Fraxini cortex: Progresses in phytochemistry, pharmacology and ethnomedicinal uses.

ETHNOPHARMACOLOGICAL RELEVANCE: Fraxini cortex, which has been widely used as a traditional Chinese medicine for 2000 years, is made from the dried bark of four plant species: Fraxinus chinensis subsp. rhynchophylla (Hance) A.E.Murray, Fraxinus chinensis Roxb., Fraxinus chinensis subsp. chinensis and Fraxinus stylosa Lingelsh.. In Chinese traditional medicine, it possesses the properties of heat-clearing and dampness-drying, asthma relief and cough suppression, as well as vision improvement. It is utilized for treating bacterial disorders, enteritis, leukorrhea, chronic bronitis, painful red eyes with swelling, lacrimation due to windward exposure, psoriasis, and other diseases or related symptoms. AIM OF THE STUDY: Fraxini cortex is abundant in chemical constituents and has garnered significant attention from plant chemists, particularly regarding coumarins, as evidenced by the recently identified three coumarin compounds. Considering the current dearth of systematic reporting on studies pertaining to Fraxini cortex, herein we provide a comprehensive summary of the advancements in phytochemistry, pharmacology, detection methods, and ethnomedicinal applications of Fraxini cortex. MATERIALS AND METHODS: We conducted a comprehensive search across online data sources (Web of Science, Public Medicine (PubMed), China National Knowledge Infrastructure (CNKI), as well as Chinese dissertations) and traditional Chinese medicine classics to gather the necessary literature resources for this review. RESULTS: Briefly, The Fraxini cortex yielded a total of 132 phytochemicals, including coumarins, lignans, secoiridoids, phenylethanol glycosides, flavonoids, triterpenoids, and other compounds. Among them, the main active ingredients are coumarins which possess a diverse range of pharmacological activities such as anti-inflammatory effects, anti-tumor properties, prevention of tissue fibrosis and oxidation damage as well as cardioprotective effects. CONCLUSIONS: All types of research conducted on Fraxini cortex, particularly in the field of ethnopharmacology, phytochemistry, and pharmacology, have been thoroughly reviewed. However, certain traditional applications and pharmacological activities of Fraxini cortex lack scientific evaluation or convincing evidence due to incomplete methodologies and ambiguous results, as well as a lack of clinical data. To validate its pharmacological activity, clinical efficacy, and safety profile, a systematic and comprehensive research evaluation is imperative. As an important traditional Chinese medicine, Fraxini cortex should be further explored to facilitate the development of novel drugs and therapeutics for various diseases. Greater attention should be given to how it can be better utilized.

Research Progress in Pharmacology of Aesculin and Aesculetin / 中药新药与临床药理

Cortex Fraxini,a kind of traditional Chinese medicinal,has low toxicity and wide clinical application.It is widely used to treat diseases such as swelling and pain of eye,damp-heat diarrhea,leucorrhea with reddish discharge,metrorrhagia,etc..Modern pharmacological studies have found that coumarin compounds are the main active components of Fraxini Cortex,among which aesculin and aesculetin are the most representative components.Numerous studies have reported that aesculin and aesculetin exhibit abundant pharmacological activities including antibacterial,anti-inflammatory,anti-tumor,antioxidant,and the potential development and utilization of these compounds has attracted increasing attention.This paper summarized the research progress of the main pharmacological effects of aesculin and aesculetin by reviewing the relevant literature at home and abroad.Our aim is to provide a reference for the drug development and clinical application of Fraxini Cortex.

Deciphering the pharmacological mechanisms of Fraxini Cortex for ulcerative colitis treatment based on network pharmacology and in vivo studies.

