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

BACKGROUND: The active ingredients of the Chinese medical herb Paris polyphylla, P. polyphylla ethanol extract (PPE) and polyphyllin I (PPI), potentially inhibit epithelial-mesenchymal transition (EMT) in tumors. However, the roles of these ingredients in inhibiting EMT in adenomyosis (AM) remain to be explored. PURPOSE: The primary goal of the study was to uncover the underlying molecular processes through which PPE and PPI suppress EMT in AM, alongside assessing the safety profiles of these substances. METHODS: To assess the suppressive impact of PPE on adenomyosis-derived cells (AMDCs), we employed Transwell and wound healing assays. The polyphyllins (PPI, PPII, PPVII) contained in PPE were characterized using high-performance liquid chromatography (HPLC). Then, bioinformatics techniques were performed to pinpoint potential PPI targets that could be effective in treating AM. Immunoblotting was used to verify the key proteins and pathways identified via bioinformatics. Furthermore, we examined the efficacy of PPE and PPI in treating Institute of Cancer Research (ICR) mice with AM by observing the morphological and pathological features of the uterus and performing immunohistochemistry. In addition, we assessed safety by evaluating liver, kidney and spleen pathologic features and serum test results. RESULTS: Three major polyphyllins of PPE were revealed by HPLC, and PPI had the highest concentration. In vitro experiments indicated that PPE and PPI effectively prevent AMDCs invasion and migration. Bioinformatics revealed that the primary targets E-cadherin, N-cadherin and TGFß1, as well as the EMT biological process, were enriched in PPI-treated AM. Immunoblotting assays corroborated the hypothesis that PPE and PPI suppress the TGFß1/Smad2/3 pathway in AMDCs to prevent EMT from progressing. Additionally, in vivo studies showed that PPE (3 mg/kg and 6 mg/kg) and PPI (3 mg/kg and 6 mg/kg), successfully suppressed the EMT process through targeting the TGFß1/Smad2/3 signaling pathway. Besides, it was observed that lower doses of PPE (3 mg/kg) and PPI (3 mg/kg) exerted minimal effects on the liver, kidneys, and spleen. CONCLUSIONS: PPE and PPI efficiently impede the development of EMT by inhibiting the TGFß1/Smad2/3 pathway, revealing an alternative pathway for the pharmacological treatment of AM.

Adjuvant therapy of Chinese herbal medicine for the treatment of adenomyosis: A protocol for systematic review.

BACKGROUND: Adenomyosis is benign gynecologic condition with complex etiologies. Common symptoms associated with adenomyosis (AM) include menorrhagia, dysmenorrhea, chronic pelvic pain, metrorrhagia, and dyspareunia. Although Chinese herbal medicine (CHM) has often been utilized for managing AM in clinical practice in China, evidence regarding its efficacy is lacking. This systematic review protocol aims to describe a systematic review to assess the effectiveness and safety of CHM combined with Levonorgestrel-releasing intrauterine system for AM. METHODS: The following 7 databases will be searched from the publishment to December 2019: the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), Wanfang Digital Periodicals (WAN FANG), Chinese Biomedical Literature Database (CBM), Chinese Scientific Journal Database (VIP). The primary outcomes will be relief in pain and uterine bleeding. The secondary outcomes include the adverse effects, CA125 variation in peripheral blood, reduction in uterine volume, and endometrial thickness. We will use RevMan V.5.3 to conduct the meta-analysis, if possible. If it is not allowed, a descriptive analysis will be conducted. We will use risk ratio with 95% confidence interval for dichotomous data and the mean difference for continuous data. RESULTS: This study will provide the latest analysis of the currently available evidence for the efficacy of the adjuvant therapy of CHM for the treatment of AM. REGISTRATION NUMBER: OSF (DOI 10.17605/OSF.IO/A2GHY) ETHICS AND DISSEMINATION:: No ethical issues are required. The findings will be published in a peer-reviewed scientific journal.

Anti-Inflammatory Activity of Sanjie Zhentong Capsule Assessed By Network Pharmacology Analysis of Adenomyosis Treatment.

BACKGROUND: Sanjie Zhentong capsule (SZC) offers excellent effect in treating adenomyosis (AM), which is a common and difficult gynecological disease in the clinic. However, the systematic analysis of its mechanism has not been carried out yet and further studies are needed to reveal the role of SZC. METHODS: A systematic network pharmacology analysis was conducted by integrating construction of SZC compound database and AM target database, prediction of potential active compounds and targets by molecular docking combined with compound-target prediction graph (CTPG), protein-protein interaction (PPI) analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Then, the anti-inflammation experiments in vitro were performed by investigating SZC and the representative compounds regulating nitric oxide (NO), interleukin-6 (IL-6), and interleukin-10 (IL-10). RESULTS: Our findings show that SZC mainly treated AM by stimulating 28 core targets through 30 key potential active compounds, and affecting 4 crucial pathways. The treatment was associated with inflammation reaction, hormone regulation, cell adhesion, proliferation, and angiogenesis. Additionally, SZC achieved the anti-inflammatory activity by the cooperation of the compounds through inhibiting NO and IL-6, both promoting and inhibiting IL-10. CONCLUSION: This study investigated the anti-inflammatory activity of SZC based on a systematic analysis of SZC remedying AM, which was revealed to be one of the essential mechanisms. These findings will provide valuable guidance for further research of the SZC treatment of AM, and help improve the comprehension of SZC pharmacological basis as well as AM pathogenesis.

