Wenshen Xiaozheng Tang alleviates fibrosis in endometriosis by regulating differentiation and paracrine signaling of endometrium-derived mesenchymal stem cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Wenshen Xiaozheng Tang (WXT), a traditional Chinese medicine (TCM) decoction, is effective for treating endometriosis. However, the effect of WXT on endometrium-derived mesenchymal stem cells (eMSCs) which play a key role in the fibrogenesis of endometriosis requires further elucidation. AIMS OF THE STUDY: The aim of this study was to clarify the potential mechanism of WXT in improving fibrosis in endometriosis by investigating the regulation of WXT on differentiation and paracrine of eMSCs. MATERIALS AND METHODS: The nude mice with endometriosis were randomly divided into model group, WXT group and mifepristone group. After 21 days of treatment, the lesion volume was calculated. Fibrosis in the lesions was evaluated by Masson staining and expression of fibrotic proteins. The differentiation of eMSCs in vivo was explored using a fate-tracking experiment. To further clarify the regulation of WXT on eMSCs, primary eMSCs from the ectopic lesions of endometriosis patients were isolated and characterized. The effect of WXT on the proliferation and differentiation of ectopic eMSCs was examined. To evaluate the role of WXT on the paracrine activity of ectopic eMSCs, the conditioned medium (CM) from ectopic eMSCs pretreated with WXT was collected and applied to treat ectopic endometrial stromal cells (ESCs), after which the expression of fibrotic proteins in ectopic ESCs was assessed. In addition, transcriptome sequencing was used to investigate the regulatory mechanism of WXT on ectopic eMSCs, and western blot and ELISA were employed to determine the key mediator. RESULTS: WXT impeded the growth of ectopic lesions in nude mice with endometriosis and reduced collagen deposition and the expression of fibrotic proteins fibronectin, collagen I, α-SMA and CTGF in the endometriotic lesions. The fate-tracking experiment showed that WXT prevented human eMSCs from differentiating into myofibroblasts in the nude mice. We successfully isolated eMSCs from the lesions of patients with endometriosis and demonstrated that WXT suppressed proliferation and myofibroblast differentiation of ectopic eMSCs. Moreover, the expression of α-SMA, collagen I, fibronectin and CTGF in ectopic ESCs was significantly down-regulated by the CM of ectopic MSCs pretreated with WXT. Combining the results of RNA sequencing, western blot and ELISA, we found that WXT not only reduced thrombospondin 4 expression in ectopic eMSCs, but also decreased thrombospondin 4 secretion from ectopic eMSCs. Thrombospondin 4 concentration-dependently upregulated the expression of collagen I, fibronectin, α-SMA and CTGF in ectopic ESCs, indicating that thrombospondin 4 was a key mediator of WXT in inhibiting the fibrotic process in endometriosis. CONCLUSION: WXT improved fibrosis in endometriosis by regulating differentiation and paracrine signaling of eMSCs. Thrombospondin 4, whose release from ectopic eMSCs is inhibited by WXT, may be a potential target for the treatment of endometriosis.

Mpox infection of stromal cells and macrophages of macaque with endometriosis.

The mpox outbreak of 2022-2023 represented a new global health challenge and recognition of mpox as a sexually transmitted disease. The majority of cases were reported in men who have sex with men (MSM), but women are also susceptible, especially during pregnancy. We evaluated the reproductive tracts of a subset of macaques from a large rechallenge study of mpox infection with virus from the 2022 outbreak and identified intraabdominal mpox replication associated with endometriosis. Mpox virus (MPXV) was found not only in skin, but in the cervix, the uterus, and periovarian endometriotic lesions of the affected macaque. Mpox replication preferentially targeted vimentin-positive poorly differentiated endometriotic stromal tissue and infiltrating macrophages in the reproductive tract. Mpox tropism for stromal cells and macrophages has broad implications for mpox pathogenesis and associated clinical syndromes. In addition, women with endometriosis may be at heightened risk for adverse outcomes associated with mpox infection. The rhesus macaque provides rare insight into this disease and the potential complications of mpox infection in the context of genitourinary tract disease.

Research progress of ferroptosis in female infertility.