BACKGROUND: Ulcerative colitis (UC) is a common type of inflammatory bowel disease. Due to the elusive pathogenesis, safe and effective treatment strategies are still lacking. Fraxini Cortex (FC) has been widely used as a medicinal herb to treat some diseases. However, the pharmacological mechanisms of FC for UC treatment are still unclear. METHODS: An integrated platform combining network pharmacology and experimental studies was introduced to decipher the mechanism of FC against UC. The active compounds, therapeutic targets, and the molecular mechanism of action were acquired by network pharmacology, and the interaction between the compounds and target proteins were verified by molecular docking. Dextran sulfate sodium (DSS)-induced colitis model was employed to assess the therapeutic effect of FC on UC, and validate the molecular mechanisms of action predicted by network pharmacology. RESULTS: A total of 20 bioactive compounds were retrieved, and 115 targets were predicted by using the online databases. Ursolic acid, fraxetin, beta-sitosterol, and esculetin were identified as the main active compounds of FC against UC. PPI network analysis identified 28 FC-UC hub genes that were mainly enriched in the IL-17 signaling pathway, the TNF signaling pathway, and pathways in cancer. Molecular docking confirmed that the active compounds had high binding affinities to the predicted target proteins. GEO dataset analysis showed that these target genes were highly expressed in the UC clinical samples compared with that in the healthy controls. Experimental studies showed that FC alleviated DSS-induced colitis symptoms, reduced inflammatory cytokines release, and suppressed the expression levels of IL1ß, COX2, MMP3, IL-17 and RORγt in colon tissues. CONCLUSION: FC exhibits anti-UC properties through regulating multi-targets and multi-pathways with multi-components. In vivo results demonstrated that FC alleviated DSS-induced colitis.

Analysis on Quality Standard of Fraxini Cortex（Fraxinus chinensis） Dispensing Granules Based on Standard Decoction / 中国实验方剂学杂志

ObjectiveTo establish the quality standard for Fraxini Cortex（Fraxinus chinensis） dispensing granules based on standard decoction， and to provide a basis for the quality control of this dispensing granules. MethodHigh performance liquid chromatography（HPLC） specific chromatograms of 15 batches of Fraxini Cortex（F. chinensis） standard decoctions and 3 batches of Fraxini Cortex（F. chinensis） dispensing granules were established with the mobile phase of 0.1% phosphoric acid aqueous solution（A）-acetonitrile（B） for gradient elution（0-10 min， 12%-15%B； 10-30 min， 15%-32%B） and the detection wavelength of 220 nm. And similarity evaluation， cluster analysis and principal component analysis（PCA） were also carried out. HPLC quantitative analysis of multi-components by single marker（QAMS） was established to determine the contents of the main components in the standard decoctions and dispensing granules. The contents of the corresponding components in Fraxini Cortex（F. chinensis） decoction pieces were also detected， and the transfer rates from decoction pieces to standard decoctions and dispensing granules were calculated. ResultThe similarities between specific chromatograms of 15 batches of Fraxini Cortex（F. chinensis） standard decoctions and 3 batches of Fraxini Cortex（F. chinensis） dispensing granules were all>0.9， and 7 common peaks were identified. The results of cluster analysis and PCA showed that there was some differences in the composition of different batches of standard decoctions， but did not show aggregation of origin. As the standard decoctions， the extract rate was 6.18%-11.62%， the contents of esculin， syringin， fraxin， esculetin， fraxetin， calceolarioside B were 44.92-103.51， 1.36-11.87， 33.26-90.73， 4.63-29.75， 2.40-16.86， 2.49-17.35 mg·g-1， and the transfer rates from decoction pieces to standard decoction were 25.21%-42.54%， 52.57%-88.84%， 43.43%-79.45%， 49.15%-88.27%， 49.22%-72.69%， 27.66%-47.67%， respectively. The extract rates of Fraxini Cortex（F. chinensis） dispensing granules were 10.4%-10.7%， the transfer rates of the above six components from decoction pieces to dispensing granules were 42.76%-43.17%， 80.01%-80.90%， 59.59%-59.88%， 51.35%-52.67%， 60.50%-60.93%， 37.98%-38.37%， respectively， which were generally consistent with the transfer rates from decoction pieces to standard decoctions. ConclusionThe established quality control standard of Fraxini Cortex（F. chinensis） dispensing granules based on standard decoctions is reasonable and reliable， which can provide reference for the quality control and process research of this dispensing granules.

A simple and effective method for identification of Fraxini Cortex from different sources by multi-mode fingerprint combined with chemometrics.

