Ghareeb Mosad A, Sobeh Mansour, El-Maadawy Walaa H, Mohammed Hala Sh, Khalil Heba, Botros Sanaa, Wink Michael
Medicinal Chemistry Department, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba (P.O. 30), Giza 12411, Egypt.
Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, 44883-2462 Heidelberg, Germany.
Antioxidants (Basel). 2019 Sep 19;8(9):415. doi: 10.3390/antiox8090415.
Cyclophosphamide (CP) is a potent anti-neoplastic and immunosuppressive agent; however, it causes multi-organ toxicity. We elucidated the protective activities of (EG) leaf extract against CP-induced hepato-renal toxicity. Mice were treated with EG for 15 days plus CP on day 12 and 13 of the experiment. Using HPLC-DAD-ESI-MS/MS, 26 secondary metabolites were identified in EG leaf extract. Out of them, 4 polyphenolic compounds were isolated: (1) 4-(-β-d-xylopyranosyloxy)-3,5-di-hydroxy-benzoic acid, (2) 4-(-α-l-rhamnopyranosyloxy)-3,5-di-hydroxy-benzoic acid, (3) gallic acid, and (4) methyl gallate. Effects of EG extract on biochemical parameters, gene expression, and immune-histopathological changes were assessed in comparison to mesna positive control. Results showed that EG improved CP-increased serum ALT, AST, creatinine, and blood urea nitrogen levels. The hepatic and renal tissue levels of MDA, nitric oxide, protein carbonyl, TNF-α, IL-6, and immunohistochemical expression of nuclear factor kappa-B (NF-kB) and caspase-3 were reduced. Also, hepatic and renal GSH contents, and nuclear factor E2-related factor 2 (NRf2)/ hemoxygenase-1 (HO-1) signaling levels were increased. Histopathological findings supported our findings where hepatic and renal architecture were almost restored. Results revealed the protective effects of EG against CP-induced hepato-renal toxicity. These effects may be related to EG antioxidant, anti-inflammatory, and anti-apoptotic properties coupled with activation of Nrf2/HO-1 signaling.
环磷酰胺（CP）是一种强效抗肿瘤和免疫抑制剂；然而，它会导致多器官毒性。我们阐明了（EG）叶提取物对CP诱导的肝肾毒性的保护作用。在实验的第12天和第13天，给小鼠连续15天用EG处理并同时给予CP。使用高效液相色谱 - 二极管阵列 - 电喷雾串联质谱法（HPLC-DAD-ESI-MS/MS），在EG叶提取物中鉴定出26种次生代谢产物。其中，分离出4种多酚类化合物：（1）4 - （-β-D-吡喃木糖氧基）-3,5 - 二羟基苯甲酸，（2）4 - （-α-L-吡喃鼠李糖氧基）-3,5 - 二羟基苯甲酸，（3）没食子酸，以及（4）没食子酸甲酯。与美司钠阳性对照相比，评估了EG提取物对生化参数、基因表达和免疫组织病理学变化的影响。结果表明，EG改善了CP升高的血清谷丙转氨酶（ALT）、谷草转氨酶（AST）、肌酐和血尿素氮水平。肝和肾组织中的丙二醛（MDA）、一氧化氮、蛋白质羰基、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）水平以及核因子κB（NF-κB）和半胱天冬酶-3的免疫组化表达降低。此外，肝和肾中的谷胱甘肽（GSH）含量以及核因子E2相关因子2（Nrf2）/血红素加氧酶-1（HO-1）信号水平升高。组织病理学结果支持了我们的发现，即肝和肾结构几乎恢复。结果揭示了EG对CP诱导的肝肾毒性的保护作用。这些作用可能与EG的抗氧化、抗炎和抗凋亡特性以及Nrf2/HO-1信号的激活有关。
