Pharmacological and Therapeutic Applications of Esculetin

Abstract

Esculetin is a coumarin compound, which belongs to the class of benzopyrone enriched in various plants such as Sonchus grandifolius, Aesculus turbinata, etc. Free radicals lead to the development of oxidative stress causing inflammation, arthritis, cancer, diabetes, fatty liver disease, etc. These further reduce the efficacy of anticancer drugs, activate inflammatory signaling pathways, degrade joints and cartilage, and disrupt the glycemic index and normal function of liver enzymes. For instance, the current treatment modalities used in arthritis such as non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatoid drugs, and lipoxygenase inhibitors present limited efficacy and adverse effects. Thus, there is a constant need to find newer and safer alternatives. Esculetin has an immense antioxidative potential thereby alleviating arthritis, diabetes, malignancies, and hepatic disorders. Structurally, esculetin contains two hydroxyl groups, which enhance its ability to function as an antioxidant by inhibiting oxidative stress in pathological conditions. Leukotriene B4 synthesis, NF-κB and MPAK pathway activation, and inflammatory cytokine production are the main causes of bone and joint deterioration in arthritis, whereas esculetin treatment reverses these factors and relieves the disease condition. In contrast, lipid peroxidation caused by upregulation of TGF-β-mediated expression and dysfunction of antioxidant enzymes is inhibited by esculetin therapy, thus reducing liver fibrosis by acting on the PI3K/FoxO1 pathway. Therefore, targeting NF-κB, pro-inflammatory cytokines, TGF-β and oxidative stress may be a therapeutic strategy to alleviate arthritis and liver fibrosis.

Keywords: arthritis; cancer; chromatography; diabetes; esculetin; fatty liver; inflammation; oxidative stress; pharmacokinetic.

Figure 1

Structure of coumarin compounds.

Figure 2

Anti-cancer effects of esculetin: Esculetin downregulates the IGF1/PI3K/AKT, IGF1/MAPK, JNK, ERK, NF-κB, P27, Survivin, and Bcl-2. Esculetin also inhibits cell proliferation by inhibiting the STAT3 phosphorylation and cyclin D1, D3, DK4, and DK2, leading to apoptosis and suppression of cancer. ↑: Overexpression; ↓: low expression; ⊣: inhibition.

Figure 3

Antioxidant effect of esculetin: Esculetin blocks the activity of H₂O₂ which further inhibits the MMP-1 and lipid peroxidation in cell membranes. Esculetin prevents the brain from amyloid-induced oxidative stress via activating the Nrf2 and increasing the levels of glutathione, thus inhibiting oxidative stress. ↑: Overexpression; ↓: low expression; ⊣: inhibition.

Figure 4

Anti-inflammatory effects of esculetin: Esculetin inhibits the action of cyclooxygenase, NF-κB, NO, LPS, heme oxygenase, RhoA/Rho kinase pathway, and ERK1/2 phosphorylation, inhibiting the inflammatory reactions. ↑: Overexpression; ↓: low expression; ⊣: inhibition.

Figure 5

Anti-arthritic effects of esculetin: Esculetin inhibits the degradation of cartilage through the suppression of MMP-1, MMP-3, MMP-13, and leukotriene B4, leading to the inhibition of arthritis. ⊣: inhibition.

Figure 6

Anti-diabetic effects of esculetin: Esculetin downregulates the expression of PPARγ, H3S10phospho, H3S28phospho, H3K9Ac, H3K4me2, and H3K9me2, hyperacetylation of histone H3 lysine (K) 14 and 18 and attenuates diabetes and its associated complications. ↑: Overexpression; ⊣: inhibition. •: RBC; •: Sugar.

Figure 7

Hepatoprotective effects of esculetin: Esculetin downregulates the expression of SREBP1c, fatty acid synthetase, and TGF-β-mediated hepatic fibrosis. Esculetin also activates AMPK signaling pathway and inhibits the action of PPARγ, Fasn, Pap, and Dgat2, thus inhibiting the pathogenesis of the fatty liver disease. ↑: Overexpression; ⊣: inhibition.

Figure 8

Synthesis of esculetin using microwave irradiation method.

Figure 9

Synthesis of esculetin using p-benzoquinone, sulfuric acid and acetoacetate.

Figure 10

Synthesis of esculetin using p-benzoquinone, sulfuric acid and acetic anhydride.

Figure 11

Synthesis of esculetin from glucose.