Elsevier Acta Medica Okayama 18785352 14 3 2021 New metal complexes derived from diacetylmonoxime-n(4)antipyrinylthiosemicarbazone: Synthesis, characterization and evaluation of antitumor activity against Ehrlich solid tumors induced in mice 102993 EN Bishoy El-Aarag Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University Fathy El-Saied Department of Chemistry, Faculty of Science, Menoufia University Tarek Salem Department of Biochemistry, College of Medicine, Qassim University Nesrin Khedr Department of Chemistry, Faculty of Science, Menoufia University Shaden A.M. Khalifa Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University Hesham R. El-Seedi Department of Chemistry, Faculty of Science, Menoufia University The present study aimed to synthesize new metal complexes of diacetylmonoxime-N(4)antipyrinylthiosemicarbazone ligand and evaluate their antitumor activity. New complexes with ferric, cobalt, nickel and copper ions were prepared. Elemental, 1H Nuclear magnetic resonance, Mass spectroscopy, Electron paramagnetic resonance, Fourier Transform InfraredSpectroscopy, Ultraviolet–visible and thermal gravimetricanalysis were used to characterize the obtained complexes 1–11. An in vivo tumor model was established to investigate the effect of the naked ligand and its metal complexes 2, 5 and 8. Ehrlich ascites carcinoma solid tumor was induced in mice through subcutaneous inoculation of Ehrlich ascites carcinoma cells. The volumes of the formed solid tumors, the alanine transaminase, aspartate transaminase, albumin concentration in the serum, as well as the levels of Ki67 and p53 proteins in tumor and liver tissues were detected. All the tested complexes, especially complex 5, possessed proliferative inhibition manifested as the reduction of the tumor volume, Alanine aminotransferase & Aspartate aminotransferase activity, and the level of the Ki67 protein. Additionally, they restored the albumin concentration to normal levels as well increased the level of pro-apoptotic p53 protein. In conclusion, the antitumor activity of the newly synthesized metal complexes against Ehrlich ascites carcinoma solid tumors was proved to be mediated by the inhibition of Ki67 and induction of p53 proteins. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1420-3049 24 13 2019 Alpinia zerumbet (Pers.): Food and Medicinal Plant with Potential In Vitro and In Vivo Anti-Cancer Activities 2495 EN Maram Hussein Zahra Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University Tarek A. R. Salem Department of Biochemistry, College of Medicine, Qassim University Bishoy El-Aarag Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University Nermeen Yosri Department of Chemistry, Faculty of Science, Menoufia University Samah EL-Ghlban Biochemistry Division, Chemistry Department, Faculty of Science, Menoufia University Kholoud Zaki Department of Chemistry, Faculty of Science, Menoufia University Amel H. Marei Department of Chemistry, Faculty of Science, Menoufia University Aida Abd El-Wahed Department of Chemistry, Faculty of Science, Menoufia University Aamer Saeed Department of Chemistry, Quaid-i-Azam University Alfi Khatib Department of Pharmaceutical Chemistry, Faculty of Pharmacy, International Islamic University Malaysia Mohamed F. AlAjmi Pharmacognosy Group, College of Pharmacy, King Saud University Abdulrahman M. Shathili Al-Rayan Research and Innovation Center, Al-Rayan Colleges Jianbo Xiao Institute of Chinese Medical Sciences, University of Macau Shaden A. M. Khalifa Clinical Research Centre, Karolinska University Hospital Hesham R. El-Seedi Department of Chemistry, Faculty of Science, Menoufia University BACKGROUND/AIM:Plants play an important role in anti-cancer drug discovery, therefore, the current study aimed to evaluate the biological activity of Alpinia zerumbet (A. zerumbet) flowers.<br/> METHODS:The phytochemical and biological criteria of A. zerumbet were in vitro investigated as well as in mouse xenograft model.<br/> RESULTS:A. zerumbet extracts, specially CH2Cl2 and MeOH extracts, exhibited the highest potent anti-tumor activity against Ehrlich ascites carcinoma (EAC) cells. The most active CH2Cl2 extract was subjected to bioassay-guided fractionation leading to isolatation of the naturally occurring 5,6-dehydrokawain (DK) which was characterized by IR, MS, 1H-NMR and 13C-NMR. A. zerumbet extracts, specially MeOH and CH2Cl2 extracts, exhibited significant inhibitory activity towards tumor volume (TV). Furthermore, A. zerumbet extracts declined the high level of malonaldehyde (MDA) as well as elevated the levels of superoxide dismutase (SOD) and catalase (CAT) in liver tissue homogenate. Moreover, DK showed anti-proliferative action on different human cancer cell lines. The recorded IC50 values against breast carcinoma (MCF-7), liver carcinoma (Hep-G2) and larynx carcinoma cells (HEP-2) were 3.08, 6.8, and 8.7 µg/mL, respectively.<br/> CONCLUSION:Taken together, these findings open the door for further investigations in order to explore the potential medicinal properties of A. zerumbet. