Growth Of Endometrial Tissue Research Articles

The modulation of endometriosis by lncRNA MALAT1 via NF-κB/iNOS.

Endometriosis (Ems) is one benign disorder that frequently leads to chronic pelvic pain, dysmenorrhea or even infertility. Featured as the ectopic growth of active endometrial tissues on tissues beyond the muscular layer, Ems has complicated pathogenesis mechanisms that are not fully illustrated. Long non-coding (lnc) RNA MALAT1 participates in various biological activities, including cell growth, proliferation, apoptosis, organogenesis, inflammation, and tumors. However, its expression and function in Ems are not clear yet. Real-time PCR measured differential expression of MALAT1 in normal and ectopic endometrial tissues. Cultured endometrial cells were transfected with siRNA for MALAT1, whose expression was measured by real-time PCR. MTT assay measured endometrial cell proliferation, whose invasion was measured by transwell assay. Western blot tested the expression and NF-κB/iNOS, and MMP9 proteins. LncRNA MALAT1 showed upregulation in ectopic endometrial tissues (p<0.05 comparing to control group). Transfection of MALAT1 siRNA suppressed its expression in endometrial cells, inhibited cell proliferation or invasion, enhanced caspase 3 activity, decreased NF-κB/iNOS or MMP-9 expression (p<0.05 comparing to control group). LncRNA MALAT1 can facilitate endometrial cell apoptosis and modulate MMP-9 expression via NF-κB/iNOS pathway, thus, mediating Ems pathogenesis.

Endometrial cells contribute to preexisting endometriosis lesions in a mouse model of retrograde menstruation†.

Endometriosis is characterized by extrauterine growth of endometrial tissue accompanied by adverse clinical manifestations including chronic pelvic pain and infertility. Retrograde menstruation, the efflux of endometrium into the peritoneal cavity during menstruation, is believed to contribute to implantation of endometrial tissue and formation of endometriotic lesions at ectopic sites. While it is established through various rodent and nonhuman primate models that endometrial tissue fragments, as well as nondissociated stroma and glands, are capable of seeding endometriosis in a manner mimicking retrograde menstruation, the ability of single endometrial cells to participate in endometriotic processes has not been evaluated due to their failure to establish macroscopic endometriosis. We designed a model by which this capacity can be assessed by examining the integration of individual uterine cells into existing endometriosis lesions in mice. Endometriosis was induced in C57BL/6J female mice followed by intraperitoneal injection of GFP-labeled single uterine cells. We found that freshly introduced uterine cells can successfully integrate and contribute to various cell populations within the lesion. Strikingly, these cells also appeared to contribute to neo-angiogenesis and inflammatory processes within the lesion, which are commonly thought of as host-driven phenomena. Our findings underscore the potential of individual uterine cells to continuously expand lesions and participate in the progression of endometriosis. This model of retrograde menstruation may therefore be used to study processes involved in the pathophysiology of endometriosis.

Scar Endometriosis: Experience of a Surgeon

Introduction: Cesarean section is a common obstetric surgery worldwide. As incision wound in such a surgery is exposed abundantly to endometrial tissue, incision scar endometriosis can occur. This study reports a surgeon’s experience in managing such an uncommon entity. The aim of this study was to identify risk factors for developing SCE and show the clinical spectrum of presentation. This study also shows our experience in surgical management of surgical scar endometriosis. Extra pelvic endometriosis is defined as the presence and growth of functional endometrial tissue outside the pelvis. Cesarean scar endometriosis (CSE) is a rare form of extra pelvic endometriosis that is usually confused with other surgical problems leading to delay in diagnosis.&#x0D; Materials and Methods: We reviewed the case records of patients who were diagnosed as CSE in the surgery department of BIRDEM GENERAL HOSPITAL-2 from September 2013 till September 2018.&#x0D; Results: We found 8 patients of scar endometriosis in 5 years making it one of the rare conditions. The age of the patients range 23–39 years and interval from symptoms to treatment varied from 16 months to 64 months. Five patients had presented to surgery department and 3 were referred from obstetric department. Cyclic pain and swelling in scar area were the most common presenting symptoms. All patients underwent excision of the mass with no recurrence of symptoms at a follow up ranging from 9 to 60 months.&#x0D; Conclusion: Increasing awareness of this condition among doctors can help in early diagnosis and treatment with gratifying results. Precaution during obstetrical surgery to avoid undue contamination of the wound can reduce incidence of scar endometriosis.&#x0D; Medicine Today 2019 Vol.31(1): 42-45

