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- MakaleAçık Erişim2026Scopus SJRQ1A natural nephroprotective adjuvant for cancer chemotherapy: Rosmarinic acid disrupts IL-17 A-Ferroptosis coupling in Ifosfamide-induced renal injury
Süzen Celbek, Büşra; Şimşek, Hasan; Akaras, Nurhan; Kandemir, Özge; Kızıl, Hamit Emre; Mutlu, Hüseyin; Kandemir, Fatih Mehmet
Rosmarinic acid (RA) is a natural polyphenol with established pleiotropic protective effects. Ifosfamide (IFA) is a potent antineoplastic agent whose clinical utility is severely limited by dose-dependent nephrotoxicity, primarily mediated by its metabolite, chloroacetaldehyde (CAA). This study aimed to investigate whether RA protects against IFA-induced nephrotoxicity and to elucidate the underlying molecular mechanisms. Male Wistar albino rats (n = 7 per group) were allocated into four groups: Control, RA-only (50 mg/kg, p.o., 2 days), IFA-only (a single 500 mg/kg, i.p. dose), and IFA + RA. Serum biochemical markers (urea, creatinine), renal oxidative stress parameters (MDA, GSH, SOD, CAT, GPx), gene expression levels (NF-κB, TNF-α, IL-1β, IL-17 A, ACT1, TRAF6, Caspase-3, Bax, Bcl-2, PTGS2, GPX4, TfR1), and histopathological/immunohistochemical analyses (KIM-1, Nephrin, Caspase-3) were performed 24 h post-administration. IFA induced severe renal dysfunction, marked oxidative stress, and extensive histopathological damage. Mechanistically, IFA initiated a pathogenic cascade activating intrinsic apoptosis and ferroptosis, driven by a self-sustaining IL-17 A-TRAF6-NF-κB inflammatory loop. RA co-treatment (50 mg/kg) significantly reversed all functional, biochemical, and histological damage by strategically breaking this crosstalk, restoring redox homeostasis, and simultaneously restraining both cell death programs. In conclusion, RA protects against IFA nephrotoxicity by targeting the critical inflammation-ferroptosis coupling, positioning it as a highly promising adjuvant candidate for clinical use to mitigate IFA-induced renal injury.
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İncele - MakaleYalnız künye2026Scopus SJRQ3Synthesis and cytotoxic activity studies of novel heterocyclic thiosemicarbazone compounds as anticancer agents
Güllü, Eda; Hasanoğlu Özkan, Elvan; Kızıl, Hamit Emre; Nartop, Dilek
Herein, novel heterocyclic thiosemicarbazone compounds (Hb1, Hb2, Hb3) containing pyrimidine, imidazole, pyridine, and phenyl rings were synthesized via the condensation method as potential therapeutic agents for the treatment of non-small cell lung cancer. The structure of novel heterocyclic compounds was elucidated by using some spectroscopic techniques (organic elemental analysis, fourier transform infrared spectroscopy, proton/carbon nuclear magnetic resonance spectroscopy, scanning electron microscopy and energy dispersive X-ray image, and molar conductance measurement). The antiproliferative activity of novel heterocyclic thiosemicarbazone compounds using CVDK-8 cell viability assay. The viability assay was examined against A549 human non-small cell lung cancer cell line. All heterocyclic thiosemicarbazone compounds exhibited varying degrees of dose-dependent cytotoxic activity against A549 NSCLC cells. The results showed that the pyridine-based heterocyclic compound (Hb3) was the most potent antiproliferative agent, demonstrating a dose-dependent reduction in cell viability at concentrations of 50 µg/mL and higher.
