBS syndrome. The DEPs of gynecological CCBS syndrome in the intersection part were again cross-mapped with the DEPs of gynecological CCBS syndrome obtained by the research group according to the TCM theory of "different TCM syndromes in same disease" theory in the early stage, so as to obtain the DEPs of gynecological CCBS syndrome that were shared by the two parts. The common DEPs were subjected to bioinformatics analysis, and were verified by enzyme-linked immunosorbent assay (ELISA). A total of 67 common DEPs were identified in CCBS syndrome, of which 33 DEPs were upregulated and 34 DEPs were downregulated. The functional classification of DEPs involved in metabolic process, energy production and conversion, immune system process, antioxidant activity, response to stimulus, and biological adhesion. The subcellular location mainly located in the cytoplasm, nucleus, and extracellular. Gene ontology (GO) enrichment analysis showed that the upregulated DEPs mainly concentrated in lipid transport, cell migration, and inflammatory reaction, and the downregulated DEPs mostly related to cell junction, metabolism, and energy response. Protein domain enrichment analysis and clustering analysis revealed that the DEPs mainly related to cell proliferation and differentiation, cell morphology, metabolism, and immunity. The Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis clustering analysis showed that the upregulated DEPs were involved in inflammation and oxidative damage, while the downregulated DEPs were involved in inflammation, cell adhesion, cell apoptosis, and metabolism. The results of ELISA showed significantly increased levels of Cell surface glycoprotein MUC18 (MCAM) and Apolipoprotein C1 (APOC1), and significantly decreased levels of Vasodilator-stimulated phosphoprotein (VASP), Fatty acid-binding protein 5 (FABP5), and Vinculin (VCL) in patients with CCBS syndrome compared with healthy women. We speculated that cold evil may affect the immune process, inflammatory response, metabolic process, energy production and conversion, oxidative damage, endothelial cell dysfunction, and other differential proteins expression to cause CCBS syndrome in gynecological diseases.

Intergenerational associations of adverse and positive maternal childhood experiences with young children's psychosocial well-being.

Background: Maternal adverse childhood experiences (ACEs) are believed to have negative consequences on offspring health. However, positive childhood experiences (PCEs) may be concurrent with ACEs, and little is known about how ACEs and PCEs transmit intergenerationally in the context of each other.Objective: To explore the independent effect of maternal ACEs and PCEs on offspring psychosocial well-being and how ACEs and PCEs are intergenerationally transmitted in their context.Method: Data were 2587 mother-child dyads in Anhui provinces of China. Mothers retrospectively reported their ACEs and PCEs, as well as provided demographic characteristics and their children's psychosocial well-being. Logistic regression models were performed to explore the associations of maternal ACEs and PCEs with offspring psychosocial well-being.Results: Separate unadjusted logistic regression models showed that children with mothers reported high ACEs scores were more likely to have psychosocial challenges (total difficulties and prosocial problems), while children whose mothers reported high PCEs scores were less likely to have psychosocial challenges. When we added maternal ACEs and PCEs to a same model, we found that PCEs slightly neutralised the negative effects of ACEs on offspring's total difficulties and prosocial problems. When stratified by sample, mothers with high PCE scores and higher maternal ACEs were related with a higher risk of offspring total difficulties; mothers with low levels of ACEs and high PCEs tend to report a lower risk of offspring total difficulties.Conclusions: Results suggest that PCEs are positively and intergenerationally transmitted. Results suggest that PCEs are positively and intergenerationally transmitted. More programme should be provided to increase maternal PCEs. When preventing the intergenerational transmission of ACEs, specific interventions should be provided to mothers with different levels of PCEs.

Positive childhood experiences positively transmit intergenerationally.Stronger relationship between maternal ACEs and risk of offspring total difficulties was observed among mothers with above-average positive childhood experiences scores.A stronger relationship between maternal PCEs and fewer offspring total difficulties was observed among mothers with low adverse maternal childhood experiences scores.