Ferroptosis is a novel type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides in cells and is closely related to various diseases. Female infertility is a global health concern, which is associated with a variety of factors. The etiology remains unknown in many women with infertility. With further investigation into the pathogenesis of infertility, a growing number of studies have demonstrated the close connections between infertility and ferroptosis. Through a literature review, it is found that ferroptosis is closely involved in endometriosis- and polycystic ovarian syndrome (PCOS)-associated infertility and tubal factor infertility. Iron overload increases the resistance to ferroptosis, and ferroptosis in some cells accelerates endometrial lesion growth. Moreover, iron overload may be hazardous to oocytes. This review may shed some light on the diagnosis and treatment of female infertility.

Single-cell analysis identifies distinct macrophage phenotypes associated with prodisease and proresolving functions in the endometriotic niche.

Endometriosis negatively impacts the health-related quality of life of 190 million women worldwide. Novel advances in nonhormonal treatments for this debilitating condition are desperately needed. Macrophages play a vital role in the pathophysiology of endometriosis and represent a promising therapeutic target. In the current study, we revealed the full transcriptomic complexity of endometriosis-associated macrophage subpopulations using single-cell analyses in a preclinical mouse model of experimental endometriosis. We have identified two key lesion-resident populations that resemble i) tumor-associated macrophages (characterized by expression of Folr2, Mrc1, Gas6, and Ccl8+) that promoted expression of Col1a1 and Tgfb1 in human endometrial stromal cells and increased angiogenic meshes in human umbilical vein endothelial cells, and ii) scar-associated macrophages (Mmp12, Cd9, Spp1, Trem2+) that exhibited a phenotype associated with fibrosis and matrix remodeling. We also described a population of proresolving large peritoneal macrophages that align with a lipid-associated macrophage phenotype (Apoe, Saa3, Pid1) concomitant with altered lipid metabolism and cholesterol efflux. Gain of function experiments using an Apoe mimetic resulted in decreased lesion size and fibrosis, and modification of peritoneal macrophage populations in the preclinical model. Using cross-species analysis of mouse and human single-cell datasets, we determined the concordance of peritoneal and lesion-resident macrophage subpopulations, identifying key similarities and differences in transcriptomic phenotypes. Ultimately, we envisage that these findings will inform the design and use of specific macrophage-targeted therapies and open broad avenues for the treatment of endometriosis.

Progesterone receptor B over progesterone receptor A prevents recurrence in bilateral endometriomas.

OBJECTIVE: Endometriosis is a disease in which stromal cells and endometrial glands extend outside of the uterine cavity. Nevertheless, treatment failure and recurrence cause difficulties in management. This study aimed to evaluate the receptor-level components of bilateral endometriomas in the recurrence state. METHODS: Our retrospective cohort study was conducted with patients who underwent surgery for bilateral endometriomas between 2015 and 2021. In total, 113 patients were allocated. A total of 76 patients did not meet the eligibility criteria, and the data of 37 patients were evaluated. Medical treatments, recurrences, and postoperative follow-up data were collected. In archived tissue samples, measurements of progesterone receptor A and progesterone receptor B, histoscores and immunoreactivity scores, and their ratios were calculated in the group that received no postoperative medical treatment. Criteria for recurrence were a repeat operation and/or the detection of a new endometrioma>2 cm at the follow-up examination. RESULTS: No recurrence was observed in 73.0% (n=27) of the cases, whereas recurrence was observed in 27.0% (n=10) of the participants. Patients without recurrence had significantly higher progesterone receptor B histoscore/progesterone receptor A histoscore and progesterone receptor B immunoreactivity score/progesterone receptor A immunoreactivity score results (p=0.01). Nevertheless, when the histoscores and immunoreactivity scores for both receptors were contrasted separately, there was no appreciable difference between them. CONCLUSION: The dominance of progesterone receptor B over progesterone receptor A was inversely proportional to the recurrence status in bilateral endometriomas. Furthermore, our study revealed that assessing receptor levels alone did not result in a significant difference in recurrence.

Clinical efficacy of dienogest against endometriomas with a maximum diameter of ≥4 cm.

