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Öğe LFM-A13, a potent inhibitor of polo-like kinase, inhibits breast carcinogenesis by suppressing proliferation activity and inducing apoptosis in breast tumors of mice(Springer, 2018) Sahin, Kazim; Tuzcu, Mehmet; Yabas, Mehmet; Orhan, Cemal; Sahin, Nurhan; Ozercan, Ibrahim H.The goals of the present study were to define the anticancer activity of LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide), a potent inhibitor of Polo-like kinase (PLK), in a mouse mammary cancer model induced by 7,12-dimethylbenz(a)anthracene (DMBA) in vivo and explore its anticancer mechanism(s). We also examined whether the inhibition of PLK by LFM-A13 would improve the efficiency of paclitaxel in breast cancer growth in vivo. To do this, female BALB/c mice received 1 mg of DMBA once a week for 6 weeks with oral gavage. LFM-A13 (50 mg/kg body weight) was administered intraperitoneally with DMBA administration and continued for 25 weeks. We found that LFM-A13, paclitaxel, and their combination have a significant effect on the DMBA-induced breast tumor incidence, mean tumor numbers, average tumor weight, and size. At the molecular level, the administration of LFM-A13 hindered mammary gland carcinoma development by regulating the expression of PLK1, cell cycle-regulating proteins cyclin D1, cyclin dependent kinase-4 (CDK-4), and the CDK inhibitor, p21. Moreover, LFM-A 13 treatment upregulated the levels of I kappa B, the pro-apoptotic proteins Bax, and caspase-3, and down-regulated p53 and the antiapoptotic protein Bcl-2 in mammary tumors. The combination of LFM-A13 with paclitaxel was found to be more effective compared with either agent alone. Collectively, these results suggest that LFM-A13 has an anti-proliferative activity against breast cancer in vivo and that LFM-A13 and paclitaxel combination could be a strategy for the treatment of breast cancer.Öğe A Next Generation Formulation of Curcumin Ameliorates Experimentally Induced Osteoarthritis in Rats via Regulation of Inflammatory Mediators(Frontiers Media Sa, 2021) Yabas, Mehmet; Orhan, Cemal; Er, Besir; Tuzcu, Mehmet; Durmus, Ali Said; Ozercan, Ibrahim Hanifi; Sahin, NurhanOsteoarthritis (OA) is a chronic and debilitating disease of the knee joint. OA of the knee is initiated by physical damage and accumulated oxidative stress, followed by an exaggerated inflammation leading to cartilage damage. Currently, no effective and safe therapeutic option capable of restoring articular cartilage tissue and joint architecture is available. We here report a novel and highly bioavailable formulation of curcumin, labeled as Next Generation Ultrasol Curcumin (NGUC), which was 64.7 times more bioavailable than natural 95% curcumin extract as demonstrated in rat bioavailability studies. We further investigated the protective effect of NGUC against monosodium iodoacetate (MIA)-induced knee OA in rats. Analysis of X-ray and histopathological images revealed that NGUC supplementation restored joint architecture and reduced swelling of joints induced by MIA. NGUC treatment caused a significant reduction in the levels of inflammatory mediators such as TNF-alpha, IL-1 beta, IL-6, COMP, and CRP, and expressions of MMP-3, 5-LOX, COX-2, and NF kappa B in synovial tissue of rats with MIA-induced OA. NGUC also decreased serum MDA level and increased the levels of antioxidant enzymes SOD, CAT, and GPX. Thus, our results indicate that a novel formulation of curcumin with enhanced bioavailability effectively ameliorates the pathophysiology of OA.Öğe Phytochemical Profiling and Biological Activity of Achillea sintenisii Hub.-Mor(Wiley-V C H Verlag Gmbh, 2023) Eruygur, Nuraniye; Buyukyildirim, Tugsen; Tetik Rama, Seyma; Ayaz, Fatma; Tekin, Mehmet; Tuzcu, Mehmet; Akcakavak, GokhanAchillea (Asteraceae) species have been traditionally used for their different therapeutical properties. In this study, phytochemical composition of aerial parts of A. sintenisii which is endemic in Turkey was determined with Liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS). To evaluate the wound healing potential, the cream formulation prepared from A. sintenisii was tested on the linear incision wound model in mice. In vitro enzyme inhibitory activity tests were performed on elastase, hyaluronidase, and collagenase. In the histopathological examination, angiogenesis and granulation tissue formation were significantly increased in A. sintenisii treatment groups compared to the negative control group. As a result of this study, it is thought that the enzyme inhibition and antioxidant activity of the plant may contribute to the wound healing process. According to LC/MS/MS analysis result, quinic acid (24.261 mu g/mg extract) and chlorogenic acid (14.97 mu g/mg extract) were identified as main constituents of the extract.Öğe Prevention of DMBA-induced mammary gland tumors in mice by a dual-function inhibitor of JAK3 and EGF receptor tyrosine kinases(Taylor & Francis Ltd, 2020) Sahin, Kazim; Yabas, Mehmet; Orhan, Cemal; Tuzcu, Mehmet; Sahin, Taha K.; Ozercan, Ibrahim H.; Qazi, SanjiveObjectives: We tested the chemopreventive effect of WHI-P131 in side by side evaluation with the standard anti-breast cancer drug paclitaxel in the well-established 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer model. Methods: One hundred BALB/cmice were divided into five groups. (i) Control (ii) DMBA (iii) DMBA+ Paclitaxel (10 mg/kg) (iv) DMBA+WHI-P131 (Janex1, 50 mg/kg of BW, i.p, three times per week) (J) (v) DMBA+P+J. The duration of study was 25 weeks. Results: Our findings demonstrate that WHI-P131 impedes DMBA-induced carcinogenesis, reduces size, weight, and load of tumors (P < 0.001) in DMBA-challenged mice and improves their survival outcome (P < 0.01). The tumors developing despite WHI-P131 chemoprevention displayedattenuated levels of JAK3, STAT3, and NF-kappa B as well as increased I-kappa B expression (P < 0.001). Notably, these tumors exhibited significantly decreased levels of phosphorylated AKT-PI3-Kinase pathway signaling proteins p-mTOR, p-p70S6K1, and p-4E-BP1 (P < 0.001). Our findings are consistent with a model in which DMBA-induced malignant clones with low-level expression of the six signature proteins JAK3/STAT3/NF-kappa B/p-mTOR, p-p70S6K1/p-4E-BP1, albeit not as aggressive as their JAK3/STAT3/NF-kappa B overexpressing counterparts are capable of escaping chemo-preventive effects of WHI-P131. Conclusion: These insights may provide the foundation for new chemo-preventive strategies in which WHI-P131 is applied to prevent the development of aggressive forms of breast cancer.
