PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection
Permanent URI for this collectionhttps://hdl.handle.net/11147/7645
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Article K41-A Enhances the Antiproliferative Efficacy of Cisplatin in Neuroblastoma by Modulating Apoptosis and Autophagy(Oxford University Press, 2026) Sanlav, Gamze; Kum Ozsengezer, Selen; Altun, Zekiye; Bedir, Erdal; Aktas, Safiye; Olgun, NurObjectives Neuroblastoma (NB), the most common extracranial tumor in childhood, has a poor prognosis, especially in cases with MYC gene amplification. Cisplatin (CDDP) is widely used in treatment, but its effectiveness is limited due to chemotherapy resistance. Autophagy plays a dual role in cancer progression, either promoting survival or contributing to cell death.Methods This study explores the anticancer effects of K41-A, a polycyclic polyether molecule, alone and in combination with CDDP in SH-SY5Y and KELLY NB cell lines, the HE-IOC1 noncancerous cochlear cell line, and the NB xenograft model.Key findings For the first time, we demonstrate that K41-A, either alone or combined with CDDP, significantly inhibits cell proliferation selectively in NB cells, sparing noncancerous cells. This study confirmed that K41-A alone and in combination with CDDP induced changes in both apoptotic and autophagic cell death components in NB, resulting in antiproliferative activity in vitro and in vivo. In addition, the combination with CDDP enhanced the therapeutic efficacy of K41-A.Conclusions These results highlight the potential of K41-A as a candidate drug for the treatment of NB.Article Citation - WoS: 1Citation - Scopus: 1Optimization of Biotransformation Processes of <i>camarosporium Laburnicola</I> To Improve Production Yields of Potent Telomerase Activators(Bmc, 2024) Kuecueksolak, Melis; Coban, Hasan Bugra; Bedir, ErdalBackground Telomerase activators are promising agents for the healthy aging process and the treatment/prevention of short telomere-related and age-related diseases. The discovery of new telomerase activators and later optimizing their activities through chemical and biological transformations are crucial for the pharmaceutical sector. In our previous studies, several potent telomerase activators were discovered via fungal biotransformation, which in turn necessitated optimization of their production. It is practical to improve the production processes by implementing the design of experiment (DoE) strategy, leading to increased yield and productivity. In this study, we focused on optimizing biotransformation conditions utilizing Camarosporium laburnicola, a recently discovered filamentous fungus, to afford the target telomerase activators (E-CG-01, E-AG-01, and E-AG-02). Results DoE approaches were used to optimize the microbial biotransformation processes of C. laburnicola. Nine parameters were screened by Plackett-Burman Design, and three significant parameters (biotransformation time, temperature, shaking speed) were optimized using Central Composite Design. After conducting validation experiments, we were able to further enhance the production yield of target metabolites through scale-up studies in shake flasks (55.3-fold for E-AG-01, 13-fold for E-AG-02, and 1.96-fold for E-CG-01). Conclusion Following a process optimization study using C. laburnicola, a significant increase was achieved in the production yields. Thus, the present study demonstrates a promising methodology to increase the production yield of potent telomerase activators. Furthermore, C. laburnicola is identified as a potential biocatalyst for further industrial utilization.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: 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).Article Citation - WoS: 36Citation - Scopus: 38Phytochemical Screening and Evaluation of the Antimicrobial and Antioxidant Activities of Ferula Caspica M. Bieb. Extracts(King Saud University, 2019) Kahraman, Çiğdem; Topçu, Gülaçtı; Bedir, Erdal; Tatlı, İ. İrem; Ekizoğlu, Melike; Akdemir, Zeliha S.Chloroform, ethyl acetate and methanol extracts from the aerial parts of Ferula caspica M. Bieb. were tested for their antioxidant capacities by CUPRAC, ABTS, FRAP, Folin-Ciocalteu and aluminum chloride methods and for antimicrobial activities by the broth microdilution method. Chloroform and ethyl acetate extracts showed the highest antioxidant capacity and antimicrobial activity. Three known sesquiterpene derivatives; 1-(2',4'-dihydroxyphenyl)-3,7,11-trimethyl-3-vinyl-6(E), 10-dodecadien-1-one (1), 2,3-dihydro-7-hydroxy-2,3-dimethyl-2-[4',8'-dimethyl-3',7'-nonadienyl]-furo[3,2,c]coumarin (2), 2,3-dihydro-7-hydroxy-2,3-dimethyl-3-[4',8'-dimethyl-3',7'-nonadienyl]-furo[3,2,c]coumarin(3); phenylpropanoid; laserine/2-epilaserine (4/5) and steroid mixtures; stigmasterol and beta-sitosterol (6/7) were isolated from chloroform extract; three known flavonoids; kaempferol-3-O-beta-glucopyranoside (8), kaempferol-3-O-alpha-rhamnopyranoside (9), quercetin-3-O-beta-glucopyranoside (10), and one benzoic acid derivative; 2,4-dihydroxybenzoic acid (11) were isolated from the ethyl acetate extract. The structures were elucidated by spectroscopic methods. (C) 2019 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University.Article Citation - WoS: 23Citation - Scopus: 22Microbial Transformation of Cycloastragenol and Astragenol by Endophytic Fungi Isolated From Astragalus Species(American Chemical Society, 2019) Ekiz, Güner; Yılmaz, Sinem; Yusufoğlu, Hasan; Ballar Kırmızıbayrak, Petek; Bedir, ErdalBiotransformation