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1420-3049 24 18 2019 Synthesis, Characterization, and In Vivo Anti-Cancer Activity of New Metal Complexes Derived from Isatin-N(4)antipyrinethiosemicarbazone Ligand Against Ehrlich Ascites Carcinoma Cells EN Fathy El-Saied Department of Chemistry, Faculty of Science, Menoufia University Bishoy El-Aarag Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University Tarek Salem Department of Molecular Biology, Genetic Engineering & Biotechnology Institute, University of Sadat City Ghada Said Department of Chemistry, Faculty of Science, Menoufia University Shaden A. M. Khalifa Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University Hesham R. El-Seedi Department of Chemistry, Faculty of Science, Menoufia University The current study aimed to synthesize new metal coordination complexes with potential biomedical applications. Metal complexes were prepared via the reaction of isatin-N(4)anti- pyrinethiosemicarbazone ligand 1 with Cu(II), Ni(II), Co(II), Zn(II), and Fe(III) ions. The obtained metal complexes 2–12 were characterized using elemental, spectral (1H-NMR, EPR, Mass, IR, UV-Vis) and thermal (TGA) techniques, as well as magnetic moment and molar conductance measurements. In addition, their geometries were studied using EPR and UV–Vis spectroscopy. To evaluate the in vivo anti-cancer activities of these complexes, the ligand 1 and its metal complexes 2, 7 and 9 were tested against solid tumors. The solid tumors were induced by subcutaneous (SC) injection of Ehrlich ascites carcinoma (EAC) cells in mice. The impact of the selected complexes on the reduction of tumor volume was determined. Also, the expression levels of vascular endothelial growth factor (VEGF) and cysteine aspartyl-specific protease-7 (caspase-7) in tumor and liver tissues of mice bearing EAC tumor were determined. Moreover, their effects on alanine transaminase (ALT), aspartate transaminase (AST), albumin, and glucose levels were measured. The results revealed that the tested compounds, especially complex 9, reduced tumor volume, inhibited the expression of VEGF, and induced the expression of caspase-7. Additionally, they restored the levels of ALT, AST, albumin, and glucose close to their normal levels. Taken together, our newly synthesized metal complexes are promising anti-cancer agents against solid tumors induced by EAC cells as supported by the inhibition of VEGF and induction of caspase-7. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1422-0067 20 20 2019 Protective Effects of Flavone from Tamarix aphylla against CCl4-Induced Liver Injury in Mice Mediated by Suppression of Oxidative Stress, Apoptosis and Angiogenesis EN Bishoy El-Aarag Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University Asmaa Khairy Chemistry Department, Faculty of Science, Menoufia University Shaden A. M. Khalifa Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University Hesham R. El-Seedi Chemistry Department, Faculty of Science, Menoufia University The current study aimed to investigate, for the first time, the beneficial effects of 3,5-dihydroxy-4′,7-dimethoxyflavone isolated from Tamarix aphylla L. against liver injury in mice. Liver injury was induced by intraperitoneal (i.p.) injection of carbon tetrachloride (CCl4) at a dose of 0.4 mL/kg mixed in olive oil at ratio (1:4) twice a week for 6 consecutive weeks. The administration of CCl4 caused significant histopathological changes in liver tissues while the pre-treatment with the flavone at dose of 10 and 25 mg/kg ameliorated the observed liver damages. Also, it markedly reduced hepatic malondialdehyde (MDA) level as well as increased the activities of liver superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (Gpx) compared with their recorded levels in CCl4 model group. Moreover, the immunohistochemical analysis demonstrated the enhancement in the protein level of B-cell lymphoma-2 (Bcl-2) while the protein levels of cysteine-aspartic acid protease-3 (caspase-3), Bcl-2-associated x protein (Bax), transforming growth factor-β1 (TGF-β1) and CD31 were suppressed following the flavone treatement. These results suggest that the flavone can inhibit liver injury induced in mice owning to its impact on the oxidation, apoptotic and angiogenesis mechanisms. Further pharmacological investigations are essential to determine the effectiveness of the flavone in human. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1420-3049 24 8 2019 Melittin Exerts Beneficial Effects on Paraquat-Induced Lung Injuries in Mice by Modifying Oxidative Stress and Apoptosis EN Bishoy El-Aarag Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University Mohamed Magdy Department of Chemistry, Faculty of Science, Menoufia University Mohamed F. AlAjmi Department of Pharmacognosy, College of Pharmacy, King Saud University Shaden A. M. Khalifa Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University Hesham R. El-Seedi Department of Chemistry, Faculty of Science, Menoufia University Melittin (MEL) is a 26-amino acid peptide with numerous biological activities. Paraquat (PQ) is one of the most widely used herbicides, although it is extremely toxic to humans. To date, PQ poisoning has no effective treatment, and therefore the current study aimed to assess for the first time the possible effects of MEL on PQ-induced lung injuries in mice. Mice received a single intraperitoneal (IP) injection of PQ (30 mg/kg), followed by IP treatment with MEL (0.1 and 0.5 mg/kg) twice per week for four consecutive weeks. Histological alterations, oxidative stress, and apoptosis in the lungs were studied. Hematoxylin and eosin (H&E) staining indicated that MEL markedly reduced lung injuries induced by PQ. Furthermore, treatment with MEL increased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity, and decreased malonaldehyde (MDA) and nitric oxide (NO) levels in lung tissue homogenates. Moreover, immunohistochemical staining showed that B-cell lymphoma-2 (Bcl-2) and survivin expressions were upregulated after MEL treatment, while Ki-67 expression was downregulated. The high dose of MEL was more effective than the low dose in all experiments. In summary, MEL efficiently reduced PQ-induced lung injuries in mice. Specific pharmacological examinations are required to determine the effectiveness of MEL in cases of human PQ poisoning. No potential conflict of interest relevant to this article was reported.