Activation of the YY1-UGT2B7 Axis Promotes Mammary Estrogen Homeostasis Dysregulation and Exacerbates Breast Tumor Metastasis.

Metastasis is the most common pathway of cancer death. The lack of effective predictors of breast cancer metastasis is a pressing issue in clinical practice. Therefore, exploring the mechanism of breast cancer metastasis to uncover reliable predictors is very important for the clinical treatment of breast cancer patients. In this study, tandem mass tag quantitative proteomics technology was used to detect protein content in primary breast tumor tissue samples from patients with metastatic and nonmetastatic breast cancer at diagnosis. We found that the high expression of yin-yang 1(YY1) is strongly associated with poor prognosis in high-grade breast cancer. YY1 expression was detected in both clinical tumor tissue samples and tumor tissue samples from mammary-specific polyomavirus middle T antigen overexpression mouse model mice. We demonstrated that upregulation of YY1 expression was closely associated with breast cancer metastasis and that high YY1 expression could promote the migratory invasive ability of breast cancer cells. Mechanistically, YY1 directly binds to the UGT2B7 mRNA initiation sequence ATTCAT, thereby transcriptionally regulating the inhibition of UGT2B7 expression. UGT2B7 can regulate the development of breast cancer by regulating estrogen homeostasis in the breast, and the abnormal accumulation of estrogen, especially 4-OHE2, promotes the migration and invasion of breast cancer cells, ultimately causing the development of breast cancer metastasis. In conclusion, YY1 can regulate the UGT2B7-estrogen metabolic axis and induce disturbances in estrogen metabolism in breast tumors, ultimately leading to breast cancer metastasis. Disturbances in estrogen metabolism in the breast tissue may be an important risk factor for breast tumor progression and metastasis SIGNIFICANCE STATEMENT: In this study, we propose for the first time a regulatory relationship between YY1 and the UGT2B7/estrogen metabolism axis and explore the molecular mechanism. Our study shows that the YY1/UGT2B7/estrogen axis plays an important role in the development and metastasis of breast cancer. This study further elucidates the potential mechanisms of YY1-mediated breast cancer metastasis and the possibility and promise of YY1 as a predictor of cancer metastasis.

Testosterone Supplementation Promotes Estrogen Synthesis of Buffalo Cumulus Cells Surrounding In Vitro-Matured Oocytes.

Cumulus cells (CCs) synthesize estrogens that are essential for follicular development. However, the effects of androgen on estrogen production in buffalo CCs remain unknown. In the present study, the impacts of testosterone on estrogen synthesis of buffalo CCs surrounding in vitro-matured oocytes were investigated. The results showed that testosterone supplementation improved both the expression levels of estrogen synthesis-related genes (CYP11A1, CYP19A1, and 17ß-HSD) and the secretion levels of estradiol in buffalo CCs surrounding in vitro-matured oocytes. Furthermore, testosterone treatment enhanced the sensitivity of buffalo CCs surrounding in vitro-matured oocytes to follicle-stimulating hormone (FSH). This study indicated that testosterone supplementation promoted the estrogen synthesis of buffalo CCs surrounding in vitro-matured oocytes mainly through strengthening the responsiveness of CCs to FSH. The present study serves as a foundation of acquiring high-quality recipient oocytes for buffalo somatic cell nuclear transfer.

Comparison of in vitro Toxicities of 8-Prenylnaringenin, Tartrazine and 17ß-Estradiol, Representatives of Natural and Synthetic Estrogens, in Rat and Human Hepatoma Cell Lines.

BACKGROUND: Phytoestrogens have been praised for their beneficial health effects, whereas synthetic xenoestrogens have been connected to ailments. AIMS: To ascertain whether the toxicities of natural and synthetic estrogens differ, we examined the potent phytoestrogen 8-prenylnaringenin (8-PN), the common synthetic xenoestrogen tartrazine, and the physiological estrogen 17ß-estradiol (E2). METHODS: These three compounds were tested for cytotoxicity, cell proliferation and genotoxicity in human HepG2 and rat H4IIE hepatoma cells. RESULTS: All three estrogens elicited cytotoxicity at high concentrations in both cell lines. They also inhibited cell proliferation, with E2 being the most effective. They all tended to increase micronuclei formation. CONCLUSION: Natural estrogens were no less toxic than a synthetic one.

ß-Estradiol Supplementation Regulates Cholesterol Synthesis Independent of Unsaturated Fat Consumption in Adult Zebrafish.

