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Activated peritoneal macrophages are associated with endometriosis and may play a central role in its aetiology by releasing interleukin-1beta (IL-1beta) in response to refluxed endometrium. Pari passu with the establishment of endometriotic implants is the development of a vascular supply. In this study we investigated the angiogenic properties of...
Context in source publication
Citations
... Endometriosis is a chronic benign gynecological disease that is characterized by the presence of endometriotic tissue outside the uterine cavity [1]. It is an estrogen-dependent lesions [5][6][7]. Many angiogenic growth factors have been shown to be overexpressed in endometriotic lesions and in the peritoneal fluid of women with endometriosis [8,9]. ...
Purpose
Neoangiogenesis is necessary for adhesion and invasiveness of endometriotic lesions in women affected by endometriosis. Vascular endothelial growth factor (VEGF) is one of the main components of angiogenesis and is part of the major pathway tissue factor (TF)-protease activated receptor-2 (PAR-2)-VEGF that leads to neoangiogenesis. Specificity protein 1 (SP1) is a transcriptional factor that has recently been studied for its crucial role in angiogenesis via a specific pathway. We hypothesize that by blocking angiogenetic pathways we can suppress endometriotic lesions. Gonadotrophin-releasing hormone-agonists (GnRH-a) are routinely used, especially preoperatively, in endometriosis. It would be of great interest to clarify which angiogenetic pathways are affected and, thereby, pave the way for further research into antiangiogenetic effects on endometriosis.
Methods
We used quantitative real-time polymerase chain reaction (qRT-PCR) to study mRNA expression levels of TF, PAR-2, VEGF, and SP1 in endometriotic tissues of women who underwent surgery for endometriosis and received GnRH-a (leuprolide acetate) preoperatively.
Results
VEGF, TF, and PAR-2 expression is significantly lower in patients who received treatment ( p < 0,001) compared to those who did not, whereas SP1 expression is not altered ( p = 0.779).
Conclusions
GnRH-a administration does affect some pathways of angiogenesis in endometriotic lesions, but not all of them. Therefore, supplementary treatments that affect the SP1 pathway of angiogenesis should be developed to enhance the antiangiogenetic effect of GnRH-a in patients with endometriosis.
Trial registration
Clinicaltrial.gov ID: NCT06106932.
... Endometriotic lesions have the ability to create cytokines and growth factors that regulates their vascularization and proliferation [30] . It was also reported that the neovascularization of endometriotic lesions is significantly aided by the dominant Interleukin (IL)-1 released by active peritoneal macrophages, IL-1 [31] . Estradiol promotes endometrial Vascular Endothelial Cell Growth Factor (VEGF) production, and its levels are associated with neovascularization and increased vascular permeability during the late proliferative phase [32] . ...
... It is generally believed that the formation of numerous new blood vessels is related to the etiology of endometriosis [162]. This is also confirmed by the increased VEGF levels found in the peritoneal fluid of patients with endometriosis [101], but it has yet to be verified whether these high concentrations of VEGF originate from the ectopic lesions themselves [172,173] or from activated MՓs [37]. Thus, researchers speculate that the elevated level of VEGF in peritoneal fluid has notable clinical significance in the progression of the disease. ...
Endometriosis is defined as a disorder in which the glands and stroma of the endometrium grow and shed periodically outside the uterine cavity. Highly prevalent in women of reproductive age, the most common clinical manifestations are chronic pelvic pain and infertility. The pathogenesis of endometriosis may be multifactorial, including factors of anatomy, immunity, inflammation, hormones (estrogen), oxidative stress, genetics, epigenetics, and environment. There are generally three types of endometriotic disease, namely peritoneal, ovarian, and deep infiltration. For the same patient, there may be a single or multiple types concurrently. The different manifestations of these types suggests that they each have their own etiology. Numerous studies have shown that the evasion of endometrial cells from peritoneal immune surveillance helps establish and maintain peritoneal endometriosis, but the specific mechanism is not well understood. Likewise, the molecular mechanisms of endometriosis-related infertility have not been clearly elucidated. This review attempts to identify the role of peritoneal immunity in peritoneal endometriosis and related infertility, especially in the aspects of molecular mechanisms.
... Multiple studies have demonstrated the association of endometriosis occurrence with chemokine/cytokine interactions, for example, estrogen-regulated chemokine elevation promotes the migration of bone marrow-derived stem cells and mesenchymal stem cells, playing key roles in ectopic endometrium [17,18]; cytokines regulate mitosis and angiogenesis, accelerating the implantation and growth of ectopic endometrium on the peritoneal surface [19]. Meanwhile, this process triggers inflammatory cascades, inducing the secretion of angiogenic factors, tumor necrosis factors, and monocyte chemokine, which contribute to the adhesion of ectopic endometrium [20]. Activation of the PPAR pathway inhibits the expression of adhesion factors during inflammation, diminishing the adhesion of endometrioid tissue to ectopic sites [21], while reducing inflammatory secretion of endometrial basal cells [22]. ...
