Network pharmacology and molecular docking reveal the mechanism of resveratrol in oral squamous cell carcinoma treatment / 口腔疾病防治

Objective@#To explore the molecular mechanism of resveratrol (RES) in the treatment of oral squamous cell carcinoma (OSCC) through the use of biological information methods such as network pharmacology and molecular docking and to provide a theoretical reference for the clinical application of RES in the treatment of OSCC.@*Methods@#The Swiss Target Prediction(http://www.swisstargetprediction.ch), SEA (http://sea.bkslab.org)database, and Pharm mapper database(http://lilab-ecust.cn) were used to retrieve RES-related targets, and the DISGENET (www.disgenet.org), OMIM (https://omim.org) and GeneCards (https://www.genecards.org) databases were used to screen OSCC disease targets. The intersection of drugs and disease targets was determined, and Cytoscape 3.7.2 software was used to construct a "drug-diseasetarget pathway" network. The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database was used to construct a target protein interaction network, and the DAVID database was used for enrichment analysis of key proteins. Finally, molecular docking validation of key proteins was performed using AutoDock and PyMOL. The enrichment analysis and molecular docking results were integrated to predict the possible molecular mechanisms of RES treatment in OSCC; western blot was used to determine the effect of resveratrol at different concentrations (50, 100) μmol/L on the expression of Src tyrosine kinase (SRC), epidermal growth factor receptor (EGFR), estrogen receptor gene 1 (ESR1), and phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway proteins in OSCC HSC-3 cells.@*Results@#A total of 243 targets of RES drugs and 6 094 targets of OSCC were identified. A total of 116 potential common targets were obtained by intersecting drugs with disease targets. These potential targets mainly participate in biological processes such as in vivo protein self-phosphorylation, peptide tyrosine phosphorylation, transmembrane receptor protein tyrosine kinase signaling pathway, and positive regulation of RNA polymerase Ⅱ promoter transcription, and they interfere with the PI3K/AKT signaling pathway to exert anti-OSCC effects. The docking results of resveratrol with OSCC molecules indicated that key targets, such as EGFR, ESR1, and SRC, have good binding activity. The results of cell-based experiments showed that resveratrol inhibited the protein expression of SRC, EGFR, ESR1, p-PI3K, and p-AKT in HSC-3 cells in a dose-dependent manner.@*Conclusion@#RES can inhibit the expression of its targets EGFR, ESR1, SRC, p-PI3K, and p-AKT in OSCC cells.

Estrogen deficiency influences SEC23A gene expression in the odontogenic region of incisors ­ a murine model study / A deficiência de estrógeno influencia a expressão gênica de SEC23A na região odontogênica de incisivos ­ um estudo em modelo murino

Recent scientific evidence suggests a close relationship between estrogen deficiency and vitamin D- related genes. Estrogen and vitamin D were involved with alterations in odontogenesis and tooth eruption process. Objective: The aim of the present study was to evaluate the influence of estrogen deficiency on the expression of genes related to the activation and degradation of vitamin D in the odontogenic region of incisors in a murine model. Material and Methods: This is an experimental clinical study that used female Wistar Hannover rats. The animals were randomly divided into two groups according to the intervention received: Hypoestrogenism Group ­ animals submitted to estrogen deficiency by ovariectomy surgery and Control Group ­ animals submitted to sham surgery. Surgical intervention was performed in the prepubertal period; the animals were followed throughout the pubertal period. After euthanasia, the hemimandibles were removed to evaluate the mRNA expression of the vitamin D-related genes AMDHD1, CYP24A1, NADSYN1 and SEC23A in the odontogenic region of incisors through real time PCR. Student's t test was used to compare means. Kruskal-Wallis test and Dunn's posttest were also used. The level of significance was 5%. Results: SEC23A was overexpressed in the estrogen deficiency condition in the odontogenic region (p=0.021). Conclusion: Estrogen deficiency may influence the expression of the SEC23A gene involved in the activation and degradation of vitamin D in the odontogenic region of incisors in a murine model(AU)

Evidências científicas recentes sugerem uma estreita relação entre a deficiência de estrógeno e os genes relacionados à vitamina D. O estrógeno e a vitamina D estão envolvidos com alterações na odontogênese e no processo de erupção dentária. Objetivo: O objetivo do presente estudo foi avaliar a influência da deficiência de estrógeno na expressão de genes relacionados à ativação e degradação da vitamina D na região odontogênica de incisivos em modelo murino. Material e Métodos: Trata-se de um estudo clínico experimental que utilizou ratas Wistar Hannover fêmeas. Os animais foram divididos aleatoriamente em dois grupos de acordo com a intervenção recebida: Grupo Hipoestrogenismo ­ animais submetidos à deficiência de estrógeno pela cirurgia de ovariectomia e Grupo Controle ­ animais submetidos à cirurgia simulada. A intervenção cirúrgica foi realizada no período pré-púbere; os animais foram acompanhados durante todo o período puberal. Após a eutanásia, as hemimandíbulas foram removidas para avaliar a expressão de mRNA dos genes AMDHD1, CYP24A1, NADSYN1 e SEC23A, relacionados à vitamina D, na região odontogênica de incisivos por meio de PCR em tempo real. O teste t de Student foi utilizado para comparar as médias. Também foram utilizados o teste de Kruskal-Wallis e o pós-teste de Dunn. O nível de significância foi de 5%. Resultados: SEC23A foi superexpresso na condição de deficiência de estrógeno na região odontogênica (p=0,021). Conclusão: A deficiência de estrógeno pode influenciar a expressão do gene SEC23A envolvido na ativação e degradação da vitamina D na região odontogênica de incisivos em modelo murino (AU)

