Uterine smooth muscle tumors include a broad range of neoplasms, from benign leiomyomas (LMs) to malignant leiomyosarcomas (LMS), as well as intermediate forms classified as Smooth Muscle Tumors of Uncertain Malignant Potential (STUMP). An accurate diagnosis of these tumor types is essential for their appropriate clinical management; however, it remains challenging due to possible overlapping of histological features. In this study, a multidisciplinary approach combining Fourier Transform Infrared Imaging (FTIRI) spectroscopy, a label-free and non-destructive analytical technique, with histology and statistical analyses have been exploited for investigating the morpho-chemical characteristics of these uterine smooth muscle tumors. The analysis aimed to identify new reliable and diagnostic spectral markers, complementary to traditional histology, and thus useful for improving accuracy in cases with uncertain morphological features. Tissue samples including different leiomyoma histological subtypes, such as usual, cellular, apoplectic, and bizarre, were analyzed and compared with LMS and healthy myometrium. The analysis of IR data, submitted to univariate and multivariate statistical approaches, such as Principal Component Analysis (PCA) and Hierarchical Cluster Analysis (HCA), revealed distinctive spectral profiles associated with each tumor type and indicated changes in collagen content and organization as key features for a reliable discrimination not only between benign and malignant tissues but also among different LM histotypes.

OBJECTIVE:To study the effects of extracellular vesicles (EVs) derived from primary myometrial and leiomyoma cells, as well as suitable cell lines, and to evaluate the release of EVs after omega-3 fatty acid treatment and their impact on fibronectin protein expression in recipient myometrial cells. DESIGN:Case-control laboratory study. SUBJECTS:Patients with uterine fibroids. EXPOSURE:Primary cells were obtained from uterine tissue samples (leiomyoma and healthy myometrium) of premenopausal women (41-49 years) undergoing surgery. Immortalized myometrial (A00-9) and leiomyoma (A00-10) cell lines were also used. MAIN OUTCOME MEASURE:Cross-sectional in vitro study comparing untreated and omega-3-treated primary and immortalized myometrial and leiomyoma cells. Extracellular vesicles were isolated after 48 hours of treatment, characterized by nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM), and then used to treat myometrial cell lines. Fibronectin expression was measured in recipient cells. RESULTS:Extracellular vesicles were isolated and fractionated into small (s) and large (l) EVs. Small extracellular vesicle release was significantly induced by eicosapentaenoic acid treatment. These vesicles derived from leiomyoma cells showed a trend toward increased fibronectin expression in recipient myometrial cells, whereas EVs from omega-3-treated leiomyoma cells showed attenuated effects. Those from myometrial cells, treated or untreated, did not alter fibronectin expression. Results were consistent across biological replicates (n = 3). CONCLUSION (S):These data suggest that leiomyoma-derived EVs contribute to fibrotic changes in surrounding myometrium and that omega-3 fatty acids can modulate EV release and EV-mediated profibrotic signaling. This may represent a potential proof-of-concept strategy for managing fibroid-associated fibrosis, although further in vivo validation is required.

The reconstruction of the external auricle remains one of the most challenging tasks in plastic surgery due to its complex anatomical architecture. Recent advances in 3D bioprinting have opened new possibilities for manufacturing cost-effective, patient-specific structures, enhancing accessibility to custom-made solutions in clinical applications. Sodium alginate (SA) is a promising biomaterial capable of mimicking the extracellular matrix of auricular cartilage; however, its inherent limitations in structural fidelity and mechanical stiffness hinder its performance in bioprinting. In this study, we investigated the combination of SA with cellulose nanocrystals (CNC) to develop optimized bioink formulations. Several SA/CNC concentrations were evaluated and compared in terms of printability, shape fidelity both post-printing and post-crosslinking, with final crosslinking performed using 80 mM CaCl₂. It has been found that the most effective formulation consisted of 3% (w/v) SA and 4% (w/v) CNC. This composition demonstrated excellent structural fidelity, with a mean area discrepancy of only 0.88 mm² after printing and a deformation of just 6.49% after crosslinking. Using a 3D computer-aided design (CAD) model, this optimized bioink was employed to print an auricle-like scaffold incorporating human fibroblasts. The optical and fluorescence microscopy assessment, together with Field Emission Scanning Electron microscopy (FE-SEM) analysis revealed strong cellular adhesion and proliferation within the printed construct. The obtained results support the potential of the SA/CNC-based hydrogel as a viable bioink for the 3D bioprinting of living auricular tissues and, more broadly, for applications in regenerative medicine.

