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  • The selective estrogen receptor modulators SERMs are

    2020-11-26

    The selective estrogen receptor modulators (SERMs) are another type of estrogen receptor ligands. The main difference between SERMs and xenoestrogens relies on the fact that SERMs present functional duality and are able to act both as agonists and antagonists of the estrogen receptors in different tissues (Martinkovich, Shah, Planey, & Arnott, 2014; Shang & Brown, 2002; Smith & O'Malley, 2004). At the molecular level, SERMs employ their antagonistic actions by competing with estradiol for binding to an inner hydrophobic pocket within the ligand-binding domain of ERα (Bourguet, Germain, & Gronemeyer, 2000; Shiau et al., 1998; Wärnmark et al., 2002). Binding of this estradiol agonist induces a conformational change in the LBD that results in sealing the ligand binding pocket. Some of the most important SERMs include tamoxifen, raloxifene, clomifene, ormeloxifene, and toremifene (Farooq, 2015). One of the most used SERMs in the treatment of breast cancer, tamoxifen, acts as an antagonist in breast tissue, but as an agonist in the uterus. Therefore, while tamoxifen is often the selected treatment for ER-positive breast cancer, it can also stimulate endometrial cell growth leading to uterine cancer (Hu, Hilakivi-Clarke, & Clarke, 2015). While most SERMs are mainly selective for ERα, there are a few synthetic steroidal analogs that can regulate the actions of ERβ, or both receptors (Blizzard et al., 2007; Blizzard et al., 2006; Blizzard et al., 2007; Papapetropoulos, 2007). Finally, in addition to the organic ligands mentioned above, there are also inorganic compounds in the form of heavy metal ions that present estrogenic activity. These are collectively known as metalloestrogens. Examples of these include: aluminum (Al), antimony (Sb), barium (Ba), cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), lead (Pb), mercury (Hg), nickel (Ni), arsenite (), selenite () and vanadate () (Farooq, 2015). Studies have shown that these metalloestrogens are able to coordinate to specific amino AZ 628 residues within the ligand-binding domain of the nuclear estrogen receptors, thus blocking binding of estradiol in a non-competitive manner (Stoica, Katzenellenbogen, & Martin, 2000; Stoica et al., 2000a, Stoica et al., 2000b).
    Discussion Estrogen receptors regulate a multitude of biological and physiological processes. These are tightly controlled by complex mechanisms involving either genomic nuclear direct binding to specific DNA sequences, or activation of intracellular cascades resulting in non-genomic control of transcription. Over the past 60years since the discovery of the first nuclear estrogen receptors, and the almost 20years since the discovery of the membrane receptor, multiple mechanisms of action have been discovered and characterized. These involve a multitude of intracellular kinases, transcription and growth factors, membrane receptors, coregulators, and natural and synthetic ligands. The information obtained in these studies has helped in the design of therapeutic strategies for diseases involving the estrogen receptors such as many cancers, as well as in the treatment of endocrine conditions affecting fertility and resulting from menopause. While there are still many diseases for which estrogens have been implicated but the role of their receptors has not been elucidated, the knowledge gained in the past six decades together with new advances in precision medicine and molecular diagnostic techniques will allow for the development of more personalized strategies to prevent and treat conditions that are affected by estrogens and other steroid hormones.
    Acknowledgments
    Introduction Partial hepatectomy (PH) induces hepatocyte proliferation and liver regeneration [1,2]. We focused on the molecules that triggering hepatocyte proliferation. Several cytokine signals are involved in triggering liver regeneration. Liver regeneration is impaired/delayed in the Interleukin 6 (IL-6), and tumor necrosis factor α (TNFα) KO mice [1,2]. Our previous study showed that estradiol is also involved in triggering hepatocyte proliferation [3,4]. Moreover, hepatocyte proliferation was delayed and reduced because of ovariectomy and orchiectomy lacking estradiol [4].