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Öğe Effect of n-Hexane Extract from Tanacetum argenteum (Lam.) Willd. subsp. argenteum on the Secretion of Proinflammatory Cytokines in THP-1 Cell Line(Society of Pharmaceutical Sciences of Ankara (FABAD), 2024) Arzuk E.; Karakuş F.; Albayrak G.; Ergüç A.; Tan I.; Atiş E.Inflammation is an initial biological process that involves the activation of the immune system in response to injury, infection or exposure to toxic agents. During this process, cytokines, small proteins produced by immune cells, play a vital role in regulating the immune response. Inflammatory cytokines, including interleukins, tumor necrosis factor-?, nitric oxide, and interferon-gamma, initiate the immune response and promote inflammation. Natural products are frequently a source of potential anti-inflammatory compounds, and screening natural products can lead to the discovery of novel bioactive compounds. The present study aimed to investigate the effects of n-hexane extract from Tanacetum argenteum subsp. argenteum on the lipopolysaccharide-induced inflammatory response in human macrophages THP-1 cell. Cells were incubated with different concentrations of n-hexane extract, and the inhibitor effects of the extract exposure on various cytokine secretions were determined. The findings demonstrated that n-hexane extract dramatically decreased the levels of interleukin-6, interleukin-1?, and tumor necrosis factor-? in differentiated THP-1 cells, indicating the remarkable anti-inflammatory potential of the extract. The n-hexane extract inhibited the secretion of interleukin-6 and interleukin-1? even at the lowest dose of 1 ?g/ml. However, a significant reduction in tumor necrosis factor-? secretion was observed at 5 ?g/ml and above concentrations. Importantly, the results of the study indicated that both the n-hexane extract and its active component, parthenolide, exhibit comparable effects. Furthermore, in silico analysis of toxicogenomic data revealed the interactions between the active component of the n-hexane extract and interleukin-6, interleukin- 1?, and tumor necrosis factor. © 2024 Society of Pharmaceutical Sciences of Ankara (FABAD). All rights reserved.Öğe INVESTIGATION OF CYTOTOXIC AND APOPTOTIC EFFECTS OF PRANGOS HEYNIAE H. DUMAN & M. F. WATSON EXTRACTS ON HEPG2 CELLS; [PRANGOS HEYNIAE H. DUMAN & M. F. WATSON EKSTRELERİNİN HEPG2 HÜCRELERİNDEKİ SİTOTOKSİK VE APOPTOTİK ETKİLERİNİN ARAŞTIRILMASI](University of Ankara, 2024) Arzuk E.; Albayrak G.; Ergüç A.; Atiş E.; Tan İ.; Baykan Ş.Objective: This study aims to investigate the anticancer potential of Prangos Heyniae H. Duman & M. F. Watson root extracts against human hepatoma cells, and examine the molecular mechanisms potentially involved in extract-induced cytotoxicity. Material and Method: HepG2 cells were treated with chloroform, n-hexane, or methanol extracts from roots of P. heyniae to investigate the possible effects on cell viability. Following the determination of IC50 values by the MTT test, n-hexane, and methanol extracts were excluded because of their selectivity indices. The chemical characterization of chloroform extract was performed by HPLC to understand the chemical composition-bioactivity relationship. Alterations induced by chloroform extract on mitochondrial membrane potential and caspase-3 activation were further investigated. In addition, cell viability was measured in the presence of different selective inhibitors of pathways to define the type of cell death pathway contributing to cytotoxicity. Result and Discussion: Chloroform extract but not n-hexane or methanol extracts led to strong and selective inhibition of cell viability on HepG2 cells. In addition, cytotoxicity increased by chloroform extract was only restored in the presence of a pan-caspase apoptosis inhibitor. Also, treatment of HepG2 cells with chloroform extract impaired mitochondrial membrane potential and led to significant caspase-3 activation. Oxypeucedanin, isoimperatorin, and osthole were detected as the major components of the chloroform extract. These results represent that apoptosis may be involved in the anticancer effect of coumarin and furanocoumarin derivatives in chloroform extract. © 2024 University of Ankara. All rights reserved.