Effect of Dioscorea villosa extract and the phytoestrogen diosgenin on ovariectomized mice with zymosan-induced arthritis

Abstract Humans are exposed to natural compounds such as phytoestrogens primarily through diet and supplements. These compounds promote health by alleviating the symptoms and illnesses associated with menopause and arthritis. Diosgenin (DSG) occurs naturally in plants such as Dioscorea villosa (DV) and binds to estrogen receptors, so it may have similar effects to this hormone, including against arthritis. Thus, we investigated the effect of chronic treatment with dry extract of DV and its phytoestrogen DSG on ovariectomized mice with arthritis. We found that dry extract of Dioscorea villosa (DV) contains the phytoestrogen diosgenin (DSG) in its composition. Furthermore, arthritic mice treated with DV and DSG showed reduced neutrophil accumulation in the articular cartilage. Also, the dry extract of DV administered orally (v.o) did not alter the leukocyte count in the joints or promote changes in the reproductive tract. However, DSG altered these parameters, with possible beneficial effects by reducing symptoms related to reproductive aging. Thus, oral treatment with dry extract of DV and subcutaneous (s.c) treatment with DSG showed promise by acting against inflammation caused by arthritis and reducing symptoms in the reproductive tract due to menopause.

Expression and clinical significance of miR-141-5p as a biomarker in the serum of patients with early spontaneous abortion

Abstract Aim miR-141-5p expression in patients with Early Spontaneous Abortion (ESA) and its correlation with hormone levels during pregnancy were investigated. Methods A total of 70 pregnant women with ESA were selected as the research group, and 70 normal pregnant women who chose abortion for non-medical reasons were selected as the Con group. Serum β-HCG, Progesterone (P), and Estrogen (E2) were detected by enzyme-linked immunosorbent assay. Differentially expressed miRNAs were screened by miRNA microarray analysis. miR-141-5p expression was detected by RT-qPCR, and its correlation with serum β-HCG, P, and E2 levels was analyzed. The diagnostic value of miR-141-5p for ESA was evaluated by the ROC curve. Results Serum β-HCG, P, and E2 were decreased and serum miR-141-5p was increased in patients with ESA. Pearson correlation analysis showed that serum β-HCG, P, and E2 levels were negatively correlated with miR-141-5p expression levels. ROC curve showed that miR-141-5p had a diagnostic value for ESA. Conclusions miR-141-5p is related to hormone levels during pregnancy and is expected to become a new candidate diagnostic marker for ESA.

Incidence and Outcomes Associated with Menopausal Status in COVID-19 Patients: A Systematic Review and Meta-analysis / Incidência e resultados associados ao estado da menopausa em pacientes com COVID-19: Uma revisão sistemática e metanálise

Abstract Objective Menopause causes several changes in the body that may affect the response to COVID-19. We aimed to investigate the possible association between menopausal status and incidence and outcomes in COVID-19 patients. Methods Combinations of keywordsCOVID-19, menopause, and estrogen were used to search the PubMed, Embase, Web-of-Science, and Scopus databases for articles reporting the incidence and outcomes of COVID-19 (discharge, length-of-admission, intensive care, or mortality) in premenopausal women, available through December 29, 2022. Data from studies comparing the incidence of COVID-19 infection with the age-matched male population were pooled and meta-analyzed using a random-effects model. Results Overall, 1,564 studies were retrieved, of which 12 were finally included in the systematic review to compare disease outcomes, and 6 were meta-analyzed for the incidence of COVID-19 in premenopausal and postmenopausal women. All studies reported better COVID-19-associated outcomes in premenopausal women compared with postmenopausal women. After adjusting for confounding factors, three studies found better outcomes in postmenopausal women, and two found no association between menopausal status and COVID-19 outcomes. Our meta-analysis found a higher incidence of COVID-19 infection among premenopausal women than postmenopausal women, when compared with age-matched men (odds ratio = 1.270; 95% confidence interval: 1.086-1.486; p= 0.003). Conclusion The incidence of COVID-19 was significantly higher in premenopausal women than in postmenopausal women when compared with age-matched men. Although premenopausal women may have more favorable COVID-19-associated outcomes, the presumed preventive effect of estrogens on the incidence and related outcomes of COVID-19 in premenopausal women cannot be proven at present. Further longitudinal studies comparing pre- and post-menopausal women are required to provide further insight into this matter.