Objective:
The enigmatic nature of Endometriosis (EMS) pathogenesis necessitates investigating alterations in signaling pathway activity to enhance our comprehension of the disease's characteristics.
Methods:
Three published gene expression profiles (GSE11691, GSE25628, and GSE7305 datasets) were downloaded, and the "combat" algorithm was employed for batch correction, gene expression difference analysis, and pathway enrichment difference analysis. The protein-protein interaction (PPI) network was constructed to identify core genes, and the relative enrichment degree of gene sets was evaluated. The Lasso regression model identified candidate gene sets with diagnostic value, and a risk scoring diagnostic model was constructed for further validation on the GSE86534 and GSE5108 datasets. CIBERSORT was used to assess the composition of immune cells in EMS, and the correlation between EMS diagnostic value gene sets and immune cells was evaluated.
Results:
A total of 568 differentially expressed genes were identified between eutopic and ectopic endometrium, with 10 core genes in the PPI network associated with cell cycle regulation. Inflammation-related pathways, including cytokine-receptor signaling and chemokine signaling pathways, were significantly more active in ectopic endometrium compared to eutopic endometrium. Diagnostic gene sets for EMS, such as homologous recombination, base excision repair, DNA replication, P53 signaling pathway, adherens junction, and SNARE interactions in vesicular transport, were identified. The risk score's area under the curve (AUC) was 0.854, as indicated by the receiver operating characteristic (ROC) curve, and the risk score's diagnostic value was validated by the validation cohort. Immune cell infiltration analysis revealed correlations between the risk score and Macrophages M2, Plasma cells, resting NK cells, activated NK cells, and regulatory T cells.
Conclusion:
The risk scoring diagnostic model, based on pathway activity, demonstrates high diagnostic value and offers novel insights and strategies for the clinical diagnosis and treatment of Endometriosis.
... As shown in Figure 5, the levels of all the cytokines were markedly increased by LPS treatment; however, IL-6 secretion was significantly suppressed by EUFOC treatments (Figure 5c) but not TNF-α and IL-1β (Figure 5a,b). TNF-α is a major endogenous mediator in the early stage of inflammatory response, while IL-1β is a pro-inflammatory cytokine produced during the inflammatory response and a major cytokine involved in the inflammatory response [51]. Therefore, our findings indicated that the EUFOC exhibited an anti-inflammatory effect by inhibiting the late stage of inflammatory response, but not the early stage and proinflammatory response. ...
... As shown in Figure 5, the levels of all the cytokines were markedly increased by LPS treatment; however, IL-6 secretion was significantly suppressed by EUFOC treatments ( Figure 5c) but not TNF-α and IL-1β (Figure 5a,b). TNF-α is a major endogenous mediator in the early stage of inflammatory response, while IL-1β is a pro-inflammatory cytokine produced during the inflammatory response and a major cytokine involved in the inflammatory response [51]. Therefore, our findings indicated that the EUFOC exhibited an antiinflammatory effect by inhibiting the late stage of inflammatory response, but not the early stage and pro-inflammatory response. ...
In this study, we aimed to develop natural and/or functional materials with antioxidant and anti-inflammatory effects. We obtained extracts from natural plants through an oil and hot-water extraction process and prepared an extract composite of an effective unsaturated fatty acid complex (EUFOC). Furthermore, the antioxidant effect of the extract complex was evaluated, and the anti-inflammatory effect was explored by assessing its inhibitory effect on nitric oxide production through its HA-promoting effect. We conducted a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay to evaluate the cell viability of the EUFOC, and the results showed that EUFOC was not cytotoxic at the test concentrations. In addition, it showed no endogenous cytotoxicity in HaCaT (human keratinocyte) cells. The EUFOC showed excellent 1,1-diphenyl-2-picrylhydrazyl- and superoxide-scavenging abilities. Moreover, it exerted an inhibitory effect on NO production at concentrations that did not inhibit cell viability. The secretion of all the cytokines was increased by lipopolysaccharide (LPS) treatment; however, this was inhibited by the EUFOC in a concentration-dependent manner. In addition, hyaluronic acid content was markedly increased by the EUFOC in a dose-dependent manner. These results suggest that the EUFOC has excellent anti-inflammatory and antioxidant properties, and hence, it can be used as a functional material in various fields.
... Vascularization of the ectopic tissue is supported by a variety of factors including pro-inflammatory mediators, notably interleukin 1β (IL1β) produced by activated macrophages at the site of engraftment. This strong signaling molecule triggers production of interleukin 6 (IL6) and vascular endothelial growth factor (VEGF) by the grafts, facilitating the blood vessel ingrowth [45,46]. Stromal cells of the ectopic lesions have also been shown to produce interleukin 8 (IL8) -another pro-inflammatory cytokine with pro-angiogenic properties [47]. ...
