Potential Mechanisms of Guizhi Fuling Wan in Treating Endometriosis: An Analysis Based on TCMSP and DisGeNET Databases.

ETHNOPHARMACOLOGICAL RELEVANCE: Guizhi Fuling Wan (GFW), is a traditional Chinese herbal formula that consists of Cinnamomi Ramulus (Guizhi), Poria Cocos(Schw.) Wolf. (Fuling), Persicae Semen (Taoren), Radix Paeoniae Rubra (Chishao), and Cortex Moutan (Mudanpi). This formula has been used in traditional Chinese medicine for more than 1800 years to treat disorders caused by stagnation of circulation and qi (air). AIM OF THE STUDY: Based on pre-clinical and clinical studies, this review aimed to reveal the potential mechanisms of GFW in inhibiting endometriosis. The enhancement of therapeutic effects of western medications on endometriosis by GFW was also shown. MATERIALS AND METHODS: A bibliographic assessment of publications on "Guizhi Fuling Wan" and "endometriosis" indexed in PubMed, Science Direct, and China National Knowledge Infrastructure (CNKI) was conducted. Five pre-clinical studies and 13 clinical studies were selected for this review. Moreover, the targeted molecules of each herb were first extracted from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database and Analysis Platform followed by obtaining the endometriosis-related genes from DisGeNET. Subsequently, pathway and gene ontology analyses using David Bioinformatics Resources explored the potential mechanisms of therapeutic effects of GFW in treating endometriosis. RESULTS: Pre-clinical and clinical studies showed that GFW might inhibit the growth of endometriotic lesion through the modulation of immunity, apoptosis-regulating molecules, and angiogenesis-associated factors, while enhancing the therapeutic effects of western medications in treating endometriosis. Furthermore, pathway and gene ontology analyses demonstrated that GFW might attenuate the disease primarily by affecting AGE-RAGE signaling pathway in diabetic complications (hsa04933) as well as pathways involved in Kaposi sarcoma-associated herpesvirus infection (hsa05167), human cytomegalovirus infection (has05163), and fluid shear stress and atherosclerosis (hsa05418). These pathways were all involved in the regulation of inflammation, angiogenesis, and apoptosis and commonly affected by all herbs. CONCLUSIONS: The current review revealed that endometriosis is highly associated with aberrant inflammatory, angiogenic, and apoptotic activities. The therapeutic effects of GFW on endometriosis are likely to act through regulating these activities.

A systematic review of the mechanistic actions of microRNAs within integrated traditional Chinese medicine and western medical treatment for endometriosis.

Endometriosis (EM), also known as Zhengjia in traditional Chinese medicine, is a common disease that significantly impacts women's health. An integrated treatment approach combining traditional Chinese medicine (TCM) and western medicine has demonstrated significant clinical efficacy in the management of this condition. Specifically, it has been effective in addressing blood circulation and other diseases. MicroRNAs (miRNAs), which are molecules important in gene regulation, have been implicated in various physiologic and pathologic processes. In this review, we systematically summarized the potential mechanisms underlying the integrated EM treatment, with a focus on the role of microRNAs (miRNAs). Current research suggests that integrated TCM and western medicine treatment may exert their therapeutic effects on EM by influencing the expression of miRNAs. Through miRNA modulation, such a treatment approach may inhibit the growth of ectopic lesions and alleviate clinical symptoms. This review will shed light on the specific miRNAs that have been implicated in the integrated treatment of EM, as well as their potential mechanisms of action. By consolidating the existing evidence, we aim to provide clinicians and researchers with a clearer understanding of the therapeutic benefits of the integrated approach and potentially identify new avenues for improving clinical treatment outcomes. Ultimately, this review will contribute to the growing body of knowledge in this field, providing a basis for further research and the development of more targeted and efficient treatment strategies for EM.

Epigallocatechin Gallate for the Treatment of Benign and Malignant Gynecological Diseases-Focus on Epigenetic Mechanisms.

The most common malignant gynecologic diseases are cervical, uterine, ovarian, vaginal, and vulvar cancer. Among them, ovarian cancer causes more deaths than any other cancer of the female reproductive system. A great number of women suffer from endometriosis, uterine fibroids (UFs), adenomyosis, dysmenorrhea, and polycystic ovary syndrome (PCOS), which are widespread benign health problems causing troublesome and painful symptoms and significantly impairing the quality of life of affected women, and they are some of the main causes of infertility. In addition to the available surgical and pharmacological options, the effects of supporting standard treatment with naturally occurring compounds, mainly polyphenols, are being studied. Catechins are responsible for the majority of potential health benefits attributed to green tea consumption. Epigallocatechin gallate (EGCG) is considered a non-toxic, natural compound with potential anticancer properties. Antioxidant action is its most common function, but attention is also drawn to its participation in cell division inhibition, apoptosis stimulation and epigenetic regulation. In this narrative review, we describe the role of EGCG consumption in preventing the development of benign reproductive disorders such as UF, endometriosis, and PCOS, as well as malignant gynecologic conditions. We discuss possible epigenetic mechanisms that may be related to the action of EGCG.

