Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection
Permanent URI for this collectionhttps://hdl.handle.net/11147/7148
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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 Lipoxygenase Inhibitory Activity Evaluation of Achillea Biebersteinii Afan. by Activity-Guided Fractionation(Elsevier Ireland Ltd, 2026) Subasi, Bilgen; Gunbatan, Tugba; Gurbuz, Ihan; Dilmac, Elif; Bedir, Erdal; Demirci, FatihEthnopharmacological relevance: Achillea biebersteinii Afan. is traditionally utilized as folk medicine for a broad range of therapeutic applications, especially for promoting the maturation of abscesses, wound healing; against inflammation, and rheumatism in T & uuml;rkiye. Aim of the study: The anti-inflammatory potential of A. biebersteinii was evaluated through activity-guided fractionation (AGF) targeting lipoxygenase (15-LOX) inhibition. Materials and methods: Different chromatographic techniques were used for the AGF of the ethyl acetate extract of A. biebersteinii aerial parts. The in vitro 15-LOX inhibitory activity evaluation was performed to address the antiinflammatory activity. The structures of purified compounds from the fractions were confirmed by LC-HRMS, 1H NMR, and 13C NMR analyses, respectively. Results: The fractionation and isolation process culminated in the identification of three key flavonoids namely; patulitrin, axillarin, quercetagetin-7-O-beta-glucopyranoside, and 4,5-dicaffeoylquinic acid, which showed statistically remarkable 15-LOX inhibitory activity with inhibition rates of 82.27%, 96.81 %, 84.65% and 77.47 %, respectively. Two flavonoids were isolated by using the AGF method, where quinic acid was spotted to have significant 15-LOX inhibitory activity. Conclusion: These findings support the future therapeutic potential of A. biebersteinii as a natural antiinflammatory source.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.Review Citation - WoS: 1Citation - Scopus: 2Organ-On Platforms for Drug Development, Cellular Toxicity Assessment, and Disease Modeling(Tubitak Scientific & Technological Research Council Turkey, 2024) Khurram, Muhammad Maaz; Cinel, Gokturk; Yesil Celiktas, Ozlem; Bedir, ErdalOrgans-on-chips (OoCs) or microphysiological platforms are biomimetic systems engineered to emulate organ structures on microfluidic devices for biomedical research. These microdevices can mimic biological environments that enable cell-cell interactions on a small scale by mimicking 3D in vivo microenvironments outside the body. Thus far, numerous single and multiple OoCs that mimic organs have been developed, and they have emerged as forerunners for drug efficacy and cytotoxicity testing. This review explores OoC platforms to highlight their versatility in studies of drug safety, efficacy, and toxicity. We also reflect on the potential of OoCs to effectively portray disease models for possible novel therapeutics, which is difficult to achieve with traditional 2D in vitro models, providing an essential basis for biologically relevant research.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: 9Citation - Scopus: 8Astragalus Saponins, Astragaloside Vii and Newly Synthesized Derivatives, Induce Dendritic Cell Maturation and T Cell Activation(MDPI, 2023) Yakuboğulları, Nilgün; Çağır, Ali; Bedir, Erdal; Sağ, DuyguAstragaloside VII (AST VII), a triterpenic saponin isolated from Astragalus species, shows promise as a vaccine adjuvant, as it supported a balanced Th1/Th2 immune response in previous in vivo studies. However, the underlying mechanisms of its adjuvant activity have not been defined. Here, we investigated the impact of AST VII and its newly synthesized semi-synthetic analogs on human whole blood cells, as well as on mouse bone marrow-derived dendritic cells (BMDCs). Cells were stimulated with AST VII and its derivatives in the presence or absence of LPS or PMA/ionomycin and the secretion of cytokines and the expression of activation markers were analyzed using ELISA and flow cytometry, respectively. AST VII and its analogs increased the production of IL-1β in PMA/ionomycin-stimulated human whole blood cells. In LPS-treated mouse BMDCs, AST VII increased the production of IL-1β and IL-12, and the expression of MHC II, CD86, and CD80. In mixed leukocyte reaction, AST VII and derivatives increased the expression of the activation marker CD44 on mouse CD4+ and CD8+ T cells. In conclusion, AST VII and its derivatives strengthen pro-inflammatory responses and support dendritic cell maturation and T cell activation in vitro. Our results provide insights into the mechanisms of the adjuvant activities of AST VII and its analogs, which will be instrumental to improve their utility as a vaccine adjuvant. © 2023 by the authors.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.