• Korean Journal of Pharmacognosy
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• v.53 no.4
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• pp.181-191
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• 2022

As the incidence of skin cancer increases every year, non-surgical treatment methods for cancer are being sought. Esculetin, a natural dihydroxy coumarin, is attracting attention as a therapeutic agent for certain diseases, such as cancer, based on its broad pharmacological activity. In this study, the anticancer ability of esculetin was evaluated using the epidermoid carcinoma cell line A431. As a result of evaluating the apoptosis ability of esculetin by MTT assay, apoptosis was observed in a time-concentration-dependent manner regardless of the presence or absence of FBS. As a result of quantitative real-time PCR, esculetin reduced cyclin D1 mRNA in a time-concentration-dependent manner. In addition, as a result of western blotting, esculetin significantly inhibited phosphorylation of ERK, JNK, and p38 in a concentration-dependent manner. The results of this study suggest that esculetin has the potential to be used as an effective natural medicine for the treatment of skin cancer.

• Journal of the Society of Cosmetic Scientists of Korea
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• v.40 no.1
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• pp.89-94
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• 2014

Stem bark extracts of Fraxinus rhynchophylla Hance were found to contain two major bioactive components, esculetin and esculin. Esculetin substantially inhibited melanogenesis in B16F10 melanoma cells, with an $IC_{50}$ value of $2.8{\mu}M$, and reduced melanin synthesis in Melan-A cells. Moreover, esculetin suppressed melanin biosynthesis by inhibiting mushroom tyrosinase activity, with an $IC_{50}$ value of $40{\mu}M$. Taken together, these results suggest that esculetin could serve as an effective skin-lightening agent that inhibits melanin production by regulating the activity of melanogenic enzymes.

• Journal of Applied Biological Chemistry
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• v.64 no.3
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• pp.317-322
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• 2021

Among the different cardiovascular disorders (CVDs), the activation of platelets is a necessary step. Based on this knowledge, therapeutic treatments for CVDs that target the disruption of platelet activation are proving to be worthwhile. One such substance, a bioactive 6,7-dihydroxy derived from coumarin, is 6,7-Dihydroxy-2H-1-benzopyran-2-one (esculetin). This compound has demonstrated several pharmacological effects on CVDS as well as various other disorders including diabetes, obesity, and renal failure. In various reports, esculetin and its effect has been explored in experimental mouse models, human platelet activation, esculetin-inhibited collagen, and washed human platelets exhibiting aggregation via arachidonic acid. Yet, esculetin affected aggregation with agonists like U46619 or thrombin in no way. This study investigated esculetin and how it affected human platelet aggregation activated through U46619. Ultimately, we confirmed that esculetin had an effect on the aggregation of human platelets when induced from U46619 and clarified the mechanism. Esculetin interacts with the downregulation of both phosphoinositide 3-kinase/Akt and mitogen-activated protein kinases, important phosphoproteins that are involved in activating platelets and their signaling process. The effects of esculetin reduced TXA₂ production, phospholipase A₂ activation, and platelet secretion of intracellular granules (ATP/serotonin), ultimately causing inhibition of overall platelet aggregation. These results clearly define the effect of esculetin in inhibiting platelet activity and thrombus formation in humans.

• Korean Journal of Pharmacognosy
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• v.52 no.3
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• pp.127-133
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• 2021

Platelet activation plays a major role in cardiovascular disorders (CVDs). Thus, disrupting platelet activation represents an attractive therapeutic target on CVDs. Esculetin, a bioactive 6,7-dihydroxy derivative of coumarin, possesses pharmacological activities against obesity, diabetes, renal failure, and CVDs. In other report, the effect of esculetin has been examined in human platelet activation and experimental mouse models, and esculetin inhibited collagen- and arachidonic acid-induced platelet aggregation in washed human platelets. However, it had no effects on other agonists such as thrombin and U46619, and its mechanism is not also clearly known. This study investigated the effect of esculetin on collagen-induced human platelet aggregation, and we clarified the mechanism. Esuletin has effects on the down regulation of PI3K/Akt and MAPK, phosphoproteins that act in the signaling process in platelet aggregation. The effects of esculetin reduced of TXA₂ production and phospholipase A₂ activation, and intracellular granule secretion including ATP and serotonin, leading to inhibit platelet aggregation. These results clearly clarified the effect of esculetin in inhibiting platelet activity and thrombus formation in humans.

