Endometriosis Research Articles

The dysfunction of CD8+ T cells triggered by endometriotic stromal cells promotes the immune survival of endometriosis.

Endometriosis is defined as an oestrogen-dependent and inflammatory gynaecological disease of which the pathogenesis remains unclear. This study aimed to investigate the cellular heterogeneity and reveal the effect of CD8+ T cells on the progress of endometriosis. Three ovarian endometriosis patients were collected, and single-cell RNA sequencing (scRNA-seq) progressed and delineated the cellular landscape of endometriosis containing five cell clusters. The endometrial cells (EMCs) were the major component, of which the mesenchymal cells were preponderant and characterized with increased inflammation and oestrogen synthesis in endometriosis. The proportion of T cells, mainly CD8+ T cells rather than CD4+, was reduced in endometriotic lesions, and the cytokines and cytotoxicity of ectopic T cells were depressed. CD8+ T cells depressed the proliferation of ESCs through inhibiting CDK1/CCNB1 pathway to arrest the cell cycle and triggered inflammation through activating STAT1 pathway. Correspondingly, the coculture with ESCs resulted in the dysfunction of CD8+ T cells through upregulating STAT1/PDCD1 pathway and glycolysis-promoted metabolism reprogramming. The endometriotic lesions were larger in nude mouse models with T-cell deficiency than the normal mouse models. The inhibition of T cells via CD90.2 or CD8A antibody increased the endometriotic lesions in mouse models, and the supplement of T cells to nude mouse models diminished the lesion sizes. In conclusion, this study revealed the global cellular variation of endometriosis among which the cellular count and physiology of EMCs and T cells were significantly changed. The depressed cytotoxicity and aberrant metabolism of CD8+ T cells were induced by ESCs with the activation of STAT1/PDCD1 pathway resulting in immune survival to promote endometriosis.

Loss of KLF15 impairs endometrial receptivity by inhibiting EMT in endometriosis.

The impaired endometrial receptivity is a major factor contributing to infertility in patients with endometriosis (EM), but the underlying mechanism remains unclear. Our study aimed to investigate the role of Kruppel-like factor 15 (KLF15) in endometrial receptivity and its regulation in EM. We observed a significant decrease in KLF15 expression in the mid-secretory epithelial endometrial cells of EM patients compared to normal females without EM. To confirm the role of KLF15 in endometrial receptivity, we found a significantly reduced KLF15 expression and a significant decrease in embryo implantation number in the rat model via uterine horn infection with siRNA. This highlights the importance of KLF15 as a regulator receptivity. Furthermore, through ChIP-qPCR, we discovered that the progesterone receptor (PR) directly binds to KLF15 promoter regions, indicating that progesterone resistance may mediate the decrease in KLF15 expression in EM patients. Additionally, we found that the mid-secretory endometrium of EM patients exhibited impaired epithelial-mesenchymal transition (EMT). Knockdown of KLF15 upregulated E-cadherin and downregulated vimentin expression, leading to inhibited invasiveness and migration of Ishikawa cells. Overexpression KLF15 promotes EMT, invasiveness, and migration ability, and increases the attachment rate of JAR cells to Ishikawa cells. Through RNA-seq analysis, we identified TWIST2 as a downstream gene of KLF15. We confirmed that KLF15 directly binds to the promoter region of TWIST2 via ChIP-qPCR, promoting epithelial cell EMT during the establishment of endometrial receptivity. Our study reveals the involvement of KLF15 in the regulation of endometrial receptivity and its downstream effects on EMT. These findings provide valuable insights into potential therapeutic approaches for treating non-receptive endometrium in patients with EM.

Targeting osteopontin alleviates endometriosis and inflammation by inhibiting the RhoA/ROS axis and achieves non-invasive in vitro detection via menstrual blood.