Identification of a Benzimidazolecarboxylic Acid Derivative (BAY 1316957) as a Potent and Selective Human Prostaglandin E2 Receptor Subtype 4 (hEP4-R) Antagonist for the Treatment of Endometriosis.

The presence and growth of endometrial tissue outside the uterine cavity in endometriosis patients are primarily driven by hormone-dependent and inflammatory processes-the latter being frequently associated with severe, acute, and chronic pelvic pain. The EP4 subtype of prostaglandin E2 (PGE2) receptors (EP4-R) is a particularly promising anti-inflammatory and antinociceptive target as both this receptor subtype and the pathways forming PGE2 are highly expressed in endometriotic lesions. High-throughput screening resulted in the identification of benzimidazole derivatives as novel hEP4-R antagonists. Careful structure-activity relationship investigation guided by rational design identified a methyl substitution adjacent to the carboxylic acid as an appropriate means to accomplish favorable pharmacokinetic properties by reduction of glucuronidation. Further optimization led to the identification of benzimidazolecarboxylic acid BAY 1316957, a highly potent, specific, and selective hEP4-R antagonist with excellent drug metabolism and pharmacokinetics properties. Notably, treatment with BAY 1316957 can be expected to lead to prominent and rapid pain relief and significant improvement of the patient's quality of life.

Transvaginal ultrasound (USTV) for Deep Pelvic Endometriosis: How “To Do” do it

Endometriosis is characterized by the growth of endometrial tissue outside the uterine cavity. The standard gold diagnosis for endometriosis is the surgery. For surgical planning, the imaging diagnosis is fundamental to obtain complete excision and patient's treatment. The transvaginal ultrasounds after bowel preparation should be the first line in the diagnosis and endometriosis staging. The hiperechoic uterus serosa must be seen intact. Looking for pelvic adhesions, the ovary often is fixed to the uterus. Vaginal gel before the exam helps to detect small lesions. Intestinal Lesions: perform after bowel preparation, provide the lesions size, wall layers infiltration degree, circumference of bowel involvement and the distance from the anal verge to the inferior lesion margin. Bladder: minimal amount of urine in the bladder to study the vesical wall. The aim of this study is to describe and illustrate radiologic signs, surgery and pathologic correlations of deep endometriosis, from a reference Center, presenting a pre surgical protocol study using ultrasound technique.

Deep pelvic endometriosis: “Tips and Tricks” by transvaginal ultrasound (USTV). Correlating finding of USTV, MR imaging and laparoscopy

Endometriosis is characterized by the growth of endometrial tissue outside the uterine cavity. The standard gold diagnosis for endometriosis is the surgery. For surgical planning, the imaging diagnosis is fundamental to obtain complete excision and patient's treatment. The transvaginal ultrasounds after bowel preparation should be the first line in the diagnosis and endometriosis staging. Magnetic Resonance imaging provides complementary information and its always necessary in cases with ureteral involvement, extensions adhesions, heterogeneous ovarian cysts and large uterus. The aim of this study is to describe and illustrate radiologic signs, surgery and pathologic correlations of deep endometriosis, from a reference Center, presenting a pre surgical protocol study using ultrasound technique and magnetic resonance imaging. This presentation is dedicated to the evaluation of: uterus, retrocervical and retrouterine regions, uterosacral ligaments, uterine insertion of the round ligaments, Douglas pouch, ovaries and adnexal regions, vagina, rectovaginal septum, bladder, urinary system, intestinal lesions (rectosigmoid colon, sigmoid descending, colon transition, vermiform appendix, ileum and ceccum).

