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71.
《Expert opinion on drug discovery》2013,8(4):395-409
Introduction: It has long been considered that the most significant risks for breast cancer are gender and age but, as many other tumors, this cancer has also been undeniably linked to gene mutations. The vast majority of breast cancers in postmenopausal women are estrogen-responsive, a hormone which is biosynthesized from blood-circulating androgens through an aromatization reaction, catalyzed by aromatase (AR). One strategy, therefore, to combat breast cancer, has been to find compounds that can inhibit the activity of aromatase to reduce estrogen levels. Areas covered: The authors provide a broad and updated overview of the general structure–activity relationships and on the latest ligand- and structure-based approaches applied to the discovery of potent, selective and safer breast cancer drugs. Specifically the authors review the most consolidated techniques, based on structure–activity relationships, pharmacophore mapping, rigid and flexible molecular docking, as well as sophisticated and reliable protocols simulating critical biological events. Expert opinion: The recently solved X-ray structures of aromatase represent solid milestones to breathe new life into the search of newer chemotypes with reduced risks of cross-reactivity toward other CYPs and safer pharmacological profiles. We anticipate that great benefits will arrive from the wealth of information obtained by integrating genomics, site-directed mutagenesis experiments with protein modeling. Furthermore, we welcome the advent of GPU technology that, in conjunction with dedicated algorithms, grants scientists an unprecedented point of view on physiologically relevant phenomena, occurring on the µs time scale, such as ligand binding/unbinding. 相似文献
72.
Sugunadevi Sakkiah Wenjing Guo Bohu Pan Rebecca Kusko Weida Tong 《journal of environmental science and health part c-environmental carcinogenesis & ecotoxicology reviews》2013,31(4):192-218
Endocrine disrupting chemicals (EDCs) mimic natural hormones and disrupt endocrine function. Humans and wildlife are exposed to EDCs might alter endocrine functions through various mechanisms and lead to an adverse effects. Hence, EDCs identification is important to protect the ecosystem and to promote the public health. Leveraging in-vitro and in-vivo experiments to identify potential EDCs is time consuming and expensive. Hence, quantitative structure–activity relationship is applied to screen the potential EDCs. Here, we summarize the predictive models developed using various algorithms to forecast the binding activity of chemicals to the estrogen and androgen receptors, alpha-fetoprotein, and sex hormone binding globulin. 相似文献
73.
目的探讨黄芪改善低血糖所致神经内分泌反向调节(counterregulatory responses,CRR)受损的可能机制。方法手术留置大鼠颈静脉和颈动脉导管,并随机分为黄芪组和对照组;术后第3天起分别给予1.5 ml黄芪提取液、0.9%NaCl溶液,连续7天。其中第7天起反复低血糖法造模连续3天,第11天进行高胰岛素低血糖钳夹实验,取血样检测中心血糖、肾上腺素(Epinephrine)、去甲肾上腺素(Norepinephrine)、肾上腺皮质激素(Cortisol)、胰高糖素(Glucagon);中枢糖敏感区域下丘脑室旁核(PVN)免疫组织化学染色,观察c-fos的表达。结果黄芪干预后急性低血糖时血糖轻度降低,对基础血糖并没有影响。黄芪组Epinephrine、Cortisol较对照组有显著升高。黄芪组PVN部位c-fos表达明显高于对照组。结论黄芪能增加低血糖时部分反向调节激素的分泌,可能与激活下丘脑糖敏感神经细胞的活性有关。 相似文献
74.
《Journal of applied toxicology : JAT》2017,37(3):339-346
The effects of endocrine disruptors, including anti‐androgenic chemicals, on aquatic environments have received increased attention in recent years. Currently, the method used to screen chemicals for anti‐androgenic activity is called the androgenized female stickleback screen, and it was established by the Organization of Economic Cooperation and Development in 2011 using the three‐spined stickleback. However, screening chemicals for anti‐androgenic activity has yet to be established using Japanese medaka. Thus, the purpose of this study was to establish a screening method for anti‐androgenic activity utilizing the number of papillary processes in Japanese medaka (Oryzias latipes ) as an indicator of the chemical's anti‐androgenic activity. Thus, at 35 days post‐fertilization, medaka were exposed to fenitrothion, an anti‐androgenic compound, for 28 days. In the control group, the formation of papillary processes was observed in XY medaka, but not in XX medaka. However, after fenitrothion exposure, the number of papillary processes was significantly decreased in a dose‐dependent manner in XY medaka; in the 300 μg l−1 concentration group, four of 11 XY medaka showed no papillary processes even if there were no significant effects on total length and wet body weight compared with the control group. Our results indicate that the number of papillary processes in Japanese medaka can be used as an indicator of anti‐androgenic activity and that this model may prove useful as a chemical screening method. Copyright © 2016 John Wiley & Sons, Ltd. 相似文献
75.
