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Book Part Citation - Scopus: 6Cannabinoids as Prospective Anti-Cancer Drugs: Mechanism of Action in Healthy and Cancer Cells(Springer, 2023) Boyacıoğlu,Ö.; Korkusuz,P.Endogenous and exogenous cannabinoids modulate many physiological and pathological processes by binding classical cannabinoid receptors 1 (CB1) or 2 (CB2) or non-cannabinoid receptors. Cannabinoids are known to exert antiproliferative, apoptotic, anti-migratory and anti-invasive effect on cancer cells by inducing or inhibiting various signaling cascades. In this chapter, we specifically emphasize the latest research works about the alterations in endocannabinoid system (ECS) components in malignancies and cancer cell proliferation, migration, invasion, angiogenesis, autophagy, and death by cannabinoid administration, emphasizing their mechanism of action, and give a future perspective for clinical use. © 2022, The Author(s), under exclusive license to Springer Nature Switzerland AG.Article Effects of Pomegranate Seed Oil on Lower Extremity Ischemia-Reperfusion Damage: Insights into Oxidative Stress, Inflammation, and Cell Death(MDPI, 2025) Bozok, Ummu Gulsen; Ergorun, Aydan Iremnur; Kucuk, Aysegul; Yigman, Zeynep; Dursun, Ali Dogan; Arslan, MustafaAim: This study sought to clarify the therapeutic benefits and mechanisms of action of pomegranate seed oil (PSO) in instances of ischemia–reperfusion (IR) damage in the lower extremities. Materials and Methods: The sample size was determined, then 32 rats were randomly allocated to four groups: Control (C), ischemia–reperfusion (IR), low-dose PSO (IR + LD, 0.15 mL/kg), and high-dose PSO (IR + HD, 0.30 mL/kg). The ischemia model in the IR group was established by occluding the infrarenal aorta for 120 min. Prior to reperfusion, PSO was delivered to the IR + LD and IR + HD groups at doses of 0.15 mL/kg and 0.30 mL/kg, respectively, followed by a 120 min reperfusion period. Subsequently, blood and tissue specimens were obtained. Statistical investigation was executed utilizing Statistical Package for the Social Sciences version 20.0 (SPSS, IBM Corp., Armonk, NY, USA). Results: Biochemical tests revealed significant variations in total antioxidant level (TAS), total oxidant level (TOS), and the oxidative stress index (OSI) across the groups (p < 0.0001). The IR group had elevated TOS and OSI levels, whereas PSO therapy resulted in a reduction in these values (p < 0.05). As opposed to the IR group, TASs were higher in the PSO-treated groups. Histopathological analysis demonstrated muscle fiber degeneration, interstitial edema, and the infiltration of cells associated with inflammation in the IR group, with analogous results noted in the PSO treatment groups. Immunohistochemical analysis revealed that the expressions of Tumor Necrosis Factor-alpha (TNF-α), Nuclear Factor kappa B (NF-κB), cytochrome C (CYT C), and caspase 3 (CASP3) were elevated in the IR group, while PSO treatment diminished these markers and attenuated inflammation and apoptosis (p < 0.05). The findings demonstrate that PSO has a dose-dependent impact on IR injury. Discussion: This research indicates that PSO has significant protective benefits against IR injury in the lower extremities. PSO mitigated tissue damage and maintained mitochondrial integrity by addressing oxidative stress, inflammation, and apoptotic pathways. Particularly, high-dose PSO yielded more substantial enhancements in these processes and exhibited outcomes most comparable to the control group in