Resumo Objetivo A menopausa causa diversas alterações no corpo que podem afetar a resposta ao COVID-19. Nosso objetivo foi investigar a possível associação entre o status da menopausa e a incidência e os resultados em pacientes com COVID-19. Métodos Combinações de palavras-chave COVID-19, menopausa e estrogênio foram usadas para pesquisar os bancos de dados PubMed, Embase, Web-of-Science e Scopus para artigos relatando a incidência e os resultados do COVID-19 (alta, tempo de internação, tratamento intensivo cuidados ou mortalidade) em mulheres na pré-menopausa, disponível até 29 de dezembro de 2022. Dados de estudos comparando a incidência de infecção por COVID-19 com a população masculina da mesma idade foram agrupados e meta-analisados usando um modelo de efeitos aleatórios. Resultados No geral, 1.564 estudos foram recuperados, dos quais 12 foram finalmente incluídos na revisão sistemática para comparar os resultados da doença e 6 foram meta-analisados para a incidência de COVID-19 em mulheres na pré e pós-menopausa. Todos os estudos relataram melhores resultados associados ao COVID-19 em mulheres na pré-menopausa em comparação com mulheres na pós-menopausa. Após o ajuste para fatores de confusão, três estudos encontraram melhores resultados em mulheres na pós-menopausa e dois não encontraram associação entre o status da menopausa e os resultados do COVID-19. Nossa meta-análise encontrou uma maior incidência de infecção por COVID-19 entre mulheres na pré-menopausa do que mulheres na pós-menopausa, quando comparadas com homens da mesma idade (odds ratio = 1,270; intervalo de confiança de 95%: 1,086-1,486; p = 0,003). Conclusão A incidência de COVID-19 foi significativamente maior em mulheres na pré-menopausa do que em mulheres na pós-menopausa quando comparadas com homens da mesma idade. Embora as mulheres na pré-menopausa possam ter resultados mais favoráveis associados ao COVID-19, o efeito preventivo presumido dos estrogênios na incidência e nos resultados relacionados ao COVID-19 em mulheres na pré-menopausa não pode ser comprovado no momento. Mas estudos longitudinais comparando mulheres pré e pós-menopausa são necessários para fornecer mais informações sobre este assunto.

Differential Effect of ITE on the Aryl Hydrocarbon Receptor Signaling in Breast Cancer Tissue: A Histopathological Study / Efecto Diferencial de ITE en la Señalización del Receptor de Hidrocarburo de Arilo en Tejido de Cáncer de Mama: Un Estudio Histopatológico

SUMMARY: Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is highly expressed in various types of cancers including breast cancer. However, the role of AhR with its endogenous ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) on the progression of breast cancer remains poorly understood. We aimed to investigate cell proliferation and migration states in breast cancer after activating AhR with the endogenous ligand ITE. Breast cancer tissue was evaluated by cell lines, immunohistochemistry, reverse transcription-polymerase chain reaction, cell proliferation, flow cytometry, migration assays and western blot techniques. We found that AhR was widely expressed in breast cancer tissues and metastasis lymph node tissues, but not in normal tissues. The expression AhR was independent between the age, grades and TNM classifications for breast cancer tissues. ITE treatment significantly induced the activation of AhR in a time-dependent manner in both MCF-7 and T47D breast cancer cell lines. Meanwhile, ITE did not affect the cell migration but significantly suppressed the cell proliferation in estrogen receptor positive (ER+) MCF-7 andT47D cells, which probably attribute to the induction of cell cycle arrest in G1 phase and shortened S phase. Further mechanism study showed that ERK1/2 and AKT signaling were required for the activation of AhR in MCF-7 cells. These data suggest that AhR is a potential new target for treating patients with breast cancer. ITE may be more potentially used for therapeutic intervention for breast cancer with the kind of ER(+).

El receptor de hidrocarburo de arilo (AhR) es un factor de transcripción activado por ligando que se expresa en gran medida en varios tipos de cáncer, incluido el cáncer de mama. Sin embargo, el papel de AhR con su ligando endógeno 2- (1'H-indol-3'-carbonil)-tiazol-4-ácido carboxílico metil éster (ITE) en la progresión del cáncer de mama sigue siendo poco conocido. Nuestro objetivo fue investigar la proliferación celular y los estados de migración en el cáncer de mama después de activar AhR con el ligando endógeno ITE. El tejido de cáncer de mama se evaluó mediante líneas celulares, inmunohistoquímica, reacción en cadena de la polimerasa con transcriptasa inversa, proliferación celular, citometría de flujo, ensayos de migración y técnicas de transferencia Western. Descubrimos que AhR se expresó ampliamente en tejidos de cáncer de mama y en linfonodos con metástasis, pero no en tejidos normales. La expresión AhR fue independiente entre la edad, grados y clasificaciones TNM para tejidos de cáncer de mama. El tratamiento con ITE indujo significativamente la activación de AhR de manera dependiente del tiempo en las líneas celulares de cancer de mama MCF-7 y T47D. Mientras tanto, ITE no afectó la migración celular, pero suprimió significativamente la proliferación celular en células MCF-7 y T47D con receptor de estrógeno positivo (ER+), lo que probablemente se atribuye a la inducción de la detención del ciclo celular en la fase G1 y la fase S acortada. Un estudio adicional del mecanismo mostró que las señales de ERK1/2 y AKT eran necesarias para la activación de AhR en las células MCF-7. Estos datos sugieren que AhR es un nuevo objetivo potencial para el tratamiento de pacientes con cáncer de mama. ITE puede ser utilizado más potencialmente en la intervención terapéutica para el cáncer de mama con el tipo de ER (+).