- MakaleAçık Erişim2026Scopus SJRQ2Synthesis and pharmacokinetic profiling of a novel pyrimidine imidazole based thiosemicarbazone derivative for BRAF inhibition in lung cancer therapy
Ekincioğlu, Yavuz; Kızıl, Hamit Emre; Güllü, Eda; Özkan, Elvan Hasanoğlu; Nartop, Dilek
This study presents the design, synthesis, and comprehensive evaluation of a novel thiosemicarbazone derivative containing a pyrimidine-imidazole (C11H11N8SCl) as a potential BRAF inhibitor for the treatment of non-small cell lung cancer. The compound was synthesized by a condensation reaction and characterized by elemental analysis, molar conductivity, SEM-EDS, FT-IR, 1H, and 13C-NMR spectral techniques. DFT calculations at the B3LYP/6-311 + + G(d, p) level revealed a HOMO-LUMO gap of 2.8 eV, indicating appropriate molecular stability and reactivity. Molecular docking studies with BRAF (PDB ID: 1UWH) demonstrated favorable binding affinity (-6.85 kcal/mol) with key interactions at ILE512, HIS509, HIS584, GLN529, GLU585, LYS590, VAL510, and LEU587 residues. In vitro cytotoxicity assays revealed that the compound possesses anticancer potential against H-460 cells, with a significant inhibitory effect observed at a concentration of 200 µg/mL. Combined with its favorable binding affinity toward BRAF kinase, these results suggest that the pyrimidine-imidazole thiosemicarbazone may serve as a potential lead scaffold for further development in targeted lung cancer therapy.ADME profiling confirmed the compound’s compliance with Lipinski’s rule of five parameters, supporting its potential as an orally active drug candidate. These findings suggest that our pyrimidine-imidazole thiosemicarbazone represents a promising scaffold for the development of targeted BRAF inhibitors for lung cancer therapy.
- MakaleYalnız künye2026Scopus SJRQ2Multi-Pathway Renoprotection by Betanin Against Docetaxel Nephrotoxicity: Modulation of Inflammation, ER Stress, Apoptosis, and Ferroptosis
Süzen Celbek, Büşra; Akaras, Nurhan; Şimşek, Hasan; Mutlu, Hüseyin; Kızıl, Hamit Emre; Kandemir, Özge; Aygörmez, Serpil; Kandemir, Fatih Mehmet
Docetaxel (DTX), a cornerstone chemotherapeutic agent, has its clinical utility significantly limited by dose-dependent nephrotoxicity. This study investigated the multi-pathway renoprotective mechanisms of betanin (BTN), a natural antioxidant derived from beetroot, against DTX-induced kidney injury. Male Wistar rats received DTX (30 mg/kg, i.p., single dose) with or without BTN (100 mg/kg/day, p.o.) for 7 days. DTX induced severe renal dysfunction with elevated serum urea and creatinine, and significant oxidative stress characterized by increased MDA and decreased GSH, GPx, SOD, and CAT. Molecular analysis demonstrated widespread upregulation of pro-inflammatory (NF-κB, TNF-α, IL-1β), endoplasmic reticulum stress (PERK, ATF6), pro-apoptotic (Caspase-3, Bax, Apaf-1), and pro-ferroptotic (PTGS2, TfR1) mediators, with concurrent downregulation of protective Bcl-2 and GPx4. Histopathological examination revealed extensive tubular injury, while immunohistochemical analysis showed markedly increased kidney injury marker KIM-1 and decreased aquaporin-1 expression. Remarkably, BTN co-administration significantly attenuated all biochemical, molecular, and structural derangements, restored tissue architecture, and normalized KIM-1 and AQP-1 expression. In conclusion, betanin provides robust, multi-pathway renoprotection against docetaxel-induced nephrotoxicity by concurrently targeting oxidative stress, inflammation, ER stress, apoptosis, and ferroptosis.
