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Öğe A multifaceted assessment of strigolactone GR24 and its derivatives: from anticancer and antidiabetic activities to antioxidant capacity and beyond(Frontiers Media Sa, 2023) Pyrzanowska-Banasiak, Agata; Tumer, Tugba Boyunegmez; Bukowska, Bozena; Krokosz, AnitaBackground: Strigolactones are signaling molecules produced by plants, the main functions are the intracorporeal control of plant development and plant growth. GR24 strigolactone is one of the synthetic strigolactones and due to its universality and easy availability, it is a standard and model compound for research on the properties and role of strigolactones in human health.Purpose: In this research work, the impact of mainly GR24 strigolactone on the human body and the role of this strigol-type lactone in many processes that take place within the human body are reviewed.Study design: The article is a review of publications on the use of GR24 strigolactone in studies from 2010-2023. Publications were searched using PubMed, Elsevier, Frontiers, and Springer databases. The Google Scholar search engine was also used. For the review original research papers and reviews related to the presented topic were selected.Results: The promising properties of GR24 and other strigolactone analogs in anti-cancer therapy are presented. Tumor development is associated with increased angiogenesis. Strigolactones have been shown to inhibit angiogenesis, which may enhance the anticancer effect of these gamma-lactones. Furthermore, it has been shown that strigolactones have anti-inflammatory and antioxidant properties. There are also a few reports which show that the strigolactone analog may have antimicrobial and antiviral activity against human pathogens.Conclusion: When all of this is considered, strigolactones are molecules whose versatile action is their undeniable advantage. The development of research on these phytohormones makes it possible to discover their new, unique properties and surprising biological activities in relation to many mammalian cells.Öğe Association between polymorphisms of EPHX1 and XRCC1 genes and the risk of childhood acute lymphoblastic leukemia(Springer Heidelberg, 2012) Tumer, Tugba Boyunegmez; Sahin, Gurses; Arinc, EmelMicrosomal epoxide hydrolase, EPHX1, plays a central role in the detoxification of potentially genotoxic epoxide intermediates. In this study, we firstly aimed to investigate the relationship between EPHX1 Tyr113His and His139Arg variants, and the risk of incidence of childhood acute lymphoblastic leukemia (ALL) in Turkish population, comprised of 190 healthy controls and 167 ALL patients. In exon 3 Tyr113His polymorphism, 113His/His homozygous mutant genotype with slow activity was 18.6% in ALL patients and 9% in controls, indicating 113His/His slow activity genotype was significantly associated with an increased risk of childhood ALL (OR: 2.3, 95% CI, 1.2-4.4, P = 0.01). No significant association was found between exon 4 His139Arg variant and the risk of ALL. When both exon 3 Tyr113His and exon 4 His139Arg polymorphisms were considered together, only the exon 3 113His/His, homozygous mutant, slow activity genotype with exon 4 wild-type genotype 139His/His was significantly increased the risk of ALL 2.4-fold (OR: 2.4, P = 0.02). We also evaluated whether haplotype analysis for EPHX1 Tyr113His polymorphism together with DNA protein XRCC1 Arg399Gln variant known for its deficient DNA repair capacity would represent more prominent risk factors for the development of childhood ALL. Accordingly, the co-presence of Tyr113His variant of EPHX1 and Arg399Gln variant of XRCC1 in the same individuals significantly increased the risk of childhood ALL up to 2.1-fold (OR = 2.1, P = 0.03). Moreover, homozygous mutant genotype for both genes significantly and considerably increased the risk of childhood ALL 8.5-fold (OR: 8.5, P = 0.03). In conclusion, individuals with EPHX1 113His/His slow activity genotype may not detoxify reactive carcinogenic epoxides efficiently, binding of reactive epoxides to DNA cause DNA damage. With the inadequate polymorphic DNA repair protein, XRCC1, this situation ultimately leads to significantly increased susceptibility for childhood ALL.