How does osteopontin (OPN) in endometriosis ectopic stromal cells (EESCs) participate in the pathogenesis of endometriosis and achieve non-invasive detection in vitro? Targeted OPN regulates endometriosis's necroptosis and inflammatory state by inhibiting the RhoA/reactive oxygen species (ROS) axis, thereby alleviating endometriosis and enabling non-invasive detection of menstrual blood in vitro. Endometriosis is a chronic inflammatory disease. Recent studies have shown that OPN plays an important role in disease progression by regulating cell death and inflammation. The study included 20 patients diagnosed with endometriosis (confirmed by laparoscopy and histology) and 10 controls without endometriosis. Endometriotic stromal cells were isolated from endometrial samples, while menstrual blood endometrial cells (MESCs) were isolated from menstrual blood. These cells were then cultured in vitro and utilized in subsequent experiments. OPN expression in EESCs was assessed using inflammatory factor sequencing, immunohistochemical staining (IHC), quantitative real-time PCR (qRT-PCR) analysis, and Western blotting (WB). The biological behavior of OPN and its effects on inflammatory factors were examined using EdU, wound-healing, Transwell, and ELISA assays. Necroptosis in EESCs and its impact on inflammatory factors were detected through qRT-PCR, WB, and Calcein-AM/PI fluorescence assays. The examination of mitochondrial stress in EESCs involved the use of the Mitochondrial Membrane Potential (ΔΨm) Assay, ROS detection, and Calcein-AM Loading/cobalt chloride Quenching. qRT-PCR, WB, and other experiments were conducted to verify the regulation of necroptosis and inflammatory factor levels in EESCs by OPN through the RhoA/ROS axis. Knockdown of OPN and its inhibitory effect on endometriosis lesion size were confirmed using AAV9 virus, IHC, qRT-PCR, WB, and other experiments. Additionally, OPN expression in MESCs was detected using transcriptome sequencing, RT-PCR, WB, and other experiments. In vitro assays demonstrated a significant upregulation of OPN in EESCs, and the knockdown of OPN effectively inhibited necroptosis and the release of inflammatory factors. OPN inhibited necroptosis and inflammatory factor release by mediating RhoA-dependent ROS production and blocking mixed lineage kinase domain-like protein phosphorylation at the cell membrane. In vivo, targeting of OPN can inhibit the growth of endometriosis lesions. Clinically, OPN was also significantly upregulated in the menstrual blood of patients with endometriosis. N/A. Due to limitations in obtaining surgical specimens, our study primarily involved collecting endometriosis tissues from women during the proliferative and secretory phases of the menstrual cycle. We observed a significant overexpression of OPN in the samples used for our investigation. However, the expression of OPN in endometriosis tissues during the intermenstrual phase remains unknown. Our findings highlight the pivotal role of the OPN/RhoA/ROS axis in the regulation of necroptosis and the release of inflammatory factors. OPN knockdown exerts a therapeutic effect in vivo, and the high expression detection of OPN in menstrual blood in vitro. In summary, targeting OPN provides possibilities for the treatment and detection of endometriosis. This study was supported by the National Natural Science Foundation of China (82071626), the Zhejiang Province Public Welfare Technology Application Research Project (LGF21H040010), and the Clinical Research project of the Second Affiliated Hospital of Wenzhou Medical University (1010293). The authors have no conflicts of interest.

MtDNA regulates cGAS-STING signaling pathway in adenomyosis

In various hyperproliferative disorders, damaged mitochondria can release mitochondrial DNA (mtDNA) into the cytoplasm, activating the cGAS-STING signaling pathway and subsequent immune imbalances. Our previous research has demonstrated that hypoxia plays a role in the development of adenomyosis (AM) by inducing mitochondrial dysfunction. However, the precise involvement of the cGAS-STING signaling pathway and mtDNA in AM remains unclear. Therefore, this study aims to investigate the relationship between mtDNA secretion, changes in the cGAS-STING signaling pathway, and the abnormal cellular proliferation observed in AM. We found the cGAS, STING, TBK1, p-TBK1, IRF3, and p-IRF3 proteins levels were significantly elevated in the tissues of patients with AM compared to the control group. Additionally, there was an increase in the expression of the pro-inflammatory cytokines IL-6 and IFN-α in the AM tissues. Hypoxia-induced an increase in the proliferation and migration abilities of endometrial stromal cells (ESCs), accompanied by the activation of the cGAS-STING signaling pathway and elevated levels of IFN-α. Furthermore, hypoxia promoted the leakage of mtDNA into the cytoplasm in AM ESCs, and the deletion of mtDNA reduced the activation of the cGAS-STING pathway. Moreover, knockdown of the STING gene inhibited the expression of TBK1, p-TBK1, IRF3, and p-IRF3 and suppressed the secretion of the inflammatory cytokines IL-6 and IFN-α. Furthermore, the migration and invasion abilities of AM ESCs were significantly diminished after STING knockdown. These findings provide valuable insights into the role of mtDNA release and the cGAS-STING signaling pathway in the pathogenesis of AM.