- MakaleAçık Erişim2025Scopus SJRQ2An Integrated In Vitro and In Silico Investigation of the Bioactive Properties of Wild Glycyrrhiza glabra var. glandulifera
Kızıl, Hamit Emre; Ulcay, Sibel; Ekincioğlu, Yavuz; Öğütçü, Hatice; Ağar, Güleray
This investigation examined methanol extracts obtained from the whole plant (encompassing all organs except roots), flowers, and fruits of wild Glycyrrhiza glabra var. glandulifera, a liquorice cultivar indigenous to the Cappadocia region of Türkiye, constituting the first comprehensive in vitro and in silico analysis of this species within the region. Anatomical identification revealed distinctive structural characteristics, including thick-walled epidermal cells in the stem, organized clusters of collenchyma cells, and well-defined sclerenchyma layers encompassing the vascular bundles. The petiole exhibited a characteristic heart-shaped morphology containing three vascular bundles, while foliar analysis demonstrated the presence of stomata on both adaxial and abaxial surfaces, accompanied by a bifacial mesophyll arrangement. The extracts demonstrated remarkable antimicrobial efficacy against both Gram-positive and Gram-negative bacteria, as well as various fungal species. Furthermore, significant cytotoxic activity was observed against non-small cell lung cancer (H460), with the whole plant extract exhibiting IC50 values of 117.8 µg/mL (24 h) and 105.6 µg/mL (48 h). Flower extracts demonstrated IC50 values of 116.8 µg/mL (24 h) and 112.7 µg/mL (48 h), while fruit extracts displayed superior potency with IC50 values of 104.4 µg/mL (24 h) and 63.09 µg/mL (48 h). Molecular docking analyses, conducted utilizing AutoDock Tools 1.5.6 and BIOVIA Discovery Studio Visualizer 4.5, revealed significant protein-ligand interactions, yielding optimal binding energy and inhibition constant values of -9.57 kcal/mol and 96.92 nM, respectively. The RMSD values were calculated based on structural variations between ligand-protein complexes during re-docking procedures. These findings underscore the substantial biological potential of Glycyrrhiza glabra var. glandulifera from Cappadocia, necessitating further comprehensive investigation.
AtıfScopus6WoS6OpenAlex5İncele - MakaleAçık Erişim2025Scopus SJRQ1Pharmacological Potential and Bioactive Components of Wild Anatolian Sage (Salvia aethiopis L.)
Bilginoğlu, Emine; Kızıl, Hamit Emre; Öğütcü, Hatice; Ağar, Güleray; Bağcı, Yavuz
Salvia aethiopis L., a member of the Lamiaceae family, has gained attention due to its bioactive compounds with potential therapeutic applications. This study investigated the chemical composition and biological activities of S. aethiopis ethanol extract collected from Karaman province, Türkiye. The phenolic profile of the plant was characterized using LC–MS/MS analysis, which revealed substantial amounts of rosmarinic acid, ferulic acid, caffeic acid, and p-coumaric acid. The antimicrobial activity of the extracts was evaluated against various Gram-positive and Gram-negative bacteria, as well as fungal strains, using the agar well diffusion method. The results demonstrated potent antibacterial effects, particularly against Staphylococcus aureus, Micrococcus luteus, and Klebsiella pneumoniae. Furthermore, the cytotoxic potential of S. aethiopis was assessed on H-460 non-small cell lung cancer cells. The extract exhibited a dose-dependent cytotoxic effect, with a significant reduction in cell viability after 24 and 48 h of treatment, yielding IC50 values of 80.08 and 56.19 μg/mL, respectively. These findings suggest that S. aethiopis possesses promising antimicrobial and anticancer properties, which could contribute to the development of novel therapeutic agents.
AtıfScopus8WoS7OpenAlex7İncele - MakaleAçık Erişim2025Scopus SJRQ1Dietary Carvacrol Attenuates Cyclophosphamide-Induced Neurotoxicity: Implications for Food-Derived Neuroprotection and Molecular Mechanisms
Kızıl, Hamit Emre
Carvacrol (CRV) is a phenolic monoterpene abundant in culinary herbs such as oregano and thyme and is well known for its potent antioxidant, anti-inflammatory, and neuroprotective properties. This study investigated the ability of CRV to counteract neurotoxicity induced by cyclophosphamide (CP), a widely used antineoplastic agent. Male Wistar albino rats were divided into five groups and received CP and/or CRV treatments. Neurotoxicity and neuroprotection were evaluated through biochemical assays, real-time PCR, histopathological and immunohistochemical analyses, and behavioral testing (Morris Water Maze). CP administration led to significant increases in oxidative stress markers, disruption of antioxidant enzyme activities, upregulation of inflammatory mediators (NF-κB, TNF-α, iNOS), dysregulation of apoptotic regulators (increased Bax and Casp-3, decreased Bcl-2), alterations in autophagy markers (Beclin-1, LC3A, LC3B), and suppression of Notch1/Hes1 signaling. Histopathological analyses revealed neuronal degeneration, vascular hyperemia, and increased GFAP and 8-OHdG expression in brain tissue. CRV treatment, particularly at higher doses, effectively mitigated these biochemical, molecular, and histological alterations. Notably, CRV administration preserved spatial learning and memory function in CP-treated rats, as demonstrated by the Morris Water Maze test, indicating functional neuroprotection. These findings highlight the multifaceted neuroprotective mechanisms of CRV and suggest its potential as a food-derived bioactive compound for development into functional foods or dietary supplements to improve the quality of life for cancer patients undergoing chemotherapy.