Integration of 16 S rRNA gene sequencing, metabonomics and metagenome analysis to investigate the mechanism of Sparganium stoloniferum-Curcuma phaeocaulis in treating of endometriosis in rats.

BACKGROUND: Endometriosis is a gynecological disease that causes severe chronic pelvic pain and infertility in women. The therapeutic efficacy of the traditional herbal combination of Sparganium stoloniferum-Curcuma phaeocaulis (Sangleng-Ezhu, SL-EZ) in the treatment of endometriosis has been established. However, the precise mechanism by which this treatment exerts its effects remains elusive. METHODS: To gain further insights, UPLC-MS/MS was employed to identify the primary chemical constituents of SL-EZ in serum. Additionally, network pharmacology was utilized to analyze the active ingredients and their corresponding targets. Furthermore, the impact of SL-EZ on ectopic endometrial growth in endometrial implants was assessed using a rat model. The therapeutic mechanism of SL-EZ in rats with endometriosis was further investigated through the application of 16 S rRNA gene sequencing, metagenomic sequencing, and metabolomics. RESULTS: The primary compounds in serum were zederone, p-coumaric acid, dehydrocostus lactone, curdione, curcumol. The growth of ectopic lesions in a rat model was effectively inhibited by SL-EZ. In comparison to the control group, the endometriotic rats exhibited a decrease in α-diversity of the gut microbiota, an increase in the Firmicutes/Bacteroidetes ratio, and a reduction in the abundance of Ruminococcaceae. Following SL-EZ intervention, the potential probiotic strains Lactobacillus gasseri and Lactobacillus johnsonii were able to restore the intestinal microenvironment at the species level. The altered metabolites were significantly correlated with Verrucomicrobia, Proteobacteria, and Bacteroidetes. The metabolomic analysis demonstrated significant alterations in intestinal metabolites. And SL-EZ intervention also exerted regulatory effects on various metabolic pathways in gut microbiota, including aminoacyl-tRNA biosynthesis, monobactam biosynthesis, cyanoamino acid metabolism, glycine, serine and threonine metabolism, plant secondary metabolite biosynthesis, and amino acid biosynthesis. CONCLUSION: The identification of novel treatment formulations for endometriosis was achieved through the utilization of network pharmacology and gut microbiota analyses. Our findings revealed simultaneous alterations in the microbiota within the rat model of endometriosis. The therapeutic efficacy of SL-EZ in treating endometriosis is attributed to its ability to restore the gut microbiota and regulate metabolism. This investigation offers valuable insights into the therapeutic mechanisms of traditional Chinese medicine (TCM) for endometriosis.

Efficacy and safety of a novel pain management device, AT-04, for endometriosis-related pain: study protocol for a phase III randomized controlled trial.

BACKGROUND: Endometriosis-related pain encompassing dysmenorrhea, dyspareunia, and chronic pelvic pain, reduces the quality of life in premenopausal women. Although treatment options for endometriosis alleviate this pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. The Angel Touch device (AT-04) is a portable magnetic fields irradiation device that incorporates a combination of mixed alternative magnetic fields at 2 kHz and 83.3 MHz. A phase III trial confirmed the efficacy and safety of AT-02, a prototype of AT-04, for pain relief in patients with fibromyalgia. METHODS: This is a phase III, multicenter, prospective, randomized, sham device-controlled, double-blind, parallel study. The participants will be premenopausal women aged > 18 years who have endometriosis-related pain with at least moderate severity. Considering dropouts, 50 participants have been deemed appropriate. Eligible women will be centrally registered, and the data center will randomly allocate them in a 1:1 ratio to the intervention and control groups. Women in the intervention group will receive electromagnetic wave irradiation generated by AT-04 and those who in the control group will wear a sham device for 16 weeks, and both groups will wear AT-04 for another 4 weeks. The primary outcome measure is the change in the Numeric Rating Scale score at 16 weeks compared with the baseline. Secondary outcome measures are efficacy for pelvic pain including dysmenorrhea and non-menstrual pain, and chronic pelvic pain not related to menstruation, dysmenorrhea, and dyspareunia, and improvement of quality of life during the study period. Safety will be evaluated by device defects and the frequency of adverse events. The study protocol has been approved by the Clinical Study Review Board of Chiba University Hospital, Chiba, Japan, and will be conducted in accordance with the principles of the Declaration of Helsinki and the Japanese Clinical Trials Act and relevant notifications. DISCUSSION: This study aims to develop a novel method of managing endometriosis-related pain. The AT-04 is an ultralow-invasive device that can be used without inhibiting ovulation, suggesting potential benefits to women of reproductive-age. Trial registration number Japan Registry of Clinical Trials (jRCTs032230278).