MiRNAs related in signaling pathways of women's reproductive diseases: an overview.

One of the main health issues that can affect women's health is reproductive diseases, such as polycystic ovary syndrome (PCOS), endometriosis (EMs), uterine leiomyomas (ULs), and ovarian cancer (OC). Although these diseases are very common, we do not have a complete understanding of their underlying cellular and molecular mechanisms. It is important to mention that the majority of patients are diagnosed with these diseases at later stages because of the absence of early diagnostic techniques and dependable molecular indicators. Hence, it is crucial to discover novel and non-invasive biomarkers that have prognostic, diagnostic and therapeutic capabilities. MiRNAs, also known as microRNAs, are small non-coding RNAs that play a crucial role in regulating gene expression at the post-transcriptional level. They are short in length, typically consisting of around 22 nucleotides, and are highly conserved across species. Numerous studies have shown that miRNAs are expressed differently in various diseases and can act as either oncogenes or tumor suppressors. The author conducted a comprehensive review of all the pertinent papers available in web of science, PubMed, Google Scholar, and Scopus databases. We achieved three goals: providing readers with better information, enhancing search results, and making peer review easier. This review focuses on the investigation of miRNAs and their involvement in various reproductive disorders in women, including their molecular targets. Additionally, it explores the role of miRNAs in the development and progression of these disorders.

Therapeutic efficacy and anti-inflammatory mechanism of baicalein on endometriosis progression in patient-derived cell line and mouse model

BackgroundBaicalein is a flavonoid extracted from the roots of Scutellaria baicalensis G. that has anti-inflammatory and antitumor effects. However, therapeutic mechanisms of baicalein in patients with endometriosis in vivo have yet to be elucidated. As a chronic inflammatory gynecological disease, endometriosis causes pain and infertility, and has no complete treatment to date. Current treatment strategies cause several side effects and have high recurrence rates. PurposeThis study aimed to identify the in vivo therapeutic effects of baicalein on endometriosis and verify the action mechanisms of baicalein, focusing on regulating inflammation. MethodsIn this study, an autologous transplant mouse model and patient-derived immortalized human ovarian endometriotic stromal cells (ihOESCs) were used to investigate the therapeutic activities of baicalein. The mouse model was administered with 40 mg/kg baicalein by oral gavage for 4 weeks, and the treatment outcomes of baicalein-treated mice were compared with vehicle- and dienogest-treated groups. ihOESCs were treated with 0–5 μg/ml baicalein for in vitro studies. ResultsBaicalein significantly alleviated the progression of endometriosis in mouse models. Baicalein reduced the expression of proinflammatory cytokines in endometriotic lesions and ihOESCs, and cytokine expression and T cell proportions in mouse spleen. in vitro results showed that baicalein increased mitochondrial calcium flux and induced mitochondrial depolarization and ROS generation in ihOESCs. Ultimately, baicalein inactivated the MAPK/PI3K signaling and induced cell death in ihOESCs. ConclusionIn conclusion, baicalein effectively attenuated the progression of endometriosis through its anti-inflammatory activities. Baicalein can be an alternative or supplemental treatment for endometriosis to ameliorate the side effects of hormonal therapy.

Mining phase separation-related diagnostic biomarkers for endometriosis through WGCNA and multiple machine learning techniques: a retrospective and nomogram study.

