Bioengineering / Biyomühendislik
Permanent URI for this collectionhttps://hdl.handle.net/11147/4529
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Book Part Astragalus sp.(CRC Press, 2023) Yakuboğulları, Nilgün; Bedir, ErdalAstragalus is one of the largest genera in Turkey and is widely distributed worldwide. The phytochemical studies on Turkish Astragalus species have presented 112 new compounds besides 63 known compounds. The overriding basis for biological activity studies is the traditional use of Astragalus roots in the Southeastern Region of Turkey to cure leukemia. As the isolated compounds did not show cytotoxic properties, a hypothesis that the biological activity of Astragalus saponins might result from the activation of the immune system came up. While Astragalus polysaccharides are used for their strong immunomodulatory activities in Chinese medicine, there are a few articles revealing the immunostimulatory properties of Astragalus saponins. Here, we summarized the compounds isolated from Turkish Astragalus species and concentrated on the immunomodulatory activities of these compounds to put forward their potential as saponin-based vaccine adjuvants. © 2024 selection and editorial matter, Ufuk Koca-Caliskan; individual chapters, the contributors.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: 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: 5Citation - Scopus: 5Screening of Cytotoxicity and Dna Topoisomerase Iia Inhibitory Activity of Turkish Onosma Species(TÜBİTAK, 2021) Güzel, Özge; Duman, Seda; Yılmaz, Sinem; Karakoyun, Çiğdem; Kul, Demet; Pirhan, Ademi Fahri; Bedir, ErdalOnosma L., the largest genus of Boraginaceae, is represented by 105 species in Turkey with an endemism rate of 52%. Phytochemical studies indicate that Boraginaceae plants mainly comprise naphthoquinones with a wide range of biological activities including anticancer, antiinflammatory, wound healing, and antioxidant effects. However, few taxa of the genus Onosma have been investigated in detail for their bioactivities. Considering the high rate of endemism and an inadequate number of bioactivity screening studies in literature, we aimed to evaluate the cytotoxic effects and topoisomerase inhibitory activities of some Onosma species growing in southwestern Turkey. Here, we describe a comprehensive cytotoxic activity screening study on petroleum ether, dichloromethane, and methanol extracts of the roots of 20 identified and one unidentified Onosma taxa. The MTT cell viability assay has been performed to investigate the cytotoxicity of the extracts against seven cancer cell lines (MCF-7, HeLa > Hep G2, A549, Capan-1, HCC-1937, and DU-145) and a noncancerous cell line (MRC-5), while doxorubicin was served as a positive standard. The petroleum ether extracts of O. aksoyii Aytac&Turkmen, O. isaurica Boiss. and Heldr., O. taurica Pallas ex Willd. var. taurica and O. alborosea Fisch. & C.A. Mey subsp. alborosea var. alborosea were determined as the most active ones based on their IC50 values. DNA topoisomerase Ila inhibition assay was conducted on the petroleum ether and dichloromethane extracts of these four active species, and almost all tested extracts demonstrated strong inhibition on the enzyme at a concentration of 0.1 mg/mL. Our cytotoxicity screening results were consistent with the findings of the topoisomerase Ila inhibition test. This study advocates the significant role of Onosma species in the field of anticancer drug discovery.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.Article Citation - WoS: 12Citation - Scopus: 12Evaluation of Adjuvant Activity of Astragaloside Vii and Its Combination With Different Immunostimulating Agents in Newcastle Disease Vaccine(Academic Press, 2021) Yakuboğulları, Nilgün; Çöven, Furkan Ozan; Cebi, Nusin; Çöven, Fethiye; Çöven, Nejdet; Genç, Rukan; Bedir, ErdalAstragaloside VII (AST-VII), a major cycloartane saponin isolated from Turkish Astragalus species, turned out to be one of the most active metabolites demonstrating Th1/Th2 balanced immune response. As Quillaja saponins are extensively used in adjuvant systems, this study made an attempt to improve AST-VII based adjuvant systems by using different immunostimulatory/delivery agents (monophosphoryllipid A (MPL), Astragalus polysaccharide (APS) and squalene) and to induce cellular and humoral immune response against a viral vaccine. For this purpose, Newcastle Disease vaccine (NDV) was chosen as a model vaccine. Swiss albino mice were immunized subcutaneously with LaSota vaccines in the presence/absence of AST-VII or developed adjuvant systems. AST-VII administration both in live/inactivated LaSota vaccines induced neutralizing and NDV specific IgG, IgG1 and IgG2b antibodies response as well as IL-2 and IL-4 production. APS based delivery systems enhanced the production of neutralizing antibody and the minor augmentation of IFN-? and IL-2 levels. Squalene emulsion (SE) alone or combined with AST-VII were effective in NDV restimulated splenocyte proliferation. As a conclusion, AST-VII and AST-VII containing adjuvant systems demonstrated Th1/Th2 balanced antibody and cellular immune responses in NDV vaccines. Thus, these systems could be developed as vaccine adjuvants in viral vaccines as alternative to saponin-based adjuvants.