Dysmenorrhea is a prevalent condition among women of reproductive age, causing significant pelvic pain during menstruation. While conventional treatments such as NSAIDs and hormonal contraceptives are commonly used, they may cause side effects, leading to interest in alternative therapies. This review investigates the potential of natural compounds and complementary treatments in alleviating dysmenorrhea symptoms, comparing their effectiveness and safety to standard pharmacological treatments.Search was conducted in PubMed, Scopus, Web of Science, and Google Scholar, focusing on human studies involving natural compounds and alternative therapies for dysmenorrhea. Both clinical trials and observational studies were included.Several natural compounds were identified with potential benefits for managing dysmenorrhea. Herbal remedies such as ginger, fennel, and chamomile demonstrated anti-inflammatory effects and pain reduction. Omega-3 fatty acids and magnesium supplements showed significant efficacy in reducing pain intensity. Complementary therapies, including acupuncture and psychological support, were also highlighted as effective in enhancing pain relief and improving overall well-being.Natural compounds and complementary therapies offer promising, safer alternatives to conventional treatments for dysmenorrhea. Further research is needed to validate their long-term efficacy and establish clear clinical guidelines. While natural compounds offer a promising alternative for dysmenorrhea management, particularly for patients unresponsive to NSAIDs, the current evidence base is limited by small sample sizes and methodological heterogeneity. Future research must prioritize large-scale, rigorously designed randomized controlled trials to establish standardized dosing, long-term safety profiles, and definitive clinical guidelines. Integrating these approaches, especially when combined with psychological support, could significantly improve the quality of life for women suffering from dysmenorrhea.

Nearly 25 centuries ago, Hippocrates proclaimed, "Let food be thy medicine, and medicine be the food" [...].

In the last years, considerable innovation has been made regarding bioprinting, particularly in the development of cell-loaded hydrogels. The specific properties of the bioinks are crucial for printing an adequate cell-laden hydrogel structure. In this research, we aimed to develop a 3D-printable hydrogel using a natural biocompatible polymer. The process is based on the use of sodium alginate subjected to calcium ion cross-linking for immediate stiffness after printing. Using the Cellink INKREDIBLE+ printer (Cellink Inc., Goteborg, Sweden), 3D structures were successfully produced. The developed bioink exhibited a viscosity suitable for extrusion printing while ensuring its structural integrity at the same time. Next, 3D spheroids developed by using bioinks were morphologically characterized by using light, a fluorescent microscope, and field emission scanning electron microscopy (FESEM). In conclusion, the properties of the construct obtained using the lab-formulated biocompatible polymer hydrogel suggest its potential use as a framework for three-dimensional cell culture, with possible applications in both fields of research and regenerative medicine.

OBJECTIVE:This study aimed to evaluate adipose tissue of lipedema patients. METHODS:Gluteo-femoral (affected area) and interscapular (nonaffected area) adipose tissue from 10 lean patients affected by lipedema stage 1 to 2 was studied and compared with tissue from 10 patients with obesity and 12 lean patients. RESULTS:The main features were alterations of capillaries with wall thickening (p ≤ 0.0001), endothelial and pericyte hyperplasia (p = 0.03 and p = 0.004), hypodense areas in basal membrane, and endothelial degeneration with exfoliation of degenerated cells into the capillary lumen. Adipocytes were larger (hypertrophic) in affected (P ≤ 0.0001) and nonaffected (p = 0.0003) areas compared with those with obesity and who were lean (both p ≤ 0.0001). Frequently the cytoplasm of adipocytes contained massive deposition of calcium crystals as revealed by Von Kossa staining (p = 0.023) and electron microscopy. CD68 immunoreactive macrophages were more abundant in affected areas (p = 0.005), and their number was similar to that found in fat from patients with obesity (p = 0.17). Despite adipocyte hypertrophy and inflammation, lack of the healthy marker perilipin-1 and the presence of crown-like structures were only rarely seen, while they were quite frequent in patients with obesity. CONCLUSIONS:Our data support the idea that cell alterations happen in the early stages of adipocyte development (endothelium/pericyte) in the adipose organ of women affected by lipedema.