Increased circulating miR-370-3p regulates steroidogenic factor 1 in endometriosis.

Endometriosis is a gynecologic disease common among reproductive-aged women caused by the growth of endometrial tissue outside the uterus. Altered expression of numerous genes and microRNAs has been reported in endometriosis. Steroidogenic factor 1 (SF-1), an essential transcriptional regulator of multiple genes involved in estrogen biosynthesis, is aberrantly increased and plays an important role in the pathogenesis of endometriosis. Here, we show the expression of SF-1 in endometriosis is regulated by miR-370-3p. Sera and tissue were collected from 20 women surgically diagnosed with endometriosis and 26 women without endometriosis. We found that miR-370-3p levels were decreased in the serum of patients with endometriosis while SF-1 mRNA levels were inversely upregulated in endometriotic lesions compared with respective controls. Transfection of primary endometriotic cells with miR-370-3p mimic or inhibitor resulted in the altered expression of SF-1 and SF-1 downstream target genes steroidogenic acute regulatory protein (StAR) and CYP19A1. Overexpression of miR-370-3p inhibited cell proliferation and induced apoptosis in endometriotic cells. This study reveals that miR-370-3p functions as a negative regulator of SF-1 and cell proliferation in endometriotic cells. We suggest a novel therapeutic strategy for controlling SF-1 in endometriosis.

Exosome-mediated microRNA-138 and vascular endothelial growth factor in endometriosis through inflammation and apoptosis via the nuclear factor-κB signaling pathway.

Endometriosis (Ems) is a condition that refers to the ectopic implantation and growth of endometrial tissue outside the uterine cavity. The aim of the present study was to investigate the role of microRNA-138 (miR-138) in Ems and the possible underlying mechanism. Flow cytometry was measured CD11b level, cell proliferation was measured using MTT assay and lactate dehydrogenase (LDH) assays was analyzed using LDH activity kits. Cell apoptosis was measured using Annexin V-FITC/PI double staining apoptosis detection kit and DAPI assays. ELISA assay and western blot analysis were used to measure protein expression determination. It was first observed that miR-138 expression was markedly downregulated and the CD11b level was reduced in Ems mice compared with the control group. Subsequently, miR-138 expression was downregulated in the uterine endothelial cells co-cultured with THP-1 cells, which resulted in decreased apoptosis and increased inflammation in the uterine endothelial cells. By contrast, upregulation of miR-138 by mimic transfection increased the proliferation and reduced inflammation in uterine endothelial cells. In addition, in the co-culture of uterine endothelial and THP-1 cells, downregulation of miR-138 induced the expression of nuclear factor (NF)-κB and vascular endothelial growth factor (VEGF) proteins in THP-1 cells. Furthermore, treatment with an NF-κB inhibitor and downregulation of miR-138 in the co-culture of uterine endothelial and THP-1 cells reduced inflammation. VEGF inhibitor treatment and downregulation of miR-138 in this cell co-culture promoted the proliferation of uterine endothelial cells. These results suggested that uterine endothelial cells promoted miR-138 to induce exosome-mediated inflammation and apoptosis in Ems through the VEGF/NF-κB signaling pathway.