Gail S. Prins Heather B. Patisaul Scott M. Belcher Laura N. Vandenberg 《Basic & clinical pharmacology & toxicology》2019,125(Z3):14-31
Bisphenol A (BPA) is a high‐production chemical used in a variety of applications worldwide. While BPA has been documented as an endocrine‐disrupting chemical (EDC) having adverse health‐related outcomes in multiple studies, risk assessment for BPA has lagged due to reliance on guideline toxicology studies over academic ones with end‐points considered more sensitive and appropriate. To address current controversies on BPA safety, the United States National Institute of Environmental Health Sciences (NIEHS), the National Toxicology Program (NTP) and the Food and Drug Administration (FDA) established the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY‐BPA) using the NCTR Sprague‐Dawley rats. The goal of CLARITY‐BPA is to perform a traditional regulatory toxicology study (Core study) in conjunction with multiple behavioural, molecular and cellular studies by academic laboratories focused on previously identified BPA‐sensitive organ systems (Academic studies). Combined analysis of the data from both study types will be undertaken by the NTP with the aim of resolving uncertainties on BPA toxicity. To date, the Core study has been completed and a draft report released. Most of the academic studies have also been finalized and published in peer‐reviewed journals. In light of this important milestone, the PPTOX‐VI meeting held in the Faroe Islands, 27‐30 May 2018 devoted a plenary session to CLARITY‐BPA with presentations by multiple investigators with the purpose of highlighting key outcome. This MiniReview synthesizes the results of three academic studies presented at this plenary session, evaluates recently published findings by other CLARITY‐BPA academic studies to provide an early combined overview of this emerging data and places this in the context of the Core study findings. This co‐ordinated effort revealed a plethora of significant BPA effects across multiple organ systems and BPA doses with non‐monotonic responses across the dose range utilized. Remarkably consistent across most studies, including the Core study, are low‐dose effects (2.5, 25 and 250 μg BPA/kg body‐weight). Collectively, the findings highlighted herein corroborate a significant body of evidence that documents adverse effects of BPA at doses relevant to human exposures and emphasizes the need for updated risk assessment analysis. 相似文献
76.
Hua-Chun Luo Zhi-Chao Fu Xin-Peng Wang Lv-Juan Cai Feng-Mei Wang Qin Yin Guishan Lin Zhong-Hua Chen Shao-Guang Liao 《Medicine》2020,99(51)
On the basis of endocrine therapy for patients with low burden metastatic prostate cancer (LBMP), the clinical efficacy and quality of life were compared between prostate-only directed radiotherapy (PODT) and prostate and metastasis radiotherapy (PMRT).From November 2009 to November 2015, total 91 patients newly diagnosed with LBMP were retrospectively analyzed, of which 52 patients received PODT and 39 patients received PMRT. The biochemical failure free interval (IBF), prostate specific survival (PCSS), and overall survival (OS) time were compared between the 2 groups, and expanded prostate cancer index composite (EPIC) scale was used to evaluate the difference in quality of life between the 2 groups.The median IBF of the PODT group was 31 months, which was significantly lower than the 39 months of the PMRT group (P < .05); the 5-year OS and PCSS were 58.9%, 65.3% in PODT group, and 58.9%, 71.79% in PMRT group, respectively. There was no significant between the 2 groups (P > .05); the side effects of acute radiotherapy in PMRT group were significantly higher than PODT group (P < .05), especially in bone marrow suppression and gastrointestinal reactions; The scores of urinary system function and intestinal system function in PMRT group were significantly higher than PODT group at the end of radiotherapy, 3 months after radiotherapy, and 6 months after radiotherapy (P < .05). The score of sexual function in PMRT group was significantly lower than that in PODT group after radiotherapy (P < .05), and higher than that in PORT group at other follow-up time points (P < .05). The hormone function was decreased at each follow-up time point in 2 groups, and there was no significant difference between the 2 groups (P > .05).Patients with LBMP receiving PMRT can improve IBF, but cannot increase PCSS and OS, and increase the incidence of acute radiation injury. 相似文献
77.
