Chlorogenic acid, rutin, and quercetin from Lysimachia christinae alleviate triptolide-induced multi-organ injury in vivo by modulating immunity and AKT/mTOR signal pathway to inhibit ferroptosis and apoptosis

by Selleckchem | Apr 18 2023

Drug-induced organ injury is one of the key factors causing organ failure and death in the global public. Triptolide (TP) is the main immunosuppressive component of Tripterygium wilfordii Hook. f. (Leigongteng, LGT) for the first-line management of autoimmune conditions, but it can cause serious multi-organ injury. Lysimachia christinae (Jinqiancao, JQC) is a detoxifying Chinese medicine and could suppress LGT's toxicity. It contains many immune enhancement and organ protection components including chlorogenic acid (CA), rutin (Rut), and quercetin (Que). This study aimed to explore the protection of combined treatments of these organ-protective ingredients of JQC on TP-induced liver, kidney, and heart injury and initially explore the mechanisms. Molecular docking showed that CA, Rut, and Que. bound AKT/mTOR pathway-related molecules intimately and might competitively antagonize TP. Corresponding in vivo results showed that the combination activated TP-inhibited protein of AKT/mTOR pathway, and reversed TP-induced excessive ferroptosis (excessive Fe 2+ and lipid peroxidation malondialdehyde accumulation, decreased levels of antioxidant enzymes catalase, glutathione peroxidase, glutathione-s transferase, reduced glutathione, and superoxide dismutase, and down-regulated P62/nuclear factor erythroid-2-related factor 2/heme oxygenase-1 pathway), and apoptosis (activated apoptotic factor Fas and Bax and inhibited Bcl-2) in the organ of mice to varying degrees. In conclusion, the combined treatments of CA, Rut, and Que. from JQC inhibited TP-induced multi-organ injury in vivo, and the mechanism may largely involve immunomodulation and activation of the AKT/mTOR pathway-mediated cell death reduction including ferroptosis and apoptosis inhibition.

Comments：

This study explored the protective effects of a combination of organ-protective ingredients from Lysimachia christinae (Jinqiancao) on triptolide (TP)-induced liver, kidney, and heart injury. TP is an immunosuppressive component of Tripterygium wilfordii Hook. f. (Leigongteng) commonly used to manage autoimmune conditions but can cause serious multi-organ injury. Jinqiancao is a detoxifying Chinese medicine known to contain immune enhancement and organ protection components such as chlorogenic acid (CA), rutin (Rut), and quercetin (Que).

Molecular docking studies showed that CA, Rut, and Que intimately bound AKT/mTOR pathway-related molecules and might competitively antagonize TP. The in vivo results of the combination treatment showed that it activated the AKT/mTOR pathway, reversed TP-induced excessive ferroptosis and apoptosis, and inhibited TP-induced multi-organ injury in mice to varying degrees. Ferroptosis is a form of cell death caused by the accumulation of lipid peroxides and iron-dependent reactive oxygen species. Apoptosis is a programmed cell death mechanism that occurs in response to various cellular stresses.

The study concluded that the combined treatment of CA, Rut, and Que from Jinqiancao could protect against TP-induced multi-organ injury in vivo by activating the AKT/mTOR pathway and reducing cell death including ferroptosis and apoptosis inhibition. The mechanism may involve immunomodulation and the activation of the AKT/mTOR pathway-mediated cell death reduction. These findings suggest that Jinqiancao could be a potential therapeutic option for managing drug-induced organ injury.