Anti-Apoptotic and Antioxidant Activities of the Mitochondrial Estrogen Receptor Beta in N2A Neuroblastoma Cells

Estrogens are steroid hormones that play a crucial role in the regulation of the reproductive and non-reproductive system physiology. Among non-reproductive systems, the nervous system is mainly affected by estrogens due to their antioxidant, anti-apoptotic, and anti-inflammatory activities, which are mediated by membranous and nuclear estrogen receptors, and also by non-estrogen receptor-associated estrogen actions. Neuronal viability and functionality are also associated with the maintenance of mitochondrial functions. Recently, the localization of estrogen receptors, especially estrogen receptor beta, in the mitochondria of many types of neuronal cells is documented, indicating the direct involvement of the mitochondrial estrogen receptor beta (mtERβ) in the maintenance of neuronal physiology. In this study, cell lines of N2A cells stably overexpressing a mitochondrial-targeted estrogen receptor beta were generated and further analyzed to study the direct involvement of mtERβ in estrogen neuroprotective antioxidant and anti-apoptotic actions. Results from this study revealed that the presence of estrogen receptor beta in mitochondria render N2A cells more resistant to staurosporine- and H2O2-induced apoptotic stimuli, as indicated by the reduced activation of caspase-9 and -3, the increased cell viability, the increased ATP production, and the increased resistance to mitochondrial impairment in the presence or absence of 17-β estradiol (E2). Thus, the direct involvement of mtERβ in antioxidant and anti-apoptotic activities is documented, rendering mtERβ a promising therapeutic target for mitochondrial dysfunction-associated degenerative diseases.

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Coumestrol alleviates oxidative stress, apoptosis and cognitive impairments through hippocampal estrogen receptor-beta in male mouse model of chronic restraint stress

Pharmaceutical Sciences ◽

10.34172/ps.2021.44 ◽

2021 ◽

Author(s):

Kiarash Fekri ◽

Javad Mahmoudi ◽

Saeed Sadigh-Eteghad ◽

Fereshteh Farajdokht ◽

Alireza Mohajjel Nayebi

Keyword(s):

Oxidative Stress ◽

Estrogen Receptor ◽

Estrogen Receptors ◽

Restraint Stress ◽

Cognitive Impairments ◽

Estrogen Receptor Beta ◽

Second Phase ◽

Chronic Restraint Stress ◽

Negative Consequences ◽

Receptor Beta

Background: Coumestrol is well-known as a natural estrogen receptor-beta modulator. Since the role of estrogen receptors in controlling stressful situations has already been reported and their cognitive functions in hippocampus seem to be independent of sexual tasks, the aim of this study was to investigate the improving effects of this phytoestrogen on negative consequences of exposing male mice to chronic restraint stress. Methods: This study was divided into two separate but consecutive phases. In the first phase, the possible effects of Coumestrol (30, 60, 120 µg.kg-1.day-1, i.p.) and its vehicle (sesame oil) on restraint stress-induced cognitive impairments, oxidative stress and apoptosis were evaluated. During the second phase, a selective estrogen receptor-beta antagonist was used to investigate the possible involvement of beta-type estrogen receptors in these processes. Morris water maze and novel object recognition tests were performed to evaluate memory while elevated plus maze test was used to measure the level of anxiety. Spectroscopy and western blotting methods were also employed to evaluate oxidative and apoptotic status in hippocampal tissue. Furthermore, serum level of corticosterone was measured for each group. Results: Behavioral tests indicated memory enhancing and anxiolytic effects of coumestrol. Biochemical evaluations also proved its antioxidant and anti-apoptotic potential. On the other hand, the mentioned behavioral and biochemical improvements were reversed in the group treated with estrogen receptor-beta antagonist. Conclusion: Coumestrol may ameliorate negative consequences of exposure to chronic stress such as oxidative stress, apoptosis and cognitive impairments, via the modulation of beta-type estrogen receptors in hippocampus.

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Faculty Opinions recommendation of A selective estrogen receptor-beta agonist causes lesion regression in an experimentally induced model of endometriosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.724924485.793514478 ◽

2016 ◽

Author(s):

Warren Nothnick

Keyword(s):

Estrogen Receptor ◽

Estrogen Receptor Beta ◽

Beta Agonist ◽

Lesion Regression ◽

Receptor Beta ◽

Experimentally Induced

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Faculty Opinions recommendation of Estrogen receptor beta modulates breast cancer cells functional properties, signaling and expression of matrix molecules.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726362790.793520134 ◽

2016 ◽

Author(s):

Ludwig Kiesel ◽

Martin Gotte

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Cells ◽

Functional Properties ◽

Breast Cancer Cells ◽

Estrogen Receptor Beta ◽

Receptor Beta

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Activation of Estrogen Receptor-Beta-Dependent Transcription by Estrogen-Independent Pathways

10.21236/ada413466 ◽

2002 ◽

Author(s):

Carolyn L. Smith

Keyword(s):

Estrogen Receptor ◽

Estrogen Receptor Beta ◽

Receptor Beta

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Natural Herbal Estrogen-Mimetics (Phytoestrogens) Promote the Differentiation of Fallopian Tube Epithelium into Multi-Ciliated Cells via Estrogen Receptor Beta

Molecules ◽

10.3390/molecules26030722 ◽

2021 ◽

Vol 26 (3) ◽

pp. 722

Author(s):

Maobi Zhu ◽

Sen Takeda ◽

Tomohiko Iwano

Keyword(s):

Estrogen Receptor ◽

Cell Differentiation ◽

Epithelial Cells ◽

Fallopian Tube ◽

Ciliated Cell ◽

Estrogen Receptor Beta ◽

Notch Pathway ◽

Secretory Cells ◽

Ciliated Cells ◽

Receptor Beta

Phytoestrogens are herbal polyphenolic compounds that exert various estrogen-like effects in animals and can be taken in easily from a foodstuff in daily life. The fallopian tube lumen, where transportation of the oocyte occurs, is lined with secretory cells and multi-ciliated epithelial cells. Recently, we showed that estrogen induces multi-ciliogenesis in the porcine fallopian tube epithelial cells (FTECs) through the activation of the estrogen receptor beta (ERβ) pathway and simultaneous inhibition of the Notch pathway. Thus, ingested phytoestrogens may induce FTEC ciliogenesis and thereby affect the fecundity. To address this issue, we added isoflavones (genistein, daidzein, or glycitin) and coumestan (coumestrol) to primary culture FTECs under air–liquid interface conditions and assessed the effects of each compound. All phytoestrogens except glycitin induced multi-ciliated cell differentiation, which followed Notch signal downregulation. On the contrary, the differentiation of secretory cells decreased slightly. Furthermore, genistein and daidzein had a slight effect on the proportion of proliferating cells exhibited by Ki67 expression. Ciliated-cell differentiation is inhibited by the ERβ antagonist, PHTPP. Thus, this study suggests that phytoestrogens can improve the fallopian tube epithelial sheet homeostasis by facilitating the genesis of multi-ciliated cells and this effect depends on the ERβ-mediated pathway.

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