Fraxini Cortex has a long history of being used as a medicinal plant in traditional Chinese medicine. However, it is challenging to differentiate and make quality evaluations for Fraxini Cortex from different origins due to their similarities in morphological features, as well as general chemical composition using traditional chemical analytical methods. In this study, a simple and effective method was developed to identify Fraxini Cortex from different origins by multi-mode fingerprint combined with chemometrics. Digital images of the high-performance thin-layer chromatography profiles were converted to grayscale intensity, and the common patterns of high-performance thin-layer chromatography fingerprints were generated with ChemPattern software. Authentication and quality assessment were analyzed by similarity analysis, hierarchical cluster analysis, principal component analysis, and multivariate analysis of variance. The ultra-high-performance liquid chromatography fingerprints were analyzed by similarity analysis, principal component analysis, and orthogonal partial least square-discriminant analysis. When combined with chemometrics, high-performance thin-layer chromatography and ultra-high-performance liquid chromatography fingerprint provided a simple and effective method to evaluate the comprehensive quality of Fraxini Cortex, and to distinguish its two original medicinal materials (Fraxinus chinensis Roxb. and Fraxinus rhynchophylla Hance.) recorded in the Chinese Pharmacopeia and its three adulterants (Fraxinus mandschurica Rupr., Fraxinus pennsylvanica Marsh., and Juglans mandshurica Maxim.). A similar workflow may be applied to establish a differentiation method for other medicinal and economic plants.

Research on the pharmacodynamics and mechanism of Fraxini Cortex on hyperuricemia based on the regulation of URAT1 and GLUT9.

Fraxini Cortex (also known as Qinpi, QP) has been used for the treatment of hyperuricemia with a significant difference on efficacy of QP from different regions. However, it`s still unknown whether proportion of components is the key and why same kind of herbs have different therapeutic effects. In this study, different sources of QP were collected from Shaanxi Qinpi extracts (SQPE), Henan Qinpi extracts (HQPE), Hebei Qinpi extracts (GQPE) provinces in China. Rat model of hyperuricemia with hypoxanthine combined with potassium oxonate were established to determine the levels of blood urea nitrogen (BUN), serum uric acid (SUA), urine uric acid (UUA) and creatinine (Cr). Hematoxylin-eosin staining (H&E) and Periodic Acid-Schiff staining (PAS) were performed for renal pathology while Western blot analysis and real-time PCR analysis for proteins and mRNA expression levels. High-performance liquid chromatograph (HPLC) was used for components and composition analysis. Our results demonstrated that QPE from different regions could alleviate hyperuricemia via increasing significantly the SCr and BUN levels whereas decreasing markedly UCr, SUA and UUA levels. Additionally, QPE could also improve the pathological changes of the kidneys. The protein and mRNA levels of urate reabsorption transporter 1 (URAT1) and glucose transporter 9 (GLUT9) were down-regulated by QPE treatment. SQPE hold a better activity on improving hyperuricemia and regulating URAT1 and GLUT9. HPLC analysis showed that the proportion of four components aesculin, aesculetin, fraxin, fraxetin were 9.002: 0.350: 8.980: 0.154 (SQPE); 0.526: 0.164: 7.938: 0.102 (HQPE); 12.022: 1.65: 0.878: 1.064 (GQPE). These data indicate that this proportion of effective components may be an important factor for efficacy of QP and had implications for the treatment of hyperuricemia.

Effect of Integration of Habitat Processing and Pieces Processing on Anti-inflammatory of Cortex Fraxini / 世界科学技术-中医药现代化

Objective: To compare the anti-inflammatory effect of Fraxini Cortex pieces between integrated production process and traditional processing method. Methods: The model of rat paw swelling induced by carrageenan was used to study the anti-inflammatory and swelling reliving effects of water extracts of Cortex Fraxini with different methods. The main chemical components of the 2 kinds of Cortex Fraxini herbal pieces were determined by high performance liquid phase. Results: Compared with the blank group, the water extracts of the 2 kinds of Cortex Fraxini could reduce the swelling of the rats and improve the various indicators of inflammation. However, the anti-inflammatory and swelling reliving effects of the integrated processing of Cortex Fraxini were more significant. The contents of 4 main active ingredients of esculine, fraxin, aesculetin and fraxetin in the integrated processing of Cortex Fraxini were higher than that of the traditionally processed Cortex Fraxini. The total amount of 4 kinds of coumarins in the integrated Cortex Fraxini was about 1.5 times that of the traditionally processed water extract of Cortex Fraxini. Conclusion: The integrated processing and traditional processing of Cortex Fraxini have similar effects on anti-inflammatory effects, and have the superiority of reducing the loss of active ingredients, which is worthy of popularization and application.