Endometriosis is a chronic inflammatory disorder that negatively impacts reproductive health via endometriosis-related pain, infertility, and endometriosis-associated ovarian cancer. Although current therapeutic options for endometriosis are effective for the endometriosis-related pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. This is the first randomized controlled trial to investigate the efficacy and safety of a novel portable pain management device, AT-04, that incorporates a combination of mixed alternating magnetic fields, for endometriosis-related pain. This is a multicenter, prospective, sham device-controlled, double-blind, parallel study. Enrolled women will have undergone standard hormonal treatment for endometriosis at baseline, and this allows for assessing whether the device remains effective when used in conjunction with existing treatment methods. The study also will explore the impact of AT-04 on reducing the size of ovarian endometriotic cysts that reflect the activity of endometriosis. The study reflects the strong desire by physicians to liberate women from the unbearable pain associated with endometriosis. The sole efficacy of AT-04 in treating endometriosis-related pain is difficult to evaluate as there is a possibility that menstrual cycles may influence the assessment of pain and quality of life. However, the study findings regarding the effectiveness of AT-04 for the treatment of endometriosis-related pain may benefit women with endometriosis who have pain that is not effectively relieved by other treatments. Consequently, it may contribute to the improvement of reproductive health within society.

Effect of curcumin on painful symptoms of endometriosis: A triple-blind randomized controlled trial.

Endometriosis is one of the most common gynecological disorders. This study aimed to determine the effect of curcumin on painful symptoms of endometriosis and the quality of life in affected women. This randomized controlled trial was conducted on 68 women with endometriosis referred to Shahid Beheshti Infertility Center in Isfahan, Iran, 2022. The participants were allocated to intervention (n = 34) and control (n = 34) groups by the blocked randomization method. Curcumin capsules with a dose of 500 mg were given to the intervention group twice a day for 8 weeks, and the placebo with the same dose was given to the control group. The questionnaires of Endometriosis Health Profile, painful symptoms of endometriosis, and visual analogue scale were used to collect data. Independent t, ANCOVA, and Mann-Whitney U-tests were used to compare the outcomes between the study groups. After the intervention, based on the ANCOVA with the adjusting of the baseline values and Mann-Whitney U-test, there was no statistically significant difference in the amounts of usual pain (p = 0.496) and pain at its worst (p = 0.320), quality of life (p = 0.556), and visual pain (p = 0.845). The results showed that using curcumin does not affect the painful symptoms and quality of life of women with endometriosis. Future clinical trials are needed to investigate and highlight the role of curcumin in endometriosis.

Anti-inflammatory, antioxidant, antiangiogenic, and therapeutic efficacy of neroli oil in rats with endometriotic lesions.

INTRODUCTION: Endometriosis is a serious health problem among women of reproductive age, with pelvic pain and infertility. Given the limited success of current treatments, this study explores Neroli oil (N.O.) effects on inflammation, oxidation, angiogenesis, and tissue remodeling implicated in endometriosis. MATERIALS AND METHODS: Albino Wistar female rats were used to simulate an endometriosis model. Groups were established for comparison: a control, an endometriosis model, a N.O.-treated group, and a N.O.-treated group postendometriosis induction. The study focused on Tumor necrosis factor-alpha (TNF-α), Interleukin 6, Interleukin 8, vascular endothelial growth factor (VEGF), myeloperoxidase, Matrix metalloproteinase-1 (MMP-1), nitric oxide, superoxide dismutase, catalase, and anti-mullerian hormone values, as well as histopathological evaluations of endometriotic foci. RESULTS: AMH values showed a significant increase in the endometriosis group treated with N.O. compared with the endometriosis group (p < 0,01).A statistically significant decrease was found in MMP-1 level in the endometriosis group that underwent N.O. (p < 0.001). Increased CAT (p < 0.0001) and decrease in nitric oxide (p < 0.01) are found in N.O.-treated endometriosis group. TNF-α levels in the endometriosis group showed a statistically significant increase in the endometriosis group when compared with the control and sham group (p < 0.001, p < 0.01 respectively). In our study, a statistically significant increase was observed in VEGF levels (p < 0.001) in endometriosis group and significant decrease in the N.O. administered endometriosis model group. Groups treated with N.O. showed decreased inflammation and congestion scores. Histopathological assessments demonstrated reduced inflammation and tissue remodeling signs in endometriotic foci. CONCLUSION: This study highlights the potential of N.O. in the treatment of endometriosis, owing to its anti-inflammatory, antioxidant, and antiangiogenic properties that can disrupt chronic processes. Our findings lend support to utilization of herbal remedies for the management of endometriosis, thereby emphasizing the necessity for additional comprehensive investigations in the future.