Öğe Direct and Indirect Antioxidant Activity of Polyphenol- and Isothiocyanate-Enriched Fractions from Moringa oleifera(Amer Chemical Soc, 2015) Tumer, Tugba Boyunegmez; Rojas-Silva, Patricio; Poulev, Alexander; Raskin, Ilya; Waterman, CarrieMoringa oleifera Lam. is a fast-growing, tropical tree with various edible parts used as nutritious food and traditional medicine. This study describes an efficient preparatory strategy to extract and fractionate moringa leaves by fast centrifugal partition chromatography (FCPC) to produce polyphenol and isothiocyanate (ITC) rich fractions. Characterization and further purification of these fractions showed that moringa polyphenols were potent direct antioxidants assayed by oxygen radical absorbance capacity (ORAC), whereas moringa ITCs were effective indirect antioxidants assayed by induction of NAD(P)H quinone oxidoreductase 1 (NQO1) activity in Hepa1c1c7 cells. In addition, purified 4-[(a-l-rhamnosyloxy)benzyl]isothiocyanate and 4-[(4'-O-acetyl-a-l-rhamnosyloxy)benzyl]isothiocyanate were further evaluated for their ORAC and NQO1 inducer potency in comparison with sulforaphane (SF). Both ITCs were as potent as SF in inducing NQO1 activity. These findings suggest that moringa leaves contain a potent mixture of direct and indirect antioxidants that can explain its various health-promoting effects.Öğe DNA repair XRCC1 Arg399Gln polymorphism alone, and in combination with CYP2E1 polymorphisms significantly contribute to the risk of development of childhood acute lymphoblastic leukemia(Pergamon-Elsevier Science Ltd, 2010) Tumer, Tugba Boyunegmez; Yilmaz, Duygu; Tanrikut, Cihan; Sahin, Gurses; Ulusoy, Gulen; Arinc, EmelIt is now well established that genetic polymorphisms impairing the DNA repair capacity can disrupt the genomic integrity and potentially modulate individual's susceptibility to various cancers. In this study, we investigated the possible association of X-ray repair cross-complimenting group 1 (XRCC1) Arg399Gln and Arg194Trp variants with the risk of incidence of childhood acute lymphoblastic leukemia (ALL) in Turkish population comprised of 190 healthy controls and 167 ALL patients. For Arg399Gln polymorphism, the heterozygous (Arg/Gln) and homozygous mutant (Gln/Gln) genotypes were significantly more common in the ALL patients than the controls (OR: 1.6, p = 0.04). Particularly, the Gln399Gln genotype significantly increased the risk of disease up to 2.0-fold (OR: 2.0, p = 0.04). Besides, Gln399Gln genotype has been found to be associated with considerably increased risk of ALL among females (OR = 2.9, p = 0.03). In case of codon 194 polymorphism, no significant associations have been found with risk of childhood ALL. In addition, none of the combinations of XRCC1 codon 194 and 399 polymorphisms have been found to be significantly associated with childhood ALL risk. In the scope of this study, we have also showed that the co-presence of XRCC1 codon 399 and CYP2E1*5B and *6 polymorphisms (data for CYP2E1 polymorphisms drawn from previously published study conducted in our lab) in the same individuals considerably increased the risk for childhood ALL to 3.7-fold with borderline significance (p = 0.049). The observed combined effect was considerably more prominent among females (OR = 17.4, p = 0.001) and need to further investigation. This is the first study showing combined associations of XRCC1 399Gln, CYP2E1*5B and *6 alleles with the risk of development of childhood ALL. (C) 2010 Elsevier Ltd. All rights reserved.