biochemical, histological, and immunohistochemical investigations. These findings underscore the potential of PSO as an efficacious natural treatment agent for IR injury. Nevertheless, additional research is required to articulate this definitively.Article Citation - WoS: 4Citation - Scopus: 4Anticancer Investigation of Platinum and Copper-Based Complexes Containing Quinoxaline Ligands(Elsevier, 2022) El-Beshti, Hager Sadek; Yildizhan, Yasemin; Kayi, Hakan; Cetin, Yuksel; Adiguzel, Zelal; Gungor-Topcu, Gamze; Ozalp-Yaman, SenizThis research focuses on synthesis and anticancer activity of trans-[(dichloro)bisdipyridlquinoxalino] and [(dichloro)bisdithienylquinoxalino]copper(II)/platinum(II) compounds as prodrug candidates. The binding interaction of these compounds with calf thymus DNA (CT-DNA) and human serum albumin (HSA) of the complexes were assessed with UV titration, thermal decomposition, viscometric, and fluorometric measurements. The nature of the binding of the complexes on DNA were revealed as electrostatic interaction between the cationic metal complexes ion and the negative phosphate groups of CT-DNA upon removal of the counter ion, chloride. In addition, our complexes induced a surface contact through the hydrophobic region of protein. Antitumor activity of the complexes against human glioblastoma A172, LN229, and U87 cell lines and human lung A549, human breast MDA-231, human cervix HeLa, and human prostate PC-3 cell lines were investigated by examining cell viability, oxidative stress, apoptosis, and migration/invasion. Cytotoxicity of the complexes was evaluated by MTT test. The U87 and HeLa cells were investigated as the cancer cells most sensitive to our complexes. The exerted cytotoxic effect of dipyridlquinoxalino and dithienylquinoxalino copper(II)/platinum(II) complexes was attributed to the formation of the reactive oxygen species in vitro. It is clearly demonstrated that trans-[(dichloro)bisdithenylquinoxalino]copper (II) (Cu(dtq)) has the highest DNA degradation potential and anticancer effect among the tested complexes by leading apoptosis. Wound healing and invasion analysis results also supported the anticancer activity of Cu(dtq). (C) 2021 Elsevier B.V. All rights reserved.Doctoral Thesis Kinoksalin Ligantları İçeren Yeni Antıtumor Aktif Bakır ve Platin Temelli Komplekslerin Tasarımı, Sentezi ve Biyolojik Aktiviteleri(2022) Elbeshtı, Hager Sader; Yaman, Şeniz ÖzalpBugün dünya genelinde kanser en önde gelen ölüm sebebidir. Bu nedenle biyotıp ve sağlık bilimlerinde daha iyi ve güncel antineoplastik ajanlar geliştirilmesi büyük bir önem taşımaktadır. Metal temelli ilaçların kanserle savaşmak için yüksek bir potansiyele sahip olduğu bilinmektedir. Elde edilen verilerin ışığında yapılan bu araştırma ön ilaç adayı olarak (2,3-di-piridin-2-il-kinoksalin) (dpq), (2,3-di-tiyenyl-2-il-kinoksalin) (dtq), (2,3,2',3'-tetra-piridin-2-il-[6,6']bikinoksalin) (tpbq) ve (2,3,2',3'-tetra-tiyenyl-2-il-[6,6']bikinoksalin) içeren bakır(II)/platin(II) bileşiklerinin sentezi ve antikanser aktivitelerini hedeflemektedir. Sentezlenen bileşiklerin buzağı timus DNA'sı (CT-DNA) ve insan serum albümini (HSA) ile bağlanma etkileşimleri UV titrasyonu, termal bozunma, viskometrik ve florometrik ölçümlerle değerlendirilmiştir. Yapılan çalışmalar sonucunda Pt(tpbq)Cl2, Pt(ttbq)Cl2 ve Cu(tpbq)Cl2 dışında sentezlenen tüm komplekslerin CT-DNA'ya elektrostatik etkileşim ile bağlandığı, bu etkileşimin komplekslerde yer alan oynak klor iyonlarının yapıdan uzaklaşması ile oluşan kompleks katyon ile CT-DNA'nın