OBJECTIVE: This prospective observational study aims to demonstrate the clinical efficacy of dienogest in treating endometriomas with a maximum diameter of ≥4 cm. METHODS: Patients (n = 81) with endometriomas (diameter of ≥4 cm) were enrolled and administered orally with dienogest (2 mg daily) and followed up for a year [Ethical approval code: 2020 Research 343]. Further, the efficacy was determined by recording the largest diameter and volume of the endometriomas, uterine volume, endometrial thickness, and the largest diameter of uterine fibroids in the patients during 0, 6, and 12 months. The pain symptoms were assessed using the Numerical Rating Scale (NRS), and the side effects of medication were monitored. With the consent, some patients underwent routine blood tests, and serum hormone, as well as Anti-Müllerian Hormone (AMH) levels were measured. RESULTS: The dienogest treatment resulted in a significant reduction of the maximum diameter of these cysts from 50.5 mm to 41 mm in 6 months and 34 mm in 12 months. In addition, the volume of the cysts significantly decreased from 37.8 ml from baseline to 18.5 ml in 6 months and 11.8 ml in 12 months. Among 26 subjects with ultrasonic signs of endometrial polyps, 92.3% of cases displayed no polyps after 12 months. No significant changes were observed in the size of uterine fibroids and AMH levels. The NRS score showed a decrease from an average of 6.6-1.2 in 12 months. CONCLUSION: Dienogest could effectively reduce the diameter and volume of endometriomas with a maximum diameter of ≥4 cm, improving anemia, as well as pain symptoms and preserving ovarian function.

NLRC5 exerts anti-endometriosis effects through inhibiting ERß-mediated inflammatory response.

BACKGROUND: Endometriosis is well known as a chronic inflammatory disease. The development of endometriosis is heavily influenced by the estrogen receptor ß (ERß), while NOD-like receptors (NLRs) family CARD domain-containing 5 (NLRC5) exhibits anti-inflammatory properties during endometriosis. However, whether NLRC5-mediated anti-inflammation is involved in the ERß-mediated endometriosis is still uncertain. This study aimed to assess that relation. METHODS: Nine cases of eutopic endometrial tissue and ten cases of ectopic endometrial tissue were collected from patients with endometriosis, and endometrial samples from ten healthy fertile women were analyzed, and the expression levels of ERß were quantified using immunohistochemistry (IHC). Subsequently, we constructed mouse model of endometriosis by intraperitoneal injection. We detected the expression of ERß, NLRC5, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-10 and measured the volume of ectopic lesions in mice with endometriosis. In vitro, human endometrial stromal cells (hESCs) were transfected respectively with ERß-overexpressing and NLRC5-overexpressing plasmids. We then assessed the expression of ERß and NLRC5 using quantitative real-time PCR (qRT-PCR) and western blot analysis. Furthermore, we measured the concentrations of TNF-α, IL-6, and IL-10 in the cell culture supernatant through enzyme-linked immunosorbent assay (ELISA). Additionally, we evaluated the migration and invasion ability of hESCs using transwell and wound healing assays. RESULTS: Inhibition of NLRC5 expression promotes the development of ectopic lesions in mice with endometriosis, upregulates the expression of pro-inflammatory factors TNF-α and IL-6, and downregulates the expression of anti-inflammatory factor IL-10. The high expression of NLRC5 in endometriosis depended on the ERß overexpression. And ERß promoted the migration of hESCs partially depend on inflammatory microenvironment. Lastly, NLRC5 overexpression inhibited ERß-mediated development and inflammatory response of endometriosis. CONCLUSIONS: Our results suggest that the innate immune molecule NLRC5-mediated anti-inflammation participates in ERß-mediated endometriosis development, and partly clarifies the pathological mechanism of endometriosis, expanding our knowledge of the specific molecules related to the inflammatory response involved in endometriosis and potentially providing a new therapeutic target for endometriosis.

Integrin ß3 enhances glycolysis and increases lactate production in endometriosis.

