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Chemopreventive Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The results of in vitro experiments have suggested that quercetin can inhibit the oxidation of other molecules, and so it is often classed as an antioxidant. This has some theoretical basis on the grounds that it has a polyphenolic structure that may stop oxidation by scavenging free radicals involved in oxidative chain reactions. Other results from in vitro experiments suggest that it has estrogenic activity through activation of both ERα and ERβ estrogen receptors with binding IC50 values of 1015 nM and 113 nM, respectively. Based on these figures, it would appear to be ERβ selective (by 9-fold), but approximately 2–3 orders of magnitude less potent than the endogenous hormone 17β-estradiol. It has also been reported that, in human breast tumor cell lines, quercetin can act as an agonist of the GPER (G Protein-Coupled Estrogen Receptor) and can activate or inhibit the activities of a range of other proteins. For example, it has also been reported to be a nonspecific protein kinase enzyme inhibitor. However, given that quercetin is metabolized so quickly after oral absorption, it is unlikely that any of these in vitro observations can be related to in vivo effects in humans.
Hormonal Regulation in the Treatment of Fibroids
Published in John C. Petrozza, Uterine Fibroids, 2020
Victoria Fitz, Steven L. Young
Estrogens signal primarily through two specific nuclear receptors, ER-alpha and ER-beta, though additional membrane-bound ER-alpha and the G-protein-coupled estrogen receptor (GPER) on the cell surface can also mediate estrogen responses. Estrogen is able to induce human fibroid cell proliferation in vitro [3] as well as fibroid growth in a rat model in vivo and in rat leiomyoma cells in vitro [4,5]. The production of estradiol by some leiomyomas [6] also suggests autocrine or intracrine pathways for estrogen to promote growth. Estrogen receptors alpha and beta are found in higher concentration in leiomyoma cells compared with surrounding normal myometrium. Estrogen activates fibroblasts within leiomyomas leading to proliferation and ECM deposition [7]. These and many other studies strongly implicate a role for estradiol in leiomyoma growth.
Endocrine Functions of Brain Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
Estrogen and progesterone modulate DA activity in the striatum and nucleus accumbens (NAc) under several conditions [33]. For example, there are estrous cycle-dependent variations in the basal extracellular concentration of striatal DA, in amphetamine (AMPH)-stimulated DA release, and in striatal DA-mediated behaviors. Ovariectomy attenuates basal extracellular DA, AMPH-induced striatal DA release, and behaviors mediated by the striatal DA system. Estrogen rapidly and directly acts on the striatum and NAc via a G protein-coupled membrane estrogen receptor (GPER) to enhance DA release and DA-mediated behaviors. In male rats, estrogen does not affect striatal DA release, and the removal of testicular hormones is also without effect. It has been proposed that estrogen induces rapid changes in neuronal excitability by acting on membrane receptors located in striatal GABAergic neurons and DA terminals. This modulates the dopaminergic terminal excitability, resulting in enhanced DA release.
G protein-coupled estrogen receptor (GPER/GPR30) levels in pelvic floor muscles and its association with estrogen status in female rabbits
Published in Gynecological Endocrinology, 2022
Sharet Y. Rodríguez-Jaimes, Guadalupe C. Hernández-Hernández, Laura G. Hernández-Aragón, Octavio Sánchez-García, Margarita Martínez-Gómez, Estela Cuevas-Romero, Francisco Castelán
Both ERα and ERβ belong to the nuclear receptor superfamily, so genomic actions are often assumed. However, some ERα isoforms, including the ERα46 and ERα36, can trigger non-genomic rapid actions [6]. Furthermore, the G-protein coupled estrogen receptor (GPER, a.k.a. GPER-1 and GPR30), through signaling pathways like MAPKs, PI3K/Akt, and PLC/IP3, participates in energy metabolism, inflammation, muscle contraction, and vascular relaxation, among others [7,8]. Several tissues express the GPER, including skeletal muscles and female pelvic organs (i.e. the uterus and vagina) [8–12]. Remarkably, GPER mRNA levels differ between hindlimb muscles (i.e. the extensor digitorum longus, EDL) in female mice and rats [8,10]. Furthermore, one study in rats suggest the GPER expression might be dependent on estrogens [8].
Kaempferol-induced GPER upregulation attenuates atherosclerosis via the PI3K/AKT/Nrf2 pathway
Published in Pharmaceutical Biology, 2021
Zhuo Feng, Changyuan Wang, Yue Jin, Qiang Meng, Jingjing Wu, Huijun Sun
Compelling evidence confirmed that membrane G protein-coupled oestrogen receptor (GPER), a newly discovered ER activated by classic oestrogen and phytoestrogens, is associated with numerous diseases (Barton and Prossnitz 2015; Grande et al. 2020). In particular, the expression of GPER modulated by the regulator changed the concentration of oestrogen and further affected the deterioration of AS in postmenopausal women. In addition, GPER regulators stimulate the PI3K signal pathway to fight various diseases (Fan et al. 2018); this pathway is associated with the expression level of oestrogen (Pollard and Daniel 2019). Notably, PI3K/AKT/Nrf2 pathway is the most widely studied. However, whether kaempferol, as an activator of GPER, attenuates AS via modulation of the PI3K/AKT/Nrf2 signalling pathway is elusive.
Estrogen and estrogen receptors in kidney diseases
Published in Renal Failure, 2021
Hao-Yang Ma, Shuang Chen, Yang Du
The mechanisms of estrogen action are categorized into classical (genomic) and rapid (non-genomic) ones. In the classical pathway, estrogen binds to the ERs in the cytoplasm, leading to ER dimerization and translocation to the nucleus, where the estrogen–ER complex interacts with ERE sequences in target genes [16]. This process typically occurs within hours [65]. In recent decades, however, rapid or ‘non-genomic’ effects of estrogen (also termed non-nuclear or membrane initiated steroid signaling) has been reported [66]. This occurs through the ER located in or adjacent to the plasma membrane, or through other non-ER plasma membrane-associated estrogen-binding proteins, which usually takes seconds or minutes [67]. GPER has been identified as one of the main estrogen-sensitive receptors responsible for the rapid non-genomic action of estrogen [68]. The classical (genomic) and non-genomic estrogen signaling pathways are illustrated in Figure 1 [22,69].