Obesity is a public health concern resulting in a variety of health complications, including heart disease and insulin resistance. Estrogens have been associated with a reduced risk of obesity, but this relationship remains incompletely understood. We assessed the role of 17ß-estradiol (E2) in mitigating complications associated with obesity by supplementing E2 in the diets of overfed zebrafish. We report that dietary E2 supplementation protects against weight gain and modulates de novo cholesterol synthesis in a sex-specific manner. Our studies lead us to propose a model in which E2 regulates hmgcr expression independently of unsaturated fat consumption. These data can be used to develop sex-specific treatments for obesity-related health conditions.

The complementary roles of iron and estrogen in menopausal differences in cardiometabolic outcomes.

Biological hormonal changes are frequently cited as an explanatory factor of sex and menopause differences in cardiometabolic diseases (CMD) and its associated risk factors. However, iron metabolism which varies between sexes and among women of different reproductive stages could also play a role. Recent evidence suggest that iron may contribute to CMD risk by modulating oxidative stress pathways and inflammatory responses, offering insights into the mechanistic interplay between iron and CMD development. In the current review, we provide a critical appraisal of the existing evidence on sex and menopausal differences in CMD, discuss the pitfall of current estrogen hypothesis as sole explanation, and the emerging role of iron in CMD as complementary pathway. Prior to menopause, body iron stores are lower in females as compared to males, but the increase during and after menopause, is tandem with an increased CMD risk. Importantly, basic science experiments show that an increased iron status is related to the development of type 2 diabetes (T2D), and different cardiovascular diseases (CVD). While epidemiological studies have consistently reported associations between heme iron intake and some iron biomarkers such as ferritin and transferrin saturation with the risk of T2D, the evidence regarding their connection to CVD remains controversial. We delve into the factors contributing to this inconsistency, and the limitation of relying on observational evidence, as it does not necessarily imply causation. In conclusion, we provide recommendations for future studies on evaluating the potential role of iron in elucidating the sex and menopausal differences observed in CMD.

Qixian granule inhibits ferroptosis in vascular endothelial cells by modulating TRPML1 in the lysosome to prevent postmenopausal atherosclerosis.

ETHNOPHARMACOLOGICAL RELEVANCE: QiXian Granule (QXG) is an integrated traditional Chinese medicine formula used to treat postmenopausal atherosclerotic (AS) cardiovascular diseases. The previous studies have found that QXG inhibited isoproterenol (ISO)-induced myocardial remodeling. And its active ingredient, Icraiin, can inhibit ferroptosis by promoting oxidized low-density lipoprotein (xo-LDL)-induced vascular endothelial cell injury and autophagy in atherosclerotic mice. Another active ingredient, Salvianolic Acid B, can suppress ferroptosis and apoptosis during myocardial ischemia/reperfusion injury by reducing ubiquitin-proteasome degradation of Glutathione Peroxidase 4 (GPX4) and down-regulating the reactive oxygen species (ROS)- c-Jun N-terminal kinases (JNK)/mitogen-activated protein kinase (MAPK) pathway. AIM OF THE STUDY: The objective of this research was to assess the possible impact of QXG on atherosclerosis in postmenopausal individuals and investigate its underlying mechanisms. MATERIALS AND METHODS: Female ApoE-/- mice underwent ovariectomy and were subjected to a high-fat diet (HFD) to establish a postmenopausal atherosclerosis model. The therapeutic effects of QXG were observed in vivo and in vitro through intraperitoneal injection of erastin, G-protein Coupled Estrogen Receptor (GPER) inhibitor (G15), and silent Mucolipin Transient Receptor Potential Channel 1 (TRPML1) adenovirus injection via tail vein. UPLC-MS and molecular docking techniques identified and evaluated major QXG components, contributing to the investigation of QXG's anti-postmenopausal atherosclerotic effects. RESULTS: QXG increased serum Estradiol levels, decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, which indicated QXG had estrogen-like effects in Ovx/ApoE-/- mice. Furthermore, QXG demonstrated the potential to impede the progression of AS in Ovx/ApoE-/- mice, as evidenced by reductions in serum triglycerides (TG), total cholesterol (TC), and low-density lipoprotein-cholesterol (LDL-C) levels. Additionally, QXG inhibited ferroptosis in Ovx/ApoE-/- mice. Notably, UPLC-MS analysis identified a total of 106 active components in QXG. The results of molecular docking analysis demonstrated that Epmedin B, Astragaloside II, and Orientin exhibit strong binding affinity towards TRPML1. QXG alleviates the progression of atherosclerosis by activating TRPML1 through the GPER pathway or directly activating TRPML1, thereby inhibiting GPX4 and ferritin heavy chain (FTH1)-mediated iron pendant disease. In vitro, QXG-treated serum suppressed proliferation, migration, and ox-LDL-induced MMP and ROS elevation in HAECs. CONCLUSION: QXG inhibited GPX4 and FTH1-mediated ferroptosis in vascular endothelial cells through up-regulating GPER/TRPML1 signaling, providing a potential therapeutic option for postmenopausal females seeking a safe and effective medication to prevent atherosclerosis. The study highlights QXG's estrogenic properties and its promising role in combating postmenopausal atherosclerosis.