Uterine leiomyomas are the most common benign, monoclonal, gynaecological tumors in a woman’s uterus, while leiomyosarcoma is a rare but aggressive condition caused by the malignant transformation of the myometrium. To overcome the common obstacles related to the methods usually used to study these pathologies, we aimed to devise three-dimensional models of myometrium, uterine leiomyoma and leiomyosarcoma cell lines, using two different types of biocompatible scaffolds. Specifically, we exploited the agarose gel matrix in common 6-well plates and the alginate matrix using Bioprinting INKREDIBLE + (CELLINK), a pneumatic extruded base equipped with a system with double printheads, and a UV printer LED curing system. Both methods allowed the development of 3D spheroids of all three cell types, that were also suitable for morphological investigations. We showed that all cell types embedded in both agarose and alginate formed spheroids in their growth medium. The spheroids successfully proliferated and self-organized into complex structures, developing a sustainable system that emulated the condition of the tissues through the accumulation of extracellular matrix. These models could be useful for a better understanding of pathophysiology, etiopathogenesis, and testing new methods or molecules from a preventive and therapeutic point of view.

OBJECTIVE:To determine whether the bioactive sphingolipid sphingosine 1-phosphate (S1P) modulates cellular proliferation and synthesis of fibrotic proteins in leiomyoma differently than myometrial cells. DESIGN:A basic science study using human leiomyoma and myometrial cells. SUBJECTS:Not applicable. This is an in vitro study performed on cellular models. EXPOSURE:Leiomyoma and myometrial cells were treated with S1P, as well as with selective antagonists for S1P-specific G protein-coupled receptors and secondarily with inhibitors of extracellular signal-regulated kinase 1/2 (ERK1/2) and ezrin. MAIN OUTCOME MEASURES:The main outcome measures included cellular proliferation and fibrogenesis. Bromodeoxyuridine Cell Proliferation Assay was employed to measure deoxyribonucleic acid synthesis and proliferation, whereas western blot analysis was used to assess the expression of the fibrotic markers N-cadherin, α-smooth muscle actin, transgelin, and collagen type I alpha 1. RESULTS:Sphingosine 1-phosphate stimulates cellular proliferation of leiomyoma but not myometrial cells. The mitogenic effect elicited by S1P relies on the engagement of its specific receptor S1P2 and is mediated by ERK1/2 and ezrin activation. Furthermore, S1P exerts a profibrotic effect in a S1P-specific G protein-coupled receptor-dependent manner in leiomyoma but not myometrial cells. CONCLUSIONS:These results, besides extending the knowledge on the molecular mechanism underlying uterine leiomyoma development and fibrosis, demonstrate the pathogenetic role of S1P in leiomyoma and support the rationale for targeting S1P signaling pathway as innovative potential treatment.

