Yazar "Ozbil, Mehmet" seçeneğine göre listele

Listeleniyor 1 - 4 / 4
  • [ X ]
    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 Boyunegmez
    Phytohormones 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.
  • [ X ]
    Öğe
    Identification and inhibition of PIN1-NRF2 protein-protein interactions through computational and biophysical approaches
    (Nature Portfolio, 2025) Ozleyen, Adem; Duran, Gizem Nur; Donmez, Serhat; Ozbil, Mehmet; Doveston, Richard G.; Tumer, Tugba Boyunegmez
    NRF2 is a transcription factor responsible for coordinating the expression of over a thousand cytoprotective genes. Although NRF2 is constitutively expressed, its stability is modulated by the redox-sensitive protein KEAP1 and other conditional binding partner regulators. The new era of NRF2 research has highlighted the cooperation between NRF2 and PIN1 in modifying its cytoprotective effect. Despite numerous studies, the understanding of the PIN1-NRF2 interaction remains limited. Herein, we described the binding interaction of PIN1 and three different 14-mer long phospho-peptides mimicking NRF2 protein using computer-based, biophysical, and biochemical approaches. According to our computational analyses, the residues positioned in the WW domain of PIN1 (Ser16, Arg17, Ser18, Tyr23, Ser32, Gln33, and Trp34) were found to be crucial for PIN1-NRF2 interactions. Biophysical FP assays were used to verify the computational prediction. The data demonstrated that Pintide, a peptide predominantly interacting with the PIN1 WW-domain, led to a significant reduction in the binding affinity of the NRF2 mimicking peptides. Moreover, we evaluated the impact of known PIN1 inhibitors (juglone, KPT-6566, and EGCG) on the PIN1-NRF2 interaction. Among the inhibitors, KPT-6566 showed the most potent inhibitory effect on PIN1-NRF2 interaction within an IC50 range of 0.3-1.4 mu M. Furthermore, our mass spectrometry analyses showed that KPT-6566 appeared to covalently modify PIN1 via conjugate addition, rather than disulfide exchange of the sulfonyl-acetate moiety. Altogether, such inhibitors would also be highly valuable molecular probes for further investigation of PIN1 regulation of NRF2 in the cellular context and potentially pave the way for drug molecules that specifically inhibit the cytoprotective effects of NRF2 in cancer.
  • [ X ]
    Öğe
    Selagibenzophenone B and Its Derivatives: SelB-1, a Dual Topoisomerase I/II Inhibitor Identified through In Vitro and In Silico Analyses
    (Amer Chemical Soc, 2024) Donmez, Serhat; Lapinskaite, Ringaile; Atalay, Hazal Nazlican; Tokay, Esra; Kockar, Feray; Rycek, Lukas; Ozbil, Mehmet
    The development of multitargeted drugs represents an innovative approach to cancer treatment, aiming to enhance drug effectiveness while minimizing side effects. Herein, we sought to elucidate the inhibitory effect of selagibenzophenone B derivatives on the survival of cancer cells and dual topoisomerase I/II enzyme activity. Results demonstrated that among the compounds, SelB-1 selectively inhibited the proliferation and migration of prostate cancer cells while exhibiting minimal effects on healthy cells. Furthermore, SelB-1 showed a dual inhibitory effect on topoisomerases. Computational analyses mirrored the results from enzyme inhibition assays, demonstrating the compound's strong binding affinity to the catalytic sites of the topoisomerases. To our surprise, SelB-1 did not induce apoptosis in prostate cancer cells; instead, it induced autophagic gene expression and lipid peroxidation while reducing GSH levels, which might be associated with ferroptotic death mechanisms. To summarize, the findings suggest that SelB-1 possesses the potential to serve as a dual topoisomerase inhibitor and can be further developed as a promising candidate for prostate cancer treatment.
  • [ X ]
    Öğe
    Strigolactone Analogs: Two New Potential Bioactiphores for Glioblastoma
    (Amer Chemical Soc, 2022) Antika, Gizem; Cinar, Zeynep Ozlem; Secen, Esma; Ozbil, Mehmet; Tokay, Esra; Kockar, Feray; Prandi, Cristina
    Strigolactones (SLs), carotenoid-derived phytohormones, control the plant response and signaling pathways for stressful conditions. In addition, they impact numerous cellular processes in mammalians and present new scaffolds for various biomedical applications. Recent studies demonstrated that SLs possess potent antitumor activity against several cancer cells. Herein, we sought to elucidate the inhibitory effects of SL analogs on the growth and survival of human brain tumor cell lines. Among four tested SLs, we showed for the first time that two lead bioactiphores, indanone-derived SL and EGO10, can inhibit cancer cell proliferation, induce apoptosis, and induce G1 cell cycle arrest at low concentrations. SL analogs were marked by increased expression of Bax/Caspase-3 genes and downregulation of Bcl-2. In silico studies were conducted to identify drug-likeness, blood-brain barrier penetrating properties, and molecular docking with Bcl-2 protein. Taken together, this study indicates that SLs may be promising antiglioma agents, presenting novel pharmacophores for further preclinical and clinical assessment.