ITRAQ-based proteomics analysis of human ectopic endometrial stromal cells treated by Maqian essential oil.

BACKGROUND: Endometriosis is a common and complex syndrome characterized by the presence of endometrial-like tissue outside the uterus. Chinese medicine has been recently found to show good efficacy in treating endometriosis. Our previous results revealed that Maqian fruit essential oil (MQEO) could inhibit the proliferation and induce apoptosis of ectopic endometrial stromal cells (EESCs), but the mechanisms remain unclear. In this study, we aim to explore the molecular mechanism of MQEO's specific effects in EESCs. METHODS: We conducted a quantitative proteomics analysis by iTRAQ on EESCs treated with MQEO or DMSO. Then deep analysis was performed based on differentially expressed proteins, including Gene Ontology enrichment analysis, pathway enrichment analysis and protein interaction analysis. Candidate protein targets were subsequently verified by western blotting. RESULTS: Among 6575 identified proteins, 435 proteins exhibited altered expression levels in MQEO-treated EESCs. Of these proteins, most were distributed in signal transduction as well as immune system and the most significantly altered pathway was complement and coagulation cascades. Moreover, two differentially expressed proteins (Heme oxygenase 1 and Acyl-CoA 6-desaturase) were verified and they can be potential biomarkers for endometriosis treatment. CONCLUSIONS: Our proteomic analysis revealed distinct protein expression patterns induced by MQEO treatment in EESCs, highlighting the potential of MQEO for endometriosis treatment and biomarker discovery.

Ethanol extract of basil (Ocimum Basilicum L.) leaves inhibits endometriosis growth in a mouse model by modulating vascular endothelial growth factor (VEGF) expression.

The objective of this study was to examine the effect of administering an ethanol extract obtained from basil leaves on the expression of vascular endothelial growth factor (VEGF) and the severity of endometriosis lesions in a mouse model. A total of 28 female mice, aged 2-3 months and weighing 20-30 grams, were randomly divided into four groups: the control group (C), treatment group 1 (T1) receiving a dose of basil leaf ethanol extract (0.21 mg/g-BW), treatment group 2 (T2) receiving a higher dose (0.42 mg/g BW), and treatment group 3 (T3) receiving the highest dose (0.84 mg/g-BW). Each group underwent a 14-day treatment period, and tissue samples were collected on the 29th day. An immunohistochemical examination was conducted to assess the expression of VEGF and evaluate the severity of endometriosis lesions. The statistical analysis of VEGF expression revealed a significant difference (p=0.026; p<0.05), with the most pronounced effects observed when administering basil leaf ethanol extract at doses of 0.21 mg/g-BW and 0.42 mg/g-BW. Although not statistically significant (p=0.271; p<0.05), a reduction in the severity of endometriosis lesions was observed following the administration of basil leaf ethanol extract at doses of 0.21 mg/g-BW and 0.42 mg/g-BW. Administering basil leaf ethanol extract at doses of 0.21 mg/g-BW and 0.42 mg/g-BW effectively decreased VEGF expression and limited the severity of endometriosis lesions.

[Outcomes and measurements of randomized controlled trial for traditional Chinese medicine in treatment of endometriosis].

This study aims to analyze the outcomes and measurements of randomized controlled trial(RCT) for traditional Chinese medicine(TCM) treatment of endometriosis(EM) and provide a basis for the building of the core outcome set(COS) of EM. The RCT for TCM treatment of EM was retrieved from medical literature databases with the time interval from inception to February 3, 2022. The Cochrane risk of bias assessment tool was employed to evaluate the risk of bias of the included RCT, and descriptive analyses of the extracted information were carried out. A total of 519 RCTs were included, with the sample sizes ranging from 28-582 patients and 239 outcome indicators(8 outcome indicators per RCT on average). According to the functional properties, the reported outcome indicators were classified into 7 indicators: clinical efficacy assessment, indicators of clinical symptoms and signs, TCM symptom efficacy indicators, physical and chemical examinations, quality of life, long-term prognosis, and safety events. All the 519 RCTs had problems, such as the lack of differentiation between primary and secondary outcome indicators(1.73% RCTs reported such differen-tiation), poor quality, confused criteria for composite outcome indicators and arbitrary combination of indicators(45 criteria for the single outcome indicator of efficiency), and messy measurements(as many as 18 measurements for TCM symptom score). In addition, as a chronic disease, EM requires long-term management. The outcome indicators vary for the patients in different disease stages, such as EM pain, EM infertility, and post-operative EM, while the specific outcome indicator sets for different EM populations remain to be developed. In addition, the time point of measurement for EM long-term outcomes remains unclear, and the definition of TCM syndromes lacks standards. The RCT for TCM treatment had a variety of problems, such as the lack of differentiation of outcome indicators, confusion in criteria and measurements, lack of specific outcome indicator sets for different EM populations, and unclear time points for long-term outcomes. Therefore, the studies about COS need to be carried out urgently.

