Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia.
Department of Immunology and Hematology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
Oxid Med Cell Longev. 2022 Aug 26;2022:4212331. doi: 10.1155/2022/4212331. eCollection 2022.
Herein, the molecular pathogenic pathways implicated in renal injury triggered by amikacin (AK), together with the alleviating actions of -caryophyllene (BCP), were investigated. Adult male Wistar rats ( = 32) were disseminated to the four following groups ( = 8/group): normal group, positive control animals (PC) that received AK intraperitoneal injections for 14 days (500 mg/kg/day), and rats that received AK simultaneously with small (200 mg/kg/day) and high doses (400 mg/kg/day) of BCP. The PC renal tissues revealed abnormal histology alongside increased apoptosis and significantly elevated serum creatinine and urea with marked proteinuria and oliguria relative to the normal rats. Moreover, renal tissues from the PC animals also showed substantial upregulations in NF-B/TGF-/KIM-1, whilst Nrf2/AMPK/AKT/PCNA declined, at the gene and protein levels in comparison to the normal rats. Additionally, the levels of markers of oxidative stress (MDA/HO/protein adducts) and inflammation (TNF-/IL-1/IL-6/IL-18/TLR/HSP25) were substantially higher in the PC renal specimens, whereas the antioxidants (GSH/GPx/SOD1/CAT) and interleukin-10 decreased, relative to the NC group. Both BCP protocols improved the biochemical markers of renal functions, alleviated renal histopathology and apoptosis, and decreased NF-B/TGF-/KIM-1 alongside the concentrations of oxidative stress and proinflammatory markers, whilst promoting Nrf2/AMPK/AKT/IL-10/PCNA and the targeted antioxidants. However, the improving effects in the high-dose regimen were markedly stronger than those observed in animals treated with low dose of BCP. In conclusion, the present report is the first to connect NF-B/TGF-/KIM-1 proinflammatory and Nrf2/AMPK/AKT antioxidative stress pathways with the pathogenesis of AK-induced nephrotoxicity. Additionally, the current report is the first to disclose alleviating activities for BCP against AK-triggered nephrotoxicity by modulating multiple antioxidative stress with anti-inflammatory molecular pathways.
本文研究了阿米卡星（AK）引起的肾损伤所涉及的分子发病途径，以及 - 石竹烯（BCP）的缓解作用。成年雄性 Wistar 大鼠（ = 32）分为以下四组（每组 = 8）：正常组、腹腔注射 AK（500mg/kg/天）14 天的阳性对照组（PC）、同时接受小剂量（200mg/kg/天）和高剂量（400mg/kg/天）BCP 的 AK 组。PC 肾组织显示出异常的组织学特征，同时伴随着细胞凋亡增加，与正常大鼠相比，血清肌酐和尿素显著升高，且蛋白尿和少尿明显。此外，与正常大鼠相比，PC 动物的肾组织中 NF-B/TGF-/KIM-1 的表达显著上调，而 Nrf2/AMPK/AKT/PCNA 下调，在基因和蛋白水平上均如此。此外，PC 肾组织中氧化应激标志物（MDA/HO/蛋白加合物）和炎症标志物（TNF-/IL-1/IL-6/IL-18/TLR/HSP25）的水平显著升高，而抗氧化剂（GSH/GPx/SOD1/CAT）和白细胞介素-10 降低。两种 BCP 方案均改善了肾功能的生化标志物，缓解了肾组织病理学和细胞凋亡，降低了 NF-B/TGF-/KIM-1 及氧化应激和促炎标志物的浓度，同时促进了 Nrf2/AMPK/AKT/IL-10/PCNA 和目标抗氧化剂。然而，高剂量方案的改善效果明显强于低剂量 BCP 处理组。总之，本报告首次将 NF-B/TGF-/KIM-1 促炎和 Nrf2/AMPK/AKT 抗氧化应激途径与 AK 诱导的肾毒性发病机制联系起来。此外，本报告首次揭示了 BCP 通过调节多种抗氧化应激和抗炎分子途径对 AK 引起的肾毒性的缓解作用。