Öğe Effects of Strigolactones on NLRP3 Activation, Nitrosative Stress, and Antioxidant Mox Phenotype: In Vitro and In Silico Evidence(Amer Chemical Soc, 2024) Antika, Gizem; Cinar, Zeynep Ozlem; Donmez, Serhat; Secen, Esma; Ozbil, Mehmet; Prandi, Cristina; Tumer, Tugba BoyunegmezPhytohormones have significant roles in redox metabolism, inflammatory responses, and cellular survival mechanisms within the microenvironment of the mammalian brain. Herein, we identified the mammalian molecular targets of three representative strigolactone (SL) analogues structurally derived from apocarotenoids and the functional equivalent of plant hormones. All tested SL analogues have an inhibitory effect on NLRP3 inflammasome-mediated IL-1 beta release in murine microglial cells. However, IND and EGO10 became prominent among them due to their high potency at low micromolar doses. All SL analogues dose-dependently suppressed the release and expression of proinflammatory factors. For EGO10 and IND, IC50 values for iNOS-associated NO secretion were as low as 1.72 and 1.02 mu M, respectively. In silico analyses revealed that (S)-EGO10 interacted with iNOS, NLRP3, and Keap1 ligands with the highest binding affinities among all stereoisomeric SL analogues. Although all compounds were effective in microglial Mox phenotype polarization, 4-Br-debranone exhibited a differential pattern for upregulating Nrf2-driven downstream enzymes.Öğe EPHX1 GENE TYR113HIS VARIANT ALONE, or in COMBINATION with XRCC1 ARG399GLN POLYMORPHISM SIGNIFICANTLY and CONSIDERABLY INCREASED THE RISK of CHILDHOOD ACUTE LYMPHOBLASTIC LUKEMIA(Taylor & Francis Inc, 2010) Tumer, Tugba Boyunegmez; Yilmaz, Duygu; Tanrikut, Cihan; Ulusoy, Gulen; Arinc, Emel[Anstract Not Available]Öğe Inhibitory Effects of Spirulina platensis on Carcinogen-Activating Cytochrome P450 Isozymes and Potential for Drug Interactions(Sage Publications Inc, 2013) Savranoglu, Seda; Tumer, Tugba BoyunegmezSpirulina platensis (SP) has been considered as potential food source of 21st century due to its remarkable nutrient profile and therapeutic benefits. However, the cytochrome P450 (CYP)-mediated drug/chemical interaction potential of SP has not yet been pursued. We investigated the effects of SP on the expressions and enzymatic activities of main CYP isozymes. After the rats were orally administered with SP daily for 5 consecutive weeks, there were significant downregulations in hepatic expression levels and inhibition in enzymatic activities of CYP1A2 and CYP2E1 compared to controls. In addition, a significant decrease was observed in CYP2C6-associated enzyme activity with no remarkable changes in messenger RNA (mRNA)/protein levels. The SP application resulted in significant increases in mRNA/protein levels of both CYP2B1 and CYP3A1 without a significant change in enzyme activities. These findings partly explain the chemopreventive properties of SP toward various organ toxicities, mutagenesis, and carcinogenesis; however, its coadministration with some CYP substrates may lead to undesirable drug interactions.Öğe Insights on the Use of ?-Lipoic Acid for Therapeutic Purposes(Mdpi, 2019) Salehi, Bahare; Yilmaz, Yakup Berkay; Antika, Gizem; Tumer, Tugba Boyunegmez; Mahomoodally, Mohamad Fawzi; Lobine, Devina; Akram, Muhammadalpha-lipoic acid (ALA, thioctic acid) is an organosulfur component produced from plants, animals, and humans. It has various properties, among them great antioxidant potential and is widely used as a racemic drug for diabetic polyneuropathy-associated pain and paresthesia. Naturally, ALA is located in mitochondria, where it is used as a cofactor for pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase complexes. Despite its various potentials, ALA therapeutic efficacy is relatively low due to its pharmacokinetic profile. Data suggests that ALA has a short half-life and bioavailability (about 30%) triggered by its hepatic degradation, reduced solubility as well as instability in the stomach. However, the use of various innovative formulations has greatly improved ALA bioavailability. The R enantiomer of ALA shows better pharmacokinetic parameters, including increased bioavailability as compared to its S enantiomer. Indeed, the use of amphiphilic matrices has capability to improve ALA bioavailability and intestinal absorption. Also, ALA's liquid formulations are associated with greater plasma concentration and bioavailability as compared to its solidified dosage form. Thus, improved formulations can increase both ALA absorption and bioavailability, leading to a raise in therapeutic efficacy. Interestingly, ALA bioavailability will be dependent on age, while no difference has been found for gender. The present review aims to provide an updated on studies from preclinical to clinical trials assessing ALA's usages in diabetic patients with neuropathy, obesity, central nervous system-related diseases and abnormalities in pregnancy.