Exposure to environmental concentrations of hexachlorobenzene induces alterations associated with endometriosis progression in a rat model

Hexachlorobenzene (HCB) is a dioxin-like compound widely distributed and is a weak ligand of the aryl hydrocarbon receptor (AhR). Endometriosis is a disease characterized by growth of endometrial tissue in ectopic sites. Our aim was to investigate the impact of HCB on the endocrine, invasion and inflammatory parameters in a rat endometriosis model surgically induced. Female rats were exposed to HCB (1, 10 and 100 mg/kg b.w.) during 30 days. Results showed that HCB increases endometriotic like-lesions (L) volume in a dose-dependent manner. In L, HCB10 increases microvessel density (immunohistochemistry) and the vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2) and AhR levels (Western Blot), while HCB1 enhances aromatase expression (Western Blot). In addition, in eutopic endometrium (EU), HCB10/HCB100 augments microvessel density, VEGF and MMP-9 expression, while HCB1/HCB10 increases tumor necrosis factor-α (TNF-α) content in peritoneal fluid (ELISA). Interestingly, both L and EU from HCB-treated rats exhibited higher estrogen receptor α (ERα) (immunohistochemistry) and metalloproteases (MMP)-2 and −9 levels (Western Blot), as well as lower progesterone receptor (PR) expression (immunohistochemistry) than in control rats. Environmentally relevant concentrations of HCB could contribute to abnormal changes associated with endometriosis progression and development.

Distinct molecular pathways in ovarian endometrioid adenocarcinoma with concurrent endometriosis.

Women with endometriosis, a benign growth of endometrial tissue outside the uterine cavity, are at increased risk of specific histotypes of epithelial ovarian cancer, such as ovarian endometrioid adenocarcinoma (OEA). Women with OEA who have endometriosis at time of surgical staging demonstrate improved clinical prognosis compared to women with OEA without evidence of endometriosis. However, the molecular contributions of the endometriotic tumor microenvironment to these ovarian cancers remain poorly understood. As a starting point, we used a platform for genome-wide transcriptomic profiling to compare specimens of OEA from women with and without concurrent endometriosis and benign reproductive tract tissues, including proliferative endometrium and typical and atypical endometrioma samples (n = 20). Principle component analysis revealed distinct clustering between benign and malignant samples as well as malignant samples with and without concurrent endometriosis. Examination of gene signatures revealed that OEA with concurrent endometriosis contained a unique molecular signature compared to OEA without concurrent endometriosis, distinguished by 682 unique genes differentially expressed (fold change < or >1.5, p < 0.01). Bioinformatic analysis of these differentially expressed gene products using ingenuity pathway analysis revealed activation of NFkB signaling, an inflammatory signaling pathway constitutively active in endometriosis. DAVID functional annotation clustering further revealed enrichment in RAS signaling as both cytoskeleton organization and GTPase regulator activity relied heavily on RAS protein signal transduction. Gene set enrichment analysis highlighted immune and inflammatory nodes involved in OEA with concurrent endometriosis. These observations provide novel resources for understanding molecular subtleties potentially involved in OEA within the context of the endometriotic tumor microenvironment.

SULFATION PATHWAYS: Contribution of intracrine oestrogens to the aetiology of endometriosis.

Endometriosis is an incurable hormone-dependent inflammatory disease that causes chronic pelvic pain and infertility characterized by implantation and growth of endometrial tissue outside the uterine cavity. Symptoms have a major impact on the quality of life of patients resulting in socioeconomic, physical and psychological burdens. Although the immune system and environmental factors may play a role in the aetiology of endometriosis, oestrogen dependency is still considered a hallmark of the disorder. The impact of oestrogens such as oestrone and particularly, oestradiol, on the endometrium or endometriotic lesions may be mediated by steroids originating from ovarian steroidogenesis or local intra-tissue production (intracrinology) dependent upon the expression and activity of enzymes that regulate oestrogen biosynthesis and metabolism. Two key pathways have been implicated: while there is contradictory data on the participation of the aromatase enzyme (encoded by CYP19A1), there is increasing evidence that the steroid sulphatase pathway plays a role in both the aetiology and pathology of endometriosis. In this review, we consider the evidence related to the pathways leading to oestrogen accumulation in endometriotic lesions and how this might inform the development of new therapeutic strategies to treat endometriosis without causing the undesirable side effects of current regimes that suppress ovarian hormone production.