Sex drives colonic mucin sialylation in wild mice.

Mucin protein glycosylation is important in determining biological properties of mucus gels, which form protective barriers at mucosal surfaces of the body such as the intestine. Ecological factors including: age, sex, and diet can change mucus barrier properties by modulating mucin glycosylation. However, as our understanding stems from controlled laboratory studies in house mice, the combined influence of ecological factors on mucin glycosylation in real-world contexts remains limited. In this study, we used histological staining with 'Alcian Blue, Periodic Acid, Schiff's' and 'High-Iron diamine' to assess the acidic nature of mucins stored within goblet cells of the intestine, in a wild mouse population (Mus musculus). Using statistical models, we identified sex as among the most influential ecological factors determining the acidity of intestinal mucin glycans in wild mice. Our data from wild mice and experiments using laboratory mice suggest estrogen signalling associates with an increase in the relative abundance of sialylated mucins. Thus, estrogen signalling may underpin sex differences observed in the colonic mucus of wild and laboratory mice. These findings highlight the significant influence of ecological parameters on mucosal barrier sites and the complementary role of wild populations in augmenting standard laboratory studies in the advancement of mucus biology.

From Gut to Hormones: Unraveling the Role of Gut Microbiota in (Phyto)Estrogen Modulation in Health and Disease.

The human gut microbiota regulates estrogen metabolism through the "estrobolome," the collection of bacterial genes that encode enzymes like ß-glucuronidases and ß-glucosidases. These enzymes deconjugate and reactivate estrogen, influencing circulating levels. The estrobolome mediates the enterohepatic circulation and bioavailability of estrogen. Alterations in gut microbiota composition and estrobolome function have been associated with estrogen-related diseases like breast cancer, enometrial cancer, and polycystic ovarian syndrome (PCOS). This is likely due to dysregulated estrogen signaling partly contributed by the microbial impacts on estrogen metabolism. Dietary phytoestrogens also undergo bacterial metabolism into active metabolites like equol, which binds estrogen receptors and exhibits higher estrogenic potency than its precursor daidzein. However, the ability to produce equol varies across populations, depending on the presence of specific gut microbes. Characterizing the estrobolome and equol-producing genes across populations can provide microbiome-based biomarkers. Further research is needed to investigate specific components of the estrobolome, phytoestrogen-microbiota interactions, and mechanisms linking dysbiosis to estrogen-related pathology. However, current evidence suggests that the gut microbiota is an integral regulator of estrogen status with clinical relevance to women's health and hormonal disorders.

[Effect and mechanism of Yueju Pills on breast cancer induced by DMBA in rats].

This paper aims to explore the inhibitory effect of Yueju Pills on breast cancer and decipher the underlying mechanism. A total of 92 SPF-grade SD female rats were involved in this study, and 14 of them were randomly selected into control group. The remaining 78 rats were administrated with 7,12-dimethylbenzanthracene(DMBA) by gavage to establish the breast cancer model. The modeled rats were randomized into model, tamoxifen(1.9 mg·kg~(-1)·d~(-1)), and low-and high-dose(17, 34 g·kg~(-1)·d~(-1)) Yueju Pills groups. The mental state, food intake, and activities of the rats were observed daily, and the body weight was measured on alternate days. After 12 weeks of administration, the rats were sacrificed and the tumor weight was measured. The serum estrogen and progeste-rone levels were determined by enzyme-linked immunosorbent assay. The histopathological changes of the breast and tumor were observed by hematoxylin-eosin staining. Western blot was employed to measure the protein levels of glucose transporter 1(GLUT1), lactate dehydrogenase A(LDHA), phosphofructokinase muscle(PFKM), pyruvate kinase isozyme type M2(PKM2), hexokinase 2(HK2), nuclear factor-kappaB(NF-κB), and phosphorylated NF-κB. The intestinal microbiome was examined by 16S rRNA high-throughput sequencing. The results showed that compared with the model group, high and low-dose Yueju Pills showed the tumor inhibition rate of 15.8% and 64.5%, respectively, and the low dose group had stronger inhibitory effect. Compared with the control group, the model group presented elevated the levels of estrogen and progesterone in serum. The administration of Yueju Pills lowered such ele-vation, and the low-dose group showed stronger lowering effect(P<0.05). Compared with the model group, Yueju Pills reduced the glands with increased breast tissue, the degree of breast duct expansion, the number and area of acinar cavity, the secretions, and the layers of mammary epithelial cells. Furthermore, Yueju Pills down-regulated the expression of GLUT1, LDHA, PFKM, PKM2, HK2, and NF-κB(P<0.05) and altered the diversity, composition, structure, and abundance of intestinal flora. The results showed that Yueju Pills could inhibit breast cancer by regulating the secretion of estrogen and progesterone, glycolysis, inflammatory cytokines, and intestinal flora.

