Review Article

Phytoconstituents, Traditional Uses, and Biological Potential of Edgeworthia genus

Introduction

Medicinal plants have been considered crucial for thousands of years for human health.¹ They are the main source of remedies and the basis of many traditional medicine practices throughout the world. Medicinal plants can effectively alleviate human ailments and diseases and have advantageous health-promoting effects.^2-5 Additionally, plants are valuable sources that generate a vast array of secondary metabolites. Plants and/or their secondary metabolites represent the basis of the many foods, agrochemical, cosmetic, perfume, and pharmaceutics industries.^2-5

Thymelaraceae family is composed of 45 genera with about 900 species and includes two major subfamilies, Thymelaeoideae and Octolepidoideae. Subfamily Thymelaeoideae consists of three tribes: Synandrodaphneae, Aquilarieae, and Daphneae that are known to produce coumarins and flavonoids of different skeletons.^6,7 Edgeworthia genus is a member of Daphneae tribe, comprising five species: E. chrysantha Lindl. (Synonyms: E. papyrifera Siebold & Zucc; E. tomentosa (Thunb.) Nakai), E. gardneri (Wall.) Meisn., E. albiflora Nakai, E. longipes Lace, and E. eriosolenoides K. M. Feng & S. C. Huang. They grow in Southeastern United States, China, Japan, Korea, and India.^8,9 Among the genus members, E. gardneri and E. chrysantha are the most studied species of this genus. Edgeworthia plants are cultivated as ornamentals in urban settings due to their ease of propagation.⁷ Also, they are utilized as raw material for the production of rayon and high-quality papers like banknotes as they contain abundant low-lignin fibers with a wide range of traditional uses.⁷ Phytochemical investigations of this genus revealed the identification of various phyto-constituents, including flavonoids, coumarins, lignans, triterpenes, and steroids with promising biological properties.^10-13 To the best of our knowledge, no published work has comprehensively reviewed the available data on this genus. The current work aimed to discuss the reported literature on this genus including traditional uses, phyto-constituents, and biological properties to highlight its potential traditional and pharmacological significance.

Methodology

The literature search was carried out through different databases (Google-Scholar, Web of Science, Scopus, and PubMed) and scientific publishers (Springer, Wiley Online Library, Taylor & Francis, Elsevier, JACS, and Bentham). The following keywords were used: “Edgeworthia genus + NMR”, “Edgeworthia genus + bioactive compounds”, “Edgeworthia genus + phytochemistry”, “Edgeworthia genus + traditional uses”, “Edgeworthia genus + biological activity”. The peer-reviewed original research articles, review articles, and scientific book chapters focusing on the traditional uses, phytochemistry, or biological/pharmacological activities of Edgeworthia species, published between 1974 and September 2024 were included. The non-peer-reviewed publications, conference abstracts without full data, articles not focused on Edgeworthia, studies lacking phytochemical or biological activity information, and publications in languages other than English without an available English translation were excluded. This review comprises 61 references published between 1974 and September 2024. The relevant articles were selected, and data were extracted and categorized by compound class and biological activity. Tables were compiled to summarize the reported compounds, their sources, and biological activities.

Results

Traditional Uses and Geographical Distribution of Edgeworthia Plants

The Edgeworthia plants are commonly found throughout Asia, with China is the main source. Edgeworthia gardneri (Wall.) Meisn. grows in Darjeeling`s Birch Hill and Middle-Hill areas, where its fruits are employed as fish poison, whereas stems and roots are utilized for bubo treatment in China.¹⁰ It occurs in the Himalayan region, in northern India and from Nepal to Bhutan and western China. E. gardneri is also found in northwest Yunnan Province and at high altitude in eastern Tibet. Its dried flower buds are marketed as precious Tibetan floral tea, named “Lu luohua” for alleviating many illnesses such as hyperlipidemia,^14-16 diabetes,^14,17,18 hypertension,¹¹ obesity, ^14,15 and cardiovascular diseases.^19,20

