PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection
Permanent URI for this collectionhttps://hdl.handle.net/11147/7645
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Article Citation - WoS: 7Citation - Scopus: 7Potent Telomerase Activators From a Novel Sapogenin Via Biotransformation Utilizing Camarosporium Laburnicola, an Endophytic Fungus(BioMed Central Ltd., 2023) Küçüksolak, Melis; Yılmaz, Sinem; Ballar Kırmızıbayrak, Petek; Bedir, ErdalBACKGROUND: Cycloartane-type triterpenoids possess important biological activities, including immunostimulant, wound healing, and telomerase activation. Biotransformation is one of the derivatization strategies of natural products to improve their bioactivities. Endophytic fungi have attracted attention in biotransformation studies because of their ability to perform modifications in complex structures with a high degree of stereospecificity. RESULTS: This study focuses on biotransformation studies on cyclocephagenol (1), a novel cycloartane-type sapogenin from Astragalus species, and its 12-hydroxy derivatives (2 and 3) to obtain new telomerase activators. Since the hTERT protein levels of cyclocephagenol (1) and its 12-hydroxy derivatives (2 and 3) on HEKn cells were found to be notable, biotransformation studies were carried out on cyclocephagenol and its 12-hydroxy derivatives using Camarosporium laburnicola, an endophytic fungus isolated from Astragalus angustifolius. Later, immunoblotting and PCR-based ELISA assay were used to screen starting compounds and biotransformation products for their effects on hTERT protein levels and telomerase activation. All compounds showed improved telomerase activation compared to the control group. CONCLUSIONS: As a result of biotransformation studies, seven new metabolites were obtained and characterized, verifying the potential of C. laburnicola as a biocatalyst. Additionally, the bioactivity results showed that this endophytic biocatalyst is unique in transforming the metabolites of its host to afford potent telomerase activators. © 2023. The Author(s).Article Citation - WoS: 8Citation - Scopus: 9Neuroprotective Metabolites Via Fungal Biotransformation of a Novel Sapogenin, Cyclocephagenol(Nature Research, 2022) Küçüksolak, Melis; Üner, Göklem; Ballar Kırmızıbayrak, Petek; Bedir, ErdalCyclocephagenol (1), a novel cycloartane-type sapogenin with tetrahydropyran unit, is only encountered in Astragalus species. This rare sapogenin has never been a topic of biological activity or modification studies. The objectives of this study were; (i) to perform microbial transformation studies on cyclocephagenol (1) using Astragalus endophyte, Alternaria eureka 1E1BL1, followed by isolation and structural characterization of the metabolites; (ii) to investigate neuroprotective activities of the metabolites; (iii) to understand structure–activity relationships towards neuroprotection. The microbial transformation of cyclocephagenol (1) using Alternaria eureka resulted in the production of twenty-one (2–22) previously undescribed metabolites. Oxidation, monooxygenation, dehydration, methyl migration, epoxidation, and ring expansion reactions were observed on the triterpenoid skeleton. Structures of the compounds were established by 1D-, 2D-NMR, and HR-MS analyses. The neuroprotective activities of metabolites and parent compound (1) were evaluated against H2O2-induced cell injury. The structure–activity relationship (SAR) was established, and the results revealed that 1 and several other metabolites had potent neuroprotective activity. Further studies revealed that selected compounds reduced the amount of ROS and preserved the integrity of the mitochondrial membrane. This is the first report of microbial transformation of cyclocephagenol.Article Citation - WoS: 2Citation - Scopus: 3Non-Apoptotic Cell Death Induction Via Sapogenin Based Supramolecular Particles(Nature Publishing Group, 2022) Üner, Göklem; Bedir, Erdal; Serçinoğlu, Onur; Ballar Kırmızıbayrak, PetekThe discovery of novel chemotherapeutics that act through different mechanisms is critical for dealing with tumor heterogeneity and therapeutic resistance. We previously reported a saponin analog (AG-08) that induces non-canonical necrotic cell death and is auspicious for cancer therapy. Here, we describe that the key element in triggering this unique cell death mechanism of AG-08 is its ability to form supramolecular particles. These self-assembled particles are internalized via a different endocytosis pathway than those previously described. Microarray analysis suggested that AG-08 supramolecular structures affect several cell signaling pathways, including unfolded protein response, immune response, and oxidative stress. Finally, through investigation of its 18 analogs, we further determined the structural features required for the formation of particulate structures and the stimulation of the unprecedented cell death mechanism of AG-08. The unique results of AG-08 indicated that supramolecular assemblies of small molecules are promising for the field of anticancer drug development, although they have widely been accepted as nuisance in drug discovery studies.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.