Biology subjects

Bedir, E.

Publications and source records attributed to Bedir, E..

4 recordsLinked to original sources

bioRxiv2024

Multi-Targeted Effects of Novel Cycloastragenol Derivatives: Enhancing NRF2, Proteostasis, and Telomerase Pathways with p53 Modulation to Delay Replicative Senescence

Aging is a complex, multifactorial process driven by various cellular and molecular mechanisms, including telomere shortening, oxidative stress, and the decline of proteostasis, all of which contribute to replicative senescence and age-related diseases. Cycloastragenol (CA), a triterpenoid saponin derived from Astragalus membranaceus, has shown potential for its ability to activate telomerase, suggesting therapeutic benefits in delaying cellular aging. In this study, we explored the effects of novel CA derivatives, obtained through biotransformation as telomerase activators, on the NRF2/proteasome/telomerase axis and their potential to delay replicative senescence in human primary epidermal keratinocytes (HEKn). Our findings reveal that these CA derivatives significantly enhance NRF2 nuclear activity, leading to the upregulation of key cytoprotective enzymes essential for mitigating oxidative stress. Notably, these derivatives exhibited efficacy at much lower concentrations compared to CA, demonstrating their potential for enhanced therapeutic application. The derivatives also markedly increased proteasome activity, particularly in the {beta}1 and {beta}5 subunits, thereby preserving proteostasis--a critical factor in preventing the accumulation of damaged proteins associated with aging. Furthermore, continuous treatment with these derivatives sustained stimulatory effects, which was evidenced by increased NRF2, proteasome, and hTERT protein levels even in senescent cells and extended cellular lifespan. Additionally, we explored the impact of CA derivatives on p53-mediated pathways, demonstrating that these compounds effectively modulate the p53/p21 axis, reducing cell cycle arrest and promoting cellular proliferation. Moreover, the derivatives exhibited neuroprotective properties by attenuating glutamate-induced excitotoxicity, further underscoring their potential as multi-targeted anti-aging agents. In conclusion, our study provides strong evidence that novel CA derivatives act on multiple fronts to enhance NRF2 activity, maintain proteostasis, and modulate telomerase and p53 pathways, most at lower doses compared to CA. These actions collectively contribute to the delay of replicative senescence and the promotion of cellular longevity, positioning CA derivatives as potent candidates for developing multi-targeted anti-aging therapies that address the complex interplay of aging-related cellular processes. HighlightsO_LITelomerase-active CA derivatives enhance NRF2 activity and proteasome activity, leading to cytoprotection at lower doses than CA. C_LIO_LICA derivatives modulate the p53 pathway and cell cycle, prolonging cellular lifespan and delaying replicative senescence. C_LIO_LICA derivatives protect cells against glutamate-excitotoxicity along with decreased p53 protein levels. C_LI

biochemistry↗

bioRxiv2022

The role of Cycloastragenol at the intersection of Nrf-2/ARE, telomerase, and proteasome activity

Aging is well-characterized by the gradual decline of cellular functionality. As redox balance, proteostasis, and telomerase systems have been found to be associated with aging and age-related diseases, targeting these systems by small compounds has been considered as a promising therapeutic approach. Cycloastragenol (CA), a small molecule telomerase activator obtained from Astragalus species, has been reported to have positive effects on several age-related pathophysiologies, including ischemia, glucose intolerance, diabetes, and neurodegenerative diseases. Although CA has received intense attention as a promising compound for aging and age-related diseases, the mechanisms underlying CA activity related to redox balance, proteasome, and telomerase has not yet been reported. Here, we presented that CA increased Nrf-2 activity leading to upregulation of cytoprotective enzymes and attenuation of oxidative stress-induced ROS levels. Furthermore, CA enhanced telomerase activity by increasing not only the expression of hTERT but also its nuclear localization via the Hsp90-chaperon complex. CA alleviated the oxidative stress-induced mitochondrial hTERT levels while increasing the nuclear hTERT levels. Additionally, the proteasome activity and assembly were increased by CA. Strikingly, our data revealed that CA-mediated neuroprotection requires both Nrf-2 and hTERT induction. In conclusion, this study is the first report describing the effect of CA on these aging-related three major cellular pathways and their interrelationships. As the proteasome activator effect of CA is dependent on induction of telomerase activity, which is mediated by Nrf-2 system, CA has a great potential for healthier aging and prevention or treatment of age-related diseases by positively affecting these three cellular pathways.

cell biology↗

bioRxiv2021

Sapogenin based self-assembly structures activating a non-apoptotic cell death via multiple pathways

Induction of distinct cell death pathways is critical to deal with tumor heterogeneity and therapeutic resistance. In our previous study, we reported a promising saponin analog (AG-08) for cancer therapy inducing non-canonical necrotic cell death. Here, we describe that AG-08 forms unique supramolecular structures responsible for its biological activity. After internalization via non-canonical endocytosis pathway, these structures affect several cell signaling pathways including unfolded protein response, immune response, oxidative stress and heat stress. Moreover, we prepared 18 analogs to reveal the role of residues on the formation of supramolecular structures and biological activities. The results have demonstrated that unique structural features are required for particulate structures and unprecedented cell death mechanism. Although small molecule based supramolecular assemblies have widely been accepted as nuisance for drug discovery studies, our results indicate that they may provide a new research field for anti-cancer drug development studies.

pharmacology and toxicology↗

bioRxiv2021

Astragalus Saponins, Astragaloside VII and Newly Synthesized Derivatives, Induce Dendritic Cell Maturation and T Cell Activation Through IL-1β Production

Astragaloside VII (AST VII), a plant triterpenoid saponin isolated from Astragalus species, shows promise as vaccine adjuvant, as it supports a balanced Th1/Th2 immune response. However, the underlying mechanisms of its adjuvant activity have not been defined. Here we investigated the impact of AST VII and its newly synthesized semi-synthetic analogs on human whole blood cells, as well as on mouse bone marrow-derived dendritic cells (BMDCs). Cells were stimulated with AST VII and its derivatives in the presence or absence of LPS or PMA/ionomycin and the secretion of cytokines and the expression of activation markers were analyzed by ELISA and flow cytometry, respectively. AST VII and its analogs increased the production of IL-1{beta} in PMA/ionomycin stimulated human whole blood cells. In LPS-treated mouse BMDCs, AST VII increased the production of IL-1{beta} and IL-12, and the expression of MHC II, CD86, and CD80. The strength of the IL-1{beta} boost correlated directly with the hydrophobicity of the AST VII compounds. In mixed leukocyte reaction, AST VII and derivatives increased the expression of the activation marker CD44 on mouse CD4+ and CD8+ T cells. In conclusion, AST VII and its derivatives strengthen pro-inflammatory responses, support dendritic cell maturation, and T cell activation in vitro. Our results provide insights into the mechanisms of the adjuvant activities of AST VII and its analogs, which will be instrumental to improve their utility as vaccine adjuvant.

immunology↗