Öğe Investigation of the role of NLRP3 inflammasome activation in new-generation BCR-ABL1 tyrosine kinase inhibitors-induced hepatotoxicity(Elsevier Ireland Ltd, 2024) Arzuk E.New generation BCR-ABL1 TKIs raised attention regarding their adverse effects, including hepatotoxicity. Indeed, bosutinib and nilotinib were associated with severe hepatotoxicity compared with imatinib. Moreover, ponatinib has a boxed warning due to its potential to cause inflammatory liver damage, even death. However, the underlying mechanisms remain unclear. This study aimed to investigate the role of NLRP3 inflammasome activation in the underlying mechanism of ponatinib and bosutinib-induced hepatotoxicity. Furthermore, we determined the initiating event of this adverse outcome pathway by measuring the levels of reactive oxygen species as well as mitochondrial membrane potential in AML12 cells. The results demonstrated that ponatinib or bosutinib markedly inhibited cell viability and caused cytosolic membrane damage in cells. Moreover, drugs (IC50) dramatically induced oxidative stress and mitochondrial membrane potential disruption, which led to upregulation in the expression levels of NLRP3 inflammasome-related genes and proteins, activation of NLRP3 inflammasomes, cleavage of gasdermin-D and caspase-1, secretion of IL-1?, and cytosolic membrane damage. Furthermore, MCC950, a well-known specific inhibitor of NLRP3 inflammasome, and antioxidant N-acetyl-l-cysteine reversed the effects of drugs on the NLRP3 signaling pathway and cytosolic membranes. In summary, NLRP3 inflammasome activation is involved in new-generation BCR-ABL1 TKIs-triggered hepatotoxicity. Mitochondrial damage and reactive oxygen species accumulation were significant upstream signaling events in this signaling pathway. © 2024 Elsevier B.V.Öğe Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine analysis by an improved ELISA: An inter-laboratory comparison study(Elsevier Inc., 2016) Rossner P.; Jr.; Orhan H.; Koppen G.; Sakai K.; Santella R.M.; Ambroz A.; Rossnerova A.; Sram R.J.; Ciganek M.; Neca J.; Arzuk E.; Mutlu N.; Cooke M.S.ELISA is commonly used for the detection of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a marker of whole body oxidative stress. However, the method has been criticized for high inter-laboratory variability and poor agreement with chromatographic techniques. We performed an inter-laboratory comparison of 8-oxodG assessed in 30 urine samples and a urine spiked with four different concentrations of 8-oxodG by ELISA using standardized experimental conditions, including: sample pre-treatment with solid-phase extraction (SPE), performing analysis using a commercial kit from a single manufacturer and strict temperature control during the assay. We further compared the ELISA results with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and performed tentative identification of compounds that may contribute to the discrepancy between both methods. For all but one participating laboratory (Data 1) we observed consistent ELISA results lying mostly within 1 SD of the mean 8-oxodG concentration. Mean 8-oxodG levels assessed by ELISA correlated with the data obtained by HPLC-MS/MS (R=0.679, p<0.001). The correlation improved when Data 1 were excluded from the analysis (R=0.749, p<0.001). We identified three outlying urine samples; one with an ELISA 8-oxodG concentration lower, and two with 8-oxodG levels higher, than those measured by HPLC-MS/MS. Omitting these samples further improved inter-methodology agreement (R=0.869, p<0.001). In the outliers with high 8-oxodG estimates various aromatic and heterocyclic compounds were tentatively identified using gas chromatography-mass spectrometry (GC-MS). Application of authentic standards revealed the presence of saccharides, including d-glucose and d-galactose as putative interfering substances. In summary, assay standardization improved ELISA inter-laboratory agreement, although some variability is still observed. There are still compounds contributing to overestimation of 8-oxodG by ELISA, but only in some urine samples. Thus, despite significant improvement, ELISA still should not be considered a robust alternative to chromatographic techniques. © 2016 Elsevier Inc. All rights reserved.