Öğe Isothiocyanate-rich Moringa oleifera extract reduces weight gain, insulin resistance, and hepatic gluconeogenesis in mice(Wiley, 2015) Waterman, Carrie; Rojas-Silva, Patricio; Tumer, Tugba Boyunegmez; Kuhn, Peter; Richard, Allison J.; Wicks, Shawna; Stephens, Jacqueline M.ScopeMoringa oleifera (moringa) is tropical plant traditionally used as an antidiabetic food. It produces structurally unique and chemically stable moringa isothiocyanates (MICs) that were evaluated for their therapeutic use in vivo. Methods and resultsC57BL/6L mice fed very high fat diet (VHFD) supplemented with 5% moringa concentrate (MC, delivering 66 mg/kg/d of MICs) accumulated fat mass, had improved glucose tolerance and insulin signaling, and did not develop fatty liver disease compared to VHFD-fed mice. MC-fed group also had reduced plasma insulin, leptin, resistin, cholesterol, IL-1, TNF, and lower hepatic glucose-6-phosphatase (G6P) expression. In hepatoma cells, MC and MICs at low micromolar concentrations inhibited gluconeogenesis and G6P expression. MICs and MC effects on lipolysis in vitro and on thermogenic and lipolytic genes in adipose tissue in vivo argued these are not likely primary targets for the anti-obesity and anti-diabetic effects observed. ConclusionData suggest that MICs are the main anti-obesity and anti-diabetic bioactives of MC, and that they exert their effects by inhibiting rate-limiting steps in liver gluconeogenesis resulting in direct or indirect increase in insulin signaling and sensitivity. These conclusions suggest that MC may be an effective dietary food for the prevention and treatment of obesity and type 2 diabetes.Öğe Modulatory role of GSTM1 null genotype on the frequency of micronuclei in pesticide-exposed agricultural workers(Sage Publications Inc, 2016) Tumer, Tugba Boyunegmez; Savranoglu, Seda; Atmaca, Pelin; Terzioglu, Gulsurn; Sen, Alaattin; Arslan, SevkiIn this study, we aimed to investigate the extent of genotoxic risk and the association between null GSTM1/GSTT1 and GSTP1 Ile105Val variants and cellular DNA damage, as measured by micronucleus (MN) assay in a group of agricultural workers from Denizli, Turkey. Peripheral blood samples were collected from 116 subjects, including 58 workers who were occupationally exposed to pesticides and 58 healthy unexposed controls. The MN frequencies of each individual were assessed by cytokinesis-blocked micronuclei assays on lymphocytes. Genotypes for different GST variants were determined using polymerase chain reaction-based methods. A significant 3.4-fold increase in MN frequency was observed in workers compared with the controls (p < 0.001). Among the GST genotypes, only the GSTM1 null genotype was found to be significantly associated with an increased MN frequency in workers (p = 0.01). Individuals with a concomitant null GSTM1/GSTT1 genotype demonstrated a significant (p = 0.01) increase in MN frequency compared with those with functional isozymes in the exposed worker group. The association of the GSTM1 null genotype with higher MN frequency suggests that it may be a modifier of genotoxic risk in individuals exposed to pesticides and may thus be a candidate susceptibility biomarker for human biomonitoring studies.Öğe Multitarget Profiling of a Strigolactone Analogue for Early Events of Alzheimer's Disease: In Vitro Therapeutic Activities against Neuroinflammation(Amer Chemical Soc, 2020) Kurt, Begum; Ozleyen, Adem; Antika, Gizem; Yilmaz, Yakup Berkay; Tumer, Tugba BoyunegmezNeuropathological changes in Alzheimer's disease (AD) are directly linked to the early inflammatory microenvironment in the brain. Therefore, disease-modifying agents targeting neuroinflammation may open up new avenues in the treatment of AD. Strigolactones (SLs), subclasses of structurally diverse and biologically active apocarotenoids, have been recently identified as novel phytohormones. In spite of the remarkable anticancer capacity shown by SLs, their effects on the brain remained unexplored. Herein, the SIM-A9 microglial cell