Pharmacological activities of esculin and esculetin: A review

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TL;DR

This review summarizes the pharmacological activities of esculin and esculetin, two coumarin compounds from Cortex Fraxini, highlighting their antioxidant, anti-inflammatory, anti-tumor, antidiabetic, and antibacterial effects. Key mechanisms include free radical scavenging, modulation of the Nrf2 pathway, inhibition of NF-κB and MAPK signaling, and regulation of cell cycle and apoptosis. These findings suggest that both compounds have potential as therapeutic agents for various diseases, though further in vivo studies are needed.

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**Background:** Cortex Fraxini (Qinpi) is a traditional Chinese herbal medicine used for over 2000 years to treat diarrhea, bacillary dysentery, conjunctivitis, gout, and hyperuricemia. Its active constituents are coumarins, with esculin (a glycosidic coumarin) and esculetin (its aglycone metabolite) being the most studied. Esculin has low oral bioavailability (0.62%), while esculetin has higher bioavailability (19%). This review aims to provide comprehensive information on the pharmacological activities of these compounds.

**Methods:** A literature search was conducted using PubMed, Web of Science, and CNKI databases with keywords including "esculin," "esculetin," "Cortex Fraxini," "pharmacology," "tumor," "oxidative stress," "inflammation," "bacteria," and "diabetes." The review includes in vivo and in vitro studies on various pharmacological activities.

**Key Results:** - **Anti-inflammatory:** Esculin inhibits NF-κB signaling, reducing pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in models of ulcerative colitis, arthritis, acute lung injury, and acute kidney injury. Esculetin similarly inhibits NF-κB, STAT1/STAT3, and MAPK pathways, reducing nitric oxide, prostaglandin E2, and cytokines in LPS-activated macrophages and in vivo models of acute lung injury and colitis. - **Anti-tumor:** Esculin reduces growth, adhesion, and migration of glioblastoma U87 cells, decreases viability of triple-negative breast cancer MDA-MB-231 cells via p53-p21 pathway, and inhibits migration of nasopharyngeal carcinoma HNE-3 cells by reducing MMP-2 and MMP-9. Esculetin induces G0/G1 or S-phase cell cycle arrest in colorectal cancer LoVo cells, leukemia HL-60 cells, and hepatocellular carcinoma SMMC-7721 cells, and promotes mitochondrial apoptosis by upregulating Bax, downregulating Bcl-2, and activating caspases. It also inhibits migration of various cancer cells by downregulating MMPs. - **Antioxidant:** Esculin scavenges free radicals (EC50 = 0.141 μM), reduces nitric oxide production, and enhances SOD and GSH activities in various models. Esculetin shows ROS scavenging activity (40% at 1 µg/mL, 75% at 10 µg/mL in V79-4 cells), activates Nrf2 pathway, and increases antioxidant enzymes (SOD, catalase, GPx) in vivo. - **Antidiabetic:** Esculin (20 mg/kg/day for 2 weeks) reduces blood glucose and hepatic glucose-6-phosphatase in diabetic mice, and ameliorates diabetic nephropathy and neuropathy. Esculetin (100 mg/kg in diet) lowers blood glucose and glycosylated hemoglobin, reduces G6Pase activity, and improves insulin sensitivity in diabetic mice. - **Antibacterial:** Esculin inhibits Gram-positive (Staphylococcus aureus, Enterococcus faecalis) and Gram-negative bacteria (Escherichia coli, Salmonella), and various fungi. Esculetin inhibits E. coli O157:H7 survival and represses Shiga-like toxin stx2 gene. - **Immunomodulatory:** Esculetin reduces IgE, IgG2a, and histamine levels, suppresses Th17/Th2 cytokines, and promotes Treg differentiation in models of atopic dermatitis and asthma. - **Anti-atherosclerotic:** Esculetin reduces blood triglycerides, inhibits vascular smooth muscle cell proliferation, and prevents LDL oxidation. - **Antithrombotic:** Esculin and its pentasulfate reduce thrombus weight and prolong clotting time in rat models.

**Clinical Implications:** The review highlights the therapeutic potential of esculin and esculetin for inflammatory diseases, cancers, diabetes, infections, and cardiovascular conditions. However, most studies are preclinical; further in vivo and clinical research is needed to confirm efficacy and safety, and to address bioavailability issues (especially for esculin).