Pharmacological activities of esculin and esculetin: A review.

Esculin and esculetin are 2 widely studied coumarin components of Cortex Fraxini, which is a well-known herbal medicine with a 2000-year history. In vivo and in vitro studies have demonstrated that both have a variety of pharmacological activities, including antioxidant, anti-tumor, anti-inflammatory, antibacterial, antidiabetic, immunomodulatory, anti-atherosclerotic, and so on. Their underlying mechanisms of action and biological activities include scavenging free radicals, modulating the nuclear factor erythroid 2-related factor 2 pathway, regulating the cell cycle, inhibiting tumor cell proliferation and migration, promoting mitochondrial pathway apoptosis, inhibiting the NF-κB and MAPK signaling pathways, regulating CD4+ T cells differentiation and associated cytokine release, inhibiting vascular smooth muscle cells, etc. This review aims to provide comprehensive information on pharmacological studies of esculin and esculetin, which is of noteworthy importance in exploring the therapeutic potential of both coumarin compounds.

Esculin alleviates LPS-induced acute lung injury via inhibiting neutrophil recruitment and migration.

OBJECTIVES: Acute lung injury (ALI) poses a serious threat to human health globally, particularly with the Coronavirus 2019 (COVID-19) pandemic. Excessive recruitment and infiltration of neutrophils is the major etiopathogenesis of ALI. Esculin, also known as 6,7-dihydroxycoumarin, is a remarkable compound derived from traditional Chinese medicine Cortex fraxini. Accumulated evidence indicates that esculin has potent anti-inflammatory effects, but its pharmaceutical effect against ALI and potential mechanisms are still unclear. METHODS: This study evaluated the protective effect of esculin against ALI by histopathological observation and biochemical analysis of lung tissues and bronchoalveolar lavage fluid (BALF) in lipopolysaccharide (LPS)-challenged ALI mice in vivo. The effects of esculin on N-formyl-met-leu-phe (fMLP)-induced neutrophil migration and chemotaxis were quantitatively assessed using a Transwell assay and an automated cell imaging system equipped with a Zigmond chamber, respectively. The drug affinity responsive target stability (DARTS) assay, in vitro protein binding assay and molecular docking were performed to identify the potential therapeutic target of esculin and the potential binding sites and pattern. RESULTS: Esculin significantly attenuated LPS-induced lung pathological injury, reduced the levels of pro-inflammatory cytokines in both BALF and lung, and suppressed the activation of NF-κB signaling. Esculin also significantly reduced the number of total cells and neutrophils as well as myeloperoxidase (MPO) activity in the BALF. Esculin impaired neutrophil migration and chemotaxis as evidenced by the reduced migration distance and velocity. Furthermore, esculin remarkably inhibited Vav1 phosphorylation, suppressed Rac1 activation and the PAK1/LIMK1/cofilin signaling axis. Mechanistically, esculin could interact with ß2 integrin and then diminish its ligand affinity with intercellular adhesion molecule-1 (ICAM-1). CONCLUSIONS: Esculin inhibits ß2 integrin-dependent neutrophil migration and chemotaxis, blocks the cytoskeletal remodeling process required for neutrophil recruitment, thereby contributing to its protective effect against ALI. This study demonstrates the new therapeutic potential of esculin as a novel lead compound.

The pharmacological and pharmacokinetic properties of esculin: A comprehensive review.

Cortex fraxini is a widely used traditional Chinese medicine. Esculin is one of the main active ingredients of Cortex fraxini and has attracted more and more attention from scholars. The purpose of the review is to systematically review relevant studies on the pharmacological effects and pharmacokinetic characteristics of esculin to support its further application as therapeutic agents. Pharmacological studies have shown that the anti-inflammatory and anti-oxidative stress effects of esculin are outstanding. This indicates that esculin is promising to be used to treat a variety of diseases closely related to inflammation and oxidative damage. Esculin has anti-diabetic effect, which is closely related to improving pancreas damage, promoting insulin release, and enhancing glucose homeostasis. In addition, esculin has anti-cancer, antibiosis, anti-virus, neuroprotection, anti-thrombosis and treating eye diseases properties. Pharmacokinetic studies show that esculin can be quickly and evenly distributed in the body. However, the first pass effect of esculin is serious. In short, esculin is promising to treat many diseases, but further high quality studies are needed to firmly establish the clinical efficacy of esculin.