line was used as a phenotypic screening tool to search for the representative SL, GR24, demonstrating marked potency in the suppression of lipopolysaccharide (LPS)-induced neuroinflammatory/neurotoxic mediators by regulating NF-kappa B, Nrf2, and PPAR gamma signaling. GR24 also in the brain endothelial cell line bEnd.3 mitigated the LPS-increased permeability as evidenced by reduced Evans' blue extravasation through enhancing the expression of tight junction protein, occludin. Collectively, the present work shows the anti-neuroinflammatory and glia/neuroprotective properties of GR24, making SLs promising scaffolds for the development of novel anti-AD candidates.Öğe Natural Products and Synthetic Analogs as a Source of Antitumor Drugs(Mdpi, 2019) Sharifi-Rad, Javad; Ozleyen, Adem; Tumer, Tugba Boyunegmez; Adetunji, Charles Oluwaseun; El Omari, Nasreddine; Balahbib, Abdelaali; Taheri, YasamanCancer is a heterogeneous disease and one of the major issues of health concern, especially for the public health system globally. Nature is a source of anticancer drugs with abundant pool of diverse chemicals and pharmacologically active compounds. In recent decade, some natural products and synthetic analogs have been investigated for the cancer treatment. This article presents the utilization of natural products as a source of antitumor drugs.Öğe Optimizing bioreactor conditions for Spirulina fermentation by Lactobacillus helveticus and Kluyveromyces marxianus: Impact on chemical & bioactive properties(Elsevier Sci Ltd, 2024) Yay, Cansu; Cinar, Zeynep Ozlem; Donmez, Serhat; Tumer, Tugba Boyunegmez; Guneser, Onur; Hosoglu, Muge IsletenThis study focused on optimizing the production of fermented Spirulina (FS) products using a bioactivity-guided strategy with Lactobacillus helveticus B-4526 and Kluyveromyces marxianus Y-329 in a 3-L bioreactor. Various operating conditions, including aeration rates and pH modes, were tested. While both microorganisms thrived under all conditions, the cascade mode, controlling dissolved oxygen, enhanced protein hydrolysis and antioxidant activity, as confirmed by SDS-PAGE and DPPH/TEAC assays, respectively. Screening revealed that cascade FS significantly decreased viability of colon cancer cells (HT-29) in a dose-dependent manner, with up to a 72 % reduction. Doses <= 500 mu g mL- 1 of cascade FS proved safe and effective in suppressing NO release without compromising cellular viability. Additionally, cascade FS exhibited diverse volatile organic compounds and reducing the characteristic seaweed aroma. These findings highlight cascade FS as a promising alternative food source with improved bioactive properties, urging further exploration of its bioactive compounds, particularly bioactive peptides.Öğe Plants of the genus Spinacia: From bioactive molecules to food and phytopharmacological applications(Elsevier Science London, 2019) Salehi, Bahare; Tumer, Tugba Boyunegmez; Ozleyen, Adem; Peron, Gregorio; Dall'Acqua, Stefano; Rajkovic, Jovana; Naz, RabiaBackground: Spinacia plants, including the most recognized species of the genus Spinacia oleacea L. (spinach), have high nutritional value and high content in phytochemicals, such as flavonoids, polyphenols, carotenoids, and ascorbic acid. However, the amount of these phytochemicals depends on several factors, such as genotype, climatic conditions, and agronomic practices, harvesting, storage temperature and time. Scope and approach: This review focus on the therapeutic role of Spinacia genus as well as its contribution as food in industry. A special emphasis is also given to its biological activities including antioxidant and antimicrobial effects. Finally, the clinical efficacy of Spinacia plants, the respective roles, and mechanisms of bioactive compounds on human health are covered. Key findings and conclusions: Spinacia plants are rich in nitrate, thylakoids, glycoglycerolipids and their natural antioxidant mixture (NAO) shows renowned antioxidant, antiproliferative, anti-inflammatory, antimicrobial, anticancer and cardioprotective effects. Thus, the nutritional value and phytochemical composition of Spinacia plants make them an excellent matrix to be used in traditional medicine as also as a natural preservative ingredient in food.