BACKGROUND: Endometriosis (EMs) is a chronic disease characterized by endometrial-like tissue present outside of the uterus. Macrophages have been confirmed to participate in the development of EMs. Integrin ß3 (ITGB3), a ß-subunit of the integrin family, is crucial in tumor progression. In this study, we investigated the pivotal role of ITGB3 in endometrial stromal cells (ESCs) and its influence on the development of EMs, particularly focusing on the regulatory impact of macrophages. METHODS: In this study, we used western blot, Real-time qPCR, Immunohistochemistry to detected the high expression of ITGB3 in ESCs. ITGB3-overexpression ESCs (ITGB3-OE) was constructed and detected by RNA-seq with normal ESCs. ATP and lactate expression assay, transwell migration assay, wound healing, cell adhesion assay and other molecular biology techniques were used to explore the potential mechanisms. In vivo, we constructed the EMs mouse model and injected with cilengitite to inhibit ITGB3. RESULTS: Here, we found ITGB3 highly expressed in ectopic lesions in EMs. The increasing ITGB3 resulted in activating the glycolysis, which produced more ATP and lactate in ITGB3-OE. After culturing with lactate, the migration, proliferation and invasion ability of ESCs were enhanced, while the result in 2-DG was reversed. In vivo, the results showed that after antagonizing ITGB3, the number of ectopic lesions was decrease. CONCLUSIONS: Our findings indicate that ITGB3 up-regulated by macrophages are able to regulate the glycolysis to promote the development of EMs and lactate enhances the ability of proliferation, migration, invasion and adhesion of EMs iv vivo and in vitro.

Efficacy of colchicine and melatonin in the treatment of rat endometriosis model: An animal study.

OBJECTIVE: This study investigates the therapeutic effects of colchicine and melatonin on endometriotic implants in an experimentally created endometriosis model in rats. STUDY DESIGN: Forty-four adult female Wistar albino rats weighing between 260 and 300 g, 8 weeks old, were selected for the study. The unilateral uterine horn of rats with a bicornuate uterus was excised for 1 cm, washed with sterile saline, incised longitudinally, and the endometrium was exposed. A 0.5*0.5 cm endometrial tissue sample taken with a scalpel was implanted with suturing (4/0 Vicryl) to the abdominal wall. Forty-four rats were divided into four groups. Group 1 was randomized as the endometriosis group (control), Group 2 as endometriosis + colchicine treatment, Group 3 as endometriosis + melatonin treatment, and Group 4 as the endometriosis + melatonin + colchicine treatment group. The colchicine (Sigma Chemical Co., St Louis, Missouri) group was administered orally at a dose of 0.1 mg/kg, and the Melatonin group orally at a dose of melatonin (20 mg/kg per day). Treatment continued daily for 30 days. RESULTS: In the post-treatment focal diameter measurements, the endometrial focal diameter in the colchicine and colchicine + melatonin group was significantly lower than the control group (p=0.026). Bcl-2 levels of the colchicine group were lower than the control group and the melatonin group (p=0.021). CONCLUSION: Colchicine and melatonin reduce adhesion to the peritoneal surface in ectopic endometrial cells. It also acts by increasing apoptosis and decreasing cell survival.

CCL18 promotes endometriosis by increasing endometrial cell migration and neuroangiogenesis.

Endometriosis is an estrogen-dependent inflammatory gynecological disease whose pathogenesis is unclear. C-C motif chemokine ligand 18 (CCL18), a chemokine, is involved in several inflammatory diseases. In this study, we aimed to investigate the role of CCL18 in endometriosis and its underlying mechanisms. Human endometrium and peritoneal fluid were obtained from women with and without endometriosis for molecular studies. The expression level of CCL18 in each tissue sample was examined by RNA sequencing analysis, quantitative PCR analysis and immunohistochemistry staining. The effects of CCL18 on cell migration, tube formation and neurite growth were investigated in vitro using primary endometrial cells, human umbilical vein endothelial cells (HUVECs) and dorsal root ganglion (DRG) neurons, respectively. Moreover, the development of endometriosis in mice was studied in vivo by blocking CCL18. CCL18 was shown to be overexpressed in endometrial foci and peritoneal fluid in women with endometriosis and was positively correlated with endometriosis pain. In vitro, CCL18 promoted the migration of ectopic endometrial cells, tube formation of HUVECs, and nerve outgrowth of DRG neurons. More importantly, inhibition of CCL18 significantly suppressed lesion development, angiogenesis, and nerve infiltration in a mouse model of endometriosis. In conclusion, CCL18 may play a role in the progression of endometriosis by increasing endometrial cell migration and promoting neuroangiogenesis.