Nutraceuticals known to promote hair growth do not interfere with the inhibitory action of tamoxifen in MCF7, T47D and BT483 breast cancer cell lines.

BACKGROUND: Hair loss/thinning is a common side effect of tamoxifen in estrogen receptor (ER) positive breast cancer therapy. Some nutraceuticals known to promote hair growth are avoided during breast cancer therapy for fear of phytoestrogenic activity. However, not all botanical ingredients have similarities to estrogens, and in fact, no information exists as to the true interaction of these ingredients with tamoxifen. Therefore, this study sought to ascertain the effect of nutraceuticals (+/- estrogen/tamoxifen), on proliferation of breast cancer cells and the relative expression of ERα/ß. METHODS: Kelp, Astaxanthin, Saw Palmetto, Tocotrienols, Maca, Horsetail, Resveratrol, Curcumin and Ashwagandha were assessed on proliferation of MCF7, T47D and BT483 breast cancer cell lines +/- 17ß-estradiol and tamoxifen. Each extract was analysed by high performance liquid chromatography (HPLC) prior to use. Cellular ERα and ERß expression was assessed by qRT-PCR and western blot. Changes in the cellular localisation of ERα:ERß and their ratio following incubation with the nutraceuticals was confirmed by immunocytochemistry. RESULTS: Estradiol stimulated DNA synthesis in three different breast cancer cell lines: MCF7, T47D and BT483, which was inhibited by tamoxifen; this was mirrored by a specific ERa agonist in T47D and BT483 cells. Overall, nutraceuticals did not interfere with tamoxifen inhibition of estrogen; some even induced further inhibition when combined with tamoxifen. The ERα:ERß ratio was higher at mRNA and protein level in all cell lines. However, incubation with nutraceuticals induced a shift to higher ERß expression and a localization of ERs around the nuclear periphery. CONCLUSIONS: As ERα is the key driver of estrogen-dependent breast cancer, if nutraceuticals have a higher affinity for ERß they may offer a protective effect, particularly if they synergize and augment the actions of tamoxifen. Since ERß is the predominant ER in the hair follicle, further studies confirming whether nutraceuticals can shift the ratio towards ERß in hair follicle cells would support a role for them in hair growth. Although more research is needed to assess safety and efficacy, this promising data suggests the potential of nutraceuticals as adjuvant therapy for hair loss in breast cancer patients receiving endocrine therapy.

Ginsenoside - a promising natural active ingredient with steroidal hormone activity.

Ginsenosides are a class of natural products with hormone-like activity of triterpenoid saponins and have a variety of pharmacological activities such as anti-aging, immune regulation and cognitive improvement. With the great research interest in alternative medicine and natural products, they are gradually becoming research hotspots. Ginsenosides have a four-ring rigid steroid backbone similar to steroid hormones, and a series of experimental studies have shown that they can exhibit hormone-like activity by binding to nuclear receptors or affecting hormone levels, thereby affecting a wide range of inflammatory conditions, cancers, and menopause-related diseases. This review summarizes the mechanisms and potential health effects of ginsenosides exhibiting estrogen-like, glucocorticoid-like and androgen-like activities, providing an important reference for the exploration of safe phytohormone replacement therapy.

Identifying the effective combination of acupuncture and traditional Chinese medicinal herbs for postmenopausal osteoporosis therapy through studies of their molecular regulation of bone homeostasis.

Worldwide, as the population age, osteoporosis is becoming increasingly common, and osteoporotic fractures have a significant economic burden. Postmenopausal women are the most susceptible to developing osteoporosis and the most critical time to prevent it is during the perimenopausal and early menopausal years. In this regard, we hypothesize rational combination of acupuncture and Traditional Chinese Medicine (TCM) in the form of herbal extract could prevent osteoporosis in women. Estrogen deficiency during menopause causes low-level inflammation that stimulates the formation of osteoclasts, the bone-resorbing cells, and simultaneously inhibits the viability and function of osteoblasts, the bone-forming cells. The most potent inflammatory cytokine in skeletal homeostasis is the receptor activator of nuclear factor kappa B ligand (RANKL) that stimulates osteoclast function. Conversely, the canonical Wnt pathway is essential for osteoblastogenesis and bone formation, and estrogen deficiency leads to diminished functioning of this pathway. TCM and acupuncture could target the RANKL and the Wnt pathway in favorable ways to prevent the accelerated bone loss experienced during the early menopausal stage and promote the gain in bone mass in postmenopausal women. In this review, we propose a rational combination of specific TCM and acupuncture targeting those signaling molecules/pathways by the drugs that are in clinical use for the treatment of postmenopausal osteoporosis. Our rational approach revealed that Danshen (Radix Salviae Miltiorrhizae) could exert a synergistic effect with acupuncture. We then propose a translational path for developing the putative combination in women with postmenopausal osteoporosis to curtail the risk of osteoporotic fractures.