Venoplant Effect in the Management of the Post-operative Oedema in Plastic Surgery: Results of a Randomized and Controlled Clinical Trial.

BACKGROUND: Post-operative oedema and ecchymosis represent early post-operative complications, impacting negatively on the final aesthetic outcome of each surgical procedure. In particular, such complications are very frustrating for patients and-sometimes-are difficult to be managed by surgeons. Several strategies are available for managing oedema, although some side effects have been reported. A new promising compound for the management of oedema is Venoplant, and this study aims to assess its effectiveness in decreasing post-operative oedema. METHODS: Patients were randomly allocated for receiving three different treatments: (1) Venoplant tablets and Venoplant gel; (2) only Venoplant tablets; and (3) not treated with Venoplant. The aesthetical outcome has been evaluated using the Global Aesthetic Improvement Scale (GAIS), compiled by both patient and clinician. The GAIS scale was administered several times: the day following the surgical procedure (T0) after 3 days (T1), after 7 days (T2), after 15 days (T3) and after 1 month (T4). RESULTS: Forty-three patients participated in the study. According to patient's evaluations, at T0 in Group 1 and in Group 2 a significant statistical difference was found compared to the control group (p < 0.001 and p < 0.05, respectively). Over time, a significant reduction in swelling and ecchymosis was reported by patients treated with Venoplant (tablets alone or in combination with gel) compared to the control group. According to the physician's assessment, during the different time points of evaluation, a significant reduction in post-operative oedema in Group 1 and in Group 2 compared to the control group was found. CONCLUSION: Venoplant represents a valid therapeutic strategy for the management of post-operative oedema, guaranteeing a good level of patient satisfaction, in the absence of common side effects which are often associated with other therapies. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Esculin ameliorates cognitive impairment in experimental diabetic nephropathy and induces anti-oxidative stress and anti-inflammatory effects via the MAPK pathway.

Esculin is a derivative of coumarin, which is also an active ingredient of ash bark, and has antibacterial, anti-inflammatory, anti­allergy and skin protective effects. The underlying mechanism and protective effects of esculin on cognitive impairment in experimental diabetic nephropathy (DN) was investigated in the present study. Male C57BL/6J 6­week­old mice were injected intravenously with a single dose of streptozotocin (STZ; 30 mg/kg). At 2 weeks after the STZ injection, mice received intravenous injection with 5, 10 or 20 mg/kg esculin for 2 weeks. In the present study, the results of the Morris water maze test demonstrated that esculin significantly improved behavior and recognition memory in STZ­induced diabetic rats. Furthermore, treatment of STZ­induced diabetic rats with esculin significantly inhibited tumor necrosis factor­α, interleukin­6, malondialdehyde, monocyte chemoattractant protein­1 and intracellular adhesion molecule­1 activity levels, and increased the activity of superoxide dismutase, in the kidney, which was determined by ELISA. In addition, esculin treatment significantly suppressed the renal protein expression of activator protein 1, phosphorylated (p)­p38 mitogen activated protein kinase (MAPK) and p­c­Jun N­terminal kinase, and increased p­extracellular signal regulated kinase 1/2 protein expression, in STZ­induced diabetic rats, as determined by western blotting. These results indicate that esculin may ameliorate cognitive impairment in experimental DN, and exert anti­oxidative stress and anti­inflammatory effects, via the MAPK signaling pathway. Thus, it may serve as a potential target for cognitive impairment of DN in the future.

Esculin attenuates endotoxin shock induced by lipopolysaccharide in mouse and NO production in vitro through inhibition of NF-κB activation.