Potential anatomical determinants of retrograde menstruation: a comprehensive narrative review.

A century ago, Sampson identified three uterine anatomical structures that may determine the amount of retrograde menstruation and the likelihood of the development of endometriosis: the cervix, the intramural portion of the fallopian tubes, and the myometrium. Critical appraisal was undertaken of data published over the last 40 years on the potential effect of the characteristics of these three anatomical variables on the risk of endometriosis. There is some evidence to support the pathogenic role of the diameter of the cervical canal, stenosis of internal or external orifices, and stiffness of cervical tissue. One study showed a significant association between the morphology of the intramural tubal tract and the frequency of endometriosis. A large body of evidence points to abnormalities of the myometrial structure as the anatomical aberration most consistently associated with endometriosis. These abnormalities have largely been interpreted as signs of early-onset adenomyosis, which may precede endometriosis and even lead to its development by increasing the amount of retrograde menstruation. Future research should aim to verify whether a positive relationship exists between the substantially increased number of ovulatory menses occurring in the decade following menarche, the development of anatomical myometrial abnormalities, changes in the amount of retrograde menstruation over time, and the risk of endometriosis.

An integrated single-cell reference atlas of the human endometrium.

The complex and dynamic cellular composition of the human endometrium remains poorly understood. Previous endometrial single-cell atlases profiled few donors and lacked consensus in defining cell types. We introduce the Human Endometrial Cell Atlas (HECA), a high-resolution single-cell reference atlas (313,527 cells) combining published and new endometrial single-cell transcriptomics datasets of 63 women with and without endometriosis. HECA assigns consensus and identifies previously unreported cell types, mapped in situ using spatial transcriptomics and validated using a new independent single-nuclei dataset (312,246 nuclei, 63 donors). In the functionalis, we identify intricate stromal-epithelial cell coordination via transforming growth factor beta (TGFß) signaling. In the basalis, we define signaling between fibroblasts and an epithelial population expressing progenitor markers. Integration of HECA with large-scale endometriosis genome-wide association study data pinpoints decidualized stromal cells and macrophages as most likely dysregulated in endometriosis. The HECA is a valuable resource for studying endometrial physiology and disorders, and for guiding microphysiological in vitro systems development.

Endometriosis of the appendix: prevalence, associated lesions, and proposal of pathogenetic hypotheses. A retrospective cohort study with prospectively collected data.

OBJECTIVE: To assess the prevalence of endometriosis of the appendix and the association with other pelvic localizations of the disease and to provide pathogenesis hypotheses. METHODS: Monocentric, observational, retrospective, cohort study. Patients undergoing laparoscopic endometriosis surgery in our tertiary referral center were consecutively enrolled. The prevalence of the different localizations of pelvic endometriosis including appendix involvement detected during surgery was collected. Included patients were divided into two groups based on the presence of appendiceal endometriosis. Women with a history of appendectomy were excluded. MEASUREMENTS AND MAIN RESULTS: Four hundred-sixty patients were included for data analysis. The prevalence of appendiceal endometriosis was 2.8%. In patients affected by endometriosis of the appendix, concomitant ovarian and/or bladder endometriosis were more frequently encountered, with prevalence of 53.9% (vs 21.0% in non-appendiceal endometriosis group, p = 0.005) and 38.4% (vs 11.4%, p = 0.003), respectively. Isolated ovarian endometriosis was significantly associated to appendiceal disease compared to isolated uterosacral ligament (USL) endometriosis or USL and ovarian endometriosis combined (46.2% vs 15.4% vs 7.7%, p < 0.001). Poisson regression analysis revealed a 4.1-fold and 4.4-fold higher risk of ovarian and bladder endometriosis, respectively, and a 0.1-fold risk of concomitant USL endometriosis in patients with appendiceal involvement. CONCLUSION: Involvement of the appendix is not uncommon among patients undergoing endometriosis surgery. Significant association was detected between appendiceal, ovarian, and bladder endometriosis that may be explained by disease dissemination coming from endometrioma fluid shedding. Given the prevalence of appendiceal involvement, counseling regarding the potential need for appendectomy during endometriosis surgery should be considered.

A rare case of concomitant endometrioid adenocarcinoma arising from uterine adenomyosis and clear cell carcinoma arising from parametrial deep endometriosis.