Analysis of the cognitive and functional behavior of female rats in the periestropause after hormone therapy with estrogen.

Perimenopause is a critical period, with severe cycle irregularity and lower estrogen secretion altering redox state biomarkers, leading to behavioral changes. The estrogen hormonal therapy (EHT) being commonly used to alleviate climacteric effects. Therefore, the aim of this study was to analyze anxiolytic profile, recognition memory (short and long term), ambulation, redox status, cell synaptic activity in locus coeruleus and hippocampus of Wistar rats in the periestropause after EHT. Forty rats participated in the study; 20 were treated with corn oil (group 21Mo/Veh; corn oil/0.2 mL/sc; 2x/week) and 20 were submitted to EHT (group 21Mo/E2; 17ß-estradiol/15 µg/Kg/sc; 2x/week) for 120 days. Open field, elevated plus maze, object recognition (RO), and footprint tests were performed immediately before and at the end of the treatment period. From the decapitated brains, isolated hippocampus were destined for biochemical analysis, in turn, perfused brains were destined for histological analysis. The 21Mo/E2 group had a significantly greater total time in the central region and a significantly greater number of entries into the open arms compared to the 21Mo/Veh group, as in crossing, rearing and grooming behaviors, evidencing an anxiolytic profile. In the RO test, the 21Mo/Veh group decreased long-term memory, and the 21Mo/E2 group maintained the same index as at 17 months of age, in addition to a better balance of the hippocampal redox state, prevention of neuronal cell loss and better gait. Based on the results, it appears that exogenous E2 supplementation during periestropause may help preserve neurological functions and potentially prevent neuropsychological and neurodegenerative disorders.

Progesterone treatment reduces food intake and body weight in ovariectomized female rats.

While the effects of progesterone on body weight and appetite in pre-menopausal conditions have been well elucidated, its effects in post-menopausal conditions have not been clarified. On the contrary, the effects of estrogen on body weight and appetite in post-menopausal conditions have been well established. In this study, the effects of progesterone treatment on body weight, appetite, and fat mass in ovariectomized rats were evaluated. In addition, the central and/or peripheral levels of oxytocin (OT), leptin, and their receptors, which are potent anorectic factors, were examined. Female rats were ovariectomized and divided into control, progesterone-treated, and estrogen-treated groups. Body weight, food intake, and subcutaneous fat mass were lower in both the progesterone and estrogen groups than in the control group. The estrogen group exhibited higher serum OT levels than the control group, whereas the OT levels of the progesterone and control groups did not differ. The serum leptin levels of both the progesterone and estrogen groups were lower than those of the control group. Gene expression analysis of OT, leptin, and their receptors in the hypothalamus and adipose tissue found few significant differences among the groups. Hypothalamic neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) mRNA levels involved in appetite regulation were slightly altered in the progesterone and estrogen groups. These findings suggest that progesterone treatment may have favorable effects on body weight, appetite, and fat mass regulation in post-menopausal conditions and that the mechanisms underlying these effects of progesterone differ from those underlying the effects of estrogen.

Daily supplement of sesame oil prevents postmenopausal osteoporosis via maintaining serum estrogen and aromatase levels in rats.

Estrogen deficiency is one of the main causes of postmenopausal osteoporosis in elderly women. Hormone replacement therapy has been employed to manage postmenopausal osteoporosis; however, it has raised concerns related to heart attacks and breast cancer. Sesame oil has been reported to affect sex hormone status. The aim of the present study is to evaluate the effect of sesame oil supplement on postmenopausal osteoporosis in rats. We used female Sprague Dawley rats that underwent bilaterally ovariectomy (OVX) as an experimental postmenopausal osteoporosis animal model. These rats were orally administrated sesame oil (0.25 or 0.5 mL/kg/day) for four months as the therapeutic group. We assessed bone mineral density (BMD) and the levels of osteocalcin, procollagen-I C-terminal propeptide (PICP), collagen cross-linked N-telopeptide (NTx), estradiol, and aromatase in the sera. The daily supplementation of sesame oil significantly increased BMD, serum osteocalcin levels, and trabecular areas in the OVX-treated rats. Sesame oil also elevated serum PICP levels and decreased NTx levels in these rats. Furthermore, sesame oil effectively maintained serum estradiol and aromatase levels in the OVX-induced osteoporosis rats. In conclusion, daily supplementation of sesame oil prevents postmenopausal osteoporosis by maintaining serum estrogen and aromatase levels, while also modulating the imbalance between bone formation and resorption in osteoporosis rats.

