G蛋白偶联雌激素受体在乳制品雌激素检测中的应用潜力

乳制品作为人们广泛消费的一种食品，其安全性备受关注。研究发现，乳制品中出现的高含量的天然雌激素和滥用或非法使用的合成雌激素可能导致人体内分泌失调，甚至诱发癌症。研究还发现，雌激素与G蛋白偶联雌激素受体（G-protein coupled estrogen receptor，GPER）互相作用来控制基于钙离子通道的快速非基因组途径，该途径有别于经典的核受体（雌激素受体（estrogen receptor，ER）α和ERβ）介导的基因组途径。本文阐述了GPER与雌激素以及乳制品中雌激素检测的关系，重点介绍了乳制品中雌激素生物学检测方法的研究进展，并对GPER在乳制品雌激素检测中的应用潜力进行了分析和展望。     

植物雌激素研究概况(Ⅱ)——生理功能进展

综述了植物雌激素（包括大豆异黄酮、木酚素以及二苯乙烯）的作用机制：（1）雌激素受体（ER）相关作用，主要表现为雌激素或抗雌激素效果；（2）与一些合成性类甾醇的主要酶相互作用（间接显示雌激素活性）；（3）其它非荷尔蒙作用。还综述了植物雌激素对人类健康的潜在效果，包括调节月经周期、预防并抑制许多癌症、预防心血管疾病以及骨疏松症，还有抗氧化效果以及女性美容效果。     

雌激素处理对黄鳝MC4R的表达影响

正MC4R概述MC4R基因概述黑素皮质素受体-4(melanocortin-4 receptor,MC4R)是下丘脑腹内侧核分泌的一类肽类物质。黑素皮质素受体是G-蛋白耦联受体(G-protein coupled receptors,GPCRs)超家族的成员,是腺普酸环化酶途径中所有的7个横跨膜受体,它们的表达部位和功能都不     

长期槲皮素膳食暴露对小鼠乳腺发育的影响

目的：槲皮素等植物雌激素早期不当摄入的负面影响已逐渐为人们所关注。本研究以围青春期雌性小鼠为模型,以成年后个体乳腺组织生殖内分泌激素受体表达水平及增殖能力为指标,考察幼年期槲皮素暴露对于乳腺发育的影响。方法：以高效液相色谱四极杆飞行时间串联质谱法检测槲皮素相关代谢产物在血浆及乳腺组织局部分布状况,以免疫组织化学方法检测乳腺上皮细胞内雌、孕激素受体以及增殖相关标志性分子增殖细胞核抗原的表达水平。结果：槲皮素相应代谢产物在乳腺内含量显著高于血浆,存在典型的组织局部富集的现象;在5 mg/（kg·d）剂量下,槲皮素可显著上调乳腺上皮细胞雌激素受体（estrogen receptor,ER）α及ERβ的表达比值,并抑制孕激素受体的表达。结论：乳腺组织对于槲皮素的暴露十分敏感,围青春期槲皮素的不当摄入极有可能通过改变相应激素受体表达谱进而提高个体成年后罹患乳腺相关疾病的风险。     

异位嗅觉痕量胺相关受体研究进展

痕量胺相关受体（trace amine-associated receptors, TAARs）是一类G蛋白偶联受体,除TAAR1外,其余TAARs与嗅觉受体一样都在嗅觉上皮表达并发挥感知气味的作用。近年来,非嗅觉组织中同样发现TAARs高表达,提示TAARs可能存在重要的异位生理功能。事实上,相关研究证实内源性以及外源性特定痕量胺通过作用于不同的TAARs在非嗅觉组织中参与调节多种生理功能,表明TAARs有成为新的诊断和治疗靶点的潜力。本文系统介绍了异位嗅觉TAARs的表达、内源性以及外源性的配体、食物中的生物胺、异位嗅觉TAARs介导的信号通路以及生理和病理功能的现有研究,一方面为未来药物靶点开发、生理病理学研究提供新思路,另一方面也为食品中生物胺的生物活性研究提供新的研究方向。     

G蛋白偶联受体家族味觉受体的信号转导及应用研究进展

味觉是口中的物质与味觉受体细胞发生反应而产生的一种感觉。当呈味物质刺激味觉受体时,信号通过神经感觉系统传导到大脑,经过综合神经中枢系统的分析,从而产生味觉。近年来味觉受体、信号转导及应用研究引起了极大的关注,对细胞的大量研究结果表明不同的味觉通过不同的味觉受体产生。本文就G蛋白偶联受体（guanosine-binding protein coupled receptor,GPCR）家族味觉受体的信号转导过程及应用研究的进展进行综述。     

