The Key Molecular Mechanisms of Sini Decoction Plus Ginseng Soup to Rescue Acute Liver Failure: Regulating PPARα to Reduce Hepatocyte Necroptosis?
The Key Molecular Mechanisms of Sini Decoction Plus Ginseng Soup to Rescue Acute Liver Failure: Regulating PPARα to Reduce Hepatocyte Necroptosis?
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DOI：
10.2147/jir.s373903
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发表时间：
2022
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
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作者：
本研究旨在探讨四逆汤合人参汤对LPS/D-GalN诱导的急性肝衰竭（ALF）小鼠模型的改善作用及其分子机制。为研究SNRS对ALF小鼠的保护作用，首先将ICR小鼠分为4组：对照组（空白对照组）、模型组（LPS/D-GalN组）、SNRS组（LPS/D-GalN+SNRS组）和水飞蓟素组（LPS/D-GalN+Silymarin组），分别于LPS/D-GalN注射前48 h、24 h和注射后10 min灌胃给予治疗药物。在此基础上，加入过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptor，PPAR）α激动剂（WY 14643）和抑制剂（GW 6471），验证SNRS的治疗机制是否与其对PPARα的促进作用有关。将动物分组如下：对照组（媒介物处理的）、模型组（LPS/D-GalN+DMSO）、SNRS组（LPS/D-GalN+SNRS+DMSO）、抑制剂组（LPS/D-GalN+ GW 6471）、激动剂组（LPS/D-GalN+ WY 14643）和抑制剂+SNRS组（LPS/D-GalN+ GW 6471 +SNRS）。SNRS对ALF模型的保护作用主要体现在降低血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）以及改善肝组织病理。SNRS治疗ALF小鼠的存活率显著提高。进一步的机制研究表明，SNRS可显著促进ALF小鼠PPARα的蛋白表达，降低坏死性凋亡蛋白（RIP 3、MLKL、p-MLKL）的表达。HMGB 1的释放减少，进而抑制LPS/D-GalN诱导的TLR 4-JNK和NLRP 3炎症体信号通路的激活以及NF-κB蛋白的表达。在SNRS处理组中，发现参与脂肪酸β-氧化的关键酶CPT 1A的表达显著上调，并伴有三磷酸腺苷（ATP）水平的增加，这可能是SNRS减少坏死性凋亡的相关机制。SNRS对ALF的潜在治疗作用可能是通过促进肝组织中PPARα的表达，提高肝组织ATP水平，从而抑制肝细胞坏死凋亡，减轻肝细胞损伤，改善肝功能。
This study aimed to investigate the improvement effect of Sini Decoction plus Ginseng Soup (SNRS) on the LPS/D-GalN-induced acute liver failure (ALF) mouse model and the molecular mechanism of the SNRS effect. To study the protective effect of SNRS on ALF mice, the ICR mice were firstly divided into 4 groups: Control group (vehicle-treated), Model group (LPS/D-GalN), SNRS group (LPS/D-GalN+SNRS), and Silymarin group (LPS/D-GalN+Silymarin), the therapeutic drug was administered by gavage 48h, 24h before, and 10 min after LPS/D-GalN injection. On this basis, the peroxisome proliferator-activated receptor (PPAR) α agonist (WY14643) and inhibitor (GW6471) were added to verify whether the therapeutic mechanism of SNRS is related to its promoting effect on PPARα. The animals are grouped as follows: Control group (vehicle-treated), Model group (LPS/D-GalN+DMSO), SNRS group (LPS/D-GalN+SNRS+DMSO), Inhibitor group (LPS/D-GalN+GW6471), Agonist group (LPS/D-GalN+WY14643), and Inhibitor+SNRS group (LPS/D-GalN+GW6471+SNRS). The protective effect of SNRS on the ALF model is mainly reflected in the reduction of serum alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) as well as the ameliorated pathology of the liver tissue. The survival rate of ALF mice treated with SNRS was significantly increased. Further mechanism studies showed that SNRS significantly promoted the protein expression of PPARα and decreased the expression of necroptosis proteins (RIP3, MLKL, p-MLKL) in ALF mice. Reduced necroptosis resulted in decreased HMGB1 release, which in turn inhibited the activation of TLR4-JNK and NLRP3 inflammasome signaling pathways and the expression of NF-κB protein induced by LPS/D-GalN. The expression of CPT1A, a key enzyme involved in fatty acid β-oxidation, was found to be significantly up-regulated in the SNRS treated group, accompanied by an increased adenosine-triphosphate (ATP) level, which may be the relevant mechanism by which SNRS reduces necroptosis. The potential therapeutic effect of SNRS on ALF may be through promoting the expression of PPARα and increasing the level of ATP in liver tissue, thereby inhibiting necroptosis of hepatocytes, reducing hepatocyte damage, and improving liver function.
影响因子：
0.7
作者：
Yamaura K;Shimada M;Nakayama N;Ueno K
通讯作者：
Ueno K