PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection
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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: 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.Article Citation - WoS: 8Citation - Scopus: 12Adjuvant Potency of Astragaloside Vii Embedded Cholesterol Nanoparticles for H3n2 Influenza Vaccine(TÜBİTAK, 2020) Genç, Rukan; Yakuboğulları, Nilgün; Nalbantsoy, Ayşe; Coven, Fethiye; Bedir, ErdalAdjuvants are substances that increase the immune response to a given antigen. In the development of novel vaccine adjuvants/systems, saponins are one of the most attractive molecules due to their altered immunomodulatory activities. In this study, we tried to develop PEG (polyethylene glycol)/cholesterol-based lipid nanoparticles (LNPs) to deliver the Astragaloside VII (AST-VII) and potentiate adjuvant properties of AST-VII for the influenza vaccine. In the formation of PEG/cholesterol/AST-VII-based LNPs (PEG300: Chol-AST-VII LNPs), 3 different primary solvents (acetone, ethanol, and chloroform) were evaluated, employing their effects on hydrodynamic particle size, distribution, surface chemistry, and colloidal stability. Prepared nanoparticles were simply admixtured with inactivated influenza antigen (H3N2) and applied to PMA (phorbol 12-myristate 13-acetate)-ionomycin treated human whole blood to evaluate their cytokine release profile. PEG300: Chol-AST-VII LNPs (80.2 +/- 7.7 nm) were obtained using chloroform as a desolvation agent. Co-treatment of PMA-ionomycin with AST-VII and PEG300: Chol-AST-VII LNPs significantly increased the levels of IL-2 and IFN-gamma, compared to PMA-ionomycin alone. In the presence of H3N2, AST-VII was able to augment IL-17A, while PEG300: Chol-AST-VII LNPs stimulated the production of IFN-gamma. Hemolysis was only observed in PEG300: Chol-AST-VII LNPs (250 mu g/mL) treatment. AST-VII and AST-VII-integrated LNPs could be used as efficacious adjuvants for an inactivated H3N2 vaccine in vitro, and cytokine response through Th1/Th17 route was reported.Article Citation - WoS: 4Citation - Scopus: 5Identification of a Noncanonical Necrotic Cell Death Triggered Via Enhanced Proteolysis by a Novel Sapogenol Derivative(American Chemical Society, 2020) Üner, Göklem; Tağ, Özgür; Erzurumlu, Yalçın; Ballar Kırmızıbayrak, Petek; Bedir, ErdalSmall molecules which activate distinct cell death pathways have promising high potential for anticancer drug research. Especially, regulated necrosis draws attention as an alternative cell death mechanism to overcome the drug resistance. Here, we report that a new semisynthetic saponin analogue (AG-08) triggers necrotic cell death with unprecedented pathways. AG-08-mediated necrosis depends on enhanced global proteolysis involving calpains, cathepsins, and caspases. Moreover, AG-08 generates several alterations in lysosomal function and physiology including membrane permeabilization, redistribution toward the perinuclear area, and lastly excessive tubulation. As a consequence of lysosomal impairment, the autophagic process was abolished via AG-08 treatment. Collectively, in addition to its ability to induce necrotic cell death, which makes AG-08 a promising candidate to cope with drug resistance, its unique activity mechanisms including autophagy/lysosome impairment and enhancement of proteolysis leading a strong death capacity emphasizes its potential for anticancer drug research. ©Article Citation - WoS: 21Citation - Scopus: 21Development of Adjuvant Nanocarrier Systems for Seasonal Influenza a (h3n2) Vaccine Based on Astragaloside Vii and Gum Tragacanth (aps)(Elsevier, 2019) Yakuboğulları, Nilgün; Genç, Rukan; Coven, Fethiye; Nalbantsoy, Ayşe; Bedir, ErdalAdjuvants are chemical/biological substances that are used in vaccines to increase the immunogenicity of antigens. A few adjuvants have been developed for use in human vaccines because of their limitations including lack of efficacy, unacceptable local or systemic toxicity, the difficulty of manufacturing, poor stability, and high cost. For that reasons, novel adjuvants/adjuvant systems are under search. Astragaloside VII (AST-VII), isolated from Astragalus trojanus, exhibited significant cellular and humoral immune responses. The polysaccharides (APS) obtained from the roots of Astragalus