Kadry Mai O, Ammar Naglaa M, Hassan Heba A, Abdel Megeed Rehab M
Therapeutic Chemistry Department, National Research Center, Al Bhoouth Street, Cairo, Egypt.
J Genet Eng Biotechnol. 2022 Oct 27;20(1):147. doi: 10.1186/s43141-022-00430-4.
Methotrexate (MX), a competitive inhibitor of dihydrofolate reductase, can inhibit DNA and RNA production and is a powerful anticancer agent widely utilized in clinical practice for treating nonneoplastic maladies, as psoriasis and rheumatoid arthritis; meanwhile, its probable prescription dose and interval of administration are strictly limited due to dose-related organ damage. Former studies verified that kidney, brain, liver, and lung harms are prospective obstacles of methotrexate administration. To understand the machinery of methotrexate-prompt toxicity, various mechanisms were investigated. The former is an autophagy defense mechanism; autophagy is a self-digesting mechanism responsible for the removal of damaged organelles and malformed proteins by lysosome. The contemporary article hypothesized that turmeric or its liposomal analog could defeat autophagy of MX-induced acute toxicity. Methotrexate, in a dose of 1.5 mg/kg, was administered intravenously followed by turmeric and liposomal turmeric treatment in a dose of 5 mg/kg for 30 days in rats.
Increment in autophagy (AUTP) consent by MX administration was attenuated by concurrent treatment via turmeric and liposomal turmeric that was reliable on the alteration in apoptotic markers. The assembly of FOXO-3 in serum post methotrexate administration was suppressed by concurrent treatment via liposomal turmeric. Apoptosis/autophagic marker investigation was evaluated through the gene expression of Bax (BCL2-associated X protein)/Bcl2 (B-cell lymphoma 2)/P53 (tumor protein P53)/SiRT-1 (sirtuin silent mating-type information regulation 2 homolog 1) and FOXO-3 (forkhead box transcription factor-3)/ERDJ-4 (endoplasmic reticulum localized DnaJ homologs)/BNP (brain natriuretic peptide B) signaling. The cell death of all cells was categorized to achieve autophagy. Interestingly, Bax/Bcl2/P53/SiRT-1 signaling pathways were downregulated, contributing to inhibiting the initiation of autophagy. Meanwhile, FOXO-3/BNP/ERDJ-4 reduction-implicated noncanonical autophagy pathways were involved in methotrexate-induced autophagy, whereas this change was suppressed when turmeric was administered in liposomal form.
These outcomes recommended that liposomal turmeric prevents MX-induced acute toxicity through its autophagy, antioxidant, and antiapoptotic properties.
甲氨蝶呤（MX）是二氢叶酸还原酶的竞争性抑制剂，可抑制DNA和RNA的生成，是一种广泛应用于临床治疗非肿瘤性疾病（如银屑病和类风湿性关节炎）的强效抗癌药物；同时，由于与剂量相关的器官损伤，其可能的处方剂量和给药间隔受到严格限制。以往研究证实，肾脏、大脑、肝脏和肺部损伤是甲氨蝶呤给药的潜在障碍。为了解甲氨蝶呤引发毒性的机制，人们研究了多种机制。前者是一种自噬防御机制；自噬是一种自我消化机制，负责通过溶酶体清除受损细胞器和畸形蛋白质。当代文章推测，姜黄或其脂质体类似物可以对抗MX诱导的急性毒性的自噬。给大鼠静脉注射1.5mg/kg剂量的甲氨蝶呤，随后给予5mg/kg剂量的姜黄和脂质体姜黄治疗，持续30天。
通过姜黄和脂质体姜黄同时治疗，可减轻MX给药导致的自噬增加（AUTP），这与凋亡标志物的变化相关。脂质体姜黄同时治疗可抑制甲氨蝶呤给药后血清中FOXO-3的聚集。通过Bax（BCL2相关X蛋白）/Bcl2（B细胞淋巴瘤2）/P53（肿瘤蛋白P53）/SiRT-1（沉默信息调节因子2同源物1）和FOXO-3（叉头盒转录因子-3）/ERDJ-4（内质网定位的DnaJ同源物）/BNP（脑钠肽B）信号通路的基因表达评估凋亡/自噬标志物。将所有细胞的细胞死亡分类以实现自噬。有趣的是，Bax/Bcl2/P53/SiRT-1信号通路下调，有助于抑制自噬的启动。同时，FOXO-3/BNP/ERDJ-4减少相关的非经典自噬通路参与了甲氨蝶呤诱导的自噬，而当以脂质体形式给予姜黄时，这种变化受到抑制。
这些结果表明，脂质体姜黄通过其自噬、抗氧化和抗凋亡特性预防MX诱导的急性毒性。