The objective of this study was to investigate the role of phase separation-related genes in the development of endometriosis (EMs) and to identify potential characteristic genes associated with the condition. We used GEO database data, including 74 non-endometriosis and 74 varying-degree EMs patients. Our approach involved identifying significant gene modules, exploring gene intersections, identifying core genes, and screening for potential EMs biomarkers using weighted gene co-expression network analysis (WGCNA) and various machine learning approaches. We also performed gene set enrichment analysis (GSEA) to understand relevant pathways. This comprehensive approach helps investigate EMs genetics and potential biomarkers. Nine genes were identified at the intersection, suggesting their involvement in EMs. GSEA linked DEGs to pathways like complement and coagulation cascades, DNA replication, chemokines, apical plasma membrane processes, and diseases such as Hepatitis B, Human T-cell leukemia virus 1 infection, and COVID-19. Five feature genes (FOS, CFD, CCNA1, CA4, CST1) were selected by machine learning for an effective EMs diagnostic nomogram. GSEA indicated their roles in mismatch repair, cell cycle regulation, complement and coagulation cascades, and IL-17 inflammation. Notable differences in immune cell proportions (CD4 T cells, CD8 T cells, DCs, macrophages) were observed between normal and disease groups, suggesting immune involvement. This study suggests the potential involvement of phase separation-related genes in the pathogenesis of endometriosis (EMs) and identifies promising biomarkers for diagnosis. These findings have implications for further research and the development of new therapeutic strategies for EMs.

Dienogest in conjunction with GnRH-a for postoperative management of endometriosis.

Objective: The aim of this study is to assess the postoperative efficacy of the combined administration of dienogest (DNG) and gonadotropin-releasing hormone agonists (GnRH-a) in patients diagnosed with endometriosis (EMS), while acknowledging the extensive use of DNG in the extended therapeutic management of EMS. Methods: In this retrospective study, a cohort of 154 patients who underwent conservative surgical intervention for EMS were scrutinized. The cohort was stratified into two distinct groups based on their prescribed pharmacological regimens. Group A, 70 patients received postoperative oral administration of DNG at a dosage of 2mg/day, whereas Group B, 84 patients underwent treatment involving 3 to 4 injections of GnRH-a post-surgery, followed by DNG therapy. Parameters assessed included pelvic pain visual analog scale (VAS) scores, quality of life metrics (EHP-5), and the incidence of adverse reactions within both groups. Results: Both groups exhibited sustained low VAS scores following the prescribed treatments. The predominant occurrence of adverse bleeding patterns manifested predominantly within the initial 6months of the treatment. Notably, Group B demonstrated a significantly diminished of experiencing frequent and irregular bleeding in comparison to the DNG group (20.0% vs. 8.3%, 12.9% vs. 3.6%, p < 0.05). The administration of GnRH-a did not exacerbate the impact on bone health. Subsequent to health promotion interventions, the incidence of weight gain in both groups declined to 7.1% during the 6-month follow-up (p < 0.05). Group B exhibited a 100% satisfaction rate with the treatment, concomitant with a noteworthy reduction in EHP-5 scores (p < 0.05). Patients with deep infiltrating endometriosis (DIE) nodules displayed marginally higher postoperative VAS scores than their non-DIE counterparts (0.89 ± 0.96 vs. 0.49 ± 0.78). However, with sustained medication use, pain scores within the DIE group exhibited a continual decrease, maintaining a low level of 0.29 ± 0.67 at 12months and beyond. Conclusion: The short-term adjunctive use of GnRH-a prior to DNG treatment postoperatively in patients with EMS proves efficacious in mitigating early adverse bleeding, enhancing patient adherence, and improving overall quality of life. Notably, this therapeutic approach demonstrates favorable safety profiles and is equally effective in patients with DIE.

Novel Diagnostic Biomarker BST2 Identified by Integrated Transcriptomics Promotes the Development of Endometriosis via the TNF-α/NF-κB Signaling Pathway.

Endometriosis (EMS) is a common gynecological condition with apparent heterogeneity, lack of diagnostic markers, and unclear pathogenesis. A series of bioinformatics methods were employed to explore EMS's pathological mechanisms and potential biomarkers by analyzing the combined datasets of EMS (GSE7305, GSE7307, GSE58198, E-MTAB-694), which included 34 normal, 127 eutopic, and 46 ectopic endometrium samples. Then, wet-laboratory experiments (including Western blot, qRT-PCR, and Immunohistochemistry, Immunofluorescence, CCK-8, EdU, Wound healing, Transwell, and Adhesion assays) were applied to examine the biomarkers' expression and function in primary endometrial stromal cells. Bioinformatic analysis indicated that the core pathogenesis of EMS was dysregulated immune-inflammation and tissue remolding processes. Among the upregulated DEGs, BST2 was screened as a potential diagnostic biomarker in EMS, which associated with the revised American Fertility Society (r-AFS) stage and immune-inflammation processes of EMS. Moreover, BST2's overexpression was affirmed in the RNA and protein levels in EMS tissues. In vitro experiments demonstrated that TNF-α promoted the expression of BST2 in ESCs. And BST2 knockdown inhibited migration, invasion, adhesion, and inflammation except for the proliferation of ESCs, probably via the TNF-α/NF-κB pathway. Through a combination of wet and dry studies, we concluded that the core pathogenesis of endometriosis was dysregulated immune-inflammation and tissue remolding, and BST2 might be a potential diagnostic and therapeutic target in endometriosis.