Assessment of Knowledge Regarding Osteoporosis among Pre-Menopausal Women residing in Selected Rural Communities

Background: As a woman approaches menopause there are gradual changes in the physiology of her body. One of the prominent changes is an increase in the fragility of bone due to calcium variation causing Osteoporosis. A low level of estrogen, which occurs around the time of menopause leads to increased bone loss. A woman can undergo either primary or secondary osteoporosis. In most cases, the first 'symptom' of osteoporosis is broken bone. As osteoporosis is an emerging health problem, that creates an economic burden, it needs a special focus to promote healthy ageing. Knowledge is the best contributor to reducing the risk of premenopausal women getting osteoporosis. Methods: Total 70 pre-menopausal women living in chosen rural communities in Bagalkot were chosen with a convenient sampling technique. A structured questionnaire developed by the researcher was used to gather information concerning knowledge about osteoporosis. Chi-square analysis was used to uncover the relationship between knowledge about osteoporosis with socio-demographic factors. Results: Total 24.28% of women were having good knowledge, 54.28% were having average knowledge, and 21.42% of women were having poor knowledge about osteoporosis. A significant relationship was attained between knowledge regarding osteoporosis and occupation (?2=14.20, p<0.007) and formal education (?2=16.22, p<0.039) at the position of the significance of 0.05. Conclusion: After evaluation of knowledge on the subject of osteoporosis among pre-menopausal women, it was found that most women had average knowledge regarding osteoporosis.

Efectos de la microvibración y estrógeno en la remodelación ósea: revisión sistemática / Effects of micro-vibration and estrogen on bone: a systematic review

Introducción: la pérdida de hueso es un suceso que afecta a la totalidad del esqueleto. Así, las alteraciones musculoesqueléticas afectan a millones de personas en todo el mundo y están entre las causas más comunes de dolor crónico. Objetivo: conocer los efectos de la microvibración y estrógeno en el remodelado óseo. Material y métodos: se realizó una revisión sistemática, se buscó en siete bases de datos, se incluyeron estudios clínicos controlados realizados con ratas o ratones en el periodo de publicación del 2004 al 2022. La calidad de la evidencia sintetizada se evaluó con la escala de Jadad. Resultados: se identificaron quince artículos como estudios primarios. La microvibración reportó cambios in vivo/in vitro totalmente dependientes del estímulo que conlleva incremento de la cortical externa. A su vez, con la administración de estrógeno se reportaron efectos, específicamente, en el hueso trabecular y en el periostio, así como colágeno inmaduro que indican un recambio óseo. Conclusión: tanto la microvibración como la administración de estrógeno coadyuvan a la remodelación del tejido óseo y son aprovechables como tratamiento en el momento que exista un problema de pérdida ósea (AU)

Introduction: Bone loss is an event that affects the entire skeleton. Thus, musculoskeletal disorders affect millions of people worldwide and are among the most common causes of chronic pain. Objective: to know the effects of micro-vibration and estrogen on bone remodelling. Material and methods: a systematic review was carried out; seven databases were searched; Controlled clinical studies conducted with rats or mice in the publication period from 2004 to 2022 were included. The quality of the synthesized evidence was assessed using the Jadad scale. Results: fifteen articles were identified as primary studies. Micro vibration reported in vivo/in vitro changes dependent on the stimulus that entails an increase in the outer cortex. In turn, with the administration of estrogen, effects were reported, specifically in the trabecular bone and in the periosteum, as well as immature collagen that indicates bone turnover. Conclusion: both micro-vibration and the administration of estrogen contribute to the remodelling of bone tissue and are usable as a treatment for bone loss (AU)

A logarithmic model for hormone receptor-positive and breast cancer patients treated with neoadjuvant chemotherapy