Tanshinone â ¡A participates in the treatment of endometriosis by regulating adhesion, invasion, angiogenesis and inhibition of PI3K/Akt/mTOR signaling pathway.

Endometriosis (EMs) is a common gynecological disorder characterized by abnormal growth of the endometrial stroma and glands outside the uterus. Tanshinone IIA, the active component of Chinese medicine Danshen (Salvia miltiorrhiza Bge.), has a number of pharmacological effects such as anti­inflammation and anti­oxidation and serves a significant role in the treatment of EMs. In the present study, network pharmacology and experimental validation were used to elucidate the potential mechanism of tanshinone IIA for treating EMs. Several databases were used to collect information on EMs and tanshinone IIA and cross­targets for tanshinone IIA and EMs finally obtained. A total of 64 common targets were found between tanshinone IIA and EMs. Subsequently, a protein­protein interaction network was constructed, a total of 14 core targets were screened for enrichment analysis. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed. The network pharmacology showed that intercellular adhesion molecule (ICAM)­1, MMP­9 and VEGF are the core targets while PI3K/AKT pathway and mTOR pathway are the main signaling pathways through which tanshinone IIA regulates relevant biological processes to intervene in EMs. Finally, the therapeutic role and mechanism of tanshinone IIA on EMs was verified in vivo. Female Sprague­Dawley rats were treated by autologous transplantation to establish EMs. Serum inflammatory factors were detected by enzyme­linked immunosorbent assay (ELISA). The expression of ICAM­1, MMP­9 and VEGF in ectopic endometrial tissues of rats was determined by immunohistochemical. The expression of PI3K/Akt/mTOR pathway­related proteins and genes was detected by western blotting and quantitative PCR. It was found that tanshinone IIA treatment significantly decreased the formation of ectopic endometrium by reducing serum levels of TNF­α and IL­1ß, and down regulating the levels of ICAM­1, MMP­9 and VEGF in ectopic uterine tissue. In addition, tanshinone IIA can also block the activation of PI3K/Akt/mTOR signaling pathway by reducing the expression of related proteins and genes. In conclusion, tanshinone IIA can regulate adhesion, invasion and angiogenesis, thereby improving the pathological morphology of ectopic endometrium and inhibiting the formation of ectopic lesions. The PI3K/Akt/mTOR signaling pathway may play a key role in controlling this process.

The Place of Cannabinoids in the Treatment of Gynecological Pain.

Cannabis sativa (L), a plant with an extensive history of medicinal usage across numerous cultures, has received increased attention over recent years for its therapeutic potential for gynecological disorders such as endometriosis, chronic pelvic pain, and primary dysmenorrhea, due at least in part to shortcomings with current management options. Despite this growing interest, cannabis inhabits an unusual position in the modern medical pharmacopoeia, being a legal medicine, legal recreational drug, and an illicit drug, depending on jurisdiction. To date, the majority of studies investigating cannabis use have found that most people are using illicit cannabis, with numerous obstacles to medical cannabis adoption having been identified, including outdated drug-driving laws, workplace drug testing policies, the cost of quality-assured medical cannabis products, a lack of cannabis education for healthcare professionals, and significant and persistent stigma. Although currently lacking robust clinical trial data, a growing evidence base of retrospective data, cohort studies, and surveys does support potential use in gynecological pain conditions, with most evidence focusing on endometriosis. Cannabis consumers report substantial reductions in pelvic pain, as well as common comorbid symptoms such as gastrointestinal disturbances, mood disorders such as anxiety and depression, and poor sleep. Substitution effects were reported, with >50% reduction or cessation in opioid and/or non-opioid analgesics being the most common. However, a substantial minority report not disclosing cannabis consumption to their health professional. Therefore, while such deprescribing trends are potentially beneficial, the importance of medical supervision during this process is paramount given the possibility for withdrawal symptoms.

