Cuscuta chinensis Lam. Flavonoids (CCLF) alleviate the symptoms of sepsis-associated encephalopathy via PI3K/AKT/Nrf2/HO-1 pathway

Sepsis-associated encephalopathy (SAE) affects up to 70% ofSepsis-associated encephalopathy (SAE) affects up to 70% of patients in intensive care units with severe systemic infection. However, the exact pathological mechanisms behind SAE remain unclear. In this study, we aimed to investigate the protective effects of flavonoid components extracted from CCL seeds on SAE animals and evaluate the transcriptomic alterations in the hippocampus using RNA sequencing. Our results showed that CCL seed extract improved learning and memory abilities and structural integrity of the blood-brain barrier in CLP-induced SAE animal models. RNA sequencing revealed that CCL treatment reversed SAE-induced transcriptomic alterations in the hippocampus. Additionally, CCL significantly reduced inflammation (TNF-α， IL-2, and IL-6) and oxidative stress (MDA and SOD activity), as well as inhibited neuron apoptosis in brain tissues. Furthermore, CCL restored the PI3K/AKT signaling pathway, leading to Nrf2 nuclear translocation and HO-1 expression both in vitro and in vivo. The PI3K inhibitor LY294002 blocked CCL's anti-apoptotic, anti-inflammatory, and anti-oxidative effects, demonstrating that CCL's bioactivities are dependent on the PI3K/AKT signaling pathway. In conclusion, CCL exhibits significant neuroprotective properties and may be a promising candidate for further clinical trials in SAE treatment.