In this study acetonic extracts of leaves of Pistacia lentiscus L. var. chia (mastiha tree) grown in the south as well as in the north Chios Greek island were isolated and further fractionated to give three different polarity fractions: apolar, medium-polar, and polar. The isolated fractions were assessed as regards their main composition, cytotoxic, anti-inflammatory activities, and interference with the glucocorticoid receptor (GR) signaling, applying cytotoxic assay, luciferase assays, and Western blot analysis of apoptosis-, energy-, and inflammation-associated molecules. Differences in cell viability have been detected among different polarity leaf fractions as well as among fractions of different plant origin with polar fractions showing the highest cytotoxicity. Fractions-induced anti-inflammatory activities and suppressive effects on the dexamethasone (DEX)-induced GR transcriptional activation were unveiled. The partition protocol of leaves fractions applied uncovers the enhanced glucocorticoid-associated biological activities of the medium-polar fractions, which may be associated with their enrichment in the triterpenoids that showed structural similarity with the glucocorticoids. A reduction in GR protein levels is observed by the fraction which is shown to be associated with the medium polar-induced proteolytic degradation of the receptor. In addition, the enhanced cytotoxic, anti-inflammatory, and potential anti-glycemic activities of the fractions from the Southern P. lentiscus L. that exclusively produce the mastiha resin, is revealed, indicating that leaves fractions from mastiha tree, similarly to mastiha tree resin, may have the potential to be further analyzed for their potent applications in the pharmaceutical cosmetic and nutraceutical fields.
Glucocorticoids are steroid hormones that regulate inflammation, growth, metabolism, and apoptosis via their cognate receptor, the glucocorticoid receptor (GR). GR, acting mainly as a transcription factor, activates or represses the expression of a large number of target genes, among them, many genes of anti-inflammatory and pro-inflammatory molecules, respectively. Transrepression activity of glucocorticoids also accounts for their anti-inflammatory activity, rendering them the most widely prescribed drug in medicine. However, chronic and high-dose use of glucocorticoids is accompanied with many undesirable side effects, attributed predominantly to GR transactivation activity. Thus, there is a high need for selective GR agonist, capable of dissociating transrepression from transactivation activity. Protopanaxadiol and protopanaxatriol are triterpenoids that share structural and functional similarities with glucocorticoids. The molecular mechanism of their actions is unclear. In this study applying induced-fit docking analysis, luciferase assay, immunofluorescence, and Western blot analysis, we showed that protopanaxadiol and more effectively protopanaxatriol are capable of binding to GR to activate its nuclear translocation, and to suppress the nuclear factor-kappa beta activity in GR-positive HeLa and HEK293 cells, but not in GR-low level COS-7 cells. Interestingly, no transactivation activity was observed, whereas suppression of the dexamethasone-induced transactivation of GR and induction of apoptosis in HeLa and HepG2 cells were observed. Thus, our results indicate that protopanaxadiol and protopanaxatriol could be considered as potent and selective GR agonist.
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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