of Astragalus sapogenins (cycloastragenol (1) and astragenol (2)) by Astragalus species originated endophytic fungi resulted in the production of five new metabolites (3, 7, 10, 12, 14) together with 10 known compounds. The structures of the new compounds were established by NMR spectroscopic and HRMS analysis. Oxygenation, oxidation, epoxidation, dehydrogenation, and ring cleavage reactions were observed on the cycloartane (9,19-cyclolanostane) nucleus. The ability of the compounds to increase telomerase activity in neonatal cells was also evaluated. After prescreening studies to define potent telomerase activators, four compounds were selected for subsequent bioassays. These were performed using very low doses ranging from 0.1 to 30 nM compared to the control cells treated with DMSO. The positive control cycloastragenol and 8 were found to be the most active compounds, with 5.2- (2 nM) and 5.1- (0.5 nM) fold activations versus DMSO, respectively. At the lowest dose of 0.1 nM, compounds 4 and 13 provided 3.5- and 3.8-fold activations, respectively, while cycloastragenol showed a limited activation (1.5-fold).Article Citation - WoS: 14Citation - Scopus: 15Biotransformation of Ruscogenins by Cunninghamella Blakesleeana Nrrl 1369 and Neoruscogenin by Endophytic Fungus Neosartorya Hiratsukae(Elsevier Ltd., 2018) Özçınar, Özge; Tağ, Özgür; Yusufoğlu, Hasan; Kıvçak, Bijen; Bedir, ErdalBiotransformation of steroidal ruscogenins (neoruscogenin and ruscogenin) was carried out with Cunninghamella blakesleeana NRRL 1369 and endophytic fungus Neosartorya hiratsukae yielding mainly P450 monooxygenase products together with a glycosylated compound. Fermentation of ruscogenins (75:25, neoruscogenin-ruscogenin mixture) with C. blakesleeana yielded 8 previously undescribed hydroxylated compounds. Furthermore, microbial transformation of neoruscogenin by endophytic fungus N. hiratsukae afforded three previously undescribed neoruscogenin derivatives. While hydroxylation at C-7, C-12, C-14, C-21 with further oxidation at C-1 and C-7 were observed with C. blakesleeana, N. hiratsukae biotransformation provided C-7 and C-12 hydroxylated compounds along with C-12 oxidized and C-1(O) glycosylated derivatives. The structures of the metabolites were elucidated by 1-D (1H, 13C and DEPT135) and 2-D NMR (COSY, HMBC, HMQC, NOESY, ROESY) as well as HR-MS analyses.Article Citation - WoS: 27Citation - Scopus: 30Biotransformation of Cyclocanthogenol by the Endophytic Fungus Alternaria Eureka 1e1bl1(Elsevier Ltd., 2018) Ekiz, Güner; Duman, Seda; Bedir, ErdalThe microbial transformation of cyclocanthogenol (CCG), Astragalus sp. originated sapogenin, by the endophytic fungus Alternaria eureka 1E1BL1 isolated from Astragalus angustifolius was investigated. Hydroxylation, oxidation, epoxidation, O-methylation, ring-expansion and methyl migration reactions were observed on the triterpenoid skeleton. As a result, eight metabolites were isolated and the structures of the previously undescribed compounds were established by 1-D, 2-D NMR and HR-MS analyses.Article Citation - WoS: 20Citation - Scopus: 24Biotransformation of Neoruscogenin by the Endophytic Fungus Alternaria Eureka(American Chemical Society, 2018) Özçınar, Özge; Tağ, Özgür; Yusufoğlu, Hasan; Kıvçak, Bijen; Bedir, ErdalBiotransformation of neoruscogenin (NR, 1, spirosta-5,25(27)-diene-1β,3β-diol), the major bioactive sapogenin of Ruscus preparations, was carried out with the endophytic fungus Alternaria eureka. Fourteen new biotransformation products (2-15) were isolated, and their structures were elucidated by NMR and HRESIMS data analyses. A. eureka affected mainly oxygenation, oxidation, and epoxidation reactions on the B and C rings of the sapogenin to afford compounds 8-15. In addition to these, cleavage of the spiroketal system as in compounds 2-7 and subsequent transformations provided unusual metabolites. This is the first study reporting conversion of the spirostanol skeleton to cholestane-type metabolites 2-5. Additionally, the cleavage of the C-22/C-26 oxygen bridge yielding a furostanol-type steroidal framework and subsequent formation of the epoxy bridge between C-18 and C-22 in 7 was encountered for the first time in steroid chemistry.Article Citation - WoS: 19Citation - Scopus: 20Specialized Metabolites From the Aerial Parts of Centaurea Polyclada Dc.(Elsevier Ltd., 2017) Demir, Serdar; Karaalp, Canan; Bedir, ErdalThe genus Centaurea L. (Asteraceae) is represented by 200 taxa in the flora of Turkey and several Centaurea species are used as herbal remedies against different conditions. Previous phytochemical investigations on this genus generally revealed the isolation of sesquiterpene lactones and flavonoid derivatives. In our continuous search on Centaurea genus, a phytochemical study was performed on Centaurea polyclada DC., an endemic of West Anatolia. Previously undescribed two sesquiterpene-amino acid conjugates, an elemane and an eudesmane derivative were isolated from the aerial parts of Centaurea polyclada, together with eight known compounds; two elemane derivatives, three flavonoids, a lignan, a phenolic glucoside and a phenylpropanoid glucoside. Structural elucidation of the compounds was based on spectroscopic evidence, including 1D and 2D NMR and high-resolution mass spectrometry, chemical degradation results and reference data comparison. Sesquiterpene-amino acid conjugates are representatives of an unusual group of sesquiterpenes, and elemane-amino acid conjugates are herein reported for the first time in nature.