AtıfScopus10WoS9OpenAlex11İncele - MakaleAçık Erişim2023Scopus SJRQ2Morin ameliorates methotrexate-induced hepatotoxicity via targeting Nrf2/HO-1 and Bax/Bcl2/Caspase-3 signaling pathways
Kızıl, Hamit Emre; Caglayan, Cuneyt; Darendelioğlu, Ekrem; Ayna, Adnan; Gür, Cihan; Kandemir, Fatih Mehmet; Küçükler, Sefa
Background: Organ toxicity limits the therapeutic efficacy of methotrexate (MTX), an anti-metabolite therapeutic that is frequently used as an anti-cancer and immunosuppressive medicine. Hepatocellular toxicity is among the most severe side effects of long-term MTX use. The present study unveils new confirmations as regards the remedial effects of morin on MTX-induced hepatocellular injury through regulation of oxidative stress, apoptosis and MAPK signaling. Methods and results: Rats were subjected to oral treatment of morin (50 and 100 mg/kg body weight) for 10 days. Hepatotoxicity was induced by single intraperitoneal injection of MTX (20 mg/kg body weight) on the 5th day. MTX related hepatic injury was associated with increased MDA while decreased GSH levels, the activities of endogen antioxidants (glutathione peroxidase, superoxide dismutase and catalase) and mRNA levels of HO-1 and Nrf2 in the hepatic tissue. MTX treatment also resulted in apoptosis in the liver tissue via increasing mRNA transcript levels of Bax, caspase-3, Apaf-1 and downregulation of Bcl-2. Conversely, treatment with morin at different doses (50 and 100 mg/kg) considerably mitigated MTX-induced oxidative stress and apoptosis in the liver tissue. Morin also mitigated MTX-induced increases of ALT, ALP and AST levels, downregulated mRNA expressions of matrix metalloproteinases (MMP-2 and MMP-9), MAPK14 and MAPK15, JNK, Akt2 and FOXO1 genes. Conclusion: According to the findings of this study, morin may be a potential way to shield the liver tissue from the oxidative damage and apoptosis.
AtıfScopus74WoS71OpenAlex82İncele - MakaleAçık Erişim2020Synthesis of novel polymers containing Schiff base as potential antimutagenic and antimicrobial agents
Nartop, Dilek; Tokmak, Erkan; Özkan, Elvan Hasanoğlu; Kızıl, Hamit Emre; Öğütcü, Hatice; Ağar, Güleray; Allı, Sema
In this research study, two novel polymers including Schiff base were prepared by condensation reaction of polystyrene-A-NH2 with 5-nitro-2-thiophenecarboxaldehyde/or 5-(2-nitrophenyl)-2-furancarboxaldehyde. The synthesized polymers were evaluated using the elemental analysis, infrared spectroscopy (IR), gel permeation chromatography (GPC), thermal gravimetric analysis (TG/DTA). In addition, the antimicrobial and antimutagenic study of the polymers were reported. The antibacterial and antifungal activity were investigated using the diffusion method against pathogenic bacterial strains. PA-TC and PA-FC polymers exhibited the highest antimicrobial activity against the S. typhi H. and P. vulgaris, respectively. PA-FC polymer revealed the highest antifungal activity against C. albicans. The antimutagenic effects were evaluated using the sister chromatid exchange (SCE) and micronucleus (MN) methods against the sodium azide (NaN3) in human lymphocyte cells. The results demonstrated that the PA-FC polymer have strong antimutagenic properties, especially in the concentration of 20 µg/mL.
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