Optimization of integrative technology of primary processing for Fraxini Cortex based on response surface methodology / 中草药

Objective To optimize the processing integration technology of Fraxini Cortex based on response surface methodology. Methods The single factor experiment combined with Box-Behnken design was used to optimize the integrative technology, with five major characteristic components (aesculin, aesculetin, fraxetin, fraxin, and total coumarin) as indexes, in order to detect three factors (cutting thickness, drying temperature, and drying time), and research the effect of analgesic and anti-inflammatory of processing integration Fraxini Cortex. Results Optimum integrative technology of primary processing was as follows: cutting 6 mm Fraxini Cortex, and drying for 3.25 h at 75 ℃. The processing integration Fraxini Cortex significantly decreased the times of wrinkle reaction induced by acetic acid in mice, prolonged the latent period, and obviously or partially inhibited the feet swelling degree induced by carrageenan in rats. The analgesic effect of integrated technology group was more obvious than traditional technology group (P < 0.05). Conclusion This optimized integrative technology of Fraxini Cortex is reasonable and feasible with high accuracy. It could provide the scientific basis and innovative idea to the large-scale production of decoction pieces of Chinese materia medica and have the certain value for its promotion and application.

Simultaneous determination of nine coumarins in rat plasma by HPLC-MS/MS for pharmacokinetics studies following oral administration of Fraxini Cortex extract.

A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the simultaneous determination of nine coumarins including aesculin, aesculetin, fraxin, fraxetin, scopoletin, isoscopoletin, 6-hydroxy-7,8-dimethoxy coumarin, 8-hydroxy-6,7-dimethoxy coumarin and umbelliferone in rat plasma using nodakenin as the internal standard (IS). The plasma samples were pretreated by a one-step direct protein precipitation with methanol. The chromatographic separation was carried out on a C18 column with a gradient mobile phase consisting of methanol and water (containing 0.05% acetic acid). All analytes and IS were quantitated through electrospray ionization in negative ion multiple reaction monitoring (MRM) mode. This method was fully validated in terms of the sensitivity, specificity, accuracy, precision (intra- and inter-day), matrix effect, recovery as well as the stability of the analyte under various conditions, and the results satisfied the requirements of biological sample measurement. The validated method was successfully applied to pharmacokinetic study of the nine coumarins in rat plasma after oral administration of Fraxini Cortex aqueous extract, among which the pharmacokinetics of four coumarins including fraxetin, isoscopoletin, 6-hydroxy-7,8-dimethoxy coumarin and 8-hydroxy-6,7-dimethoxy coumarin were studied for the first time.

Advance in studies on chemical constituents of Fraxini Cortex and their pharmacological effects / 中草药

Fraxini Cortex is widely distributed in China and rich in resources, and is a kind of medicinal plants with great utilization value. From the phytochemical view, the secondary metabolites such as coumarins, lignans, secoiridoids, phenylethanoids, flavonoids, phenolic acids, and triterpenoids had been reported from this species. Its pharmacological research mainly focused on the antibacterial, antiphlogistic, anti-oxidative, lowing-uric acid, diuretic, and antineoplastic activities. The present paper reviews the phytochemistry and biological activities of Fraxini Cortex through accessing Web of Science and multiple databases for biomedicinal sciences.

Preparation, in vitro and in vivo studies of Fraxini cortex thermosensitive in-situ-forming eye gel / 中国药学杂志

OBJECTIVE: To study on characterization, irritation, the release mechanism and the elimination kinetics of Fraxini Cortex thermosensitive in-situ-forming eye gel (FC-ISG). METHODS: The non-membrane dissolution model was used to observe the release mechanism of FC-ISG. The stabilities of FC-ISG were investigated under following circumstances bright light, freeze test and accelerating test. Single-dose and multiple-dose irritations of FC-ISG were evaluated by draize test. The elimination kinetics of FC-ISG were analyzed by non-compartment model. RESULTS: FC-ISG showed good stability and non-stimulation to rabbit eyes. Drug release from FC-ISG was completely controlled by gel erosion, the release kinetics was coincided with zero-level release. AUC and MRT in FC-ISG group were significantly higher than those in control group (P<0.05). CONCLUSIONS: FC-ISG can improve the bioavailability of drug by prolonging the residence retention time of drug in cornea. FC-ISG shows a great potential in ocular application.