RESEARCH QUESTION:What is the expression pattern of Raf kinase inhibitory protein (RKIP) in different subtypes of leiomyoma (usual type, cellular, apoplectic or haemorrhagic leiomyoma, leiomyoma with bizarre nuclei and lipoleiomyoma) and leiomyosarcoma specimens, and what is its biological role in leiomyosarcoma cells? DESIGN:Leiomyoma and leiomyosarcoma specimens underwent immunohistochemistry staining. Leiomyosarcoma SK-LMS-1 cell line was RKIP knocked down and RKIP overexpressed, and cell viability, wound healing migration and clonogenicity assays were carried out. RESULTS:A higher immunohistochemical expression of RKIP was observed in bizarre leiomyomas, than in usual-type leiomyomas. Decreased expression was also found in cellular leiomyoma, with generally absent staining in leiomyosarcomas. Upon RKIP expression manipulation in SK-LMS-1 cell line, no major differences were observed in cell viability and migration capacity over time. RKIP knockout, however, resulted in a significant increase in the cell's ability to form colonies (P = 0.011). CONCLUSION:RKIP distinct expression pattern among leiomyoma histotype and leiomyosarcoma, and its effect on leiomyosarcoma cells on colony formation, encourages further studies of RKIP in uterine smooth muscle disorders.

Leiomyosarcoma is an aggressive soft tissue sarcoma derived from the smooth muscle cells of the uterus. We tested the effect of Romina strawberry extract treatment on three-dimensional cultured uterine leiomyosarcoma cells. We established 3D cultures in agarose gel, where the cells seeded were able to form spheroids. We performed the observation and counting of the spheroids with a phase-contrast optical microscope, finding a decrease in the number of spheroids formed in the plates after 24 and 48 h treatment with 250 µg/mL of cultivar Romina strawberry extract. We also characterized the spheroids morphology by DNA binding fluorescent-stain observation, hematoxylin and eosin stain, and Masson’s trichrome stain. Finally, the real-time PCR showed a reduced expression of extracellular matrix genes after strawberry treatment. Overall, our data suggest that the fruit extract of this strawberry cultivar may be a useful therapeutic adjuvant for the management of uterine leiomyosarcoma.

During their life, women are likely to develop uterine diseases, which often compromise their fertile and perimenopausal age. Besides benign lesions like leiomyomas, several malignant neoplasms can occur, such as the uterine leiomyosarcoma, which represents the most frequent malignancy among the rarest uterine cancers. It presents several variants similar to both benign and malignant neoplasms, and sometimes it shares symptoms with the benign counterpart. In this scenario, for a correct diagnosis and a successful prognosis, it is mandatory to detect new reliable markers which strengthen histopathological outcomes and let define a more appropriate and less harmful therapy. Based on this concerning evidence, in the present study, Fourier Transform Infrared Microspectroscopy has been exploited at a cellular level on uterine leiomyoma and leiomyosarcoma cell lines to (1) identify specific spectral biomarkers able to distinguish between benign and malignant lesions, and (2) evaluate the efficacy of eicosapentaenoic and docosahexaenoic acids (respectively EPA and DHA), already successfully tested. Results evidenced reliable differences in the spectral signature of benign and malignant cells, mainly in terms of lipids and nucleic acids composition. Moreover, even if EPA and DHA seemed to exert different effects on the tested cell lines, no cytotoxic and/or anti-apoptotic actions were observed after omega-3 based treatments.

The female reproductive system is a delicate and complex system in the body that can be affected by many disorders [...]

Research question: Is the hypusinated form of the eukaryotic translation initiation factor 5A (EIF5A) present in human myometrium, leiomyoma and leiomyosarcoma, and does it regulate cell proliferation and fibrosis? Design: The hypusination status of eIF5A in myometrial and leiomyoma patient-matched tissues was evaluated by immunohistochemistry and Western blotting as well as in leiomyosarcoma tissues by immunohistochemistry. Myometrial, leiomyoma and leiomyosarcoma cell lines were treated with N1-guanyl-1,7-diaminoheptane (GC-7), responsible for the inhibition of the first step of eIF5A hypunization, and the proliferation rate was determined by MTT assay; fibronectin expression was analysed by Western blotting. Finally, expression of fibronectin in leiomyosarcoma tissues was detected by immunohistochemistry. Results: The hypusinated form of eIF5A was present in all tissues examined, with an increasing trend of hypusinated eIF5A levels from normal myometrium to neoplastic benign leiomyoma up to neoplastic malignant leiomyosarcoma. The higher levels in leiomyoma compared with myometrium were confirmed by Western blotting (P = 0.0046). The inhibition of eIF5A hypusination, with GC-7 treatment at 100 nM, reduced the cell proliferation in myometrium (P = 0.0429), leiomyoma (P = 0.0030) and leiomyosarcoma (P = 0.0044) cell lines and reduced the expression of fibronectin in leiomyoma (P = 0.0077) and leiomyosarcoma (P = 0.0280) cells. The immunohistochemical staining of leiomyosarcoma tissue revealed that fibronectin was highly expressed in the malignant aggressive (central) part of the leiomyosarcoma lesion, where hypusinated eIF5A was also highly represented. Conclusions: These data support the hypothesis that eIF5A may be involved in the pathogenesis of myometrial benign and malignant pathologies.