Esculin, a coumarin compound derived from the traditional Chinese herbs such as Cortex Fraxini, has long been used for treating inflammatory and vascular diseases. In present study, we analyzed the role of esculin against macrophages and endotoxin shock induced by lipopolysaccharide (LPS) in mice. Here, we demonstrated that esculin suppressed inflammatory reactions in macrophages and protected mice from LPS-induced endotoxin shock. We found that esculin significantly inhibited the production of nitric oxide (NO) production via the inhibition of nuclear factor-κB (NF-κB) activation in macrophages. In animal model, esculin pretreatment significantly improved the survival rate of mice. LPS-induced increase of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in serum, lung, liver and kidney were markedly inhibited by esculin. IL-10, an anti-inflammatory cytokine, was up-regulated by esculin. Moreover, the histopathological analyses showed that esculin significantly attenuated the tissues injury of lung, liver, kidney in endotoxic mice. In addition, esculin significantly diminished the protein expression of NF-κB p65 in lung, liver, kidney, which resulted in lower levels of inflammatory mediators. These results suggest that esculin may be a potential drug for treatment of various inflammatory diseases.

Esculin Inhibits the Inflammation of LPS-Induced Acute Lung Injury in Mice Via Regulation of TLR/NF-κB Pathways.

In this study, we investigated anti-inflammatory effects of esculin (ESC) on lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced in mice by intratracheal instillation of LPS, and ESC (20 and 40 mg/kg) was given orally 1 h prior to LPS administration. After 6 h, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. ESC pretreatment decreased LPS-induced evident lung histopathological changes, lung wet-to-dry weight ratio, and lung myeloperoxidase activity. In addition, pretreatment with ESC inhibited inflammatory cells and proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1ß, and interleukin-6 in BALF. Furthermore, we demonstrated that ESC inhibited the Toll-like receptor-2 (TLR2), Toll-like receptor-4 (TLR4), myeloid differentiation primary response gene-88 (MyD88), and nuclear factor-κB (NF-κB) p65 in LPS-induced ALI. The results indicated that the ESC had a protective effect on LPS-induced ALI in mice.

Antioxidant and intestinal anti-inflammatory effects of plant-derived coumarin derivatives.

BACKGROUND: Coumarins, also known as benzopyrones, are plant-derived products with several pharmacological properties, including antioxidant and anti-inflammatory activities. Based on the wide distribution of coumarin derivatives in plant-based foods and beverages in the human diet, our objective was to evaluate both the antioxidant and intestinal anti-inflammatory activities of six coumarin derivatives of plant origin (scopoletin, scoparone, fraxetin, 4-methyl-umbeliferone, esculin and daphnetin) to verify if potential intestinal anti-inflammatory activity was related to antioxidant properties. METHODS: Intestinal inflammation was induced by intracolonic instillation of TNBS in rats. The animals were treated with coumarins by oral route. The animals were killed 48 h after colitis induction. The colonic segments were obtained after laparotomy and macroscopic and biochemical parameters (determination of glutathione level and myeloperoxidase and alkaline phosphatase activities) were evaluated. The antioxidant properties of these coumarins were examined by lipid peroxidation and DPPH assays. RESULTS: Treatment with esculin, scoparone and daphnetin produced the best protective effects. All coumarin derivatives showed antioxidant activity in the DPPH assay, while daphnetin and fraxetin also showed antioxidant activity by inhibiting lipid peroxidation. Coumarins, except 4-methyl-umbeliferone, also showed antioxidant activity through the counteraction of glutathione levels or through the inhibition of myeloperoxidase activity. DISCUSSION: The intestinal anti-inflammatory activity of coumarin derivatives were related to their antioxidant properties, suggesting that consumption of coumarins and/or foods rich in coumarin derivatives, particularly daphnetin, esculin and scoparone, could prevent intestinal inflammatory disease.

[The clinical efficacy and safety study of Esculin and Digitalis glycosides Eye Drops in treating ametropic asthenopia].