SUMMARY OBJECTIVE: The aim of this study was to investigate the predictive importance of the previously validated log(ER)*log(PgR)/Ki-67 predictive model in a larger patient population. METHODS: Patients with hormone receptor positive/HER-2 negative and clinical node positive before chemotherapy were included. Log(ER)*log(PgR)/Ki-67 values of the patients were determined, and the ideal cutoff value was calculated using a receiver operating characteristic curve analysis. It was analyzed with a logistic regression model along with other clinical and pathological characteristics. RESULTS: A total of 181 patients were included in the study. The ideal cutoff value for pathological response was 0.12 (area under the curve=0.585, p=0.032). In the univariate analysis, no statistical correlation was observed between luminal subtype (p=0.294), histological type (p=0.238), clinical t-stage (p=0.927), progesterone receptor level (p=0.261), Ki-67 cutoff value (p=0.425), and pathological complete response. There was a positive relationship between numerical increase in age and residual disease. As the grade of the patients increased, the probability of residual disease decreased. Patients with log(ER)*log(PgR)/Ki-67 above 0.12 had an approximately threefold increased risk of residual disease when compared to patients with 0.12 and below (odds ratio: 3.17, 95% confidence interval: 1.48-6.75, p=0.003). When age, grade, and logarithmic formula were assessed together, the logarithmic formula maintained its statistical significance (odds ratio: 2.47, 95% confidence interval: 1.07-5.69, p=0.034). CONCLUSION: In hormone receptor-positive breast cancer patients receiving neoadjuvant chemotherapy, the logarithmic model has been shown in a larger patient population to be an inexpensive, easy, and rapidly applicable predictive marker that can be used to predict response.

Expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2/neu in gallbladder carcinoma in North Indian population

Background: Gallbladder carcinoma (GBC) although rare is most frequent malignant neoplasm of biliary tract system and sixth most common malignancy of digestive tract. GBC is more common in females and there are studies which show expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 neu (HER2/neu) in GBC suggesting possible molecules for targeted therapy, but results are inconsistent. Aims and Objectives: The aim of this study was to find out expression of ER, PR, and HER2/neu in GBC in North Indian population and their possible association with clinicopathological features. Materials and Methods: A total 59 resected cases of GBC diagnosed by histopathological examination were included in the study. Expression of ER, PR, and HER2/neu was accessed by immunohistochemistry method and correlated with various clinicopathological features. Results: ER expression was absent in all GBC cases. PR expression was present in only one case. Positive expression of HER2/neu was present in 13 (22%) cases, in which 12 cases were of conventional adenocarcinoma and one case was of papillary adenocarcinoma. Well and moderately differentiated tumor had significantly higher HER2/neu expression as compared to poorly differentiated tumors (P = 0.001). Pre-obese patients had significantly higher HER2/neu expression as compared to non-obese patients (P = 0.008). Conclusion: In our study, there was no expression of estrogen and PR in GBC in North Indian population. Although small in number, there is a subset of patients who overexpress HER2/neu receptor that may benefit from targeted therapy.

Estrogen deficiency influences TNF-α and IL-1ß gene expression in the odontogenic region of dental hypofunctional condition / A deficiência de estrógeno influencia a expressão gênica de TNF-α e IL-1ß na região odontogênica de dentes em hipofunção

Objetivo: Evidências científicas sugerem que a deficiência de estrógeno e fatores genéticos influenciam o desenvolvimento do sistema estomatognático. Este estudo teve como objetivo avaliar a influência da deficiência de estrógeno na expressão gênica de TNF-α, IL-1ß, IL-6 e IL-10 durante o desenvolvimento dentário em modelo murino. Material e Métodos: Ratas Wistar Hannover foram divididas em dois grupos de acordo com a intervenção recebida: Grupo Hipoestrogenismo - cirurgia de ovariectomia e Grupo Controle - cirurgia fictícia. Para avaliar o desenvolvimento dentário, o incisivo inferior foi escolhido. O modelo de hipofunção dos incisivos inferiores foi realizado por ajuste incisal. O incisivo homólogo exercia hiperfunção dentária. Os animais foram avaliados durante todo o período puberal. Após a eutanásia, as hemimandíbulas foram removidas para avaliar a expressão gênica do TNF-α, IL-1ß, IL-6 e IL-10 na região odontogênica dos incisivos por meio de PCR em tempo real. Foi realizado o teste de Kruskal-Wallis e o pós-teste de Dunn. O nível de significância foi de 5%. Resultados: Houve diferenças estatisticamente significativas na expressão gênica de TNF-α e IL-1ß entre os grupos hipoestrogenismo e controle sob condição de hipofunção dentária (p=0,0084, p=0,0072, respectivamente). Conclusão: A deficiência de estrógeno influencia a expressão gênica de TNF-α e IL-1ß na região odontogênica de dentes hipofuncionais (AU)

