柴胡皂苷 A 和 D 通过激活 PI3K/AKT/Nrf2 通路减少氧化应激从而减轻慢性肾脏病骨骼肌萎缩。
Saikosaponin A and D attenuate skeletal muscle atrophy in chronic kidney disease by reducing oxidative stress through activation of PI3K/AKT/Nrf2 pathway.
机构信息
Department of Traditional Chinese Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, 518000, China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510000, China.
The First Clinical Medical College, Southern Medical University, Guangzhou, 510000, China.
出版信息
Phytomedicine. 2023 Jun;114:154766. doi: 10.1016/j.phymed.2023.154766. Epub 2023 Mar 21.
BACKGROUND
Skeletal muscle atrophy in chronic kidney disease (CKD) leads to a decline in quality of life and increased risk of morbidity and mortality. We have obtained evidence that oxidative stress is essential in the progression of CKD-related muscle atrophy. Whether Saikosaponin A and D, two emerging antioxidants extracted from Bupleurum chinense DC, alleviate muscle atrophy remains to be further studied. The purpose of this study was to investigate the effects and mechanisms of these two components on CKD complicated with muscle atrophy.
METHODS
In this research, muscle dystrophy model was established using 5/6 nephrectomized mice in vivo and in vitro with Dexamethasone (Dex)-managed C2C12 myotubes.
RESULTS
The results of RNA-sequencing showed that exposure to Dex affected the antioxidant activity, catalytic activity and enzyme regulator activity of C2C12 cells. According to KEGG analysis, the largest numbers of differentially expressed genes detected were enriched in the PI3K/AKT pathway. In vivo, Saikosaponin A and D remain renal function, cross-section size, fiber-type composition and anti-inflammatory ability. These two components suppressed the expression of MuRF-1 and enhanced the expression of MyoD and Dystrophin. In addition, Saikosaponin A and D maintained redox balance by increasing the activities of antioxidant enzymes while inhibiting the excessive accumulation of reactive oxygen species. Furthermore, Saikosaponin A and D stimulated PI3K/AKT and its downstream Nrf2 pathway in CKD mice. The effects of Saikosaponin A and D on increasing the inner diameter of C2C12 myotube, reducing oxidative stress and enhancing expression of p-AKT, p-mTOR, p70S6K, Nrf2 and HO-1 proteins were observed in vitro. Importantly, we verified that these protective effects could be significantly reversed by inhibiting PI3K and knocking out Nrf2.
CONCLUSIONS
In summary, Saikosaponin A and D improve CKD-induced muscle atrophy by reducing oxidative stress through the PI3K/AKT/Nrf2 pathway.
背景
慢性肾脏病（CKD）导致的骨骼肌萎缩会降低生活质量，并增加发病率和死亡率。我们已经有证据表明，氧化应激在 CKD 相关肌肉萎缩的进展中起着关键作用。从柴胡中提取的两种新兴抗氧化剂柴胡皂苷 A 和 D 是否能缓解肌肉萎缩，仍有待进一步研究。本研究旨在探讨这两种成分对 CKD 合并肌肉萎缩的作用及其机制。
方法
本研究采用体内和体外地塞米松（Dex）处理 C2C12 肌管建立肌肉萎缩模型。
结果
RNA 测序结果表明，Dex 暴露影响 C2C12 细胞的抗氧化活性、催化活性和酶调节活性。根据 KEGG 分析，检测到的差异表达基因数量最多的富集在 PI3K/AKT 通路中。在体内，柴胡皂苷 A 和 D 能维持肾功能、横截面积、纤维类型组成和抗炎能力。这两种成分抑制 MuRF-1 的表达，增强 MyoD 和 Dystrophin 的表达。此外，柴胡皂苷 A 和 D 通过增加抗氧化酶的活性抑制活性氧的过度积累，从而维持氧化还原平衡。此外，柴胡皂苷 A 和 D 在 CKD 小鼠中刺激 PI3K/AKT 及其下游 Nrf2 通路。在体外，我们观察到柴胡皂苷 A 和 D 增加 C2C12 肌管的内径，减少氧化应激，增强 p-AKT、p-mTOR、p70S6K、Nrf2 和 HO-1 蛋白表达的作用。重要的是，我们通过抑制 PI3K 和敲除 Nrf2 验证了这些保护作用可以显著逆转。
结论
综上所述，柴胡皂苷 A 和 D 通过 PI3K/AKT/Nrf2 通路减少氧化应激来改善 CKD 引起的肌肉萎缩。
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