OBJECTIVE: To study the clinical efficacy and safety of the Esculin and Digitalis glycosides Eye Drops used in the patients of ametropic asthenopia. METHODS: Multicenter clinical trial. Asthenopia patients were chosen from eleven hospitals cross China from July, 2008 to January, 2009. The experiment was conducted asthenopia patients who used the Esculin and Digitalis glycosides Eye Drops for 4 weeks continuously. Symptoms of asthenopia, UCVA (uncorrected vision acuity), refraction, amplitude of accommodation, accommodative lag, accommodative sensitivity and positive/negative relative accommodation were measured at different time points, such as treated before, 1 week and 4 week in treated after. RESULTS: After the 4-week's use of Esculin and Digitalis glycosides Eye Drops, each subjective symptom of the patients was decreased significantly (F=353.30, P<0.05). In addition, most of the objective exams of accommodation ability were significantly improved, such as UCVA (left eye: F=23.39, P<0.05; right eye: F=15.62, P<0.05), refraction (left eye: F=10.34, P<0.05; right eye: F=17.13, P<0.05), amplitude of accommodation (left eye: F=14.46, P<0.05; right eye: F=8.29, P<0.05; eyes: F=13.86, P<0.05), accommodative lag (F=14.89, P<0.05) and accommodative sensitivity (left eye: F=62.67, P<0.05; right eye: F=68.77, P<0.05; eyes: F=82.74, P<0.05). And no patient appeared any adverse reaction in whole experiment. CONCLUSIONS: Esculin and Digitalis glycosides Eye Drops is effective and safety for use in the patients of ametropia asthenopia.

Prescription pattern for treatment of hemorrhoids under the universal coverage policy of Thailand.

The Universal Coverage Policy (UCP) or "30 Baht Scheme" was launched in Thailand in 2001. The policy caused a cutback in the budgets of all public hospitals and health service centers. Traditional medicine was then viewed as an alternative to save costs. This study examines whether this had any influence on hemorrhoid treatment prescription patterns, ratio of traditional/modern medicine, or the cost of hemorrhoid treatment after the UCP was implemented at a community hospital. The traditional medicine prescribed was Petch Sang Kart and the modern alternative was Proctosedyl. All hemorrhoid prescriptions at a community hospital from October 2000 to January 2003 were surveyed. Segmented Regression Analysis was applied to evaluate prescription trends, the ratios between the types of medicine, and the hemorrhoid treatment cost. A total of 256 prescriptions were analyzed. The average number of traditional medicine prescriptions per month were more than modern medicine (41 versus 16). During the study period, the trend of modern medicine use and the treatment cost was decreased (p < 0.01). The ratio of traditional/modern medicine increased 0.2 times (p = 0.02).

Inhibitory effect of esculin on oxidative DNA damage and carcinogenesis induced by N-nitrosobis(2-oxopropyl)amine in hamster pancreas.

The effects of esculin, a natural coumarin compound, on the formation of 8-oxo-2'-deoxyguanosine (8-oxodG) and carcinogenesis induced by a chemical carcinogen, N-nitrosobis(2-oxopropyl)amine (BOP), were examined in the pancreas of female Syrian golden hamsters. Animals were given a diet containing esculin for 7 days, and killed 4~h after BOP treatment, and the contents of 8-oxodG were measured in the nuclear DNA of the pancreas. Esculin suppressed significantly the increase in the 8-oxodG content of hamster pancreas induced by BOP. Furthermore, the effect of esculin on the rapid production model experiment for pancreatic carcinogenesis using BOP was investigated. Esculin was given ad libitum as a 0.05% aqueous solution during either the initiation or promotion phases. The incidence of invasive tumors in animals given esculin during the initiation phase was significantly lower than in the control group, while the incidence in animals given esculin during the promotion phase showed no significant change. These results suggest that the intake of esculin has an inhibitory effect on BOP-induced oxidative DNA damage and carcinogenesis in hamster pancreas.

[Pharmacological activity of immunomodulators in adjuvant arthritis]. / Farmokologicheskaia aktivnost' immunokorrektorov pri ad''iuvantnom artrite.