BACKGROUND: Carcinomatous changes from the ectopic endometrial glands in endometriosis have been reported in many studies, but malignant transformation from uterine adenomyosis/adenomyoma is rare. And clear cell-like adenocarcinoma represents a seldom-encountered malignant pathological variant of ectopic endometrium. CASE PRESENTATION: This case report presents a case of a 44-year-old nulliparous woman begun with abdominal pain and intestinal obstruction. Past medical history showed laparoscopic ovarian endometriotic cyst excision. Ultrasound indicated adenomyoma and a parametrial hypoechoic nodule with abundant blood flow signals and unclear boundaries. Deep invasive endometriosis was considered preoperatively. The patient underwent laparoscopic subtotal hysterectomy and bilateral adnexa resection. Chocolate cyst-like lesion was observed in the parametral lesion. Postoperative pathological examinations suggested endometrioid adenocarcinoma arising from eutopic endometrium and adenomyoma. Ectopic endometrium in the myometrium combined with atypical hyperplasia and formation of endometrioid adenocarcinoma. Left parametrial lesions suggested poorly differentiated endometrioid adenocarcinoma combined with clear cell carcinoma. CD10 + endometrial stromal cells were observed surrounding tumor cell masses. Combined with surgical founding and pathological characters of the left parametrial adenocarcinoma, the parametrial lesions were more likely to be carcinomatous changes of the original deep endometriosis.The patient underwent subsequent transabdominal tumor cell reduction surgery and chemotherapy. CONCLUSION: We herein present a rare case of combined endometrioid adenocarcinoma arising from uterine adenomyosis and clear cell carcinoma arising from parametrial deep endometriosis that may help inspire additional studies in the future. The patient underwent robot-assisted laparoscopic subtotal hysterectomy, bilateral adnexa resection, deep endometriosis lesion resection and bilateral ureteral stent placement. Following surgery, a chemotherapy regimen of Taxol and Carboplatin was administered.

The involvement of peritoneal GATA6+ macrophages in the pathogenesis of endometriosis.

Endometriosis is a chronic inflammatory disease that causes debilitating pelvic pain in women. Macrophages are considered to be key players in promoting disease progression, as abundant macrophages are present in ectopic lesions and elevated in the peritoneum. In the present study, we examined the role of GATA6+ peritoneal macrophages on endometriosis-associated hyperalgesia using mice with a specific myeloid deficiency of GATA6. Lesion induction induced the disappearance of TIM4hi MHCIIlo residential macrophages and the influx of increased Ly6C+ monocytes and TIM4lo MHCIIhi macrophages. The recruitment of MHCIIhi inflammatory macrophages was extensive in Mac Gata6 KO mice due to the severe disappearance of TIM4hi MHCIIlo residential macrophages. Ki67 expression confirmed GATA6-dependent proliferative ability, showing different proliferative phenotypes of TIM4+ residential macrophages in Gata6f/f and Mac Gata6 KO mice. Peritoneal proinflammatory cytokines were elevated after lesion induction. When cytokine levels were compared between Gata6f/f and Mac Gata6 KO mice, TNFα at day 21 in Gata6f/f mice was higher than in Mac Gata6 KO mice. Lesion induction increased both abdominal and hind paw sensitivities. Gata6f/f mice tended to show higher sensitivity in the abdomen after day 21. Elevated expression of TRPV1 and CGRP was observed in the dorsal root ganglia after ELL induction in Gata6f/f mice until days 21 and 42, respectively. These results support that peritoneal GATA6+ macrophages are involved in the recruitment and reprogramming of monocyte-derived macrophages. The extensive recruitment of monocyte-derived macrophages in Mac Gata6 KO mice might protect against inflammatory stimuli during the resolution phase, whereas GATA6 deficiency did not affect lesion initiation and establishment at the acute phase of inflammation. GATA6+ residential macrophages act to sustain local inflammation in the peritoneum and sensitivities in the neurons, reflecting endometriosis-associated hyperalgesia.

Induction and characterization of a rat model of endometriosis.