• Biomedical Science Letters
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• v.27 no.4
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• pp.270-276
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• 2021

Physiological agents trigger a signaling process called "inside-out signaling" and activated platelets promote adhesion, granule release, and conformational changes of glycoprotein IIb/IIIa (αIIb/β₃). Activated αIIb/β₃ interacts with fibrinogen and initiates a second signaling step called "external signaling". These two signaling pathways can cause hemostasis or thrombosis, and thrombosis is a possible medical problem in arterial and venous vessels, and platelet-mediated thrombosis is a major cause of cardiovascular disease (CVD). Therefore, modulating platelet activity is important for platelet-mediated thrombosis and cardiovascular disease. Esculetin is a coumarin-based physiologically active 6,7-dihydroxy derivative known to have pharmacological activity against obesity, diabetes, renal failure and CVD. Although some studies have confirmed the effects of esculetin in human platelet activation and experimental mouse models, it is not clear how esculetin has antiplatelet and antithrombotic effects. We confirmed the effect and mechanism of action of escultein on human platelets induced by collagen. As a result, esculetin decreased Ca²⁺ recruitment through upregulation of inositol 1, 4, 5-triphosphate receptor. In addition, esculetin upregulates cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)-dependent pathways and inhibits fibrinogen binding and thrombus contraction. Our results demonstrate the antiplatelet effect and antithrombotic effect of esculetin in human platelets. Therefore, we suggest that esculetin could be a potential phytochemical for the prevention of thrombus-mediated CVD.

• Korean Journal of Pharmacognosy
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• v.54 no.1
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• pp.1-8
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• 2023

The skin is an important barrier that protects the body from harmful environments such as UV rays. When the skin is repeatedly stimulated, such as UV rays, ROS and pro-inflammatory cytokines are overproduced. As a result, the proteins and nucleic acids that make up the skin are damaged, and aging occurs. Esculetin is known to have anti-inflammatory, antioxidant and UV-induced MMP-1 inhibitory effects. However, the inhibitory effect of MMP-1 on TNF-α-induced fibroblasts is not known. Therefore, in this study, the MMP-1 inhibitory effect of esculetin was confirmed in TNF-α-induced fibroblasts. As a result of confirming the cytotoxicity of esculetin in Hs68 cells by MTT assay, there was no significant toxicity up to 200 µM. As a result of real-time PCR and ELISA, it was confirmed that esculetin inhibited the expression of MMP-1. Esculetin did not inhibit MAPK (ERK, JNK, p38) phosphorylation, but inhibited phosphorylation of the mTOR-p70S6k signaling pathway. In addition, it was confirmed that the phosphorylation of the transcription factor NF-κB was inhibited. These results suggest that esculetin has potential as an anti-aging material.

• Korean Journal of Medicinal Crop Science
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• v.14 no.3
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• pp.148-152
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• 2006

Comparison of four phenolic compounds among three different parts of Panax ginseng C.A. Meyer was performed in this study. Contents of esculetin, p-coumaric acd, quercetin, maltol in the ethyl acetate fraction were determinated by HPLC analysis. The main root has a highest concentration of p-coumaric acid and the leave has a highest concentration of quercetin and esculetin. This ethyl acetate fraction of the leaves exhibited higher depigmenting activity and lower cell toxicity than the other parts of ginseng. In addition, it showed that quercetin and esculetin among phenolic compounds highly inhibited melanin biosynthesis in ginseng. It implies that leaves of ginseng may be used as skin whitening herb. Quercetin and esculetin proved to be active compounds in the leaves of ginseng.