Data Mining Techniques for Endometriosis Detection in a Data-Scarce Medical Dataset

Endometriosis (EM) is a chronic inflammatory estrogen-dependent disorder that affects 10% of women worldwide. It affects the female reproductive tract and its resident microbiota, as well as distal body sites that can serve as surrogate markers of EM. Currently, no single definitive biomarker can diagnose EM. For this pilot study, we analyzed a cohort of 21 patients with endometriosis and infertility-associated conditions. A microbiome dataset was created using five sample types taken from the reproductive and gastrointestinal tracts of each patient. We evaluated several machine learning algorithms for EM detection using these features. The characteristics of the dataset were derived from endometrial biopsy, endometrial fluid, vaginal, oral, and fecal samples. Despite limited data, the algorithms demonstrated high performance with respect to the F1 score. In addition, they suggested that disease diagnosis could potentially be improved by using less medically invasive procedures. Overall, the results indicate that machine learning algorithms can be useful tools for diagnosing endometriosis in low-resource settings where data availability and availability are limited. We recommend that future studies explore the complexities of the EM disorder using artificial intelligence and prediction modeling to further define the characteristics of the endometriosis phenotype.

Abstract IA008: Rare ovarian cancers: the sequelae of specific interactions between cell contexts mutations and microenvironments

Abstract IA008: Rare ovarian cancers: the sequelae of specific interactions between cell contexts mutations and microenvironments

Ayurvedic Management of Primary Infertility Due to Chocolate Cyst: A Case Report

Background: Endometriosis presents in three different entities, which are frequently found together: peritoneal lesions, deep endometriosis and ovarian endometriotic cysts (endometriomas) Ovarian endometrioma is a benign estrogen dependent cystic mass arising from ectopic endometrial tissue within the ovary. It contains thick, brown, tar like fluid, which may be referred to as a chocolate cyst. The presence of endometriomas indicates more severe stage of endometriosis. Endometriomas can lead to chronic pelvic pain and infertility, and often requires surgery for treatment. Endometriosis has been found in nearly 50% of women experiencing issues with infertility, and nearly 70% of women with pelvic pain. Classic symptoms includes dysmenorrhoea, dyspareunia, menorrhagia and infertility. Management of the ovarian cyst through surgery is available to meet urgent need of the patient, but to establish a satisfactory conservative medical treatment is the need of the hour. According to Ayurveda, depending upon most common symptoms it can be compared as a syndrome complex of Granthi, Vidradhi, Udavartini Yonivyapada, Paripluta yonivyapada and Vataja Yonivyapada. It is a Tridoshaja vyadhi with vitiation of Vata And Artava. Chocolate cysts can also be managed on the line of treatment of Granthi, (nodular/glandular swellings) Vidradhi (abscess), Raktapachana and Raktaprasadana. Aim: To manage Female infertility with chocholate cyst with shodhana and shamana therapy. Materials and methods: A patient aged 25years came to outdoor patient department of Prasutitantra Evum Streeroga with the complaint of lower abdominal pain and infertility since2 years. Her Ultrasonography report reveals bilateral chocolate cyst with no dominant follicle. She has tendency of formation of recurrent chocolate cyst since 3 years. She was administered Virechana after completion of menses on 1st cycle, Dashmoola Shodhan Basti along with Uttara Basti with uttarabasti with kasisadi taila and sahachara taila in 2nd cycle, Yastimadhu Ksheera Basti for 3rd cycle along with the Uttara Basti with kasisadi taila and sahachara taila, on the fourth month Uttarabasti with 5 ml of Dhanvantra taila was done, Shigru Patra Avagaha Swedana and Jeevaniya Choorna 3 gm orally with warm milk after Basti treatment. Results: Patient has marked reduction in the size of the chocolate cyst and she conceived with the treatment protocol of 4 months Conclusion: Above mentioned treatment plan has effective result due to Shothahara, Vatanulomana, Raktaprasadana properties which may have effectively curtailed the progress of ovarian cyst and helped in treating infertility.