Uterine fibroids are the most common cause of solid pelvic tumours, occurring in 20-30% of fertile women and presenting clinical complications that seriously affect women's health. They commonly cause severe symptoms, such as heavy, prolonged menstrual bleeding and anaemia. The study of microscopic and macroscopic vascular aspects of uterine fibroids is important for understanding the clinical manifestations of uterine fibroids, for predicting the effectiveness of alternative treatments to surgery, i.e. uterine artery embolization, for improving surgery outcomes and for carrying out a differential diagnosis with other benign conditions, e.g. adenomyosis, or malignancy, e.g. leiomyosarcoma, and to develop new therapeutic approaches. In this review, current knowledge of how the vascular network and angiogenesis are implied in the formation of uterine fibroids and in the pathogenesis of related symptoms is explored, and evidence on the role of ultrasound in evaluating fibroid vascularization is summarized. This review combines anatomical, morphological and biomolecular information related to angiogenic mechanisms with diagnostic and clinical information, highlighting the various interconnections. Uterine and fibroid vascularization need further investigation to gain a deeper understanding of the pathogenetic elements that lead to the formation of uterine fibroids and their clinical manifestations.

The pathologies concerning the gynecological organs are very varied and range from tumoral pathologies to hormonal dysfunctions [...]

Collagen is one of the main components of the extracellular matrix (ECM), involved, among all, in the maintenance of the structural support of tissues. In fibrotic diseases, collagen is overexpressed, and its production determines the formation of a significantly stiffer ECM. The cross-linking of high-resolution analytical tools, able to investigate both the tridimensional organization and the secondary structure of collagen in fibrotic diseases, could be useful to identify defined markers correlating the status of this protein with specific pathological conditions. To this purpose, an innovative multidisciplinary approach based on Phase-Contrast MicroComputed Tomography, Transmission Electron Microscopy, and Fourier Transform Infrared Imaging Spectroscopy was exploited on leiomyoma samples and adjacent myometrium to characterize microstructural collagen features. Uterine leiomyoma is a common gynecological disorder affecting women in fertile age. It is characterized by a massive collagen production due to the repairing processes occurring at myometrium level, and, hence, it represents a valuable model to investigate collagen self-organization in a pathological condition. Moreover, to evaluate the sensitivity of this multidisciplinary approach, the effects of eicosapentaenoic (EPA) and docosahexaenoic (DHA) omega-3 fatty acids in collagen reduction were also investigated.

Objective: To explore the link between sphingosine 1-phosphate (S1P) signaling and leiomyoma and the possible S1P cross-talk with the fibrotic effect of activin A. Design: Case-control laboratory study. Setting: University institute and university hospital. Patient(s): Patients with uterine fibroids (n 1/4 26). Interventions(s): Tissue specimens of leiomyoma and normal myometrium were obtained from patients undergoing myomectomy or total hysterectomy. Main Outcome Measure(s): Expression of mRNA levels of the enzyme involved in S1P metabolism, S1P receptors, and S1P transporter Spns2 was evaluated in matched leiomyoma/myometrium specimens and cell populations. The effects of inhibition of S1P metabolism and signaling was evaluated on activin A-induced fibrotic action in leiomyoma cell lines. Result(s): The expression of the enzymes responsible for S1P formation, sphingosine kinase (SK) 1 and 2, and S1P2, S1P3, and S1P5 receptors was significantly augmented in leiomyomas compared with adjacent myometrium. In leiomyoma cells, but not in myometrial cells, activin A increased mRNA expression levels of SK1, SK2, and S1P2. The profibrotic action of activin A was abolished when SK1/2 were inhibited or S1P2/3 were blocked. Finally, S1P augmented by itself mRNA levels of fibrotic markers (fibronectin, collagen 1A1) and activin A in leiomyomas but not in myometrial cells. Conclusion(s): This study shows that S1P signaling is dysregulated in uterine fibroids and involved in activin A-induced fibrosis, opening new perspectives for uterine fibroid treatment. ((C)2020 by American Society for Reproductive Medicine.)