species have been used in traditional Chinese medicine and possess strong immunomodulatory properties. In the present study, the immunomodulatory effects of a newly developed nanocarrier system (APNS: APS containing carrier) and its AST-VII containing formulation (ANS: AST-VII + APNS), on seasonal influenza A (H3N2) vaccine were investigated. Inactivated H3N2 alone or its combinations with test compounds/formulations were intramuscularly injected into Swiss albino mice. Four weeks after immunization, the immune responses were evaluated in terms of antibody and cytokine responses as well as splenocyte proliferation. APNS demonstrated Th2 mediated response by increasing IgG1 antibody titers, whereas ANS showed response towards Th1/Th2 balance and Th17 by producing of IFN-gamma, IL-17A and IgG2a. Based on these results, we propose that APNS and ANS are good candidates to be utilized in seasonal influenza A vaccines as adjuvants/carrier systems. (C) 2019 Elsevier Ltd. All rights reserved.Article Citation - WoS: 24Citation - Scopus: 23Polyethers Isolated From the Marine Actinobacterium Streptomyces Cacaoi Inhibit Autophagy and Induce Apoptosis in Cancer Cells(Elsevier, 2019) Khan, Nasar; Yılmaz, Sinem; Aksoy, Semiha; Uzel, Ataç; Tosun, Çiğdem; Ballar Kırmızıbayrak, Petek; Bedir, ErdalPolyether compounds, a large group of biologically active metabolites produced by Streptomyces species have been reported to show a variety of bioactivity such as antibacterial, antifungal, antiparasitic, antiviral, and tumour cell cytotoxicity. Since some of these compounds target cancer stem cells and multi-drug resistant cancer cells, this family of compounds have become of high interest. In this study, three polyether-type metabolites (1-3), one of which was a new natural product (3), were isolated from the marine derived Streptomyces cacaoi via antimicrobial activity-guided fractionation studies. As several polyether compounds with structural similarity such as monensin have been linked with autophagy and cell death, we first assessed the cytotoxicity of these three compounds. Compounds 2 and 3, but not 1, were found to be cytotoxic in several cell lines with a higher potency towards cancer cells. Furthermore, 2 and 3 caused accumulation of both autophagy flux markers LC3-II and p62 along with cleavage of caspase-3, caspase-9 and poly (ADP-ribose) polymerase 1 (PARP-1). Interestingly, prolonged treatment of the compounds caused a dramatic downregulation of the proteins related to autophagasome formation in a dose dependent manner. Our findings provide insights on the molecular mechanisms of the polyether-type polyketides, and signify their potency as chemotherapeutic agents through inhibiting autophagy and inducing apoptosis.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: 7Citation - Scopus: 8Investigations on the Anti-Ulcerogenic Activity of Sideritis Caesarea H. Duman, Aytaç & Başer(Elsevier, 2020) Günbatan, Tuğba; Gürbüz, İlhan; Bedir, Erdal; Gençler Özkan, Ayşe Mine; Özçınar, ÖzgeEthnopharmacological relevance: Aerial parts of Sideritis caesarea H. Duman, Aytac & Baser are used for complaints such as stomach-aches, and intestinal spasms as traditional medicine in Kayseri, Turkey. Aim of study: To investigate the anti-ulcerogenic activity by using bioassay guided fractionation technique (BAGF) and to identify the compound(s) that are responsible for anti-ulcerogenic activity through ethanol-induced anti-ulcerogenic activity model in vivo. Materials and methods: Liquid-liquid partition and then different chromatographic techniques were utilized for the BAGF of the ethanol (80%) extract of the aerial parts of Sideritis caesarea. Ethanol-induced gastric ulcer method on rats was employed for the determination of the anti-ulcerogenic activity, and the ulcer index was also calculated for anti-ulcerogenic activity detection. Results: The ethanol (80%) extract of S. caesarea showed statistically potent anti-ulcerogenic activity (95.9% ulcer inhibition, p < 0.001). Among the liquid-liquid fractions, strongest anti-ulcerogenic activity was observed with the ethyl acetate fraction (91.4% inhibition, p< 0.001) and therefore BAGF studies were proceeded with the ethyl acetate fraction. Two anti-ulcerogenic flavonoids {4'-O-methylhypolaetin-7-O-[6'''-O-acetyl-beta-D-allopyranosyl-(1 -> 