Esculeoside A

Esculeoside A is an orally active spirastan steroidal alkaloid glycoside found in the ripe fruits of Lycopersicon esculentum var. cerasiforme and Lycopersicon esculentum. It serves as a cardioprotective and hypoglycemic agent. Esculeoside A modulates the NF-κB and Nrf2/Keap1 signaling pathways in cardiac tissues, reducing inflammation and apoptosis while preventing cardiomyocyte hypertrophy and lowering serum lipid levels. It also regulates glucose metabolism by modulating the expression of IRS-1, GCK, AMPK, and PEPCK, ultimately lowering fasting blood glucose and enhancing glucose tolerance. Furthermore, Esculeoside A inhibits the TLR4/p-NFκB signaling pathway, hindering dendritic cell maturation and allogeneic T cell proliferation, while suppressing the growth of breast cancer and melanoma cells. Additionally, it inhibits ACAT activity, thereby reducing cholesterol ester accumulation in macrophages. Esculeoside A is relevant for research into diabetic cardiomyopathy, type 2 diabetes, atopic dermatitis, tumors, and atherosclerotic diseases.

Esculeoside A, at concentrations ranging from 10 to 300 μM with a preincubation period of 1 hour followed by 24-hour LPS stimulation, exhibits cytotoxicity only at 300 μM in LPS-stimulated mouse bone marrow-derived dendritic cells (DCs), with no significant cytotoxic effects at 10, 30, and 100 μM. It reduces IL-12 and TNF-α cytokine production in these DCs in a dose-dependent manner. Additionally, after a 1-hour preincubation and overnight LPS stimulation, Esculeoside A inhibits phenotypic maturation of LPS-stimulated DCs by reducing surface expression of CD86 and MHC-II in a dose-dependent fashion. The compound also restores the endocytic capacity of LPS-stimulated DCs, reversing LPS-induced functional maturation when used at 30-100 μM. Following overnight LPS stimulation, mitomycin C treatment for 1 hour, and 5-day coculture, Esculeoside A diminishes the allostimulatory capacity of these DCs, decreasing their ability to induce allogeneic CD3+ T cell proliferation. Furthermore, at concentrations of 10-100 μM, it inhibits the TLR4-MyD88-NFκB signaling pathway in LPS-stimulated mouse bone marrow-derived DCs, with significant inhibition of TLR4 expression at 100 μM. Esculeoside A also inhibits the growth of MCF7 human breast cancer cells and B16F2F mouse melanoma cells, with GI50 values of 13.3 μM and 7.9 μM, respectively. At a concentration of 100 μM for 24 hours, it significantly inhibits cholesterol ester accumulation in human monocyte-derived macrophages induced by acetylated low-density lipoprotein, showing no cytotoxicity at this concentration.

Esculeoside A, when administered orally at a dose of 100 mg/kg daily for 12 weeks, can activate the Nrf2/antioxidant/NF-κB axis, improve cardiac function, and reduce oxidative stress, inflammation, and apoptosis in streptozotocin-induced diabetic cardiomyopathy in male Wistar rats without affecting glucose or insulin levels. In healthy male Wistar rats, the same regimen of Esculeoside A lowers lipids and exerts antioxidant effects without altering cardiac function, glucose, or insulin levels. For db/db mice, Esculeoside A (100 mg/kg orally, once daily for 56 consecutive days) lowers fasting blood glucose, enhances glucose tolerance, and regulates liver metabolism-related proteins, increasing glucose tolerance by up to 20.9% two hours after glucose loading. Additionally, oral administration of Esculeoside A at 100 mg/kg per day for 90 days in apolipoprotein E-deficient mice significantly reduces total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels by up to 45%, while decreasing aortic atherosclerotic lesion areas by 52%.