Focusing on the role of protein kinase mTOR in endometrial physiology and pathology: insights for therapeutic interventions.

The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase crucial for cellular differentiation, proliferation, and autophagy. It shows a complex role in the endometrium, influencing both normal and pathogenic conditions. mTOR promotes the growth and maturation of endometrial cells, enhancing endometrial receptivity and decidualization. However, it also contributes to the development of endometriosis (EMs) and endometrial cancer (EC), thus emerging as a therapeutic target for these conditions. In this review, we summarize recent research progress on the mTOR signalling pathway in the endometrium. This provides insights into female endometrial structure and function and guides the prevention and treatment of related diseases.

Physiotherapeutic differential diagnosis of back pain associated with endometriosis

Endometriosis (EM) is one of the most common gynecologic conditions in our society. The diagnosis takes an average of 7to 10years. To shorten this period, this syndrome needs more attention. The aim of this article is to show overlaps between EM and low back pain (LBP) and to describe their relevance for physiotherapeutic screening. What clinical signs do the syndromes EM and LBP have in common and to what extent can physiotherapeutic screening take gynecological aspects into account and be adapted accordingly? To answer this question, the two syndromes were screened for overlaps. These overlaps were then related to the existing literature and case studies. The current research situation shows overlaps of the two syndromes with regard to the etiology, the pain mechanism as well as apsychosocial aspect. The literature shows that more women than men are affected by LBP and other chronic pain syndromes. EM occurs almost exclusively in women and, like LBP, is considered achronic pain syndrome. Thus, acommon pain mechanism of the two syndromes is discussed in the literature. The most frequent overlap of the two syndromes is shown by the occurrence of LBP as afrequent symptom of EM. This connection can be justified by structural causes as well as by areflex pain presentation. In aphysiotherapeutic setting, evidence of EM can be observed in the history and physical examination. Considering these factors may help shorten the diagnosis time of endometriosis by referring for further evaluation if gynecologic involvement is suspected in LBP. Acomprehensive history is important and should cover urologic, gynecologic, as well as sexual history. In this article, the term woman is used to refer to the biological female sex and is not related to individual gender identity. The clinical picture mainly affects women, which is why in the following work, as far as it concerns the people suffering from the disease, it is not used in the opposite sense.

Paris polyphylla ethanol extract and polyphyllin I ameliorate adenomyosis by inhibiting epithelial–mesenchymal transition

BackgroundThe active ingredients of the Chinese medical herb Paris polyphylla, P. polyphylla ethanol extract (PPE) and polyphyllin I (PPI), potentially inhibit epithelial–mesenchymal transition (EMT) in tumors. However, the roles of these ingredients in inhibiting EMT in adenomyosis (AM) remain to be explored. PurposeThe primary goal of the study was to uncover the underlying molecular processes through which PPE and PPI suppress EMT in AM, alongside assessing the safety profiles of these substances. MethodsTo assess the suppressive impact of PPE on adenomyosis-derived cells (AMDCs), we employed Transwell and wound healing assays. The polyphyllins (PPI, PPII, PPVII) contained in PPE were characterized using high-performance liquid chromatography (HPLC). Then, bioinformatics techniques were performed to pinpoint potential PPI targets that could be effective in treating AM. Immunoblotting was used to verify the key proteins and pathways identified via bioinformatics. Furthermore, we examined the efficacy of PPE and PPI in treating Institute of Cancer Research (ICR) mice with AM by observing the morphological and pathological features of the uterus and performing immunohistochemistry. In addition, we assessed safety by evaluating liver, kidney and spleen pathologic features and serum test results. ResultsThree major polyphyllins of PPE were revealed by HPLC, and PPI had the highest concentration. In vitro experiments indicated that PPE and PPI effectively prevent AMDCs invasion and migration. Bioinformatics revealed that the primary targets E-cadherin, N-cadherin and TGFβ1, as well as the EMT biological process, were enriched in PPI-treated AM. Immunoblotting assays corroborated the hypothesis that PPE and PPI suppress the TGFβ1/Smad2/3 pathway in AMDCs to prevent EMT from progressing. Additionally, in vivo studies showed that PPE (3 mg/kg and 6 mg/kg) and PPI (3 mg/kg and 6 mg/kg), successfully suppressed the EMT process through targeting the TGFβ1/Smad2/3 signaling pathway. Besides, it was observed that lower doses of PPE (3 mg/kg) and PPI (3 mg/kg) exerted minimal effects on the liver, kidneys, and spleen. ConclusionsPPE and PPI efficiently impede the development of EMT by inhibiting the TGFβ1/Smad2/3 pathway, revealing an alternative pathway for the pharmacological treatment of AM.