中长链游离脂肪酸及其受体FFAR1和FFAR4对健康作用的研究进展

中长链游离脂肪酸不仅是机体重要的能量来源,也是机体免疫中重要的信号分子。近年来研究表明,中长链游离脂肪酸通过与游离脂肪酸受体（free fatty acid receptors,FFAR）1和FFAR4互作,调节胰岛素分泌和炎症反应来进一步调节机体免疫代谢。本综述讨论了有关中长链游离脂肪酸饮食以及在体内的代谢,重点介绍了中长链游离脂肪酸及其受体介导的信号途径对味觉信号传导、代谢调节和免疫应答中的关键生理功能影响及合成激动剂的研究进展。     

表皮生长因子对表皮细胞增殖和凋亡的调控作用

表皮生长因子(EGF)诱发细胞增殖依赖酪氨酸激酶(TPK)和G蛋白偶联(GPCR)受体及多条信号传递途径,依赖原癌基因正常的表达及受体信号分子的正常活性,依赖细胞外信号调节激酶(ERK)与JUN氨基末端激酶(JNK)两种信号途径的动力平衡。多种环境因素可通过多条凋亡信号传递途径诱发表皮细胞凋亡。EGF阻断神经酰胺的凋亡信号传递,抑制凋亡关键酶(Caspase-3)的活性,促进抑制凋亡蛋白(BCL-2)的表达,通过PLC-β途径激活多效的凋亡信号调节剂“PKC”,EGF-PKC与EGF-ERK具有协同作用,对凋亡信号传递实行严格的调控。EGF还可通过STAT信号途径激活Caspase-3,促进皮肤癌细胞的凋亡。     

短链脂肪酸及其调节肠道炎症作用的研究进展

哺乳动物体中的胃肠道微生物是细菌生态系统的组成部分,这些微生物对胃肠道发育、功能和调节有着非常重要的作用。短链脂肪酸（short-chain fatty acids,SCFAs）是由胃肠道微生物组中的有益细菌发酵产生的代谢物,主要包括乙酸（acetate）、丙酸（propionate）和丁酸（butyrate）,目前的研究多集中在微生物对宿主细胞代谢的影响上,但短链脂肪酸调节肠道炎症及其机制的研究仍值得关注。越来越多的研究表明,SCFAs具有为肠道上皮细胞提供能量、保护肠道屏障、调节肠道炎症等功能。在肠道炎症的治疗上,SCFAs可以作为信号分子在细胞表面激活G蛋白偶联受体（GPCRs）,在细胞内通过底物转运蛋白抑制组蛋白脱乙酰化酶（HDACs）,从而达到抗炎的目的。本文就SCFAs的组成和来源、机体中合成途径和分布、对肠道健康的影响、在肠道炎症中调节的分子机制以及膳食纤维对SCFAs合成的影响进行综述,重点阐述了短链脂肪酸调节肠道炎症的作用机制,为后续进一步研究提供理论依据。     

Mechanisms underlying the dualistic mode of action of major soy isoflavones in relation to cell proliferation and cancer risks

Isoflavones are phytoestrogens that have been linked to both beneficial as well as adverse effects in relation to cell proliferation and cancer risks. The present article presents an overview of these seemingly contradicting health effects and of mechanisms that could be involved in this dualistic mode of action. One mechanism relates to the different ultimate cellular effects of activation of estrogen receptor (ER) α, promoting cell proliferation, and of ERβ, promoting apoptosis, with the major soy isoflavones genistein and daidzein activating especially ERβ. A second mode of action includes the role of epigenetics, including effects of isoflavones on DNA methylation, histone modification and miRNA expression patterns. The overview presented reveals that we are only at the start of unraveling the complex underlying mode of action for effects of isoflavones, both beneficial or adverse, on cell proliferation and cancer risks. It is evident that whatever model system will be applied, its relevance to human tissues with respect to ERα and ERβ levels, co‐repressor and co‐activator characteristics as well as its relevance to human exposure regimens, needs to be considered and defined.     

Dietary flaxseed lignan or oil combined with tamoxifen treatment affects MCF‐7 tumor growth through estrogen receptor‐ and growth factor‐signaling pathways

This study aimed to elucidate which component of flaxseed, i.e. secoisolariciresinol diglucoside (SDG) lignan or flaxseed oil (FO), makes tamoxifen (TAM) more effective in reducing growth of established estrogen receptor positive breast tumors (MCF‐7) at low circulating estrogen levels, and potential mechanisms of action. In a 2×2 factorial design, ovariectomized athymic mice with established tumors were treated for 8 wk with TAM together with basal diet (control), or basal diet supplemented with SDG (1 g/kg diet), FO (38.5 g/kg diet), or combined SDG and FO. SDG and FO were at levels in 10% flaxseed diet. Palpable tumors were monitored and after animal sacrifice, analyzed for cell proliferation, apoptosis, ER‐mediated (ER‐α, ER‐β, trefoil factor 1, cyclin D1, progesterone receptor, AIBI), growth factor‐mediated (epidermal growth factor receptor, human epidermal growth factor receptor‐2, insulin‐like growth factor receptor‐1, phosphorylated mitogen activated protein kinase, PAKT, BCL2) signaling pathways and angiogenesis (vascular endothelial growth factor). All treatments reduced the growth of TAM‐treated tumors by reducing cell proliferation, expression of genes, and proteins involved in the ER‐ and growth factor‐mediated signaling pathways with FO having the greatest effect in increasing apoptosis compared with TAM treatment alone. SDG and FO reduced the growth of TAM‐treated tumors but FO was more effective. The mechanisms involve both the ER‐ and growth factor‐signaling pathways.     