2)]- 6 ''-O-acetyl-beta-D-glucopyranoside and isoscutellarein-7-O-[6'''-O-acetyl-beta-D-allopyranosyl-(1 -> 2)]-6 ''-O-acetyl-beta-D-glucopyranoside} were isolated from this fraction together with a sesquiterpene glycoside [(2E,6E)-2,6,10-trimethyl-2,6,11-dodecatriene-1,10-diol-1-O-beta-D-glucopyranoside] and two additional flavonoids {4'-O-methylhypolaetin-7-O-[6'''-O-acetyl-beta-D-allopyranosyl-(1 -> 2)]-beta-D-glucopyranoside and isoscutellarein- 7-O-[6'''-O-acetyl-beta-D-allopyranosyl-(1 -> 2)]-beta-D-glucopyranoside}. Conclusions: Traditional use of S. caesarea in the treatment of stomach-aches was supported by this study and four flavonoids were isolated by using BAGF method and two of them were determined to have significant antiulcerogenic activity. Additionally, (2E,6E)-2,6,10-trimethyl-2,6,11-dodecatriene-1,10-diol-1-O-beta-D-glucopyranoside was obtained from a Sideritis genus for the first time.Article Citation - WoS: 13Citation - Scopus: 14Evaluation of the Potential Aphrodisiac Activity of Sesquiterpenoids From Roots of Ferula Huber-Morathii Pesmen in Male Rats(Elsevier, 2020) Aydoğan, Fadime; Baykan, Sura; Soliman, Gamal A.; Yusufoğlu, Hasan; Bedir, ErdalEthnopharmacological relevance: Several species of Ferula L. genus have been used in traditional Turkish medicine as aphrodisiac to treat male sexual dysfunction. Especially, roots and oleo gum resin of F. elaeochytris Korovin, F. communis L., F. assa-foetida L. and F. gummosa Boiss. were claimed to be used for aphrodisiac activity, menstrual regulation and treatment of gastric pain in Anatolia. Ferula L. is represented by 23 taxa in Turkey, 13 of which are endemic species. F. huber-morathii Pesmen (FHM), an endemic plant, is popularly known as "helizan, cagsir". Aim of the study: This study aimed to isolate sesquiterpenoids from the roots of Ferula huber-morathii (FHM) and to confirm their aphrodisiac potential in male rats. Material and methods: In a preliminary experiment, the effects of aqueous (H2O) and chloroform (CHCl3) extracts of FHM were tested for their potential aphrodisiac activities in male rats. Then, sesquiterpene derivatives were isolated from the active chloroform extract of FHM roots (FHM-R) and characterized (TLC, 1D, 2D NMR, HR-MS and CD). Moreover, some of the isolates with adequate quantities were evaluated for their possible aphrodisiac effects on male rats. Single doses (10 mg/kg BW) of sildenafil citrate (SC, positive control), gummosin, mogoltavidin, deacetylkellerin, ferukrin acetate with kellerin, elaeochytrin-A and ferutinin were administered or-ally by gavages to male Wistar albino rats. Mount latency (ML), mount frequency (MF), intromission latency (IL), intromission frequency (IF), ejaculation latency (EL) and postejaculatory interval (PEI) were studied. In addition, copulatory efficiency (CE) and intercopulatory efficiency (ICE) were calculated. Results: The preliminary experiment revealed that the chloroform extract was the main source of the active compounds as it showed the higher aphrodisiac activity while the aqueous extract was found to be inactive. Eleven sesquiterpene derivatives, viz. gummosin, mogoltavidin, farnesiferol A, deacetylkellerin, ferukrin acetate, kellerin, teuclatriol, feruhermonin C, ferutinin, elaeochytrin A and teferidin, were isolated from the FHM-CHCl3 extract. Oral administration of deacetylkellerin, elaeochytrin-A and ferutinin significantly increased MF and IF. The ML and IL were significantly reduced, and ejaculation latencies were prolonged. Administration of these sesquiterpenoids also reduced the PEI. The present results revealed that ferutinin was the most effective aph-rodisiac compound compared to other sesquiterpenoids. The results of 10 mg/kg of ferutinin are comparable to SC, the positive control. The results revealed that gummosin, mogoltavidin and ferukrin acetate with kellerin did not significantly alter the aphrodisiac parameters. Conclusions: This study has established that the CHCl3 extract of FHM root contains sesquiterpene derivatives, especially coumarin ethers and benzoic esters. Findings of the present study demonstrate that the chloroform extract and some of the sesquiterpene derivatives significantly stimulates sexual behavior in male rats, thus suggesting that F. huber-morathii possesses an aphrodisiac activity.