Öğe Protective Role of DNA Repair XRCC3 Thr241Met Polymorphism on Development of Childhood Acute Lymphoblastic Leukemia(Taylor & Francis Inc, 2010) Tanrikut, Cihan; Tumer, Tugba Boyunegmez; Arinc, Emel[Anstract Not Available]Öğe Symphytum Species: A Comprehensive Review on Chemical Composition, Food Applications and Phytopharmacology(Mdpi, 2019) Salehi, Bahare; Sharopov, Farukh; Tumer, Tugba Boyunegmez; Ozleyen, Adem; Rodriguez-Perez, Celia; Ezzat, Shahira M.; Azzini, ElenaSymphytum species belongs to the Boraginaceae family and have been used for centuries for bone breakages, sprains and rheumatism, liver problems, gastritis, ulcers, skin problems, joint pain and contusions, wounds, gout, hematomas and thrombophlebitis. Considering the innumerable potentialities of the Symphytum species and their widespread use in the world, it is extremely important to provide data compiling the available literature to identify the areas of intense research and the main gaps in order to design future studies. The present review aims at summarizing the main data on the therapeutic indications of the Symphytum species based on the current evidence, also emphasizing data on both the efficacy and adverse effects. The present review was carried out by consulting PubMed (Medline), Web of Science, Embase, Scopus, Cochrane Database, Science Direct and Google Scholar (as a search engine) databases to retrieve the most updated articles on this topic. All articles were carefully analyzed by the authors to assess their strengths and weaknesses, and to select the most useful ones for the purpose of review, prioritizing articles published from 1956 to 2018. The pharmacological effects of the Symphytum species are attributed to several chemical compounds, among them allantoin, phenolic compounds, glycopeptides, polysaccharides and some toxic pyrrolizidine alkaloids. Not less important to highlight are the risks associated with its use. In fact, there is increasing consumption of over-the-counter drugs, which when associated with conventional drugs can cause serious and even fatal adverse events. Although clinical trials sustain the folk topical application of Symphytum species in musculoskeletal and blunt injuries, with minor adverse effects, its antimicrobial potency was still poorly investigated. Further studies are needed to assess the antimicrobial spectrum of Symphytum species and to characterize the active molecules both in vitro and in vivo.Öğe Synthesis of new imine-/amine-bearing imidazo[1,2-a]pyrimidine derivatives and screening of their cytotoxic activity(Tubitak Scientific & Technological Research Council Turkey, 2023) Gungor, Tugba; Atalay, Hazal Nazlican; Yilmaz, Yakup Berkay; Tumer, Tugba Boyunegmez; Ay, MehmetImidazo[1,2-a]pyrimidine derivatives bearing imine groups (3a-e) were successfully synthesized in moderate to good yields using microwave-assisted heating. Corresponding amine derivatives (4a-e) were also obtained by the reduction reaction of the imine derivatives (3a-e). All synthesized products were characterized by FT-IR,1H NMR, 13C NMR, and LC-MS spectroscopic techniques. In silico ADMET, Lipinski, and drug-likeness studies of the compounds were conducted and all were found to be suitable drug candidates. The cytotoxicity of the potential drug molecules was screened against the breast cancer cell lines MCF-7 and MDA-MB-231 and the healthy model HUVEC by the sulforhodamine B method. According to the antiproliferative studies, compounds 3d and 4d showed remarkable inhibition of MCF-7 cells with IC50 values of 43.4 and 39.0 mu M and of MDA-MB-231 cells with IC50 values of 35.9 and 35.1 mu M, respectively. In particular, compound 3d selectively inhibited the proliferation of MCF-7 1.6-fold and MDA-MB-231 2.0-fold relative to healthy cells. Moreover, the apoptotic mechanism studies indicated that compound 4d induced apoptosis by moderately increasing the ratio of Bax/Bcl-2 genes. Imidazo[1,2-a]pyrimidine derivative 3d, a promising cytotoxic agent, may be helpful in the discovery of new and more efficient anticancer agents for breast cancer treatment.