Leyla Akn Mustafa Kendirci Figen Narin Selim Kurtoglu Nihal Hatipoglu Ferhan Elmal 《Journal of clinical research in pediatric endocrinology》2020,12(4):393
Objective:We aimed to investigate a possible role of the endocrine disruptors phthalates, di-2-ethylhexyl phthalate (DEHP) and mono (2-ethylhexyl) phthalate (MEHP), in polycystic ovary syndrome (PCOS) aetiopathogenesis. We also wished to evaluate the relationship between phthalates and metabolic disturbances in adolescents with PCOS.Methods:A total of 124 adolescents were included. Serum MEHP and DEHP levels were determined by high-performance liquid chromatography. Insulin resistance was evaluated using homeostasis model assessment-insulin resistance, quantitative Insulin Sensitivity Check Index, fasting glucose/insulin ratio, Matsuda index, and total insulin levels during oral glucose tolerance test. Participants were further subdivided into lean and obese subgroups according to body mass index (BMI).Results:Sixty-three PCOS and 61 controls, (mean age 15.2±1.5; range: 13-19 years) were enrolled. Serum DEHP and MEHP concentrations were not significantly different between PCOS and control groups. The mean (95% confidence interval) values of DEHP and MEHP were 2.62 (2.50-2.75) μg/mL vs 2.71 (2.52-2.90) μg/mL and 0.23 (0.19-0.29) μg/mL vs 0.36 (0.18-0.54) μg/mL in PCOS and the control groups respectively, p>0.05. Correlation analysis, adjusted for BMI, showed that both phthalates significantly correlated with insulin resistance indices and serum triglycerides in adolescents with PCOS.Conclusion:Serum DEHP and MEHP concentrations were not different between adolescents with or without PCOS. However, these phthalates are associated with metabolic disturbances such as dyslipidemia and insulin resistance, independently of obesity, in girls with PCOS. 相似文献
78.
79.
Hong-Yu Chen Ya-Liang Zhou Yong-Hua Chen Xing Wang Hao Zhang Neng-Wen Ke Xu-Bao Liu Chun-Lu Tan 《World journal of gastroenterology : WJG》2020,26(25):3638-3649
BACKGROUND Pancreatic neuroendocrine neoplasms(pNENs) that produce hormones leading to symptoms are classified as functional tumors, while others are classified as nonfunctional tumors. The traditional view is that functionality is a factor that affects the prognosis of pNEN patients. However, as the sample sizes of studies have increased, researches in recent years have proposed new viewpoints.AIM To assess whether functionality is an independent factor for predicting the prognosis of pNEN patients.METHODS From January 2004 to December 2016, data of patients who underwent surgery at the primary site for the treatment of pNENs from the Surveillance, Epidemiology, and End Results(SEER) database and West China Hospital database were retrospectively analyzed.RESULTS Contemporaneous data from the two databases were analyzed separately as two cohorts and then merged as the third cohort to create a large sample that was suitable for multivariate analysis. From the SEER database, age(P = 0.006) and T stage(P 0.001) were independent risk factors affecting the survival. From the West China Hospital database, independent prognostic factors were age(P = 0.034), sex(P = 0.032), and grade(P = 0.039). The result of the cohort consisting of the combined populations from the two databases showed that race(P = 0.015), age(P = 0.002), sex(P = 0.032) and T stage(P 0.001) were independent prognostic factors. In the West China Hospital database and in the total population, nonfunctional pNETs and other functional pNETs tended to have poorer prognoses than insulinoma. However, functionality was not associated with the survival time of patients with pNETs in the multivariate analysis.CONCLUSION Functionality is not associated with prognosis. Race, age, sex, and T stage are independent factors for predicting the survival of patients with pNETs. 相似文献
80.
Sato M Kobayashi T Dobashi H Ohye H Matsubara S Murao K Miyauchi A Kobayashi S Takahara J 《Endocrine》2000,12(1):11-14
We report an interesting case of a 47-yr-old who had a large goiter and multiple rib tumors. The patient was initially suspected
of having thyroid cancer, which had metastasized on the ribs, based on imaging studies. However, laboratory tests revealed
a high level of ionized calcium and parathyroid hormone (PTH). The large goiter was diagnosed as having parathyroid tumors
owing to the high level of PTH in the tissue fluid. The biopsy specimen from a rib tumor was diagnosed as containing brown
tumors associated with primary hyperparathyroidism (PHP). The patient also had prolactinoma and pancreatic gastrinoma. Her
daughter had both prolactinoma and PHP, and her brother and her father had PHP. Thus, the patient was diagnosed as having
multiple endocrine neoplasia type 1. 相似文献