Abou-Elhamd Alaa Sayed, Kalamegam Gauthaman, Ahmed Farid, Assidi Mourad, Alrefaei Abdulmajeed Fahad, Pushparaj Peter Natesan, Abu-Elmagd Muhammad
Department of Anatomy and Histology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt.
Department of Respiratory Therapy, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia.
Front Pharmacol. 2021 May 10;12:666885. doi: 10.3389/fphar.2021.666885. eCollection 2021.
Khat ( (Vahl) Endl.) is an evergreen flowering shrub used as a stimulant in many regions worldwide including East Africa, the Arabian Peninsula, Europe, and the United States. Chewing leaves of khat induces excitement and euphoria, which are primarily attributed to two major constituents, cathinone and cathine. Khat also contains other important constituents such as cathedulins. A considerable number of studies reported side effects induced by the khat extracts to both embryos and adults. These include teratogenicity and developmental retardation, oral cancer and ulcers, high blood pressure, and myocardial infarction. So far, little attention has been paid to the effects of khat extracts on the molecular signaling interactions. We aimed in this study to investigate this through evaluating the effects of khat extracts on SKOV3, a human ovarian adenocarcinoma cell line. We show, by assays, that khat induces several cellular defects including reduced cell size, cell membrane damage, and apoptosis. At high khat extract concentrations, the cell metabolic activity, cell cycle, and cellular proliferation were affected. RT-qPCR analysis showed an increase in the gene expression of the apoptotic marker BAX, the tumor suppressor p53, and the inflammatory cytokine IL-6. Protein expression analysis by immunostaining showed downregulation of β-catenin, E-cadherin, and Ki-67 and upregulation of FZD8 and SPRY2, suggesting that Wnt and FGF signaling were implicated. SwissTargetPrediction analysis showed that khat constituents cathine, cathinone, catheduline K2, and catheduline E5 bind to family A G-protein-coupled receptor, cause many neurological diseases and disorders such as Alzheimer's, schizophrenia, depression, and anxiety, and induce many ovarian cancer-related diseases. The analysis also showed that important signaling pathways such as CREB, Wnt, FGF, IL-6, and ERK/MAPK, and that of the endometrial cancer, and cell cycle were implicated. Upstream regulators of cathine and cathinone were found to potentially target several molecules including interleukin-8, MMP2, PLAU, and micro-RNAs. In conclusion, khat induces significant cellular and molecular changes that could potentially cause a wide range of serious diseases and syndromes. Such an impact could have a heavy burden on the health care system in the countries where khat is consumed.
巧茶（(Vahl) Endl.）是一种常绿开花灌木，在世界许多地区被用作兴奋剂，包括东非、阿拉伯半岛、欧洲和美国。咀嚼巧茶的叶子会引起兴奋和欣快感，这主要归因于两种主要成分——卡西酮和去甲伪麻黄碱。巧茶还含有其他重要成分，如巧茶素。大量研究报告了巧茶提取物对胚胎和成年人的副作用。这些副作用包括致畸性和发育迟缓、口腔癌和溃疡、高血压以及心肌梗死。到目前为止，很少有人关注巧茶提取物对分子信号相互作用的影响。在本研究中，我们旨在通过评估巧茶提取物对人卵巢腺癌细胞系SKOV3的影响来对此进行研究。我们通过实验表明，巧茶会导致多种细胞缺陷，包括细胞大小减小、细胞膜损伤和细胞凋亡。在高巧茶提取物浓度下，细胞代谢活性、细胞周期和细胞增殖受到影响。RT-qPCR分析显示凋亡标志物BAX、肿瘤抑制因子p53和炎性细胞因子IL-6的基因表达增加。通过免疫染色进行的蛋白质表达分析显示β-连环蛋白、E-钙黏蛋白和Ki-67表达下调，FZD8和SPRY-2表达上调，这表明Wnt和FGF信号通路参与其中。SwissTargetPrediction分析表明，巧茶成分去甲伪麻黄碱、卡西酮、巧茶素K2和巧茶素E5与A类G蛋白偶联受体结合，会引发许多神经疾病和紊乱，如阿尔茨海默病、精神分裂症、抑郁症和焦虑症，并诱发许多与卵巢癌相关的疾病。该分析还表明，重要的信号通路如CREB、Wnt、FGF、IL-6和ERK/MAPK以及子宫内膜癌和细胞周期相关的信号通路也参与其中。去甲伪麻黄碱和卡西酮的上游调节因子被发现可能靶向包括白细胞介素-8、基质金属蛋白酶2、纤溶酶原激活物、尿激酶型（PLAU）和微小RNA在内的多种分子。总之，巧茶会引起显著的细胞和分子变化，这些变化可能会导致多种严重疾病和综合征。这种影响可能会给消费巧茶的国家的医疗保健系统带来沉重负担。
