Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection
Permanent URI for this collectionhttps://hdl.handle.net/11147/7148
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Article Semi-Synthetic Sapogenin Derivatives Inhibit Inflammation-Induced Tumorigenic Signaling Alterations in Prostate Carcinogenesis(Elsevier Science Inc, 2026) Debelec-Butuner, Bilge; Ozturk, Mert Burak; Tag, Ozgur; Akgun, Ismail Hakki; Bedir, ErdalProstatic inflammation plays a pivotal role in prostate cancer development and progression via altering key cellular mechanisms, including proliferation, metastasis, and angiogenesis. Therefore, the use of antiinflammatory drugs could provide a valid contribution to PCa prevention and treatment. In our research, we explored semi-synthetic derivatives of cycloastragenol (CA) and astragenol (AG) to assess their potential to inhibit inflammation-mediated tumorigenic signaling. Building on our previous findings, which demonstrated their inhibitory activity on NFxB, we discovered that these molecules also suppress inflammation-induced cell proliferation and migration through distinct mechanisms. They effectively alleviated inflammation by reducing levels of ROS, NO, and VEGF expression. Furthermore, these molecules partially restored the expression of AR and the tumor suppressor NKX3.1, both of which are critical in prostate tumorigenesis within an inflammatory microenvironment. They also reversed inflammation-induced activation of Akt and (3-catenin signaling, suggesting their potential to inhibit inflammation-related prostate tumorigenesis. Our study further demonstrated that these molecules exhibited dose-dependent effects on inducing cell cycle arrest and apoptosis, as evidenced by increased p21 and decreased BCL-2 protein levels, leading to activated cell death and suppressed cellular migration. In conclusion, these semi-synthetic sapogenol derivatives demonstrate significant potential as antiinflammatory and anticancer agents, offering a promising approach for targeting prostatic inflammation and inflammation-driven prostate carcinogenesis.Article Citation - WoS: 13Citation - Scopus: 15The Role of Cycloastragenol at the Intersection of Nrf2/Are, Telomerase, and Proteasome Activity(Elsevier, 2022) Yılmaz, Sinem; Bedir, Erdal; Ballar Kırmızıbayrak, PetekAging 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 with small compounds has been considered a promising therapeutic approach. Cycloastragenol (CA), a small molecule telomerase activator obtained from Astragalus species, has been reported to positively affect several age-related pathophysiologies, but the mechanisms underlying CA activity have yet to be reported. Here, we presented that CA increased NRF2 nuclear localization and activity leading to upregulation of cytoprotective enzymes and attenuation of oxidative stress-induced ROS levels. Furthermore, CA-mediated induction of telomerase activity was found to be regulated by NRF2. CA not only increased the expression of hTERT but also its nuclear localization via upregulating the Hsp90-chaperon complex. In addition to modulating nuclear hTERT levels at unstressed conditions, CA alleviated oxidative stress-induced mitochondrial hTERT levels while increasing nuclear hTERT levels. Concomitantly, H2O2-induced mitochondrial ROS level was found to be significantly decreased by CA administration. Our data also revealed that CA strongly enhanced proteasome activity and assembly. More importantly, the proteasome activator effect of CA is dependent on the induction of telomerase activity, which is mediated by NRF2 system. In conclusion, our results not only revealed the cross-talk among NRF2, telomerase, and proteasome systems but also that CA functions at the intersection of these three major aging-related cellular pathways.Article Citation - WoS: 19Citation - Scopus: 21Telomerase Activators From 20(27)-Octanor Via Biotransformation by the Fungal Endophytes(Academic Press, 2021) Duman, Seda; Ekiz, Güner; Yılmaz, Sinem; Yusufoğlu, Hasan; Ballar Kırmızıbayrak, Petek; Bedir, ErdalCycloastragenol [20(R),24(S)-epoxy-3 beta,6 alpha,16 beta,25-tetrahydroxycycloartane] (CA), the principle sapogenol of many cycloartane-type glycosides found in Astragalus genus, is currently the only natural product in the anti-aging market as telomerase activator. Here, we report biotransformation of 20(27)-octanor-cycloastragenol (1), a thermal degradation product of CA, using Astragalus species originated endophytic fungi, viz. Penicillium roseopurpureum, Alternaria eureka, Neosartorya hiratsukae and Camarosporium laburnicola. Fifteen new biotransformation products (2-16) were isolated, and their structures were established by NMR and HRESIMS. Endophytic fungi were found to be capable of performing hydroxylation, oxidation, ring cleavage-methyl migration, dehydrogenation and Baeyer-Villiger type oxidation reactions on the starting compound (1), which would be difficult to achieve by conventional synthetic methods. In addition, the ability of the metabolites to increase telomerase activation in Hekn cells was evaluated, which showed from 1.08 to 12.4-fold activation compared to the control cells treated with DMSO. Among the compounds tested, 10, 11 and 12 were found to be the most potent in terms of telomerase activation with 12.40-, 7.89- and 5.43-fold increase, respectively (at 0.1, 2 and 10 nM concentrations, respectively).