Ginsenoside Rg1 modulates PI3K/AKT pathway for enhanced osteogenesis via GPER.

BACKGROUND: Osteoporosis is a systemic skeletal disorder characterized by decreased bone density and the degradation of bone tissue microarchitecture. Ginsenoside Rg1, derived from Panax ginseng, has been a part of traditional Chinese medicine in China for centuries, particularly for treating osteoporosis. However, there remains limited research on the osteogenic potential of Rg1 within the glucocorticoid-induced osteoporosis (GIOP) model and its specific mechanisms. PURPOSE: The primary objective of this study is to investigate the osteogenic potential of Rg1 within the GIOP model and explore the signaling pathways associated with its in vivo and in vitro effects. METHODS: Cell proliferation, differentiation and mineralization were evaluated by the Cell counting kit 8(CCK8) assay, alkaline phosphatase (ALP) test and Alizarin Red S staining, respectively. The qPCR technique was used to determine the relative expression of mRNA and the western blot was used to determine the relative expression of protein. In vivo experiments, spinal vertebrae staining in zebrafish larvae was accomplished by alizarin red S staining. RESULTS: Zebrafish larvae's hatching, survival, malformation, and heart rate were unaffected by 50 µM of Rg1 in vivo, while the MEC3T3-E1 cell line's proliferation was unaffected by 50 µM of Rg1 in vitro. Meanwhile, Rg1 was shown to improve osteogenic differentiation or bone formation as well as the level of mRNA expression of osteogenic markers in vivo and in vitro. Treatment with Rg1 significantly increased the expression of G protein-coupled estrogen receptor (GPER) and pAKT. In addition, the GPER inhibitor G15 could significantly reduce the mRNA and protein expression levels of GPER and phosphorylated AKT, LY294002, a PI3K/AKT pathway inhibitor, markedly suppresses the expression of phosphorylated AKT, yet shows no significant impact on GPER expression. Both G15 and LY294002 can significantly blocked the Rg1-mediated enhancement of osteogenesis capacity in the GIOP model. In contrast, when both the agonists G1 of GPER and LY294002 were added, G1 increased the relative expression of mRNA and protein of GPER, but not the expression of osteogenic capacity and osteogenic markers. CONCLUSIONS: This study investigates the mineralization effects and mechanisms of Ginsenoside Rg1 both in vitro and in vivo. For the first time, we propose that Rg1 might regulate osteogenesis by modulating AKT phosphorylation through mediating GPER expression within the PI3K/AKT pathway in the GIOP model. This discovery introduces novel targets and avenues for osteoporosis treatment.

Characterization of the metabolites of Eucommiae Cortex in rats provides a further insight into its estrogen-like effective substances.

Eucommiae Cortex is one of important traditional Chinese medicines (TCMs) used in Asia for preventing and treating osteoporosis induced by estrogen deficiency. However, the low exposure of prototype components in Eucommiae Cortex in vivo is difficult to interpret its efficacy. Under the guidance of UPLC-Q/TOF-MS, 42 metabolites including 32 lignans and 10 phenolics, 21 of which were new compounds, were isolated from rat urine and feces after oral administration of aqueous extract of E. ulmoides Oliv. by various chromatographic techniques. Their structures were determined based on extensive physicochemical analyses and spectral data. Their absolute configurations were determined by experimental and calculated ECD spectra, along with the calculated NMR with DP4 evaluation. Additionally, all isolated metabolites were evaluated for their estrogen-like activities, and there are 15 metabolites having estrogen-like effects after assessing influences in MCF-7 cells. Further, Dual Luciferase Reporter Gene Assay was used to determine their activation with estrogen receptor, M10 and M11 mixtures, M14, M19, M33, M27, M31, M38-M41 could activate ERα, and M19 and M41 could activate ERß. These results not only clarify the pharmacological substances of Eucommiae Cortex, but also provide a basis for guiding its clinical application.

Microbial Therapy and Breast Cancer Management: Exploring Mechanisms, Clinical Efficacy, and Integration within the One Health Approach.