Objective: Scientific evidence suggests that estrogen deficiency and genetic factors have an influence on the development of the stomatognathic system. This study aimed to evaluate the influence of estrogen deficiency on the gene expression of TNF-α, IL-1ß, IL-6 and IL-10 during dental development in a murine model. Material and Methods: Wistar Hannover rats were divided into two groups according to the intervention received: Hypoestrogenism Group - ovariectomy surgery and Control Group - fictitious surgery. To evaluate the dental development, the lower incisor was chosen. The mandibular incisor hypofunction model was performed by incisal adjustment. The homologous incisor exerted a hyperfunction. The animals were evaluated throughout the pubertal period. After euthanasia, the hemimandibles were removed to evaluate the gene expression of the TNF-α, IL-1ß, IL-6 and IL-10 in the odontogenic region of the incisors through real time PCR. Kruskal-Wallis test and Dunn's posttest were performed. The level of significance was 5%. Results: There were statistically significant differences of TNF-α and IL-1ß gene expression between the hypoestrogenism and control groups under hypofunction condition (p=0.0084, p=0.0072, respectively). Conclusion: Estrogen deficiency influences TNF-α and IL-1ß gene expression in the odontogenic region of the hypofunctional teeth. (AU)

In vitro evaluation for estrogenic mechanisms of the disinfectant benzalkonium chloride as an emerging contaminant

This study aimed to evaluate in vitro the possible mechanisms underlying the estrogenic potential of benzalkonium chloride (BAC) as a disinfectant emerging contaminant. Effects of BAC at the environmentally-relevant concentrations on estrogen synthesis and estrogen receptor (ER) signaling were assessed using the H295R steroidogenesis assay and the MCF-7 proliferation assay, respectively. Results showed that exposure to BAC at concentrations of 1.0-1.5 mg/L for 48 h significantly increased estradiol production of H295R cells in a concentration-dependent manner. Transcription of steroidogenic genes 3β‐HSD2, 17β‐HSD1, 17β‐HSD4, and CYP19A were significantly enhanced by BAC. In ER-positive MCF-7 cells, exposure to 0.5-1.5 mg/L BAC for 48 h significantly promoted cell proliferation and increased the expressions of ERα and G-protein coupled estrogen receptor 1. Flow cytometry analysis showed that 0.5-1.5 mg/L BAC significantly decreased the percentage of cells in G0/G1 phase, increased the percentage in S phase, and BAC at concentrations of 1.0 and 1.5 mg/L increased the G2/M phase cells. Findings of the study suggested that BAC at environmentally-relevant concentrations might act as a xenoestrogen through its inhibitory effect on steroidogenesis and ER-mediated mechanism.

Research progress of probiotics intervening osteoporosis through intestinal tract / 中国医师杂志

Osteoporosis (OP) is a systemic bone disease characterized by decreased bone density and damage to bone microstructure, leading to brittle fractures. It is a multifactorial disease that is more common in postmenopausal women, and its high incidence and serious complications are receiving increasing attention. Currently, clinical anti-osteoporosis drugs are mainly divided into two categories: inhibiting bone resorption and promoting bone formation, including bisphosphonates, calcitonin and estrogen, etc. But the side effects and high economic cost of drugs limit the scope of their use to some extent. In recent years, the effect of intestinal flora on bone health, especially on osteoporosis, has become a potential new target for regulating bone density. Probiotics belong to intestinal flora and are defined as living microorganisms. They have initially shown good efficacy in the treatment of some bone metabolic diseases, suggesting that intestinal flora can be used as a potential target for the prevention and treatment of osteoporosis and the application of probiotics as a new therapeutic method for osteoporosis. This paper mainly reviews the relevant studies on probiotics and osteoporosis, shows the latest research progress of probiotics intervention in OP, clarifies the relevant action mechanism of probiotics intervention in OP through intestinal tract, and analyzes the research status and prospect of probiotics treatment in OP.

Mechanism research status of daidzein in the prevention and treatment of osteoporosis through estrogen-like effect / 中国药房

Osteoporosis， as a systemic bone disease with high incidence rate and high disability rate， has become a research hotspot in recent years. The daidzein in soybean isoflavones can bind with estrogen receptors， simulating the prevention and treatment of osteoporosis with estrogen-like effect. Its mechanism of action includes promoting osteoblast formation and differentiation by activating the Wnt signaling pathway， increasing bone density， and improving bone tissue health； inhibiting osteoclast differentiation and slowing down bone resorption by reducing receptor activator of nuclear factors κB ligand/ osteoprotegerin ratio， downregulating the expression of macrophage colony-stimulating factor （M-CSF）； collaborating antioxidant and immune regulation to achieve the goal of preventing and treating osteoporosis. In addition， different doses of daidzein have different effects on bone density and osteoporosis， which may be related to factors such as study design， sample selection， and individual differences.