Cannabis, whether purchased illicitly, or obtained through legal means, is commonly used by those with chronic pelvic pain, especially people with endometriosis. People report several benefits from using cannabis, including being able to reduce their normal medications including opioid based painkillers, but often don't tell their health professional about this. This could lead to issues with withdrawal symptoms, so clinicians should be aware of the high prevalence of use of cannabis in this population.

Xiaoyi Yusi decoction improves fertilization and embryo transfer outcomes in patients with endometriosis.

OBJECTIVE: To investigate the effect of - Xiaoyi Yusi decoction (XYYSD, ), a Traditional Chinese Medicine (TCM), on fertilization and embryo transfer (IVF-ET) in patients with endometriosis, and to study the mechanism underpinning the action. METHODS: Women who underwent IVF-ET were divided into three groups by simple randomization: the treatment ( 32; with TCM treatment), patient (28; with endometriosis alone), and control (33; with male factor alone) groups. The luteal phase short-acting gonadotropin-releasing hormone agonist prolonged protocol was used in all three groups. To compare the changes in TCM scores and reproductive outcomes before and after TCM intervention in patients with endometriosis, partial least-squares discriminant analysis was used to analyze the follicular fluid samples of each group and screen and compare metabolites using the MetaboAnalyst software. RESULTS: The clinical data indicated that following TCM intervention, kidney deficiency and blood stasis symptom patterns improved dramatically in patients with endometriosis and that their clinical pregnancy rate increased significantly (71.9% 57.1%, 0.05). Metabolomics showed that the two groups of samples were separated before and after TCM intervention. After TCM intervention, the intervention group was close to the control group, indicating that the TCM had a certain effect. Pathway analysis revealed that after TCM intervention, the metabolism of glycerin phospholipid, pyruvate, and citric acid was regulated. CONCLUSIONS: Through the pyruvate and glycerophospholipid metabolism pathways and tricarboxylic acid cycle, the TCM XYYSD successfully improved kidney deficiency and blood stasis symptom pattern, as well as the clinical reproductive outcomes of patients with endometriosis-related infertility.

Research into the mechanism of intervention of Wenjing decoction in endometriosis based on network pharmacology and molecular docking technology.

BACKGROUND: Endometriosis (EMs) is a frequent disease in women and is the principal cause of infertility and dysmenorrhea. Due to its high recurrence rate and serious complications, more research on EMs is needed. We used network pharmacology and molecular docking technology to predict the key active components, targets, and signaling pathways of Wen Jing decoction (WJD) in the treatment of EMs. METHODS: The components and targets of WJD were collected and identified using the Traditional Chinese Medicine Systems Pharmacology Database and BATMAN-TCM. The EMs targets were obtained from GeneCards, OMIM, TTD, Kyoto encyclopedia of genes and genomes (KEGG) and GAD Databases; the Venny diagram was used to analyze the overlap between the targets of WJD and EMs; use Cytoscape 3.8.2 software to build a drug active ingredient-target protein interaction network; after downloading the data from the String online database, Cytoscape 3.8.2 software was used to draw the intersection target protein-protein interaction network diagram. Finally, microbiotic information mapping was used to analyze gene ontology function enrichment and KEGG pathway enrichment. Molecular docking was used to predict the binding affinity of the components of WJD to the targets of EMs. RESULTS: Seventy-eight active ingredients of WJD were screened, corresponding to 108 targets, 2626 EMs-related targets and 124 intersection targets. The results of gene ontology functional enrichment analysis showed that WJD could affect 709 biological processes, 131 molecular functions and 54 cell composition. The enrichment analysis of KEGG pathway yielded 185 pathways. The treatment of EMs by WJD has the characteristics of multiple targets and multiple pathways. Molecular docking with the AutoDock Vina platform found that 5 active ingredients of WJD were successfully docked with 6 common targets. CONCLUSION: Based on network pharmacology and molecular docking, WJD was found to act on EMs through multi-targets and related signaling pathways.

[Holistic treatment of endometriosis]. / Ganzheitliche Behandlung der Endometriose.

BACKGROUND: The pain phenomena caused by endometriosis are manifold. In addition to nociceptive pain there is also a nociplastic reaction with central sensitization. Atypical symptoms, such as acyclic lower abdominal pain, radiating pain, nonspecific bladder and intestinal complaints or even depression increasingly occur in addition to the classical cyclic complaints, such as severe dysmenorrhea, cyclic lower abdominal pain, dyspareunia, dysuria and dyschezia. Due to the diffuse range of symptoms, affected patients often consult not just gynecologists but also specialists from other disciplines (internal medicine, gastroenterology, orthopedics, pain therapy, psychology etc.). OBJECTIVE: The complexity of endometriosis is presented. The resulting approaches to multimodal interdisciplinary holistic treatment are described. RESULTS: Interdisciplinary concepts should be involved in the optimal treatment of endometriosis patients along with hormonal and surgical treatment, mostly under the supervision of a gynecologist and pain management, dietary changes, psychological support and physiotherapeutic management should also be included. This article provides an overview of possible treatment strategies for chronic symptomatic endometriosis. CONCLUSION: Based on multimodal treatment strategies and regarding the complex pathophysiological alterations of this disease, the complex complaints that significantly impair the quality of life of endometriosis patients can be greatly improved.

