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Hormones as Immune Modulating Agents
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Physiological concentrations of estradiol (10-10M) significantly reduced the chemotactic response of human polymorphonuclear leukocytes to N-formyl-l-methionyl-leucyl-phenylalanine (FMLP). Preincubation with the estrogen receptor antagonist drugs clomiphene and tamoxifen eliminated this inhibitory effect [251].
Endocrine, paracrine and intracrine mechanisms of growth regulation in normal and malignant endometrial epithelium
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
Tamoxifen has an estrogen-like effect on the gene expression of IGFs and their receptors in the endometrium of postmenopausal breast cancer patients. IGF-I gene expression is up-regulated and, simultaneously, the expression of IGFBP-3 is suppressed to less than one-third of control values36. A complete estrogen receptor antagonist had opposite effects. In another study, the levels of IGF/IGF receptor mRNAs in the endometrium of tamoxifen-treated postmenopausal breast cancer patients were found to be as high as those in proliferative and early secretory phase endometrium and in endometrioid-type endometrial carcinoma37. Stimulation of uterine IGF-I and IGF receptor expression in parallel with inhibition of IGFBP-3 may therefore be another mechanism accounting for the endometrial effects of unopposed estradiol or tamoxifen treatment.
Effects of sex steroids on brain cells
Published in Barry G. Wren, Progress in the Management of the Menopause, 2020
L. M. Garcia-Segura, M. C. Fernandez-Galaz, J. A. Chowen, F. Naftolin
We have recently studied whether the effects of estrogen on hypothalamic neuronal survival and neurite growth are mediated by IGF-I29. Hypothalamic cultures exposed to estradiol or IGF-I show a significant increase in neuronal survival and in the growth of neuronal processes. Inhibition of IGF-I synthesis in the cultures with an antisense oligonucleotide to IGF-I mRNA results in a significant decrease in the stimulatory effects of 17β-estradiol on the number of neurons and the extension of neuronal processes29. This indicates that IGF-I is necessary for the manifestation of the hormonal effect, suggesting that estradiol may induce neuronal survival and differentiation by activation of IGF-I signaling cascades. We have also studied whether the effect of IGF-I on the survival and differentiation of hypothalamic neurons is dependent on the estrogen receptor29. Both the pure estrogen receptor antagonist ICI 182, 780 or an antisense oligodeoxynucleotide to the estrogen receptor mRNA blocked the effects of estradiol. This indicates that estrogen receptors are necessary for the action of IGF-1 on hypothalamic survival and neuritic growth, suggesting that IGF-I may activate, either directly or indirectly, estrogen receptors. The interaction of estradiol and insulin-like growth factor-I (IGF-I) signaling cascades in hypothalamic neuronal survival and differentiation provides a good example of the complexity of the mechanism of action of sex steroids in the brain. Further studies are necessary to establish the possible physiological and physiopathological significance of this interaction.
Latest generation estrogen receptor degraders for the treatment of hormone receptor-positive breast cancer
Published in Expert Opinion on Investigational Drugs, 2022
Ya-Chi Chen, Jiajie Yu, Ciara Metcalfe, Tom De Bruyn, Thomas Gelzleichter, Vikram Malhi, Pablo D. Perez-Moreno, Xiaojing Wang
Giredestrant is a highly potent, nonsteroidal, orally bioavailable selective estrogen receptor antagonist and degrader developed for the treatment of HR-positive breast cancer alone or in combination (e.g. with CDK4/6 inhibitors) [61,62]. Giredestrant was identified through prospective optimization of ER antagonism, ER degradation, and anti-proliferation in parallel with strategies to optimize absorption, distribution, metabolism, and excretion properties, to further improve on the profiles of GDC-0810 and GDC-0927 [61,63]. The tetrahydrocarboline core in giredestrant provides a better foundation for metabolic stability than those SERDs with a phenol moiety such as fulvestrant, GDC-0927, and elacestrant. A polar difluoropropyl alcohol in giredestrant (cLogP: 5.0) significantly attenuates lipophilicity compared with other SERDs such as amcenestrant (cLogP: 8.4), elacestrant (cLogP: 6.8), and rintodestrant (cLogP: 6.3), trending toward more drug-like properties [61]. The basic side chain in giredestrant enables a full antagonist and consistent degradation profile which has been challenging to achieve for ER ligands including GDC-0810, AZD9496, LSZ102, and rintodestrant which have an acrylic acid moiety. Giredestrant binds to the ER, outcompeting estradiol and immobilizing the receptor to suppress ER-mediated signaling and cellular proliferation; it also induces conformational changes that target the ER for degradation [62,64]. The low lipophilicity, high solubility, and high permeability make giredestrant a good candidate for oral administration [61].
Future perspectives for cryptococcosis treatment
Published in Expert Opinion on Therapeutic Patents, 2018
Juliana Santos-Gandelman, Márcio Lourenço Rodrigues, Alice Machado Silva
Though interesting and novel molecules were identified in this patent landscape, we consider the development of these compounds unlikely unless they also target other indications (given the previously mentioned market failure for cryptococcosis). Repurposing is most likely the most promising strategy for establishing novel anti-cryptococcal agents. Drug repurposing is faster and much cheaper than developing novel molecules of pharmacological potential [81,82]. Several studies are evaluating possible candidates for drug repurposing for cryptococcosis treatment [83–88]. Tamoxifen, an estrogen receptor antagonist used primarily to treat breast cancer, is one of these compounds. Tamoxifen in combination with AmpB and fluconazole is about to enter phase II clinical trials for the treatment of cryptococcal meningitis (clinical.trial.gov identifier NCT03112031). Indeed, patents demonstrating tamoxifen’s activity against Cryptococcus spp. were retrieved in our search. However, they were not summarized due to the absence of in vivo experimental evidence of such activity.
Flavonoids of Herba Epimedii stimulate osteogenic differentiation and suppress adipogenic differentiation of primary mesenchymal stem cells via estrogen receptor pathway
Published in Pharmaceutical Biology, 2016
Dawei Zhang, Li Liu, Zhenbin Jia, Xinsheng Yao, Mengsu Yang
PPAR-γ is an obligatory key regulator of adipocytic differentiation in vivo as well as ex vivo and involved in the control of fatty acid metabolism (Rosen & Spiegelman, 2000). In addition, the activation of PPAR-γ promotes adipogenesis and the suppression of PPAR-γ pathway may inhibit adipogenesis and stimulate osteoblast differentiation (Zhang et al., 2015). In the present study, the treatment of 0.06–6 μg/mL HETF decreased the expression level of PPAR-γ to 0.82-, 1.0-, and 0.79-folds, which was consistent with oil red O staining and quantification. It is also reported that other phytochemicals, for instance, kaempferol, have the protective effect against both osteoporosis and obesity by regulating cellular activities (Byun et al., 2012). Genistein was also reported to enhance the commitment and differentiation of MSCs to the osteoblast lineage and reduce the adipogenic differentiation of MSCs (Heim et al., 2004). Besides, the addition of ICI 182,780, a high affinity estrogen receptor antagonist, completely blocked the effects of HETF and ES on the expression of Run-2, BMP-2, and PPAR-γ (Figure 6). Although the expression of Runx-2, BMP-2 and PPAR-γ was slightly increased in the presence of HETF compared with ICI 182,780 alone, no significant difference was found (p < 0.05), suggesting the involvement of estrogen receptor pathway.