Role of Cyclins and Cytoskeletal Proteins in Endometriosis: Insights into Pathophysiology.

Endometriosis is a gynecological condition where endometrium-like tissue grows outside the uterus, posing challenges in understanding and treatment. This article delves into the deep cellular and molecular processes underlying endometriosis, with a focus on the crucial roles played by cyclins and cytoskeletal proteins in its pathogenesis, particularly in the context of Epithelial-Mesenchymal Transition (EMT). The investigation begins by examining the activities of cyclins, elucidating their diverse biological roles such as cell cycle control, proliferation, evasion of apoptosis, and angiogenesis among ectopic endometrial cells. A comprehensive analysis of cytoskeletal proteins follows, emphasizing their fundamental biological roles and their specific significance to endometriotic cell features. This review sheds light on the interconnected pathways through which cyclins and cytoskeletal proteins converge, contributing to the genesis and progression of endometriosis. Understanding these molecular complexities not only provides insight into the underlying causes of the disease but also holds promise for the development of specific therapeutic approaches, ushering in a new era in the management of this devastating disorder.

Prefoldin-5 Expression Is Elevated in Eutopic and Ectopic Endometriotic Epithelium and Modulates Endometriotic Epithelial Cell Proliferation and Migration In Vitro.

Endometriosis is a common disease among women of reproductive age in which endometrial tissue grows in ectopic localizations, primarily within the pelvic cavity. These ectopic "lesions" grow as well as migrate and invade underlying tissues. Despite the prevalence of the disease, an understanding of factors that contribute to these cellular attributes remains poorly understood. Prefoldin-5 (PFDN5) has been associated with both aberrant cell proliferation and migration, but a potential role in endometriosis is unknown. As such, the purpose of this study was to examine PFDN5 expression in endometriotic tissue. PFDN5 mRNA and protein were examined in ectopic (lesion) and eutopic endometrial tissue from women with endometriosis and in eutopic endometrium from those without endometriosis using qRT-PCR and immunohistochemistry, respectively, while function of PFDN5 in vitro was evaluated using cell count and migration assays. PFDN5 mRNA and protein were expressed in eutopic and ectopic endometrial tissue, predominantly in the glandular epithelium, but not in endometrium from control subjects. Expression of both mRNA and protein was variable among endometriotic eutopic and ectopic endometrial tissue but showed an overall net increase. Knockdown of PFDN5 by siRNA transfection of endometriotic epithelial 12Z cells was associated with reduced cell proliferation/survival and migration. PFDN5 is expressed in eutopic and ectopic glandular epithelium and may play a role in proliferation and migration of these cells contributing to disease pathophysiology.

Unraveling the microbial puzzle: exploring the intricate role of gut microbiota in endometriosis pathogenesis.

Endometriosis (EMs) is a prevalent gynecological disorder characterized by the growth of uterine tissue outside the uterine cavity, causing debilitating symptoms and infertility. Despite its prevalence, the exact mechanisms behind EMs development remain incompletely understood. This article presents a comprehensive overview of the relationship between gut microbiota imbalance and EMs pathogenesis. Recent research indicates that gut microbiota plays a pivotal role in various aspects of EMs, including immune regulation, generation of inflammatory factors, angiopoietin release, hormonal regulation, and endotoxin production. Dysbiosis of gut microbiota can disrupt immune responses, leading to inflammation and impaired immune clearance of endometrial fragments, resulting in the development of endometriotic lesions. The dysregulated microbiota can contribute to the release of lipopolysaccharide (LPS), triggering chronic inflammation and promoting ectopic endometrial adhesion, invasion, and angiogenesis. Furthermore, gut microbiota involvement in estrogen metabolism affects estrogen levels, which are directly related to EMs development. The review also highlights the potential of gut microbiota as a diagnostic tool and therapeutic target for EMs. Interventions such as fecal microbiota transplantation (FMT) and the use of gut microbiota preparations have demonstrated promising effects in reducing EMs symptoms. Despite the progress made, further research is needed to unravel the intricate interactions between gut microbiota and EMs, paving the way for more effective prevention and treatment strategies for this challenging condition.

