Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.
Department of Hepatobiliary and Pancreatic Surgery, The People's Hospital of Jianyang City, Jianyang, China.
Inflammation. 2023 Jun;46(3):1061-1076. doi: 10.1007/s10753-023-01792-8. Epub 2023 Mar 1.
Hepatic ischemia-reperfusion injury (HIRI) is the main reason for organ failure following liver surgery; however, its underlying causes are complex, and include oxidative stress, sterile inflammatory, and mitochondrial damage. Unfortunately, treatments for HIRI are based on supportive therapy, and no specific drugs or methods are currently available. Chlorogenic acid (CGA) is a dietary polyphenol with a wide range of pharmacological effects and it has a protective effect on HIRI; however, its specific mechanism remains unclear. In this study, we investigated that CGA pretreatment exerts protective effects against HIRI and the potential underlying mechanisms. We found that CGA pretreatment reduced ALT, AST, MDA, TNF-α, and IL-1β levels following HIRI, improved SOD and GSH levels, and alleviated pathological liver tissue damage, with the highest CGA dose (100 mg/kg.d) exerted the strongest effect. In addition, we showed that CGA pretreatment significantly decreased the levels of reactive oxygen species following HIRI, inhibited HMGB1 release by decreasing IRF-1 expression, inhibited the expression of HMGB1, TLR-4, MyD88, P-IκB-α, NF-κB P65, and P-P65, and promoted IκB-α degradation. Thus, CGA appears to inhibit oxidative stress and inflammatory responses during HIRI. Furthermore, we found that CGA pretreatment reduced hepatocyte apoptosis following HIRI, alleviated mitochondrial damage, promoted BCL-2 expression, inhibited Bax upregulation, and inhibited cytochrome C release to prevent caspase activation, thereby reducing the expression of the caspase-independent pathway components, ENDOG and AIF. Together, our findings suggest that CGA can protect against HIRI by inhibiting oxidative stress, the HMGB1/TLR-4/NF-κB signaling pathway-mediated inflammatory responses, and mitochondria-mediated apoptosis. Thus, CGA appears to be a promising therapeutic approach for treating HIRI.
肝缺血再灌注损伤（HIRI）是肝手术后器官衰竭的主要原因；然而，其根本原因复杂，包括氧化应激、无菌性炎症和线粒体损伤。不幸的是，HIRI 的治疗基于支持性治疗，目前尚无特定的药物或方法。绿原酸（CGA）是一种具有广泛药理作用的膳食多酚，对 HIRI 具有保护作用；然而，其具体机制尚不清楚。在这项研究中，我们研究了 CGA 预处理对 HIRI 的保护作用及其潜在机制。我们发现 CGA 预处理可降低 HIRI 后 ALT、AST、MDA、TNF-α 和 IL-1β 水平，提高 SOD 和 GSH 水平，并减轻肝组织病理损伤，最高 CGA 剂量（100mg/kg.d）作用最强。此外，我们表明 CGA 预处理可显著降低 HIRI 后活性氧水平，通过降低 IRF-1 表达抑制 HMGB1 释放，抑制 HMGB1、TLR-4、MyD88、P-IκB-α、NF-κB P65 和 P-P65 的表达，并促进 IκB-α 降解。因此，CGA 似乎在 HIRI 期间抑制氧化应激和炎症反应。此外，我们发现 CGA 预处理可减少 HIRI 后肝细胞凋亡，减轻线粒体损伤，促进 BCL-2 表达，抑制 Bax 上调，并抑制细胞色素 C 释放以阻止半胱天冬酶激活，从而降低半胱天冬酶非依赖性途径成分 ENDOG 和 AIF 的表达。总之，我们的研究结果表明，CGA 通过抑制氧化应激、HMGB1/TLR-4/NF-κB 信号通路介导的炎症反应和线粒体介导的细胞凋亡来保护 HIRI。因此，CGA 似乎是治疗 HIRI 的一种很有前途的治疗方法。