This comprehensive review elucidates the profound relationship between the human microbiome and breast cancer management. Recent findings highlight the significance of microbial alterations in tissue, such as the gut and the breast, and their role in influencing the breast cancer risk, development, progression, and treatment outcomes. We delve into how the gut microbiome can modulate systemic inflammatory responses and estrogen levels, thereby impacting cancer initiation and therapeutic drug efficacy. Furthermore, we explore the unique microbial diversity within breast tissue, indicating potential imbalances brought about by cancer and highlighting specific microbes as promising therapeutic targets. Emphasizing a holistic One Health approach, this review underscores the importance of integrating insights from human, animal, and environmental health to gain a deeper understanding of the complex microbe-cancer interplay. As the field advances, the strategic manipulation of the microbiome and its metabolites presents innovative prospects for the enhancement of cancer diagnostics and therapeutics. However, rigorous clinical trials remain essential to confirm the potential of microbiota-based interventions in breast cancer management.

Diagnosis and management of complications following pelvic organ prolapse surgery using a synthetic mesh: French national guidelines for clinical practice.

Complications associated with pelvic organ prolapse (POP) surgery using a synthetic non-absorbable mesh are uncommon (<5%) but may be severe and may hugely diminish the quality of life of some women. In drawing up these multidisciplinary clinical practice recommendations, the French National Authority for Health (Haute Autorité de santé, HAS) conducted an exhaustive review of the literature concerning the diagnosis, prevention, and management of complications associated with POP surgery using a synthetic mesh. Each recommendation for practice was allocated a grade (A,B or C; or expert opinion (EO)), which depends on the level of evidence (clinical practice guidelines). PREOPERATIVE PATIENTS' INFORMATION: Each patient must be informed concerning the risks associated with POP surgery (EO). HEMORRHAGE, HEMATOMA: Vaginal infiltration using a vasoconstrictive solution is not recommended during POP surgery by the vaginal route (grade C). The placement of vaginal packing is not recommended following POP surgery by the vaginal route (grade C). During laparoscopic sacral colpopexy, when the promontory seems highly dangerous or when severe adhesions prevent access to the anterior vertebral ligament, alternative surgical techniques should be discussed per operatively, including colpopexy by lateral mesh laparoscopic suspension, uterosacral ligament suspension, open abdominal mesh surgery, or surgery by the vaginal route (EO). BLADDER INJURY: When a bladder injury is diagnosed, bladder repair by suturing is recommended, using a slow resorption suture thread, plus monitoring of the permeability of the ureters (before and after bladder repair) when the injury is located at the level of the trigone (EO). When a bladder injury is diagnosed, after bladder repair, a prosthetic mesh (polypropylene or polyester material) can be placed between the repaired bladder and the vagina, if the quality of the suturing is good. The recommended duration of bladder catheterization following bladder repair in this context of POP mesh surgery is from 5 to 10 days (EO). URETER INJURY: After ureteral repair, it is possible to continue sacral colpopexy and place the mesh if it is located away from the ureteral repair (EO). RECTAL INJURY: Regardless of the approach, when a rectal injury occurs, a posterior mesh should not be placed between the rectum and the vagina wall (EO). Concerning the anterior mesh, it is recommended to use a macroporous monofilament polypropylene mesh (EO). A polyester mesh is not recommended in this situation (EO). VAGINAL WALL INJURY: After vaginal wall repair, an anterior or a posterior microporous polypropylene mesh can be placed, if the quality of the repair is found to be satisfactory (EO). A polyester mesh should not be used after vaginal wall repair (EO). MESH INFECTION (ABSCESS, CELLULITIS, SPONDYLODISCITIS): Regardless of the surgical approach, intravenous antibiotic prophylaxis is recommended (aminopenicillin + beta-lactamase inhibitor: 30 min before skin incision +/- repeated after 2 h if surgery lasts longer) (EO). When spondylodiscitis is diagnosed following sacral colpopexy, treatment should be discussed by a multidisciplinary group, including especially spine specialists (rheumatologists, orthopedists, neurosurgeons) and infectious disease specialists (EO). When a pelvic abscess occurs following synthetic mesh sacral colpopexy, it is recommended to carry out complete mesh removal as soon as possible, combined with collection of intraoperative bacteriological samples, drainage of the collection and targeted antibiotic therapy (EO). Non-surgical conservative management with antibiotic therapy may be an option (EO) in certain conditions (absence of signs of sepsis, macroporous monofilament polypropylene type 1 mesh, prior microbiological documentation and multidisciplinary consultation for the choice of type and duration of antibiotic therapy), associated with close monitoring of the patient. BOWEL OCCLUSION RELATED TO