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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE249589 | GEO | 2024/06/08

REPOSITORIES: GEO

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Project description:Background: Sepsis-associated encephalopathy (SAE) is a common and severe complication of sepsis. While several studies have reported the proteomic alteration in plasma, urine, heart, etc. of sepsis, few research focused on the brain tissue. This study aims at discovering the differentially abundant proteins in the brains of septic rats to identify biomarkers of SAE. Methods: The Prague-Dawley rats were randomly divided into sepsis (n = 6) or sham (n = 6) groups, and then the whole brain tissue was dissected at 24 h after surgery for further protein identification by TMT-LC–MS/MS-based proteomics. Ingenuity pathway analysis, Gene ontology knowledgebase, and STRING database are used to explore the biological significance of proteins with altered concentration. Results: Among the total of 3163 proteins identified in the brain tissue, 57 were increased while 38 were decreased in the sepsis group compared to the sham group. Bioinformatic analyses suggest that the differentially abundant proteins are highly related to cellular microtubule metabolism, energy production, nucleic acid metabolism, neurological disease, etc. Additionally, acute phase response signaling was possibly activated and PI3K/AKT signaling was suppressed during sepsis. An interaction network established by IPA revealed that Akt1, Gc-globulin, and ApoA1 were the core proteins. The increase of Gc-globulin and the decrease of Akt1 were confirmed by Western blot. Conclusions: Based on the multifunction of these proteins in several brain diseases, we first propose that Gc-globulin, ApoA1, PI3K/AKT pathway, and acute phase response proteins (hemopexin and cluster of alpha-2-macroglobulin) can potentially be diagnosis biomarkers, therapeutic targets, and prognosis indicators of SAE. These results may provide new insights into the pathologic mechanism of SAE, yet further research is required to explore the functional implications and clinical applications of the differentially abundant proteins in the brains of sepsis group.

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

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