Bioengineering / Biyomühendislik
Permanent URI for this collectionhttps://hdl.handle.net/11147/4529
Browse
40 results
Search Results
Article Anthraquinones and Macrocyclic Lactones From Endophytic Fungus Penicillium Roseopurpureum and Their Bioactivities(ACG Publications, 2024) Dizmen,B.; Üner,G.; Küçüksolak,M.; Gören,A.C.; Kırmızıbayrak,P.B.; Bedir,E.Endophytic fungi colonize the internal and distinct tissues of the host plants. In recent years, there has been growing interest in endophytic fungi as valuable sources for drug discovery based on their rich metabolic profiles consisting of novel and bioactive compounds. Accordingly, our preliminary study demonstrated that an endophyte, namely Penicillium roseopurpureum isolated from Astragalus angustifolius, had high chemical diversity with an antiproliferative effect. Herein, fermentation of P. roseopurpureum resulted in the production of five new anthraquinone-type compounds (2, 4, 6, 7, 8) together with several known compounds [11-methoxycurvularin (1: epimeric mixture of 1a and 1b), carviolin (3), 11-hydroxycurvularin (5: diastereoisomeric mixture of 5a and 5b) and 1-O-methylemodin (9)]. The structures of the new compounds were established by NMR spectroscopy and HR-MS analysis. Cytotoxicity studies demonstrated that none of the compounds except for 1 and 5 had antiproliferative activity against prostate cancer cell lines. Interestingly, 1 was found as cytotoxic, whereas 5 exhibited cytostatic properties. Also, 7-AAD/Annexin V staining supported these results by showing that 1 caused cellular death, while 5 did not show any increase in dead cell content in comparison to the control. Lastly, cell cycle analysis showed that compounds had distinctive cell cycle arrest patterns. © 2024 ACG Publications.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).Conference Object Citation - WoS: 1The Effects of Novel Telomerase Activators on Human Adipose-Derived Mesenchymal Stem Cell (had-Msc) Proliferation and Osteogenic Differentiation(Georg Thieme Verlag Kg, 2022) Kuru, G.; Küçüksolak, Melis; Pulat, G.; Karaman, O.; Bedir, Erdal[No Abstract Available]Conference Object Citation - WoS: 1Phytochemical Studies on Mastic Gum of Pistacia Lentiscus Var. Chia Collected From Karaburun Peninsula and Neuroprotective Activities of the Isolates(Georg Thieme Verlag, 2022) Demir, Mehmet; Üner, Göklem; Mu, Kurt; Aygün, M.; Ballar Kırmızıbayrak, Petek; Bedir, Erdal[No Abstract Available]Article Citation - WoS: 7Citation - Scopus: 7Neo-Clerodanes From Teucrium Divaricatum Subsp. Divaricatum and Their Biological Activity Assessment(Elsevier, 2023) Aydoğan, Fadime; Ali, Zülfiqar; Zülfiqar, Fazila; Karaalp, Canan; Khan, Ikhlas A.; Bedir, ErdalFifteen neo-clerodane diterpenoids (1–15), including two undescribed glycosides, teudivaricosides A (1) and B (2), together with a known iridoid glycoside (16) and a phenylpropanoid glycoside (17) from the whole plant of Teucrium divaricatum subsp. divaricatum were isolated. Their structures were determined by spectral data analysis including 1D and 2D NMR and HRESIMS. Neo-clerodane diterpenoids were evaluated for their anti-inflammatory, and antimicrobial activities. None of them showed significant antimicrobial activity against various bacterial and fungal strains (up to 20 µg/mL). All tested compounds were inactive up to the highest tested concentration of 50 µM on iNOS inhibitory activity.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: 4Citation - Scopus: 3Is Telomerase a Hidden Player? Therapeutic Potential of Natural Telomerase Activators Against Age-Related Diseases(Springer, 2022) Kuru, Gülten; Üner, Göklem; Bedir, ErdalThere is a huge demand for novel treatment and/or prevention approaches for age-related diseases, which reduce life quality and one of the main reasons for death worldwide. Many age-related diseases were found to be associated with dysfunctional telomeres, which accelerate aging process due to the decrease in repair potential of tissues. An enzyme called telomerase is mainly responsible for keeping telomeres healthful. In the last two decades, the progress in the field, including in vitro studies, preclinical data, and human trials, demonstrated that telomerase and related genes might be powerful targets for the treatment of those diseases. Considering telomerase reactivation as a treatment strategy in age-related degenerative diseases, telomerase activators obtained from natural products stand out as promising agents. Although various research showed that those activators have protective/therapeutic activity against age-related diseases, the role of telomerase activation is often neglected in studies. In this context, we focused on the natural products as telomerase activator and their activities on age-related diseases, specifically neurodegenerative, cardiovascular, and osteodegenerative disorders, in which telomere dysfunction plays a causal role. Thus, this review aims to draw attention to the possibility of telomerase activation in therapy, in which some well-known natural products such as telomerase activators might play a role.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: 5Citation - Scopus: 6Undescribed Polyether Ionophores From Streptomyces Cacaoi and Their Antibacterial and Antiproliferative Activities(Elsevier, 2022) Gezer, Emre; Üner, Göklem; Küçüksolak, Melis; Kurt, Mustafa Ünver; Doğan, Gamze; Ballar Kırmızıbayrak, Petek; Bedir, ErdalPolyether ionophores represent a large group of naturally occurring compounds mainly produced by Streptomyces species. With previously proven varieties of bioactivity including antibacterial, antifungal, antiparasitic, antiviral and anti-tumor effects, the discovery of undescribed polyethers leading to development of efficient therapeutics has become important. As part of our research on polyether-rich Streptomyces cacaoi, we previously performed modification studies on fermentation conditions to induce synthesis of specialized metabolites. Here, we report four undescribed and nine known polyether compounds from S. cacaoi grown in optimized conditions. Antimicrobial activity assays revealed that four compounds, including the undescribed (6), showed strong inhibitory effects over both Bacillus subtilis and methicillin-resistant Staphylococcus aureus (MRSA) growth. Additionally, K41-A and its C15-demethoxy derivative exhibited significant cytotoxicity. These results signified that selectivity of C15-demethoxy K41-A towards cancer cells was higher than K41-A, which prompted us to conduct mechanistic experiments. These studies showed that this uninvestigated compound acts as a multitarget compound by inhibiting autophagic flux, inducing reactive oxygen species formation, abolishing proteasome activity, and stimulating ER stress. Consequently, the optimized fermentation conditions of S. cacaoi led to the isolation of undescribed and known polyethers displaying promising activities.