In recent years, there has been an increasing interest in natural therapies to prevent or treat female diseases. In particular, many studies have focused on searching natural compounds with less side effects than standard hormonal therapies. While phytoestrogen-based therapies have been extensively studied, treatments with phytoprogestins reported in the literature are very rare. In this review, we focused on compounds of natural origin, which have progestin effects and that could be good candidates for preventing and treating female diseases. We identified the following phytoprogestins: kaempferol, apigenin, luteolin, and naringenin. In vitro studies showed promising results such as the antitumoral effects of kaempferol, apigenin and luteolin, and the anti-fibrotic effects of naringenin. Although limited data are available, it seems that phytoprogestins could be a promising tool for preventing and treating hormone-dependent diseases.

Uterine leiomyomas (fibroids or myomas) are the most common benign pelvic tumors in women. They may be small or large, single or multiple, and can result in substantial distortion of the uterine surface or cavity. Although leiomyomas are benign, they commonly result in severe symptoms such as heavy, irregular, and prolonged menstrual bleeding (associated with iron-deficient anemia), dysmenorrhea, and pelvic pain and infertility, negatively affecting women's health. Uterine fibroids have also been associated with numerous other medical disorders such as preterm labor and recurrent spontaneous abortion (1Bulun S.E. Uterine fibroids.N Engl J Med. 2013; 369: 1344-1355Crossref PubMed Scopus (340) Google Scholar). Surgery, such as hysterectomy and myomectomy, is still the only definitive treatment for symptomatic fibroids, but recurrences are common. Medical therapy includes gonadotropin-releasing hormone (GnRH) agonists or antagonists and ulipristal acetate. Those treatments play a role as presurgical treatments in reducing fibroid size as well as in reducing the symptoms. Long-term use of GnRH agonists or antagonists, however, is associated with menopausal symptoms and bone loss. Concerns also have been raised about the risk of rare but serious liver injury with ulipristal acetate treatment, limiting the use of the drug. Therefore, it is still urgent to provide new, alternative medical therapies. For this purpose, it is essential to deeply understand the pathogenetic mechanisms to provide new therapeutic targets. Uterine fibroids are monoclonal benign tumors of the smooth muscle cells of the myometrium characterized by excessive accumulation of extracellular matrix (ECM) proteins, primarily consisting of collagens, fibronectin, and proteoglycans. They are considered to be a fibrotic disease because due to the excessive inflammatory response (2Islam M.S. Ciavattini A. Petraglia F. Castellucci M. Ciarmela P. Extracellular matrix in uterine leiomyoma pathogenesis: a potential target for future therapeutics.Hum Reprod Update. 2018; 24: 59-85Crossref PubMed Scopus (106) Google Scholar). It has been well established that estrogen and progesterone are involved in the proliferation and maintenance of uterine leiomyoma and that there is a complex interaction of their signaling and their effectors (i.e., growth factors, cytokines, chemokines). Overall, leiomyoma has to be considered a disease of multifactorial pathology, involving genetic, epigenetic, and environmental factors (3Islam M.S. Protic O. Stortoni P. Grechi G. Lamanna P. Petraglia F. et al.Complex networks of multiple factors in the pathogenesis of uterine leiomyoma.Fertil Steril. 