Endometriosis is a chronic inflammatory estrogen-dependent disease characterized by the growth of endometrial-like tissue outside the physiological region. Despite the fact that this disease is common, laparoscopic surgery is currently the gold standard in the treatment of endometriosis. In this regard, it is necessary to develop new effective methods of minimally invasive therapy for endometriosis. One of the promising areas in the treatment of endometriosis is cell therapy. Cellular therapy is a vast branch of therapeutic methods with various agents. Potential cell therapies for endometriosis may be based on the principle of targeting aspects of the pathogenesis of the disease: suppression of estrogen receptor activity, angiogenesis, fibrosis, and a decrease in the content of stem cells in endometriosis foci. In addition, immune cells such as NK cells and macrophages may be promising agents for cell therapy of endometriosis. Standing apart in the methods of cell therapy is the replacement therapy of endometriosis. Thus, many studies in the field of the pathogenesis of endometriosis can shed light not only on the causes of the disease and may contribute to the development of new methods for personalized cell therapy of endometriosis.
... Moreover, inflammasome, a multiprotein complex, stimulates the secretion of IL-1β and IL-8, resulting into the multiple host responses. These studies suggest that enhanced IL-1β signaling, which occurs in response to inflammasome activation, promotes endometriotic angiogenesis [15,16]. Consistently, the peritoneal fluid of women with endometriosis has elevated IL-1β, which promotes the release of cytokines, such as Interleukin 8 (IL-8), and growth factors that contribute to neovascularization and monocyte chemotaxis in endometriotic explants [17,18]. ...
Endometriosis is a pathological condition of the female reproductive tract characterized by the existence of endometrium-like tissue at ectopic sites, affecting 10% of women between the age 15 and 49 in the USA. However, currently there is no reliable non-invasive method to detect the presence of endometriosis without surgery and many women find hormonal therapy and surgery as ineffective in avoiding the recurrences. There is a lack of knowledge on the etiology and the factors that contribute to the development of endometriosis. A growing body of recent evidence suggests an association between gut microbiota and endometriosis pathophysiology. However, the direct impact of microbiota and microbiota-derived metabolites on the endometriosis disease progression is largely unknown. To understand the causal role of gut microbiota and endometriosis, we have implemented a novel model using antibiotic-induced microbiota-depleted (MD) mice to investigate the endometriosis disease progression. Interestingly, we found that MD mice showed reduced endometriotic lesion growth and, the transplantation of gut microbiota by oral gavage of feces from mice with endometriosis rescued the endometriotic lesion growth. Additionally, using germ-free donor mice, we indicated that the uterine microbiota is dispensable for endometriotic lesion growth in mice. Furthermore, we showed that gut microbiota modulates immune cell populations in the peritoneum of lesions-bearing mice. Finally, we found a novel signature of microbiota-derived metabolites that were significantly altered in feces of mice with endometriosis. Finally, we found one the altered metabolite, quinic acid promoted the survival of endometriotic epithelial cells in vitro and lesion growth in vivo, suggesting the disease-promoting potential of microbiota-derived metabolites. In summary, these data suggest that gut microbiota and microbiota-derived metabolome contribute to lesion growth in mice, possibly through immune cell adaptations. Of translational significance, these findings will aid in designing non-invasive diagnostics using stool metabolites for endometriosis.
... In the described clinical case, the patient had changes in immunological status that are characteristic of endomteriosis: an increase in the blood levels of interleukin-1β and interleukin-8 (Table 1). It is generally accepted that IL-1β stimulates the cyclooxygenase system 2, leading to the growth of the ectopic endometrium by inducing proliferation and angiogenesis as a result of an increase in the production of growth factor VEGF [14][15][16][17], and the latter may also be mediated by IL-8 [18,19]. ...
... Total RNA from frozen tissues was isolated using an RNeasy Micro Kit (#74004, Qiagen, Hilden, Germany) according to the manufacturer's instructions. Reverse transcription was performed using d(T) 15 as a primer with 500 ng of RNA. qPCR was performed using the Mx300P system (Stratagene, La Jolla, CA, USA) using SYBR green with specific primers ( Table 3). ...