Endometriosis is a common condition that affects 5% to 10% of women during their reproductive years, although the aetiology and pathophysiology are still unknown. This study aimed to create an endometriosis model in rats to investigate the efficacy of natural and synthetic medications in treating endometriosis. An in vivo endometriotic model was established using a surgical induction method and the endocrine-disrupting drug diethylstilbestrol (DES). In brief, the experiment is categorised into three different groups. Each group contains five rats. The first group had no surgery, while in the in the second group of rats (n = 5), two small tissue grafts were fixed at the right and left walls of the abdomen. But in the in the third group of rats (n = 5), two small pieces of tissue have been grafted on the right and left abdomen walls by surgically along with DES treatments. Noninvasive photoacoustic imaging (PAI) was employed in the study to measure factors such as haemoglobin levels, oxygen saturation, and the size of endometriotic lesions. Histopathological analysis was carried out utilising staining techniques such as Hematoxylin and Eosin, Masson's Trichrome, and Periodic Acid Schiff, as well as immunohistochemistry with marker antibodies. Molecular markers in uterine tissue were examined using Western blots and real-time PCR. The developed endometriosis rat model showed a significant increase in the expression of anti-apoptotic Bcl-2, angiogenic marker VEGF and pro-inflammatory (COX-2 and IL-6) protein markers. In contrast to the control group, the treatment group had considerably lower Caspase-3 expression levels. Photoacoustic imaging (PAI) data demonstrated a constant increase in lesion size, as well as a decrease in oxygen saturation levels. The findings suggest that the in vivo endometriosis rat model may accurately assess the efficacy of natural or synthetic endometriosis treatments. This model may help in the improvement of disease understanding and the development of targeted therapeutic drugs.

Cannabidiol as a possible treatment for endometriosis through suppression of inflammation and angiogenesis.

BACKGROUND: Endometriosis is associated with a wide variety of signs and symptoms and can lead to infertility, embryo death, and even miscarriage. Although the exact pathogenesis and etiology of endometriosis is still unclear, it has been shown that it has a chronic inflammatory nature and angiogenesis is also involved in it. OBJECTIVE: This review aims to explore the role of inflammation and angiogenesis in endometriosis and suggest a potential treatment targeting these pathways. FINDINGS: Among the pro-inflammatory cytokines, studies have shown solid roles for interleukin 1ß (IL-ß), IL-6, and tumor necrosis factor α (TNF-α) in the pathogenesis of this condition. Other than inflammation, angiogenesis, the formation of new blood vessels from pre-existing capillaries, is also involved in the pathogenesis of endometriosis. Among angiogenic factors, vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α), transforming growth factor ß1 (TGF-ß1), and matrix metalloproteinases (MMPs) are more essential in the pathogenesis of endometriosis. Interestingly, it has been shown that inflammation and angiogenesis share some similar pathways with each other that could be potentially targeted for treatment of diseases caused by these two processes. Cannabidiol (CBD) is a non-psychoactive member of cannabinoids which has well-known and notable anti-inflammatory and antiangiogenic properties. This agent has been shown to decrease IL-1ß, IL-6, TNF-α, VEGF, TGFß, and MMPs in different animal models of diseases. CONCLUSION: It seems that CBD could be a possible treatment for endometriosis due to its anti-inflammatory and antiangiogenic activity, however, further studies are needed.

Identification and Validation of Prognostic Markers for Endometriosis-Associated Ovarian Cancer.

Background: Growing evidence suggests that endometriosis (EMs) is a risk factor for endometriosis-associated ovarian cancer (EAOC). The aim was to identify and validate gene signatures associated with EMs that may serve as potential biomarkers for evaluating the prognosis of patients with EAOC. Methods: The data of EMs and control samples was obtained from GEO database. The weighted gene co-expression network analysis (WGCNA) identified modular genes significantly associated with EMs. The KEGG pathway and GO functional enrichment analyses were also performed. Univariate Cox regression analysis was conducted to screen marker genes associated with the prognosis of EAOC patients. Finally, RT-qPCR and immunohistochemical verified the expression of ADAMTS19 and TUBB in normal ovarian and EAOC tissues, and the biological functions of ADAMTS19 and TUBB were preliminarily explored by CCK8 and Transwell assays. Results: The WGCNA identified 2 co-expression modules, which in total included 615 genes, and 7642 differentially expressed genes (DEGs) were detected thorough analysis of the EAOC dataset. After taking the intersection of 615 modular genes and 7642 DEGs, 214 shared genes were obtained, and univariate COX regression analysis pointed 10 genes associated with the prognosis of EAOC. Moreover, it was demonstrated by RT-qPCR and immunohistochemical staining experiments that ADAMTS19 expression was elevated, while TUBB expression was reduced in EAOC compared with normal ovarian cells and tissues. Finally, cell experiments revealed that ADAMTS19 promoted the proliferation and invasion in EAOC cells, while overexpression of TUBB inhibited these processes. Conclusions: The present study identified and validated new EMs-associated gene markers, which could serve as potential biomarkers for assessing the prognostic risk of EAOC patients. In addition, some of these genes may have significance as novel therapeutic targets and could be used to guide clinical applications.

