Echinacoside

Cisplatin-induced acute kidney injury (CI-AKI) is characterized by proximal tubular damage, increased oxidative stress, exacerbated inflammatory responses, and a rapid decline in renal function. Currently, no effective targeted therapies are available for acute kidney injury (AKI). Echinacoside (ECH), a natural phenylethanoid glycoside isolated fromEchinacea purpurea, possesses anti-inflammatory, antioxidant and cardiovascular protective effects, but its effects on CI-AKI remain unclear. This study aimed to elucidate the renoprotective effects and underlying mechanisms of ECH on AKI. In this study, we used a cisplatin-induced mouse model (in vivo) and a renal tubular epithelial cell model (in vitro). Male C57BL/6J mice were pretreated with ECH (25 or 50 mg/kg/day) for 4 days prior to cisplatin injection (20 mg/kg). Renal function, histopathology, oxidative stress markers, inflammatory parameters, and kidney injury molecule-1 expression were evaluated in both models. HK-2 cells were pretreated with ECH (25 or 100 μM) before cisplatin exposure (20 μM). Western blot analysis was used to evaluate NRF2/HO-1 signaling and NLRP3 inflammasome activation. Pharmacological inhibitors (ML385 for NRF2, ZnPP for HO-1) and NRF2 knockdown were employed to validate the underlying mechanism. ECH treatment significantly improved renal function, attenuated histopathological damage, and reduced oxidative stress and inflammatory markers both in vivo and in vitro. Mechanistically, ECH activated the NRF2/HO-1 signaling pathway and suppressed NLRP3 inflammasome activation. Inhibition or knockdown of NRF2 attenuated these protective effects. These findings demonstrate that ECH ameliorates CI-AKI by activating the NRF2/HO-1 signaling pathway to reduce oxidative stress and inflammation, suggesting its potential as a therapeutic agent for AKI.

Post-infarction heart failure is primarily driven by adverse ventricular remodeling, typified by macrophage-induced inflammation and excessive collagen accumulation. Echinacoside (ECH), a phenylethanol glycoside isolated from Cistanche, possesses diverse pharmacological properties; however, its cardioprotective actions remain incompletely understood.

To investigate the cardioprotective mechanisms of ECH, emphasizing its effects on macrophage polarization, collagen modulation, and molecular interactions STUDY DESIGN: A rat model of myocardial infarction (MI) was induced by ligation of the left anterior descending coronary artery, followed by a 28-day oral administration of ECH at 50 or 100 mg/kg/day.

Cardiac function was evaluated using echocardiography, while infarct size and myocardial fibrosis were analyzed through triphenyl tetrazolium chloride, Masson's trichrome, and Sirius red staining. Proteomic analysis was conducted to identify differentially expressed proteins and enriched signaling pathways. Macrophage phenotypes (M1 and M2) were characterized by immunofluorescence, quantitative real-time polymerase chain reaction, and ELISA. Molecular docking and 100-ns molecular dynamics simulations were performed to assess the binding of ECH to its targets. A pull-down assay combined with Western blotting confirmed direct interaction between ECH and Mrc1, while surface plasmon resonance was used to measure binding affinity.

ECH significantly reduced infarct size in a dose-responsive manner (high dose: 15% vs. 38% in MI controls, p < 0.001) and improved left ventricular ejection fraction (64.7% vs. 40.3%, p < 0.05). Proteomic profiling identified 1105 proteins with altered expression; ECH reversed MI-induced upregulation of collagen type I alpha 1 and α-smooth muscle actin, and normalized macrophage polarization markers. It downregulated pro-inflammatory M1 markers (CD86, iNOS) and anti-inflammatory M2 markers (CD206, Arg1), accompanied by reduced levels of tumor necrosis factor-α interleukin-10 and interleukin-6. These effects correlated with suppression of PI3K/AKT phosphorylation, and administration of the PI3K agonist 740 YP reversed the antifibrotic actions of ECH. Computational modeling demonstrated that ECH formed stable hydrogen-bond interactions with Mrc1 (binding energy -9.9 kcal mol⁻¹) and Mrc2 (-10.0 kcal mol⁻¹), with minimal root mean square deviation (root mean square deviation < 0.1 nm) across the 100-ns simulation. Functional binding assays corroborated strong ECH-Mrc1 affinity, in agreement with the docking predictions.

ECH attenuates post-MI ventricular remodeling by shifting macrophage polarization, inhibiting fibrotic signaling, and modulating PI3K-Akt activity. Its multitarget profile highlights its therapeutic relevance for ischemic heart failure, linking traditional herbal medicine with modern immunometabolic strategies.