PDF(Pubmed)
Abstract：
Sepsis is a potential fetal organ destruction brought on through an overzealous immunologic reaction to infection, causing severe inflammation, septic shock, and damage to different organs. Although there has been progress in the identification and controlling of clinical sepsis, the fatality rates are still significant. This study, for the first time, intended to examine the possible ameliorative impact of Nebivolol, a β1-adrenergic antagonist antihypertensive drug, against nephrotoxicity resulted from cecal ligation and puncture (CLP)-induced sepsis in rats, on molecular basis. Sixty male Wistar albino rats were chosen. Oxidative stress indicators and biochemical markers of kidney activity were evaluated. Inflammatory mediators, fibrosis- and apoptosis-related proteins and gene expressions were investigated. Moreover, renal histopathological investigation was performed. CLP-induced nephrotoxicity characterized by markedly elevated serum levels of creatinine, blood urea nitrogen, uric acid, and renal malondialdhyde. On the other hand, it decreased serum total protein level, renal superoxide dismutase activity and reduced glutathione level. Additionally, it significantly elevated the renal inflammatory mediators (tumor necrosis factor-alpha, ilnerlukin (IL)-6, and IL-1β) and Caspase-3 protein, reduced IL-10 level, amplified the expression of transforming growth factor-beta 1 (TGF-β1), p-Smad2/3 and alpha-smooth-muscle actin proteins, downregulated the B cell lymphoma-2 (Bcl-2) gene and elevated the transcription of Bcl-2-associated X-protein (Bax), p53 and Nuclear factor-kappa B (NF-κB) genes. Furtheremor, kidney tissues exhibited significant histopathological changes with CLP. On the contrary, Nebivolol significantly improved all these biochemical changes and enhanced the histopathological alterations obtained by CLP. This research showed, for the first time, that Nebivolol effectively mitigated the CLP-induced kidney dysfunction via its antioxidant, antifibrotic and anti-apoptotic activity through modulation of oxidative stress, TGF-β/NF-κB and TGF-β/Smad/p53 signaling pathways.
摘要：
脓毒症是通过对感染的过度免疫反应引起的潜在胎儿器官破坏，引起严重的炎症，感染性休克,对不同器官的损害。尽管在临床脓毒症的识别和控制方面取得了进展，死亡率仍然很高。这项研究,第一次,旨在研究奈必洛尔可能的改善作用，β1-肾上腺素能拮抗剂抗高血压药物，针对盲肠结扎穿孔（CLP）诱导的脓毒症大鼠肾毒性，在分子基础上。选择60只雄性Wistar白化病大鼠。评估氧化应激指标和肾脏活动的生化标志物。炎症介质,研究了纤维化和凋亡相关蛋白和基因表达。此外，进行肾组织病理学检查.CLP诱导的肾毒性以血清肌酐水平显着升高为特征，血尿素氮,尿酸,和肾脏丙二醛。另一方面,它降低了血清总蛋白水平，肾超氧化物歧化酶活性和谷胱甘肽水平降低。此外,它显著升高了肾脏炎症介质(肿瘤坏死因子-α，ilnerlukin（IL）-6和IL-1β）和Caspase-3蛋白，降低IL-10水平，扩增转化生长因子-β1（TGF-β1）的表达，p-Smad2/3和α-平滑肌肌动蛋白，下调B细胞淋巴瘤-2（Bcl-2）基因并升高Bcl-2相关X蛋白（Bax）的转录，p53和核因子-κB(NF-κB)基因。Furthermor,肾脏组织表现出明显的组织病理学改变。相反,奈必洛尔显着改善了所有这些生化变化，并增强了CLP获得的组织病理学改变。这项研究表明,第一次,奈比洛尔通过其抗氧化剂有效缓解了CLP诱导的肾功能障碍，通过调节氧化应激的抗纤维化和抗凋亡活性，TGF-β/NF-κB和TGF-β/Smad/p53信号通路。