2013; 100: 178-193Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). The epigenetic mechanisms include DNA methylation, histone modification, and its mediation by microRNAs (miRNA) and long-noncoding RNAs (lncRNAs). MicroRNA and lncRNA are not coding for known proteins, but they regulate gene expression at transcriptional or post-transcriptional levels. After having been considered as "junk" for a long time, they are now considered an important player in maintaining cellular homeostasis and function; they have cell- and tissue-specific expression patterns and are specifically deregulated under pathologic conditions. While miRNAs are short RNA transcripts of 18 to 24 nucleotides, lncRNAs are constituted by more than 200 nucleotides. Also, lncRNA can counteract miRNAs by sequestering them (miRNA sponges), thus regulating protein coding gene expression. In leiomyoma, some miRNAs have shown altered expression, including let7, miR-21, miR-29, miR-200, and miR-93. Functionally, these miRNAs regulate the expression of protein-coding genes associated with angiogenesis, inflammation, ECM accumulation, and tissue fibrosis. Also the expression of lncRNAs is altered in leiomyoma compared to myometrium. Noncoding RNA (miRNA and lncRNAs) interact with protein-coding genes and influence the outcome of various normal cellular activities. Their altered expression leads to a wide range of disorders including leiomyomas (4Chuang T.D. Khorram O. Expression profiling of lncRNAs, miRNAs, and mRNAs and their differential expression in leiomyoma using next-generation RNA sequencing.Reprod Sci. 2018; 25: 246-255Crossref PubMed Scopus (23) Google Scholar). The study of Chuang et al. (5Chuang T.D. Rehan A. Khorram O. The functional role of the long non-coding RNA, XIST in leiomyoma pathogenesis.Fertil Steril. 2021; 115: 238-247Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar) addressed the expression, regulation, and molecular mechanism of lncRNA functions in the development and progression of leiomyoma. The authors explored the role of lncRNA X-inactive specific transcript (XIST) in leiomyoma pathogenesis. XIST is a noncoding RNA on the X chromosome of placental mammals that acts as a major effector of the X-inactivation process. Increased expression of XIST in fibroids, as compared with myometrium, and its up-regulation by steroid hormones has been shown. Therefore, its functional role has been explored through knockdown of XIST in leiomyoma smooth muscle cell spheroids, resulting in decreased cell proliferation, overexpression of miR-29c and miR-200c, and consequent down-regulation of their respective target proteins such as collagens and fibronectin. It is interesting that overexpression of XIST in myometrial smooth muscle cells repressed miR-29c and miR-200c and induced collagens and fibronectin levels (5Chuang T.D. Rehan A. Khorram O. The functional role of the long non-coding RNA, XIST in leiomyoma pathogenesis.Fertil Steril. 2021; 115: 238-247Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). A strength of the study is that the complete regulatory mechanism was explored: from the control by steroid hormones, to the regulation of miRNAs, and finally to the effect on the ECM protein accumulation associated with fibrosis. Another strength of the study is the use of a very physiologic methodological approach with the primary three-dimensional cell culture system. Credit is also due for the loss-of-function experiments as well as the overexpression experiments, which were able to clearly show the function of XIST. The only potential limitations of this study are with its experimental in vitro approach—the results may not be readily applicable in vivo. In brief the study of Chuang et al. (5Chuang T.D. Rehan A. Khorram O. The functional role of the long non-coding RNA, XIST in leiomyoma pathogenesis.Fertil Steril. 2021; 115: 238-247Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar), performed in a three-dimensional culture system, has suggested that fibroids have increased expression of XIST, which sequesters miR-29c and miR-200c, lowering their levels and up-regulating their target genes collagen and fibronectin with consequent fibrotic behavior. These results support the importance of epigenetic mechanisms in leiomyoma formation and development, and open new opportunities to explore the potential of noncoding RNA as a new therapeutic approach. Functional role of the long noncoding RNA X-inactive specific transcript in leiomyoma pathogenesisFertility and SterilityVol. 115Issue 1PreviewTo determine the expression and functional roles of a long noncoding RNA (lncRNA) X-inactive specific transcript (XIST) in leiomyoma. Full-Text PDF