NON-CLOSURE OF THE PERITONEUM: Peritoneal closure is recommended after placement of a synthetic mesh by the abdominal approach (EO). URINARY RETENTION: Preoperative urodynamics is recommended in women presenting with urinary symptoms (bladder outlet obstruction symptoms, overactive bladder syndrome or incontinence) (EO). It is recommended to remove the bladder catheter at the end of the procedure or within 48 h after POP surgery (grade B). Bladder emptying and post-void residual should be checked following POP surgery, before discharge (EO). When postoperative urine retention occurs after POP surgery, it is recommended to carry out indwelling catheterization and to prefer intermittent self-catheterization (EO). POSTOPERATIVE PAIN: Before POP surgery, the patient should be asked about risk factors for prolonged and chronic postoperative pain (pain sensitization, allodynia, chronic pelvic or non-pelvic pain) (EO). Concerning the prevention of postoperative pain, it is recommended to carry out a pre-, per- and postoperative multimodal pain treatment (grade B). The use of ketamine intraoperatively is recommended for the prevention of chronic postoperative pelvic pain, especially for patients with risk factors (preoperative painful sensitization, allodynia, chronic pelvic or non-pelvic pain) (EO). Postoperative prescription of opioids should be limited in quantity and duration (grade C). When acute neuropathic pain (sciatalgia or pudendal neuralgia) resistant to level I and II analgesics occurs following sacrospinous fixation, a reintervention is recommended for suspension suture removal (EO). When chronic postoperative pain occurs after POP surgery, it is recommended to systematically seek arguments in favor of neuropathic pain with the DN4 questionnaire (EO). When chronic postoperative pelvic pain occurs after POP surgery, central sensitization should be identified since it requires a consultation in a chronic pain department (EO). Concerning myofascial pain syndrome (clinical pain condition associated with increased muscle tension caused by myofascial trigger points), when chronic postoperative pain occurs after POP surgery, it is recommended to examine the levator ani, piriformis and obturator internus muscles, so as to identify trigger points on the pathway of the synthetic mesh (EO). Pelvic floor muscle training with muscle relaxation is recommended when myofascial pain syndrome is associated with chronic postoperative pain following POP surgery (EO). After failure of pelvic floor muscle training (3 months), it is recommended to discuss surgical removal of the synthetic mesh, during a multidisciplinary discussion group meeting (EO). Partial removal of synthetic mesh is indicated when a trigger point is located on the pathway of the mesh (EO). Total removal of synthetic mesh should be discussed during a multidisciplinary discussion group meeting when diffuse (no trigger point) chronic postoperative pain occurs following POP surgery, with or without central sensitization or neuropathic pain syndromes (EO). POSTOPERATIVE DYSPAREUNIA: When de novo postoperative dyspareunia occurs after POP surgery, surgical removal of the mesh should be discussed (EO). VAGINAL MESH EXPOSURE: To reduce the risk of vaginal mesh exposure, when hysterectomy is required during sacral colpopexy, subtotal hysterectomy is recommended (grade C). When asymptomatic vaginal macroporous monofilament polypropylene mesh exposure occurs, systematic imaging is not recommended. When vaginal polyester mesh exposure occurs, pelvic +/- lumbar MRI (EO) should be used to look for an abscess or spondylodiscitis, given the greater risk of infection associated with this type of material. When asymptomatic vaginal mesh exposure of less than 1 cm2 occurs in a woman with no sexual intercourse, the patient should be offered observation (no treatment) or local estrogen therapy (EO). However, if the patient wishes, partial excision of the mesh can be offered. When asymptomatic vaginal mesh exposure of more than 1 cm2 occurs or if the woman has sexual intercourse, or if it is a polyester prosthesis, partial mesh excision, either immediately or after local estrogen therapy, should be offered (EO). When symptomatic vaginal mesh exposure occurs, but without infectious complications, surgical removal of the exposed part of the mesh by the vaginal route is recommended (EO), and not systematic complete excision of the mesh. Following sacral colpopexy, complete removal of the mesh (by laparoscopy or laparotomy) is only required in the presence of an abscess or spondylodiscitis (EO). When vaginal mesh exposure recurs after a first reoperation, the patient should be treated by an experienced team specialized in this type of complication (EO). SUTURE THREAD VAGINAL EXPOSURE: For women presenting with vaginal exposure to non-absorbable suture thread following POP surgery with mesh reinforcement, the suture thread should be removed by the vaginal route (EO). Removal of the surrounding mesh is only recommended when vaginal mesh exposure or associated abscess is diagnosed. BLADDER AND URETERAL MESH EXPOSURE: When bladder mesh exposure occurs, removal of the exposed part of the mesh is recommended (grade B). Both alternatives (total or partial mesh removal) should be discussed with the patient and should be debated during a multidisciplinary discussion group meeting (EO).