Endometriosis of the cervix is a rare form of genital endometriosis, which is characterized by the appearance of tissue on the vaginal part of the cervix, similar to the tissue of the mucous membrane of the uterine cavity. We describe a clinical case in which we compared the content of cytoskeletal proteins, H3 histone modifications and DNA methylation (total and 5-hydroxymethylcytosine content) in the eutopic endometrium and in tissue from endometriosis foci on the cervix. The patient had elevated levels of estradiol, interleukin-1β and interleukin-8. At the cellular level, the content of tubulin and the marker of stable microtubules were reduced in the ectopic endometrium (by 45% and 37%, p < 0.05, respectively), but the alpha-actinin-1 content was increased (by 75%, p < 0.05) with an increase in the expression of its gene. At the same time, the total level of DNA methylation in the endometriotic focus was reduced by more than 2 times with the accumulation of the intermediate product 5-hydroxymethylcytosine (the content increased by more than 3 times), probably due to an increase in the content of tet methylcytosine dioxygenase 1 (more than 4 times).
... Therefore, these results suggest that increased NLRP3 inflammasome activation in endometriotic cells by aberrant induction of autophagy is directly involved in increased IL-1b secretion in endometriotic tissues. IL-1b is a versatile pro-inflammatory cytokine that promotes endometrial cell proliferation and production of various cytokines and growth factors in endometriotic cells, leading to the development of endometriosis (Lebovic et al., 2000;Herrmann Lavoie et al., 2007;Takemura et al., 2007;Akoum et al., 2008;Kao et al., 2011;Yoshino et al., 2011). Given these roles of IL-1b, dysregulation of autophagy-dependent NLRP3 inflammasome inactivation may be an important contributing factor in the pathogenesis of endometriosis. ...
The NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome is a cytosolic multi-protein complex that induces inflammation and is known to be regulated negatively by autophagy. Previous studies reported an abnormal induction of autophagy linked to progesterone resistance in human endometriotic cells. Therefore, an aberrant autophagy induction response to progesterone might contribute to the altered inflammatory response observed in endometriotic tissues. To evaluate this hypothesis, we elucidate whether regulation of the NLRP3 inflammasome by ovarian steroids is mediated by autophagy in human endometrial stromal cells (NESCs) from patients with uterine leiomyoma (presumed normal) and whether abnormal autophagy induction in endometriotic cyst stromal cells (ECSCs) affects NLRP3 inflammasome-induced interleukin-1β (IL-1β) production. Our results show that estrogen enhanced NLRP3 inflammasome activation in NESCs, resulting in increased IL-1β production. Progesterone decreased NLRP3 inflammasome activity with an increase in autophagy induction in estrogen-treated NESCs. Inhibition of NLRP3 inflammasome activity by progesterone was blocked by autophagy inhibition. However, progesterone failed to change NLRP3 inflammasome activity and autophagy induction in estrogen-treated ECSCs. By contrast, dienogest, a specific progesterone receptor agonist, reduced NLRP3 inflammasome-mediated IL-1β production through autophagy induction in ECSCs. Furthermore, autophagy induction was decreased and NLRP3 inflammasome activity was increased in endometriotic tissues, which was reversed by pre-operative administration of dienogest. In conclusion, our results suggest that progesterone inhibits NLRP3 inflammasome activation through autophagy in endometrial stromal cells. However, this inhibitory effect is attenuated in endometriotic stromal cells due to an aberrant autophagic response to progesterone, which could lead to an altered inflammatory response in endometriosis.
... As the key proinflammatory cytokine, high expression of IL-6 can induce fibroblast proliferation, aggravate local pelvic adhesion and tubal injury, and eventually cause local tubal tissue adhesion, stenosis, and quince, leading to infertility [21,22]. In addition, high expression of IL-1β can induce tissue injury and chronic inflammation, resulting in pelvic tissue adhesion and fibrosis [23][24][25]. Furthermore, TNF-α is closely related to tubal inflammatory injury and infertility [26,27]. ...
To observe the clinical effect of traditional Chinese medicine (TCM) combined with interventional recanalization therapy in the treatment of tubal obstructive infertility, first, different treatment approaches were used on rabbits, and transmission electron microscopy (TEM) indicated that interventional recanalization combined with TCM can significantly ameliorate the pathological condition of the fallopian tube after treatment. Moreover, ELISA disclosed that the treatment could significantly reduce the levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) and increase the expression of interleukin-10 (IL-10), which demonstrated that TCM therapy can help against inflammation of the fallopian tubes. PCR array analysis revealed that BMP4, BMPR1A, SMAD2, SMAD3, SMAD4, and KLF10 expressions were upregulated, and SMAD7 expression was downregulated, proving that combined treatment could influence gene expression in the TGF-β family and further regulate the secretion of proteins in SMADs. In addition, a clinical study recorded the fallopian tube patency rate of 165 patients after 12 months. The recanalization rates in the two groups were 81.9% and 53.1%, with the higher rates in the combined medicine enema group. All these findings implied that interventional recanalization combined with TCM preparation has a stronger effect. The mechanism probably involves effects on the expression of genes in the TGF-β/SMAD and BMP/SMAD signaling pathways, with simultaneous regulation of inflammatory factors, thereby improving the ovarian environment and increasing pregnancy rates.