Future Directions in Endometriosis Research and Therapeutics

Endometriosis is a disease common among women of reproductive age characterized by pain, anxiety and infertility. Defined as the growth of endometrial tissue in ectopic locations, endometriosis remains an enigmatic disease for which current treatments are less than ideal. Much of these shortcomings to current therapy stem from our incomplete understanding on the pathogenesis of the disease. It is generally accepted that endometriosis is an estrogen-dependent disease and, as such, the majority of treatment approaches aim at reducing estrogen action and/or production. Unfortunately, this approach is not effective in all women with endometriosis and in those women where success is achieved with their use, there is potential for health-comprising side effects. The objective of this review is to summarize current approaches for treatment of endometriosis, discuss their limitations and potential reasons for lack of progress towards better therapeutics for this disease. In this review we summarize the current approaches for treatment of endometriosis, discuss their limitations and potential reasons for lack of progress towards better therapeutics for this disease. Based upon the current state of knowledge, there is a strong necessity for through assessment at the level of the genome, miRNAome and proteome as well as the importance of integrating clinically-relevant endpoints in future studies which evaluate potential endometriosis therapies in experimental models of endometriosis.

Endometriosis‐associated vaginal hyperalgesia is mediated by the balance of reactive aldehyde production and metabolism.

BackgroundEndometriosis affects ~176 million women worldwide and is characterized by the growth of endometrial tissue outside the uterus (known as endometrial ectopic cysts). How endometriosis becomes associated with painful symptoms is not clear. Here we hypothesize that endometriosis‐associated vaginal hyperalgesia is mediated by an imbalance of reactive aldehyde production and metabolism.MethodsTo test this hypothesis, we used female Sprague‐Dawley rats (n=5/group) and subjected them to a cutting‐edge model of behavioral psychophysics to assess for rat vaginal nociception. Prior to subjecting the rodents to this model, we treated rodents with the reactive aldehyde, acetaldehyde (9 mg/kg intraperitoneal) to mimic an increased production of reactive aldehydes in the intraperitoneal space. To modulate ALDH2 activity, we administered to rodents either the ALDH2 activator, Alda‐1 (1 mg/kg, diluted in DMSO, given intraperitoneal) or the ALDH2 inhibitor disulfiram (15 mg/kg, diluted in DMSO, given intraperitoneal). The ALDH2 activator were delivered 10 minutes before or after acetaldehyde (Alda‐1 + aldehyde or aldehyde +Alda‐1). Disulfiram was given 10 minutes before acetaldehyde (Disulfiram + aldehyde). As controls Alda‐1, disulfiram, saline, and DMSO were delivered alone. Changes in vaginal nociception were expressed as area‐under‐the‐curve (AUC) units and calculated using standard trapezoid methods. For statistical analysis, a one‐way ANOVA with Bonferroni's multiple comparison test was used. Data presented as mean ± SEM.ResultsAcetaldehyde‐induced vaginal hyperalgesia (44±4* vs. saline 28±2, *P&lt;0.05). Alda‐1 markedly attenuated hyperalgesia when given either before (26±3, *P&lt;0.05 vs. acetaldehyde) or after (25±3, *P&lt;0.05 vs. acetaldehyde) acetaldehyde treatment. Conversely, pretreatment with disulfiram before acetaldehyde increased vaginal hyperalgesia (61±5, *P&lt;0.05 vs. acetaldehyde). Alda‐1, DMSO, and disulfiram alone produced no significant changes in vaginal nociception.ConclusionsThese data suggest that the mechanism of endometriosis‐induced hyperalgesia is mediated by changes in reactive aldehyde production and metabolism. Increasing ALDH2 activity in rats, both prevented and alleviated reactive aldehyde‐induced vaginal hyperalgesia. These data suggest a potential novel therapeutic for treating endometriosis by targeting reactive aldehyde metabolism.Support or Funding InformationThis work was supported by the National Institutes of Child Health and Human Development K99HD093858 (SLM), a Stanford Women &amp; Sex Differences in Medicine (WSDM) Seed Grant, and an Endometriosis Foundation of America Research Award.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hematogenous Dissemination of Mesenchymal Stem Cells from Endometriosis.