Clinical features and functional activity of T- and B-cells were studied on the model of adjuvant arthritis which is the disease associated with activation of B-cells after monotherapy of rats with IM-1 (B-cell stimulator), dibazol (T-cell stimulator), alpha-tocopherol acetate (cintrol). It was established that B cells are most sensitive to the stimulation while T-cell reaction to the stimulators in disease is inhibited. Therefore, at early stages of arthritis and, probably, in other inflammatory diseases of autoimmune origin, stimulators of B-cells can be used for prophylaxis and treatment while at late stages--stimulators of T-cells.

Effect of a total extract from Fraxinus ornus stem bark and esculin on zymosan- and carrageenan-induced paw oedema in mice.

This study investigates the total ethanol extract (TE) of the stem bark of Fraxinus ornus and its constituent esculin (EN). They inhibited classical pathway (CP) and alternative pathway (AP) of complement activation in mouse serum. After intraperitoneal administration the total extract displayed antiinflammatory activity in both zymosan- and carrageenan-induced paw oedema in mice. The results suggest that the traditional use of Fraxinus ornus stem bark extracts in the treatment of inflammatory disorders is at least partially due to its coumarin constituents.

[Our experience in using the preparation Proctosedyl from the Roussel firm in pregnant women with hemorrhoids]. / Nashiiat opit ot prilaganeto na preparata "Proktosedil" na firma "Rusel" pri bremenni s khemoroidi.

The therapeutical efficacy of PROCTOSEDYL (Rousel Ltd., France) was investigated in 25 pregnant women with chronic hemorrhoids. Excellent results, including elimination of clinical symptoms and good tolerability, were achieved in 100% of the cases by the local conservative treatment only, which makes Proctosedyl especially suitable for application during pregnancy.

Comparative efficacy and tolerability of two ointment and suppository preparations ('Uniroid' and 'Proctosedyl') in the treatment of second degree haemorrhoids in general practice.

A multi-centre general practice, open study was carried out in 89 patients with second degree haemorrhoids to compare the efficacy and tolerability of two antibiotic-corticosteroid combinations ('Uniroid' and 'Proctosedyl') in ointment and suppository formulations. Patients were allocated at random into 4 groups and received treatment with one of the trial preparations for 1, 2 or 3 weeks, as required, with weekly assessments of response. There were no significant differences between the various groups at the start of treatment. Significant improvement occurred in all groups during treatment. Both suppository and ointment formulations were broadly comparable and control of symptoms was achieved from Week 2 onwards, building up to levels in excess of 90% after 3 weeks of therapy. With regard to the symptoms of pain and itching, suppositories gave marginally greater relief in the early stages of treatment, while both ointment and suppositories were associated with similar reduction in bleeding from haemorrhoids. Whereas both suppository formulations were about equal in reducing anal discharge, 'Uniroid' ointment was clinically superior to 'Proctosedyl' ointment in controlling this symptom over the 3-week trial period. No unwanted effects were experienced attributable to treatment. No statistically significant differences between the two ointment and the two suppository formulations were identified in this study and all four preparations were found to be efficacious in the majority of patients studied.

[Dynamics of the inflammatory process caused by carrageenin administration during experimental therapy]. / Dinamika protsessa vospaleniia, vyzvannogo vvedeniem karagenina, pri éksperimental'noi terapii.

Carrageenan is shown to cause acute inflammation in mucous membrane of hamster cheek pouch and rat hind foot. Rutin has no effect on the pathological process in the cheek pouch, and arrests the first phase of inflammation in the foot. Esculamine has a therapeutic effect on both phases of inflammatory reaction in the cheek pouch and foot.

[Effect of rutin and esculamine on models of aseptic inflammation]. / Vliianie rutina i éskulamina na nekotorye modeli aspeticheskogo vospaleniia.

It was shown in experiments on rats that intraabdominal administration of silver nitrate solution induces peritonitis and the subplantar administration of histamine, serotonin and prostaglandin E2 leads to an acute paw edema. Preliminary subcutaneous administration of esculamine or rutin inhibited the development of the inflammation. Esculamine proved more active here.