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Zearalenone: Insights into New Mechanisms in Human Health
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Cornelia Braicu, Alina Andreea Zimta, Ioana Berindan-Neagoe
The observed increase in early onset of puberty in girls during the last century has led to the study of many estrogen-mimetic substances. ZEA and its metabolite, α-zearanol, competes with estrogen for its receptors (ER-α and ER-β), and upon binding, it causes the cell to have the same response as in the case of estrogen. The most affected organisms are the ones exposed earlier in life, before puberty [52]. Girls with detectable levels of ZEA and α-zearanol have a poor response to GnRH inhibition by triptorelin, a drug frequently used in treating precocious puberty [53]. Early exposure in rats induces precocious puberty, similar to estradiol [44]. Among the ZEA metabolites, α-zearanol has the highest affinity for binding to the estrogen receptor and, thus, has the most powerful estrogenic activity. In the case of young girls, the high ZEA plasma level appears to be correlated to shorter stature and reduced likelihood of breast development onset; as such, ZEA might be regarded as possessing antiestrogenic effects in some cases [54]. In mice, exposure leads to earlier development of secondary sexual characteristics, such as differentiation and growth of breast tissue [52]. In human preadipocytes, ZEA triggers the expression and activity of estrogen synthetase [13]. The immortalized murine ovarian granular cells produced more estrogen after exposure to 20 μM of ZEA, which decreased the production of enzymes involved in steroid genesis: Star, Cyp11a1, and Hsd3b1, while Cyp17a1 is increased. Meanwhile, the intracellular degree of ROS is elevated in murine ovarian tissue, along with oxidized lipids, that leads to loss of mitochondrial membrane potential and finally to programmed cell death [55].
Opportunities and challenges for drug discovery in modulating Adhesion G protein-coupled receptor (GPCR) functions
Published in Expert Opinion on Drug Discovery, 2020
Andrey D. Bondarev, Misty M. Attwood, Jörgen Jonsson, Vladimir N. Chubarev, Vadim V. Tarasov, Helgi B. Schiöth
Overall, among the particularly notable advances in recent years to be considered is the characterization of two small molecular weight modulators 3-α-acetoxydihydrodeoxygedunin and dihydromunduletone. Both modulators affect ADGRG1 and ADGRG5; such a lack of selectivity is in line with a recent study [202] showing that the aGPCRs may be cross-activated via a tethered agonist. Both receptors are also characterized by a shared amino acid sequence of their peptide agonists [193], a property which appears to affect selectivity as well. In 3-α-acetoxydihydrodeoxygedunin, the presence of inhibitory activity against ADGRF1 [192] is an important observation that could also provide insights on how to achieve better selectivity. Further elucidation of the molecules’ structure-activity relationship is therefore vital for a better understanding of how to reach a satisfactory level of receptor selectivity in a small molecule modulator. It is also notable that both molecules were elucidated using common screening assay techniques, which could facilitate future drug discovery efforts. The earliest experiences in explicating beclomethasone, ezetimibe, zeranol, and flunarizine should not be overlooked either, as them provide a set of opportunities for a wider range of screening techniques in the aGPCR drug discovery. The structures of small molecular weight modulators and synaptamide are presented on Figure 4.