Endometriosis is ectopic growth of endometrial tissue traditionally thought to arise through retrograde menstruation. We aimed to determine if cells derived from endometriosis could enter vascular circulation and lead to hematogenous dissemination. Experimental endometriosis was established by transplanting endometrial tissue from DsRed+ mice into the peritoneal cavity of DsRed- mice. Using flow cytometry, we identified DsRed+ cells in blood of animals with endometriosis. The circulating donor cells expressed CXCR4 and mesenchymal stem cell (MSC) biomarkers, but not hematopoietic stem cell markers. Nearly all the circulating endometrial stem cells originated from endometriosis rather than from the uterus. Cells expressing DsRed, CXCR4, and MSCs markers were identified in the peritoneal wall and surrounding vessels of recipient mice, contributing to both endometriosis and angiogenesis. Cells originating in endometriosis lesions migrated and implanted in lung tissue and displayed makers of differentiation, indicating retained multipotency. In vitro these cells demonstrated multipotency and were able to differentiate into adipogenic, osteogenic, and chondrogenic lineages. Endometriosis lesions also expressed high levels of CXCL12, the CXCR4 receptor ligand. Serum CXCL12 levels were greater than in sham control mice. In humans with endometriosis, serum CXCL12 levels were significantly higher than controls, suggesting that the CXCL12/CXCR4 axis is operational in women with spontaneous endometriosis as well. Stem cells, rather than differentiated cells from endometriosis, enter the circulation in response to CXCL12. We identify an endometriosis-derived stem cell population, a potential mechanism of dissemination of this disease and a potential target for treatment of endometriosis. Stem Cells 2018;36:881-890.

(268) - The influence of chronic WIN 55, 212-2 treatment on vaginal hyperalgesia, VEGF, and NGF in a rat model of endometriosis

Endometriosis affects ~10% of women of reproductive age and is characterized by the growth of endometrial tissue outside the uterus. Approximately 50% of women with endometriosis suffer from debilitating chronic pelvic pain including dyspareunia (pain during sexual intercourse; vaginal hyperalgesia) and severe dysmenorrhea (menstrual pain). How the endometrial ectopic growths (cysts) contribute to painful symptoms is poorly understood. However, mounting evidence suggests the involvement of the endocannabinoid system in endometriosis and its associated pain. Cannabinoids and their receptors are known to be involved in uterine function and dysfunction, abnormal vascularization, neurite outgrowth, and neuronal guidance. Further, exogenous cannabinoids have been used for centuries to alleviate the endometriosis-associated painful symptom of dysmenorrhea. In a rat model of endometriosis (ENDO), uterus pieces are auto-transplanted onto abdominal arteries and form vascularized and innervated cysts similar to women. ENDO also produces painful symptoms similar to that of women with endometriosis, including vaginal hyperalgesia. Here, vaginal nociception was assessed behaviorally at baseline, for eight weeks after ENDO was induced (when vaginal hyperalgesia/cyst innervation stabilize), and then for eight weeks during chronic treatment with the CB1/CB2 agonist WIN 55, 212-2 (or in controls: DMSO or untreated). Cyst and uterus levels of vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) were also assessed using protein array analysis. All data were analyzed in the proestrus stage. Our data demonstrate that treatment with WIN 55, 212-2 alleviates ENDO-induced vaginal hyperalgesia, significantly decreases VEGF expression in the cysts but not uterus, and does not significantly influence NGF expression in the cysts or uterus. Overall, these data suggest that cannabinoid receptor stimulation-mediated modulation of VEGF, potentially through VEGF's influence on vascularization and/or innervation, influences endometriosis-associated vaginal hyperalgesia. Further, these results also provide additional support for targeting the endocannabinoid system for endometriosis-associated pain.