Endocannabinoids and their receptors modulate endometriosis pathogenesis and immune response.

Endometriosis (EM), characterized by the presence of endometrial-like tissue outside the uterus, is the leading cause of chronic pelvic pain and infertility in females of reproductive age. Despite its high prevalence, the molecular mechanisms underlying EM pathogenesis remain poorly understood. The endocannabinoid system (ECS) is known to influence several cardinal features of this complex disease including pain, vascularization, and overall lesion survival, but the exact mechanisms are not known. Utilizing CNR1 knockout (k/o), CNR2 k/o, and wild-type (WT) mouse models of EM, we reveal contributions of ECS and these receptors in disease initiation, progression, and immune modulation. Particularly, we identified EM-specific T cell dysfunction in the CNR2 k/o mouse model of EM. We also demonstrate the impact of decidualization-induced changes on ECS components, and the unique disease-associated transcriptional landscape of ECS components in EM. Imaging mass cytometry (IMC) analysis revealed distinct features of the microenvironment between CNR1, CNR2, and WT genotypes in the presence or absence of decidualization. This study, for the first time, provides an in-depth analysis of the involvement of the ECS in EM pathogenesis and lays the foundation for the development of novel therapeutic interventions to alleviate the burden of this debilitating condition.

Magnetic resonance imaging evaluation of gynecological mass lesions: A comprehensive analysis with histopathological correlation.

Evaluating gynecological mass lesions and reviewing their morphological characteristics based on their imaging appearance on magnetic resonance imaging (MRI), and correlating the MRI findings with histopathological findings, was the central theme of our study. This observational cross-sectional study was conducted on 60 female patients with clinically suspected gynecological mass lesions upon physical examination and/or ultrasonography, referred for MRI at a tertiary care hospital over a 1-year period between June 2022 and July 2023. A broad spectrum of differential diagnoses of gynecological masses was observed. In our study, the ratio of benign versus malignant disease was 1.6:1, with 37 benign and 23 malignant masses identified. The most common benign masses were uterine fibroids (n = 14; 23.3%), followed by endometriosis (n = 8; 13.3%), and ovarian dermoid cysts (n = 4; 6.6%). Among the malignant lesions, cervical cancer was the most common (n = 11; 18.3%), followed by endometrial carcinoma (n = 7; 11.6%), ovarian carcinoma (n = 3; 5%), and vaginal carcinoma (n = 2; 3%). Benign lesions mostly appeared hypo- to isointense on T1-weighted imaging and iso- to hyperintense on T2-weighted imaging, while malignant lesions appeared isointense on T1-weighted and hyperintense on T2-weighted imaging. Hemorrhage and fat were well appreciated on MRI and aided in diagnosis. T2 shading was present in 7 out of 8 endometriotic cysts, demonstrating a specificity of 100% and a sensitivity of 83%. For determining parametrial invasion in cervical carcinoma, MRI showed an accuracy of 91%, specificity of 100%, and positive predictive value, negative predictive value, and sensitivity of 100%, 75%, and 88%, respectively. In cases of endometrial carcinoma, MRI demonstrated a sensitivity and specificity of 87% and 91%, respectively, with a positive predictive value of 87% and a negative predictive value of 91% for identifying myometrial invasion greater than 50%. Compared to other modalities, MRI provided substantial information regarding uterine and adnexal masses and surrounding structures, facilitating accurate staging of lesions.