Antioxidant vitamins supplementation reduce endometriosis related pelvic pain in humans: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to clarify the effect of antioxidant vitamins supplementation on endometriosis-related pain. METHODS: A systematic search of PubMed, Web of Science, Cochrane Library, Scopus, and China National Knowledge Infrastructure (CNK) databases was conducted to identify relevant studies published in English and Chinese up to 16 March 2023. The search terms used were "endometriosis" OR "endometrioma" OR "endometrium" AND "antioxidant" OR "Vitamin C" OR "Vitamin E" OR "Vitamin D" OR "25-OHD" OR "25(OH)D" OR "25-hydroxyvitamin D". Eligible studies were randomized controlled trials (RCTs) that assessed pain scores using the Visual Analogue Scale (VAS). Mean differences or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the effect of antioxidant vitamins supplementation on endometriosis. The quality of the included studies was assessed using the Cochrane Risk of Bias Tool. The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. RESULTS: A total of 13 RCTs involving 589 patients were included in this meta-analysis. We identified 11 studies that evaluated the effect of antioxidant vitamins supplementation on endometriosis-related pain. The results indicated that the supplementation of antioxidant vitamins can effectively alleviate endometriosis-related pain. Subgroup analysis showed that the supplementation of vitamin E (with or without vitamin C) had a positive effect on improving clinical pelvic pain in patients with chronic pelvic pain. Conversely, supplementation of vitamin D was associated with a reduction in pelvic pain in endometriosis patients, but the difference was not statistically significant compared to the placebo. Additionally, we observed changes in oxidative stress markers following vitamin supplementation. Plasma malondialdehyde (MDA) concentration decreased in patients with endometriosis after antioxidant vitamin supplementation, and the plasma MDA level was inversely correlated with the time and dose of vitamin E and C supplementation. Furthermore, the inflammatory markers in peritoneal fluid, including RANTES, interleukin-6, and monocyte chemoattractant protein-1, significantly decreased after antioxidant therapy. These findings suggest that antioxidant vitamins may alleviate pain in endometriosis patients by reducing inflammation. CONCLUSIONS: The included studies support the potential role of antioxidant vitamins in the management of endometriosis. Supplementation with antioxidant vitamins effectively reduced the severity of dysmenorrhea, improved dyspareunia and pelvic pain, and enhanced quality of life in these patients. Therefore, antioxidant vitamin therapy could be considered as an alternative treatment method, either alone or in combination with other approaches, for endometriosis-related pain. TRIAL REGISTRATION: PROSPERO registration number: CRD42023415198.

Endometriosis Treatment: Role of Natural Polyphenols as Anti-Inflammatory Agents.

Endometriosis is an estrogen-dependent common chronic inflammatory disease defined by the presence of extrauterine endometrial tissue that promotes pelvic pain and fertility impairment. Its etiology is complex and multifactorial, and several not completely understood theories have been proposed to describe its pathogenesis. Indeed, this disease affects women's quality of life and their reproductive system. Conventional therapies for endometriosis treatment primarily focus on surgical resection, lowering systemic levels of estrogen, and treatment with non-steroidal anti-inflammatory drugs to counteract the inflammatory response. However, although these strategies have shown to be effective, they also show considerable side effects. Therefore, there is a growing interest in the use of herbal medicine for the treatment of endometriosis; however, to date, only very limited literature is present on this topic. Polyphenols display important anti-endometriotic properties; in particular, they are potent phytoestrogens that in parallel modulates estrogen activity and exerts anti-inflammatory activity. The aim of this review is to provide an overview on anti-inflammatory activity of polyphenols in the treatment of endometriosis.

Complex Extract of Polygonatum sibiricum and Nelumbinis semen Improves Menopause Symptoms via Regulation of Estrogen Receptor Beta in an Ovariectomized Rat Model.