Depleted lamin B1: a possible marker of the involvement of senescence in endometriosis?

Endometriosis is a benign disease characterized by implantation and the growth of endometrial tissue outside the uterine cavity and it shares similarities with cancer. Lamin B1, p16 and p21 play a role on cell cycle regulation, development, cell repair and its activities are related to cancers. Considering the similarities between endometriosis and cancer, the aim of the present cross-sectional study is to detect p16, p21 and Lamin B1 in the ectopic endometrium of patients with endometriosis (n=8) with eutopic (n=8) and control endometrium (n=8) and relate them to the maintenance and development of endometriosis. Biopsies were obtained from both eutopic and ectopic, from deep infiltrating lesions, endometrium frozen and used for immunofluorescent (p16) or immunohistochemistry procedures (p16, p21, lamin B1). Detected higher lamin B1 in the eutopic endometrium when compared with ectopic endometrium, with no differences between endometriosis tissue with control endometrium. Similar presence of p16 in all groups of patients and no p21 detection was observed. We observed reduced detection of lamin B1 in the ectopic endometrium raising the possibility that the presence of senescent cells might be contributing to the maintenance and progression of endometriosis by apoptosis resistance and peritoneal stress inherent of the disease.

Anti-Angiogenic Alternative and Complementary Medicines for the Treatment of Endometriosis: A Review of Potential Molecular Mechanisms.

Endometriosis is caused by the growth or infiltration of endometrial tissues outside of the endometrium and myometrium. Symptoms include pain and infertility. Surgery and hormonal therapy are widely used in Western medicine for the treatment of endometriosis; however, the side effects associated with this practice include disease recurrence and menopause, which can severely influence quality of life. Angiogenesis is the main biological mechanism underlying the development of endometriosis. Numerous natural products and Chinese medicines with potent anti-angiogenic effects have been investigated, and the molecular basis underlying their therapeutic effects in endometriosis has been explored. This review aims to describe natural products and compounds that suppress angiogenesis associated with endometriosis and to assess their diverse molecular mechanisms of action. Furthermore, this review provides a source of information relating to alternative and complementary therapeutic products that mediate anti-angiogenesis. An extensive review of the literature and electronic databases, such as the China National Knowledge Infrastructure, PubMed, and Embase, was conducted using the keywords ‘endometriosis,' ‘traditional Chinese medicine,' ‘Chinese herbal medicine,' ‘natural compounds,' and ‘anti-angiogenic' therapy. Anti-angiogenic therapy is an emerging strategy for the treatment of endometriosis. Natural anti-angiogenic products and Chinese medicines provide several beneficial clinical effects, including pain relief. In this review, we summarize clinical trials and experimental studies of endometriosis using natural products and Chinese medicines. In particular, we focus on anti-angiogenic products and alternative and complementary medicines for the treatment of endometriosis and additionally examine their therapeutic efficacy and mechanisms of action. Anti-angiogenic natural products and/or compounds provide a new approach for the treatment of endometriosis. Future work will require randomized trials with larger numbers of subjects, as well as long-term follow-up to confirm the findings described here.