Prognostic influencing factors analysis of patients with estrogen receptor-positive de novo stage Ⅳbreast cancer / 肿瘤研究与临床

Objective:To investigate the factors influencing the prognosis of patients with estrogen receptor (ER)-positive de novo stage Ⅳ breast cancer.Methods:The clinical data of 339 patients with ER-positive de novo stage Ⅳ breast cancer treated in Tianjin Medical University Cancer Hospital and Cangzhou Hospital of Integrated TCM-WM from February 2010 to December 2017 were retrospectively analyzed. Related factors such as age, time of chief complaint, the clinical T/N stage, site of metastasis, expressions of molecular markers and treatment mode were included. Univariate log-rank test and multivariate Cox regression model were used to analyze the effects of prognostic factors on patients' overall survival (OS).Results:Univariate analysis showed that there were statistically significant differences in the OS of patients stratified by clinical N stage at first diagnosis, metastasis sites at first diagnosis, ER expression, progesterone receptor (PR) expression, Ki-67 positive index and p53 expression, endocrine therapy, chemotherapy at first diagnosis, surgery and radiotherapy of the primary lesions (all P < 0.01). Multivariate Cox regression analysis results showed that metastasis sites at first diagnosis, Ki-67 positive index, surgery and radiotherapy of the primary lesions were all independent influencing factors of OS for breast cancer patients (all P < 0.01). Conclusions:Patients with ER-positive de novo stage Ⅳ breast cancer have a good prognosis when they have oligometastasis, Ki-67 positive index ≤ 20%, and they receive surgery and radiotherapy of the primary lesions.

Efficacy of Chinese medicine Kuntai capsule combined with sequential estrogen progesterone therapy in treatment of early-onset ovarian dysfunction / 中华全科医师杂志

Clinical data of 102 patients with premature ovarian failure admitted to Zhang Zhongjing Hospital from December 2018 to December 2021 were retrospectively analyzed. Fifty-one patients received (control group), and another 51 patients received Chinse medicine Kuntai capsule in addition to sequential estrogen progesterone therapy(study group); both groups were treated for 3 menstrual cycles. After treatment, the total effective rate of the study group was higher than that of the control group (94.1% (48/51) vs. 72.6% (37/51), χ2=4.07, P=0.044). After treatment, the proportion of patients with mild Kupperman score and serum estradiol level in both groups were increased, and the proportion in study group was higher than that in the control group. The proportion of patients with moderate and severe Kupperman score and the total score decreased after treatment in both groups, and the proportion of patients with moderate Kupperman score in the study group was lower than that in the control group. Serum luteinizing hormone and folliclestimulating hormone levels were significantly decreased, and the levels in study group were lower than those in the control group. The levels of resistance index and PI were significantly decreased after treatment in both group and the study group decrease more markedly (all P<0.05). The peak systolic flow velocity level was increased after treatment in both groups and the study group increased more markedly (all P<0.05). It is suggested that the application of Chinese medicine Kuntai capsule combined with sequential estrogen progesterone therapy can effectively improve the clinical therapeutic effect, stabilize sex hormones, uterine microcirculation and effectively alleviate the condition of patients with premature ovarian failure.

Effects of arsenic exposure on E2 and TRH and their receptor mRNA expressions in rats / 环境与职业医学

Background Arsenic can enter the hypothalamus to induce estrogen effect and interfere with the function of the neuroendocrine system. The thyroid endocrine system (hypothalamic-pituitary-thyroid axis) is one of the main endocrine systems, and the mechanism of arsenic-induced thyroid endocrine toxicity is still unclear. Objective To investigate the effects of different arsenic exposure levels on estradiol (E2), hypothalamic thyrotropin-releasing hormone (TRH), and their receptor (ERα, ERβ, and TRHR) mRNAs in rats and the possible hypothalamic toxic pathway and mechanism. Methods Seventy Wister rats were randomly divided a control group (sterile water); low-, medium-, and high-dose arsenic exposure groups [0.8, 4.0, and 20.0 mg·kg−1 sodium arsenite (NaAsO2)]; estrogen receptor inhibitor (ICI182780) intervention + low-, medium-, and high-dose arsenic exposure groups; with 10 animals in each group, half male and half female. Rats in the arsenic exposure groups were exposed to NaAsO2 by drinking water for 19 weeks, and rats in the intervention groups were injected with 0.5 mg·kg−1 ICI182780 via tail vein at week 9, 3 times a week. The levels of E2 and TRH in serum of rats were detected by ELISA. The expression levels of estrogen receptor α (ERα), estrogen receptor β (ERβ), and TRH receptor (TRHR) mRNAs in hypothalamus of rats were detected by real-time PCR (RT-PCR). Results (1) E2 and its receptor mRNA: Compared with the control group, the serum E2 level of female rats was increased in the low-dose and the medium-dose arsenic exposure groups (P<0.05), and the serum E2 level of male rats was increased in the low-dose, the medium-dose, and the high-dose arsenic exposure groups (P<0.05), and the change of female E2 was greater than that of male rats. Compared with the control group, the relative expression levels of ERα mRNA and ERβ mRNA in female rats were increased in the low-dose, the medium-dose, and the high-dose arsenic exposure groups (P<0.05), so were the relative expression levels of ERα mRNA in male rats (P<0.05). (2) TRH and its receptor mRNA: Compared with the control group, the serum TRH level of female rats was increased in the high-dose arsenic group (P<0.05), the relative expression level of TRHR mRNA was increased in the low-dose, the medium-dose, and the high-dose arsenic exposure groups (P<0.05). Results (1) and results (2) suggested that females were more likely than males to have abnormal changes in E2, TRH, and related receptor genes after arsenic exposure. (3) Compared with female rats in the medium-high dose arsenic exposure group, the expressions of TRH and TRHR induced by arsenic exposure were inhibited after the intervention of ICI182780 (P<0.05), suggesting that arsenic in the hypothalamus may have toxic effects on TRH and TRHR by inducing estrogen-like effects. Conclusion Arsenic exposure can induce estrogen-like effects in the hypothalamus, interfere with thyroid function, and show dose-dependent and sex differences. E2 and TRH and their receptors may be the toxic pathway of arsenic-related estrogen-like effect.