Differential hormonal regulation of estrogen receptors ERalpha and ERbeta and androgen receptor expression in rat efferent ductules

Estrogen receptors, in addition to the androgen receptor (AR), are expressed at high levels in efferent ductules of the male reproductive tract and it is now well recognized that estrogen receptor (ER) alpha is required for the maintenance of normal structure and function of the ductules. However, little is known regarding the hormonal regulation of the receptors themselves in the male. In the present study, efferent ductule ligation and castration, followed by replacement with testosterone, dihydro-testosterone (DHT) or estradiol was used to investigate the relative importance of circulating and luminal sources of steroid for the modulation of ERalpha, ERbeta and AR in rat efferent ductules. Uni- or bilateral castration and ligation did not affect the expression of ERalpha and ERbeta, but bilateral castration caused down-regulation of AR. Replacement with DHT and testosterone alone or in combination with estradiol caused the recovery of AR expression to control levels. A slight recovery of AR was also observed after estrogen replacement. ERalpha expression was decreased to nearly undetectable levels after estrogen replacement. On the other hand, ERbeta did not show evident effects following any of the treatments, suggesting a constitutive expression of this receptor. This differential modulation of the steroid hormone receptors highlights the importance of maintaining a physiological androgen-estrogen balance to regulate the structure and function of efferent ductules in the male.     

Construction of a reporter yeast strain to detect estrogen receptor signaling through aryl hydrocarbon receptor activation

The activation mechanism of estrogen receptor (ER) signaling by association with the aryl hydrocarbon receptor (AhR) was elucidated recently (Ohtake, et al., Nature 2003, 423, 545). In the present study, we established a reporter yeast strain to evaluate this ER signaling by association with the activated AhR. This yeast strain expresses human ER and AhR, and has a reporter plasmid with estrogen response elements. With this yeast strain we assayed ER activation by various AhR ligands, i.e., 2,3,7,8-tetrachlorodibenzo-p-dioxin, benzo[a]pyrene, 3-methylcholanthrene, beta-naphthoflavone, and indirubin. All these ligands induced ER activation dose-dependently and their EC50 values were 60, 180, 130, 26, and 0.5 nM, respectively. Then, we measured the activity in water collected at 5 localities in the Ishizu River system in Japan. The activities of water samples ranged from 4.8 pmol/L (1.3 ng/L) to 52 pmol/L (14 ng/ L) (17beta-estradiol (E2) equivalent). These values were higher than those measured with the yeast for ER activation through direct ligand binding to ER. The direct ER ligand binding activities of the water samples ranged from 2.5 to 5.3 pmol/L (E2 equivalent). We also measured AhR activation of the water samples using a reporter yeast for AhR ligand activity. The activities ranged from 102 to 472 pmol/L (beta-naphthoflavone equivalent). These results indicate that the water samples contain substances that bind to AhR, and these substances contribute to ER signaling through AhR activation in the yeast reporter strain. This yeast reporter strain should be a useful tool to evaluate direct and indirect ER activation by environmental samples.     

Conjugated Linoleic Acid and Postmenopausal Women's Health

Declined estrogen levels in women after menopause can cause a number of significant health issues, and various estrogen receptor ligands have been clinically evaluated for postmenopausal treatment. Conjugated linoleic acid (CLA) has been shown to display protective effects against menopausal symptoms such as bone loss and metabolic dysfunctions in both animals and humans. In particular, it inhibits the proliferations of breast and endometrial cancer cells through estrogen receptor α‐mediated mechanism(s). These findings suggest that CLA may provide beneficial effects on menopausal symptoms, while protecting the endometrium and breast from estrogen stimulation. Thus, understanding the effects of CLA on menopausal disorders and ER metabolism is important in development of novel therapeutic options for use in postmenopausal women with or without conventional estrogen therapy. In this report, we review literature regarding the impact of CLA on menopausal symptoms in cell lines, rodents, and humans, along with potential mechanism(s). We also discuss safety consideration for CLA use in humans.     

Isoflavones - from Biotechnology to Functional Foods

Isoflavones are isolated from about 300 plant species and belong to the group of phytoestrogens. Having structural similarity with estrogens, they are related to the estrogen receptors, and may exhibit estrogenic and anti-estrogenic effects. They are present in many plant nutrients (including soy, alfalfa, flax seed). The main sources of isoflavones are legumes and there are known commercial preparations of isoflavones, which are natural, safe and alternative materials that can provide an effect similar to estrogen. These compounds have effects on the health status, production characteristics of the animals (poultry, pigs), and the characteristics of the final product ingredients.