Interleukin-33 modulates inflammation in endometriosis

Endometriosis is a debilitating condition that is categorized by the abnormal growth of endometrial tissue outside the uterus. Although the pathogenesis of this disease remains unknown, it is well established that endometriosis patients exhibit immune dysfunction. Interleukin (IL)-33 is a danger signal that is a critical regulator of chronic inflammation. Although plasma and peritoneal fluid levels of IL-33 have been associated with deep infiltrating endometriosis, its contribution to the disease pathophysiology is unknown. We investigated the role of IL-33 in the pathology of endometriosis using patient samples, cell lines and a syngeneic mouse model. We found that endometriotic lesions produce significantly higher levels of IL-33 compared to the endometrium of healthy, fertile controls. In vitro stimulation of endometrial epithelial, endothelial and endometriotic epithelial cells with IL-33 led to the production of pro-inflammatory and angiogenic cytokines. In a syngeneic mouse model of endometriosis, IL-33 injections caused systemic inflammation, which manifested as an increase in plasma pro-inflammatory cytokines compared to control mice. Furthermore, endometriotic lesions from IL-33 treated mice were highly vascularized and exhibited increased proliferation. Collectively, we provide convincing evidence that IL-33 perpetuates inflammation, angiogenesis and lesion proliferation, which are critical events in the lesion survival and progression of endometriosis.

Differentiating mouse embryonic stem cells express markers of human endometrium

BackgroundModeling early endometrial differentiation is a crucial step towards understanding the divergent pathways between normal and ectopic endometrial development as seen in endometriosis.MethodsTo investigate these pathways, mouse embryonic stem cells (mESCs) and embryoid bodies (EBs) were differentiated in standard EB medium (EBM). Immunofluorescence (IF) staining and reverse-transcription polymerase chain reaction (RT-PCR) were used to detect expression of human endometrial cell markers on differentiating cells, which were sorted into distinct populations using fluorescence-activated cell sorting (FACS).ResultsA subpopulation (50%) of early differentiating mESCs expressed both glandular (CD9) and stromal (CD13) markers of human endometrium, suggestive of a novel endometrial precursor cell population. We further isolated a small population of endometrial mesenchymal stem cells, CD45−/CD146+/PDGFR-β+, from differentiating EBs, representing 0.7% of total cells. Finally, quantitative PCR demonstrated significantly amplified expression of transcription factors Hoxa10 and Foxa2 in CD13+ EBs isolated by FACS (p = 0.03).ConclusionsThese findings demonstrate that mESCs have the capacity to express human endometrial cell markers and demonstrate potential differentiation pathways of endometrial precursor and mesenchymal stem cells, providing an in vitro system to model early endometrial tissue development. This model represents a key step in elucidating the mechanisms of ectopic endometrial tissue growth. Such a system could enable the development of strategies to prevent endometriosis and identify approaches for non-invasive monitoring of disease progression.

Bone Marrow Stem Cell Chemotactic Activity Is Induced by Elevated CXCl12 in Endometriosis.

Endometriosis is an inflammatory gynecological disorder caused by the growth of endometrial tissue outside the uterus. Endometriosis produces chemokines, including CXCL12, that attract bone marrow cells to the lesions. In this study, we describe the expression, localization, and chemotactic activity of CXCL12 in endometriotic lesions. Biopsies were collected both from women with endometriosis undergoing laparoscopy and control endometrium from women without endometriosis. Expression of CXCl12 and CXCR4 messenger RNA was increased approximately 4- and 6-fold, respectively, in endometriosis compared to eutopic endometrium. Immunohistochemistry of lesions revealed that CXCR4 was expressed in the stroma and epithelium in both endometriosis and control eutopic endometrium. The level of CXCR4 protein expression was significantly higher in all cellular compartments of the endometriotic lesions compared to control endometrium. CXCL12 protein expression was also higher in endometriotic lesions and was greatest in the epithelial compartment. CXCL12 was increased more in the condition media of cultured endometriosis than in controls as measured by enzyme-linked immunosorbent assay. Transwell chamber migration was used to demonstrate 2-fold increased chemoattraction of mouse bone marrow stem cells toward CXCL12 in the endometriotic-conditioned medium compared with eutopic endometrium. Our results indicate that a preferential recruitment of stem cells to endometriosis can explain how endometriosis outcompetes eutopic endometrium in recruiting the limited supply of circulating stem cells. The CXCL12/CXCR4 signaling axis is a potential target for the treatment of endometriosis and its associated disorders.