Study on Content Determination of Coumarin in Fraxini Cortex Extract / 中国中医药信息杂志

Objective To establish a UV spectrophotometry method and an HPLC method respectively for the determination of the total content of coumarin and contents of four main constituents of coumarin in Fraxini Cortex extract.Methods UV spectrophotometry was used for the determination of the content of total coumarin in Fraxini Cortex extract. The reference substance was Aesculin, and the maximum ultraviolet absorption wavelength was 334 nm. The HPLC method was used to determine the contents of Aesculin, Fraxin, Aesculetin and Fraxetin in Fraxini Cortex extract, using gradient elution with acetonitrile-phosphate solution (0.01%) as mobile phase on Agilent ZORBAX SB-C18 chromatographic column (4.6 mm × 250 mm, 5μm) at room temperature.Results For the UV method, the linear range of the mass concentration of Aesculin was 5.76-23.04μg/mL (r=0.999 9), and the average recovery was 100.6% (RSD=1.8%). For the HPLC method, the linear ranges of the mass of Aesculin, Fraxin, Aesculetin and Fraxetin were 0.055 0-3.850 0μg (r=0.9997), 0.053 9-3.773 0μg (r=0.999 8), 0.060 0-0.660 0μg (r=0.999 9), and 0.056 2-0.618 2μg (r=0.999 9), respectively, and the average recoveries were 96.97% (RSD=1.26%), 100.80% (RSD=2.22%), 99.04% (RSD=2.47%), and 98.77% (RSD=1.94%), respectively.Conclusion Both of the two methods are simple, accurate and reliable, and can be used for the quality control of total coumarin and the main constituents of coumarin in Fraxini Cortex extract.

Purification process of total coumarin from Fraxini Cortex by macroporous resin / 中草药

Objective: To optimize the purification process of total coumarin from Fraxini Cortex using macroporous resin. Methods: The single factor methods have been used to investigate the choice of type, adsorption performance, and desorption performance and the purification of the total coumarin from Fraxini Cortex by macroporous resin. The adsorption rate, resolution, resolution rate, and transfer rate of the total coumarin from Fraxini Cortex, four kinds of coumarin constituents, such as aesculin, aesculetin, fraxin, and fraxetin were used as examining indexes. Results: The ADS-5 was the most suitable type for the purification of total coumarin from Fraxini Cortex among the seven kinds of macroporous resin. Adsorption parameters: Crude drug-the resin was 0.8 g/g which was the sample amount; The concentration of sample solution was 0.75 g crude drug/mL; The pH value of sample liquid was 4.0-4.3 (liquid sample); The speed of the sample through the resin column was 2-4 BV/h. Elution parameters: The volume of the water cleaning fluid impurities was 1 BV; The elution solvent was 25% ethanol; The elution speed was 2 BV/h; The elution volume was 3 BV. After the purification, the transfer rate of total coumarin from Fraxini Cortex was 74.27%, the transfer rate of four kinds of coumarin was 83.06%, the extract rate of total coumarin was 7.35%, the removal of impurities was 14.00%, among which the content of total coumarin was 54.72%, the contents of the four kinds of components were 36.01%, the total coumarin extraction yield was 4.02%. Conclusion: This method to purify the total coumarin from Fraxini Cortex using ADS-5 can get better purification effect, the purification process is also stable.

Comparison on HPLC fingerprints between fraxini cortex and its eye drop / 中草药·英文版

Objective: To compare the HPLC fingerprints of Fraxini Cortex and its eye drop. Methods: Using esculin and esculetin as reference substances, HPLC method was established for fingerprint chromatography of Fraxini Cortex and its eye drop. The similarity was analyzed by similarity evaluation and system cluster analysis. Results: For Fraxini Cortex, eight peaks were separated, among which four common peaks were obtained; for eye drop, eleven peaks were separated including six common peaks. Similarities of both fingerprints were good. Cluster analysis further showed that different sources resulted in the variance of ingredients in crude drug. Both materials and eye drop had some common peaks such as esculin and esculetin, on the other hand, they had some different peaks which might be caused by extracting process. Conclusion: HPLC fingerprint chromatogram could be applied for the quality control of Fraxini Cortex and its preparations; the pharmaceutical process may be responsible for the variance of ingredients. © 2013 Tianjin Press of Chinese Herbal Medicines.