Menopause is a hormone-deficiency state that causes facial flushing, vaginal dryness, depression, anxiety, insomnia, obesity, osteoporosis, and cardiovascular disease as ovarian function decreases. Hormone-replacement therapy is mainly used to treat menopause; however, its long-term use is accompanied by side effects such as breast cancer and endometriosis. To identify the effect of a complex extract of Polygonatum sibiricum (PS) and Nelumbinis semen (NS) on improving menopause without side effects, an ovariectomized rat model was established to analyze several menopause symptoms. Compared to single extracts, the complex extract restored vaginal epithelial cell thickness and decreased serotonin concentration by increasing the estrogen receptors ERα (ESR1) and ERß (ESR2), depending on the ratio. Although the complex extract exerted a lower weight-loss effect than the single extracts, improved blood-lipid metabolism was observed after increasing high-density lipoprotein cholesterol levels and decreasing low-density lipoprotein cholesterol and triglyceride levels, and ovariectomy-induced osteoporosis was alleviated by suppressing osteoclast production. Thus, by increasing only ERß expression without regulating ERα expression in the uterus, the complex extract of PS and NS may be a natural treatment for improving menopause symptoms without side effects, such as endometriosis.

Adjuvant use of melatonin for pain management in endometriosis-associated pelvic pain-A randomized double-blinded, placebo-controlled trial.

Considering the pharmacological treatment options for endometriosis-associated pain are confined to hormonal therapy and analgesics, we studied the analgesic effect of 20 mg melatonin as an adjuvant therapy in women with endometriosis-associated pain. This randomized double-blinded, placebo-controlled trial was conducted at the Research Center for Womens' Health at Södersjukhuset, a university hospital in Stockholm, Sweden. Forty women from 18 to 50 years of age with endometriosis and severe dysmenorrhea with or without chronic pelvic pain were given 20 mg Melatonin or placebo orally daily for two consecutive menstrual cycles or months. The level of pain was recorded daily on the 11-point numeric rating scale, a difference of 1.3 units was considered clinically significant. Clincaltrials.gov nr NCT03782740. Sixteen participants completed the study in the placebo group and 18 in the melatonin group. The difference in endometriosis-associated pain between the groups showed to be non-significant statistically as well as clinically, 2.9 (SD 1.9) in the melatonin group and 3.3 (SD 2.0) in the placebo group, p = 0.45. This randomized, double-blinded, placebo-controlled trial could not show that 20 mg of melatonin given orally at bedtime had better analgesic effect on endometriosis-associated pain compared with placebo. No adverse effects were observed.

[Shaofu Zhuyu Decoction attenuates fibrosis in endometriosis through regulating PTEN/Akt/mTOR signaling pathway].

The present study aimed to investigate the protective role of Shaofu Zhuyu Decoction(SFZY) against endometriosis fibrosis in mice, and decipher the underlying mechanism through the phosphatase and tensin homolog deleted on chromosome ten(PTEN)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR) pathway. Eighty-five BALB/c female mice were randomly assigned into a blank group, a model group, high-, medium, and low-dose SFZY(SFZY-H, SFZY-M, and SFZY-L, respectively) groups, and a gestrinone suspension(YT) group. The model of endometriosis was induced by intraperitoneal injection of uterine fragments. The mice in different groups were administrated with corresponding groups by gavage 14 days after modeling, and the blank group and model group with equal volume of distilled water by gavage. The treatment lasted for 14 days. The body weight, paw withdrawal latency caused by heat stimuli, and total weight of dissected ectopic focus were compared between different groups. The pathological changes of the ectopic tissue were observed via hematoxylin-eosin(HE) and Masson staining. Real-time PCR was employed to measure the mRNA levels of α-smooth muscle actin(α-SMA) and collagen type Ⅰ(collagen-Ⅰ) in the ectopic tissue. The protein levels of PTEN, Akt, mTOR, p-Akt, and p-mTOR in the ectopic tissue were determined by Western blot. Compared with the blank group, the modeling first decreased and then increased the body weight of mice, increased the total weight of ectopic focus, and shortened the paw withdrawal latency. Compared with the model group, SFZY and YT increased the body weight, prolonged the paw withdrawal latency, and decreased the weight of ectopic focus. Furthermore, the drug administration, especially SFZY-H and YT(P<0.01), recovered the pathological and reduced the area of collagen deposition. Compared with the blank group, the modeling up-regulated the mRNA levels of α-SMA and collagen-Ⅰ in the ectopic focus, and such up-regulation was attenuated after drug intervention, especially in the SFZY-H and YT groups(P<0.05,P<0.01). Compared with the blank group, the modeling down-regulated the protein level of PTEN and up-regulated the protein levels of Akt, mTOR, p-Akt, and p-mTOR(P<0.01, P<0.001). Drug administration, especially SFZY-H and YT, restored such changes(P<0.01). SFZY may significantly attenuate the focal fibrosis in the mouse model of endometriosis by regulating the PTEN/Akt/mTOR signaling pathway.