The effect and mechanism of formononetin on alleviating no-reflow after myocardial ischemia and reperfusion by up-regulating the PI3K/Akt/eNOS signal pathway activated by GPER / 药学学报

To investigate the cardioprotective effect of formononetin (FMN) on no-reflow (NR) after myocardial ischemia-reperfusion and its molecular mechanism based on integrated pharmacology and experimental verification, firstly, human breast cancer MCF-7 cells and myocardial NR rats were used to confirm the estrogenic activity and the effect of alleviating NR of FMN, respectively. Male SD rats were divided into Sham, NR, FMN (20 mg·kg-1) and sodium nitroprusside (SNP, 5.0 mg·kg-1) groups, which were administered once a day for one week, the experiment was approved by the Ethics Committee of Tianjin University of Traditional Chinese Medicine (TCM-LAEC2019095). The pharmacological analysis and in vivo study of NR rats were integrated to reveal the mechanism of FMN improving NR. The results showed that FMN had estrogenic effect and reduced NR by improving cardiac structure and function, reducing NR, ischemic myocardial area and pathological injury of cardiomyocytes. Integrated pharmacology predicts that the mechanism of FMN improving NR is mainly related to phosphatidyinositol-3-kinase-protein kinase B (PI3K-Akt) signal pathway. Phytoestrogens play a role in cardiovascular protection mainly by activating G protein-coupled estrogen receptor (GPER). GPER is also an important regulator in the upstream of PI3K-Akt signaling pathway. This study found that FMN can significantly activate GPER, p-PI3K, p-Akt and phospho-endothelial nitric oxide synthase (p-eNOS). It has good binding ability with GPER and eNOS protein. In this study, through the integration of pharmacology and experimental evaluation, it is revealed that FMN activates PI3K/Akt/eNOS signal pathway by activating GPER, thus significantly improving NR.

Pharmacodynamic substances and mechanism of Chelidonii Herba-Corydalis Rhizoma against estrogen receptor-positive breast cancer / 中国药房

OBJECTIVE To analyze the main components of Chelidonii Herba-Corydalis Rhizoma （CHCR）， and to predict pharmacodynamic substances against estrogen receptor （ER） -positive breast cancer and their potential targets and signaling pathways， followed by verifying experiments. METHODS The ethanol extract of CHCR was analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry （UPLC-Q-TOF-MS/MS）. The network pharmacology analysis was performed for the screened components. The network diagram of CHCR “active components-target-pathway” was constructed， and the enrichment pathway in vitro was validated. RESULTS A total of 58 chemical components were identified， including 57 alkaloids and 1 organic acid. A total of 38 active ingredients were screened from the network pharmacology， and 38 core targets were found in the protein-protein interaction network of “component-disease” intersection targets； 258 gene ontology entries and 137 Kyoto encyclopedia of genes and genomics pathways were obtained， mainly including estrogen signal pathway， phosphatidylinositol-3-kinase/protein kinase B （PI3K/Akt） signal pathway， etc. The results of validation test showed that the median inhibitory concentration of CHCR to MCF-7 cells was 693 μg/mL； 150， 300， 600 μg/mL CHCR could significantly reduce the expressions of phosphorylated PI3K， phosphorylated Akt， ERα protein and ESR1 mRNA （P＜0.01）. CONCLUSIONS The anti-ER-positive breast cancer effect of CHCR may be related to the regulation of ER and PI3K/Akt pathways， which has the characteristics of multi-component and multi-target effects.

Research progress on the mechanism of endocrine therapy resistance for breast cancer / 国际肿瘤学杂志

Endocrine therapy resistance is a major challenge in the treatment of hormone receptor-positive breast cancer. In recent years, endocrine resistance mechanisms have focused on ESR1 mutations or fusions, epigenetic regulation, abnormal regulation of signal transduction pathway, cell cycle regulation, cancer stem cells, metabolic reprogramming, tumor microenvironment and autophagy. Exploring the latest advances in the mechanisms of endocrine therapy resistance in breast cancer may provide more research ideas and treatment options for the precision treatment of hormone receptor-positive breast cancer.