鼠李糖乳杆菌GG通过PKC/Nrf2/PGC-1α信号通路对乙酰氨基酚诱导的肝毒性的改善作用。
Ameliorative effect of Lactobacillus rhamnosus GG on acetaminophen-induced hepatotoxicity via PKC/Nrf2/PGC-1α pathway.
作者信息
Ahmed Hend M, Shehata Hanan H, El-Saeed Gamila S M, Gabal Hoda H Abou, El-Daly Sherien M
机构信息
Medical Biochemistry Department, Medicine and Clinical Studies Research Institute, National Research Centre, Dokki, Cairo, 12622, Egypt.
Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
出版信息
J Genet Eng Biotechnol. 2022 Oct 6;20(1):142. doi: 10.1186/s43141-022-00422-4.
BACKGROUND
Acetaminophen (APAP) overdose is a common cause of hepatotoxicity. Antioxidants like N-acetyl cysteine are recommended as a therapeutic option; nevertheless, it has limitations. The search for efficient alternatives is ongoing. Probiotics are live microorganisms that maintain a healthy gut microecology. Lactobacillus rhamnosus GG (LGG) is one of the widely used probiotics. Our study aimed to assess the protective and therapeutic effects of probiotic LGG on APAP-induced hepatotoxicity and evaluate the molecular pathways behind this effect.
METHODS
Wistar Albino male rats were randomly distributed into the following experimental groups: group 1, non-treated rats (vehicle); group 2, rats received oral gavage of suspension of probiotic LGG (5 × 10 CFU GG/0.5 ml in PBS) daily for 2 weeks (probiotic control); group 3, rats received APAP dose of 2 g/kg body weight (positive control); group 4, rats received oral gavage of suspension of probiotic LGG for 2 weeks followed by a single dose of APAP injection (prophylactic); and group 5, rats received a single dose of APAP and then 24 h later treated with oral gavage of probiotic LGG daily for 2 weeks (treatment).
RESULTS
Our study revealed that administration of probiotic LGG (either as prophylactic or treatment) exhibited a remarkable reduction in APAP-induced liver injury as resembled by the decrease in liver enzymes (ALT and AST) and the histopathological features of liver sections. Moreover, the significant reduction in the oxidative marker malondialdehyde, along with the enhancement in glutathione reductase, and the significant reduction in inflammatory markers (nitric oxide and tumor necrosis factor-α) were all indicators of the efficiency of LGG in ameliorating the alterations accompanied with APAP-induced hepatotoxicity. Our findings also demonstrate that LGG administration boosted the expression of Nrf2 and PGC-1 while decreasing the expression of protein kinase C (PKC). As a result, the nuclear abundance of Nrf2 is increased, and the expression of various antioxidants is eventually upregulated.
CONCLUSION
Our study shows that probiotic LGG supplementation exerts a prophylactic and therapeutic effect against APAP-induced hepatotoxicity through modulating the expression of PKC and the Nrf2/PGC-1α signaling pathway and eventually suppressing oxidative damage from APAP overdose.
背景
对乙酰氨基酚（APAP）过量是肝毒性的常见原因。像N - 乙酰半胱氨酸这样的抗氧化剂被推荐作为一种治疗选择；然而，它有局限性。对有效替代方案的探索仍在进行中。益生菌是维持健康肠道微生态的活微生物。鼠李糖乳杆菌GG（LGG）是广泛使用的益生菌之一。我们的研究旨在评估益生菌LGG对APAP诱导的肝毒性的保护和治疗作用，并评估这种作用背后的分子途径。
方法
将Wistar白化雄性大鼠随机分为以下实验组：第1组，未处理的大鼠（溶剂对照组）；第2组，大鼠每天经口灌胃益生菌LGG悬浮液（5×10 CFU GG/0.5 ml磷酸盐缓冲盐水），持续2周（益生菌对照组）；第3组，大鼠接受2 g/kg体重的APAP剂量（阳性对照组）；第4组，大鼠经口灌胃益生菌LGG悬浮液2周，然后单次注射APAP（预防组）；第5组，大鼠单次注射APAP，然后24小时后每天经口灌胃益生菌LGG，持续2周（治疗组）。
结果
我们的研究表明，给予益生菌LGG（无论是预防还是治疗）都能显著减轻APAP诱导的肝损伤，这表现为肝酶（ALT和AST）的降低以及肝组织切片的组织病理学特征。此外，氧化标志物丙二醛的显著降低，以及谷胱甘肽还原酶的增强，还有炎症标志物（一氧化氮和肿瘤坏死因子-α）的显著降低，都是LGG改善APAP诱导的肝毒性所伴随变化的有效性指标。我们的研究结果还表明，给予LGG可提高Nrf2和PGC - 1的表达，同时降低蛋白激酶C（PKC）的表达。结果，Nrf2的核丰度增加，各种抗氧化剂的表达最终上调。
结论
我们的研究表明，补充益生菌LGG通过调节PKC的表达和Nrf2/PGC - 1α信号通路，最终抑制APAP过量引起的氧化损伤，对APAP诱导的肝毒性具有预防和治疗作用。
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