Berberine inhibits growth and inflammatory invasive phenotypes of ectopic stromal cells: Imply the possible treatment of adenomyosis.

Adenomyosis is a common chronic gynecological disorder with some tumor-like properties, including aberrant proliferation, invasion and migration. Berberine (BBR) is an isoquinoline derivative alkaloid with diverse pharmacological activities for the treatment of a wide variety of diseases. However, the effect of BBR on adenomyosis has not been understood. This study was to evaluate the potential therapeutic effect of BBR on ectopic endometrial stromal cells (EESCs) isolated from patients with adenomyosis. Our data showed that BBR significantly inhibited the proliferation and viability of eutopic endometrial stromal cells (EuESCs) and EESCs, while slightly affected the growth of normal endometrial stromal cells (NESCs). BBR markedly exhibited a growth inhibitory effect on EESCs by triggering apoptosis and cell cycle arrest, and alleviating the expression of inflammatory invasive phenotypes (IL-6, IL-8, TGF-ß, EGF, VEGF, and MMP2). The alleviation of inflammatory invasive phenotypes partly involved nuclear translocation of NFκB/p65 and stat3 activation. Taken together, BBR markedly inhibits the growth of EESCs and might be a promising new strategy for the treatment of adenomyosis.

[Treatment of adenomyosis patients by bushen huoxue sanyu decoction: a clinical study].

OBJECTIVE: To observe the clinical efficacy of Bushen Huoxue Sanyu Decoction (BHSD) in treatment of adenomyosis (AM) patients. METHODS: Seventy AM patients of Shen deficiency blood stasis syndrome (SDBSS) were randomly assigned to two groups, the CM treatment group (50 cases) and the Mirena group (20 cases). Patients in the CM treatment group were treated with BHSD, one dose per day. Levonorgestrel intrauterine system (Mirena) was placed in the uterine cavity of those in the Mirena group. The therapeutic course for all was 3 months. Changes of dysmenorrhea, menstrual quantity, SDBSS, CM syndrome, uterine volume, and serum CA125 levels were observed before and after treatment. RESULTS: Compared with before treatment in the same group, scores for dysmenorrhea integral, scores for menstrual quantity, scores for SDBSS, and scores for CM syndrome all decreased in the two groups after treatment (P < 0.01). Compared with before treatment in the same group, the uterine volume was reduced after treatment in the two groups (P < 0.05) and serum carbohydrate antigen CA125 levels decreased between the two groups (P < 0.05, P < 0.01). Compared with the Mirena group, scores for dysmenorrhea integral increased and scores for SDBSS decreased in the CM treatment group (P < 0.01, P < 0.05). There was no statistical difference in the uterine volume or serum carbohydrate antigen CA125 levels (P > 0.05). CONCLUSIONS: BHSD could effectively alleviate main symptoms of AM patients of QSBSS such as dysmenorrhea, profuse menstrual blood volume, and increased uterine volume, and lower scores for QSBSS and the total score for CM syndrome.

Epigallocatechin-3-gallate reduces myometrial infiltration, uterine hyperactivity, and stress levels and alleviates generalized hyperalgesia in mice induced with adenomyosis.

In an effort to search for novel therapeutics for adenomyosis, we sought to determine whether treatment with epigallocatechin-3-gallate (EGCG) would suppress the myometrial infiltration, improve pain behavior, lower stress level, and reduce uterine contractility in a mice model of adenomyosis. Adenomyosis was induced in 28 female ICR mice neonatally dosed with tamoxifen, while another 12 (group C) were dosed with solvent only, which served as a blank control. Starting from 4 weeks after birth, hot plate test was administrated to all mice every 4 weeks. At the 16th week, all mice induced with adenomyosis were randomly divided into 3 groups: low-dose EGCG (5 mg/kg), high-dose EGCG (50 mg/kg), and untreated. Group C received no treatment. After 3 weeks of treatment, the hot plate test was administered again, a blood sample was taken to measure the plasma corticosterone level by enzyme-linked immunosorbent assay, and then all mice were sacrificed. The depth of myometrial infiltration and uterine contractility were also evaluated. We found that the induction of adenomyosis resulted in progressive generalized hyperalgesia, along with elevated amplitude and frequency of uterine contractions as well as elevated plasma corticosterone levels. The EGCG treatment dose dependently suppressed myometrial infiltration, improved generalized hyperalgesia, reduced uterine contractility, and lowered plasma corticosterone levels. These results suggest that induced adenomyosis causes pain and elevates stress levels in mice. Uterine hyperactivity may contribute to dysmenorrhea in women with adenomyosis who might also have elevated stress level due to pain. The EGCG appears to be a promising compound for treating adenomyosis.