Galectin-3 promotes fibrosis in ovarian endometriosis.

This study aimed to investigate the potential role of galectin-3 (Gal-3) in the pathogenesis of fibrotic alterations in ovarian endometriosis (OVE). In this study, we collected the ectopic endometrial tissues and eutopic endometrial tissues from 31 OVE patients treated by laparoscopy, and the eutopic endometrial tissues from 23 non-OVE patients with leiomyoma or other benign diseases were used as control. Hematoxylin and eosin (H&E) and Masson's trichrome staining were utilized for histopathological assessment. The primary normal endometrial stromal cells (NESC), ectopic endometrial stromal cells (ECSC), and eutopic endometrial stromal cells (EUSC) were isolated. Gal-3 overexpression plasmids (Gal-OE) and short hairpin RNA targeting Gal-3 (Gal-3-shRNA) were transfected into the immortalized human endometriotic cell line 12Z, respectively. RT-qPCR, Western blot analysis, and immunohistochemistry were used to detect the mRNA and protein expression levels of Gal-3, type I collagen (COL-1), connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA), respectively. H&E and Masson staining showed that ovarian ectopic endometrium exhibited glandular hyperplasia, high columnar glandular epithelium, apical plasma secretion, more subnuclear vacuoles, and obvious fibrosis, compared with normal endometrium. The mRNA and protein levels of Gal-3 , CTGF, α-SMA, and COL-1 were all upregulated in the ectopic endometrial tissues of OVE patients compared to the eutopic endometrial tissues from OVE patients and non-OVE patients. Moreover, ECSC expressed higher levels of Gal-3, CTGF, α-SMA, and COL-1 than EUSC and NESC. Follow-up investigations demonstrated that the Gal-3 overexpression substantially increased fibrosis-related markers including CTGF, α-SMA, and COL-1 within the 12Z cell line. Conversely, Gal-3 knockdown showed the opposite effects. Gal-3 promotes fibrosis in OVE, positioning it as a prospective therapeutic target for mitigating fibrosis in endometriosis.

Brainstem nuclei responsive to cystometry in both endometriosis and cystitis rat models: C-fos immunohistochemistry study.

Although the co-occurrence of interstitial cystitis (IC) and endometriosis (ENDO) is remarkably high, the exact pathophysiology for this co-occurrence is unknown. The convergence of the inputs from the involved structures to the same neuronal centers may suggest neuronal hyperexcitability as a mechanism for this co-occurrence. The present study aimed to investigate the association between IC and ENDO, by studying the changes in brainstem responses to cystometry in a rat model of ENDO and cyclophosphamide (CYP)-induced IC using c-fos immunohistochemistry. Following cystometry the brainstem areas that had significant increase in c-fos expression in ENDO alone included: periaqueductal gray (PAG) nuclei, dorsal raphe nucleus, raphe obscurus nucleus, kolliker- Fuse areas, and area postrema. However, the brainstem areas that had increased significantly in the c-fos expression in the ENDO and CYP treated animals included: gigantocellular nucleus, lateral paragigantocellular nucleus, caudoventrolateral nucleus, rostroventrolateral/caudoventrolateral nucleus, lateral reticular nucleus, locus coeruleus, lateral PAG, raphe pallidus nucleus, raphe magnus nucleus, rostroventrolateral nucleus, dorsal motor nucleus of vagus, and solitary tract nucleus. Whereas only lateral parabrachial nucleus showed significant increase in c-fos expression in CYP treated animals alone. The results of the present study demonstrate the overlap of brainstem nuclei that are excited by urinary bladder under ENDO and IC conditions. The pattern of hyperexcitability of the brainstem nuclei may help in understating the pathophysiology of IC and ENDO conditions.