• Biomolecules & Therapeutics
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• v.24 no.2
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• pp.178-183
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• 2016

Naturally occurring coumarin compounds have received substantial attention due to their pharmaceutical effects. Esculetin is a coumarin derivative and a polyphenol compound that is used in a variety of therapeutic and pharmacological strategies. However, its effect on aldose reductase activity remains poorly understood. In this study, the potential beneficial effects of esculetin on lenticular aldose reductase were investigated in galactose-fed (GAL) rats, an animal model of sugar cataracts. Cataracts were induced in Sprague-Dawley (SD) rats via a 50% galactose diet for 2 weeks, and groups of GAL rats were orally treated with esculetin (10 or 50 mg/kg body weight). In vehicle-treated GAL rats, lens opacification was observed, and swelling and membrane rupture of the lens fiber cells were increased. Additionally, aldose reductase was highly expressed in the lens epithelium and superficial cortical fibers during cataract development in the GAL rats. Esculetin reduced rat lens aldose reductase (RLAR) activity in vitro, and esculetin treatment significantly inhibited lens opacity, as well as morphological alterations, such as swelling, vacuolation and liquefaction of lens fibers, via the inhibition of aldose reductase in the GAL rats. These results indicate that esculetin is a useful treatment for galactose-induced cataracts.

• The Korean Journal of Physiology and Pharmacology
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• v.7 no.5
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• pp.283-287
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• 2003

While nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) is beneficial for host survival, it is also detrimental to the host. Thus, regulation of iNOS gene expression may be an effective therapeutic strategy for the prevention of unwanted reactions at various pathologic conditions. During the screening process for the possible iNOS regulators, we observed that esculetin is a potent inhibitor of cytokine-induced iNOS expression. The treatment of 3T3-L1 adipocytes with the tumor necrosis factor-${\alpha}$ (TNF) induced iNOS expression, leading to enhanced NO production. TNF-induced NO production was inhibited by esculetin in a dose-dependent manner. Esculetin inhibited the TNF-induced NO production at the transcriptional level through suppression of iNOS mRNA and subsequent iNOS protein expression. These results suggest esculetin, a component of natural products, as a naturally occurring, nontoxic means to attenuate iNOS expression and NO-mediated cytotoxicity.

• Journal of Physiology & Pathology in Korean Medicine
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• v.33 no.1
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• pp.25-30
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• 2019

This study was aimed to examine the synergetic effects of photochemopreventive external agents composed of inorganic ZnO and esculetin. Zinc oxide (ZnO) is widely used in sunblocks because of its excellent biostability and little toxicity. Esculetin derived from Citrus Peel has an anti-oxidative effect. We made the hollow-shaped ZnO microsphere (MS), soaked it with esculetin (EZnO). We used SKH-1 mice to measure the photodamaging effects of UVB. The mice were divided into five groups as follows; UVB nontreated group (N), vehicle (C), esculetin (E), ZnO MS (ZnO), esculetin + ZnO MS(EZno) group. Each group of samples was topically applied to the dorsal skins before the UVB irradiation. The changes of collagen fibers in the skin tissues were observed by H & E staining and Van Gieson staining. The expression of mast cells in skin tissue was observed by immunohistochemical staining of tryptase present in the mast cell granules. Expression of inflammatory cytokines such as TNF-${\alpha}$, IL-$1{\beta}$, and MMP-9, which plays an essential role in wrinkle formation, was measured by RT-PCR. Interestingly, the composition of collagen fibers was better in the EZnO applied group than in the E or ZnO group. Moreover, mast cell expression and the expression of TNF-${\alpha}$, IL-$1{\beta}$, and MMP-9 mRNA were markedly suppressed in the EZnO group, indicating that the synergetic effects of esculetin and ZnO were excellent.