negatif fosfat grupları arasındaki elektrostatik çekimden kaynaklanabileceği öngörülmüştür. Pt(tpbq)Cl2, Pt(ttbq)Cl, ve Cu(tpbq)Cl2 komplekslerinin ise CT-DNA ile van der Waals ve hydrogen bağı oluşturduğu sonucuna varılmıştır. Ayrıca, komplekslerin HSA'nın higroskopik bölgesine tutunduğu gözlenmiştir. Komplekslerin antitümör aktiviteleri, insan glioblastoma A172, LN229 ve U87 hücre hatları, insan akciğer A549, insan meme MDA-231, insan serviks HeLa ve insan prostat PC-3 hücre hatlarında çalışılmıştır. Hücre canlılığı (MTT), oksidatif stres, apoptoz –TUNAL, in vitro-hücre göç ve istila, in vitro-Komet DNA hasar ve plazmit DNA etkileşim testleri gerçekleştirilmiştir. Sürdürülen çalışmalar sonucunda U87 ve HeLa hücreleri, komplekslerimize en duyarlı kanser hücreleri olarak belirlenmiştir. Komplekslerin sitotoksik etkilerinin bu hücre hatlarında meydana getirdikleri reaktif oksijen türlerinin oluşumudan kaynaklandığı ve Cu(dtq)2Cl2, Cu(ttbq)Cl2, Pt(ttbq)Cl2 ve Pt(tpbq)Cl2'nin test edilen kompleksler arasında apoptoz yoluyla en yüksek DNA degradasyonu potansiyeline ve antikanser etkisine sahip olduğu gösterilmiştir. Yara iyileşmesi ve istila analizi sonuçları da bu kompleklserin yüksek antikanser aktivitesini destekler niteliktedir.Article Citation - WoS: 2Citation - Scopus: 2Antiproliferative Activity of Platinum(ii) and Copper(ii) Complexes Containing Novel Biquinoxaline Ligands(Oxford Univ Press, 2024) El-Beshti, Hager Sadek; Gercek, Zuhal; Kayi, Hakan; Yildizhan, Yasemin; Cetin, Yuksel; Adiguzel, Zelal; Ozalp-Yaman, SenizNowadays, cancer represents one of the major causes of death in humans worldwide, which renders the quest for new and improved antineoplastic agents to become an urgent issue in the field of biomedicine and human health. The present research focuses on the synthesis of 2,3,2MODIFIER LETTER PRIME,3MODIFIER LETTER PRIME-tetra(pyridin-2-yl)-6,6MODIFIER LETTER PRIME-biquinoxaline) and (2,3,2MODIFIER LETTER PRIME,3MODIFIER LETTER PRIME-tetra(thiophen-2-yl)-6,6MODIFIER LETTER PRIME-biquinoxaline) containing copper(II) and platinum(II) compounds as prodrug candidates. The binding interaction of these compounds with calf thymus DNA (CT-DNA) and human serum albumin were assessed with UV titration, thermal decomposition, viscometric, and fluorometric methods. The thermodynamical parameters and the temperature-dependent binding constant (KMODIFIER LETTER PRIMEb) values point out to spontaneous interactions between the complexes and CT-DNA via the van der Waals interactions and/or hydrogen bonding, except Cu(ttbq)Cl2 for which electrostatic interaction was proposed. The antitumor activity of the complexes against several human glioblastomata, lung, breast, cervix, and prostate cell lines were investigated by examining cell viability, oxidative stress, apoptosis-terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, in vitro migration and invasion, in vitro-comet DNA damage, and plasmid DNA interaction assays. The U87 and HeLa cells were investigated as the cancer cells most sensitive to our complexes. The exerted cytotoxic effect of complexes was attributed to the formation of the reactive oxygen species in vitro. It is clearly demonstrated that Cu(ttbq)Cl2, Pt(ttbq)Cl2, and Pt(tpbq)Cl2 have the highest DNA degradation potential and anticancer effect among the tested complexes by leading apoptosis. The wound healing and invasion analysis results also supported the higher anticancer activity of these two compounds. Graphical Abstract Antitumor activity of biqunoxaline complexes.