Edgeworthia chrysantha Lindl. (Oriental paperbush) is a deciduous shrub, having distinctive three-pronged branches. E. chrysantha flowers are fragrant tubular yellow spherical clusters covered in white silky hairs that give them a frosted look. The flowers bloom in early spring and winter, making them a commonly used decorative plant. It is vastly found in Asia countries, including southern and central China, Japan, Nepal, and Korea. In China, it is predominantly present in Shanxi Province, Henan Province, and some other areas along the Chang Jiang southern side (the Yangtze River).¹² The plant bark fibers are traditionally utilized for artificial cotton, banknotes, and paper, as they contain abundant low-lignin fibers.²¹ This species is also cultivated in the southern region of USA.²²

In China, its alabastrum is employed to treat eye-related conditions such as swelling, nocturnal emissions, delacrimation, ophthalmalgia, and Nephelium.²³ Whilst the roots and barks, known locally as “Zhu Shima” in southern China, are valued in folk medicine for their analgesic and anti-inflammatory effects,²¹ as well as stem and root are applied to relieve the muscle tension, pain, and swelling, and heal rheumatism and injuries.²³ Also, roots and buds are used for treating bruises, hoarseness, neuralgia, arthralgia, and eye diseases such as visual impairment, photophobia, and epiphora.²⁴ E. chrysantha is applied to cure rheumatalgia or bone fracture as Flora Reipublicae Popularis Sinicae. Tujia ethnic population in western Hunan Province prepares daily consumed herbal tea by gathering the flower buds, drying them, and then soaking them in hot water to remove obstruction, enhance digestion, and tranquilize the mind.¹²

Botanical Characteristics

Edgeworthia species are distinguished by having tightly bunched fragrant flowers and fibrous stems. The morphological characters of these plants were listed in Table 1 (Figure 1).

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Figure 1.

Photos of Edgeworthia chrysantha (https://plants.ces.ncsu.edu/plants/edgeworthia-chrysantha/) and Edgeworthia gardneri (https://efloraofindia.com/efi/edgeworthia-gardneri/)

Figure 1.

Photos of Edgeworthia chrysantha (https://plants.ces.ncsu.edu/plants/edgeworthia-chrysantha/) and Edgeworthia gardneri (https://efloraofindia.com/efi/edgeworthia-gardneri/)

Extraction and Isolation of the Secondary Metabolites

Chromatographic separation and analysis using various chromatographic techniques such as SiO₂,²³ Sephadex LH-20,²¹ Diaion HP-20,¹⁷ AB-8 macroporous resin, gas chromatography (GC),³¹ PTLC (preparative thin layer chromatography), high-performance liquid chromatography (HPLC),³² HSCCC (high-speed counter-current chromatography),³³ MEKC (micellar electrokinetic capillary chromatography),³³ ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS),³² LC-ESI-MS/MS,³⁴ and ESI-MS/MS³⁴ in addition to spectral, CD (circular dichroism), X-ray, and chemical methods led to the separation and characterization of numerous structurally defined bioactive metabolites, primarily coumarins, flavonoids, lignans, and diterpenoids, from various plant parts including roots, stems, bark, flower buds, and leaves.

In 2006, Wang and Cheng developed micellar MEKC method that provided a rapid, efficient, and reliable method for separating and analyzing 12, 48, and 53 in the E. chrysantha alabastrum.²¹ HSCCC demonstrated efficient isolation of 5 (12.9% yield) and 25 (6.6% yield) from E. chrysantha stems with over 95% purity by HPLC analysis³³ and 47 (yield 32 mg) and 53 (yield 53 mg) from E. chrysantha flowers EtOH extract with recovery rates of 92.2 and 92.5%, respectively) validated through HPLC purity assessment and spectral comparison with authentic standards.³⁵

A study by Wen et al developed an innovative method for extracting E. chrysantha fresh flowers essential oils at different flowering stages using DLLME-UAE (dispersive liquid-liquid microextraction/ultrasound-assisted extraction) coupled with GC-IT MS (gas chromatography-ion trap mass spectrometry) with a DSI (direct-sample introduction) device³⁶ with optimal conditions including toluene,³⁶ acetone, and 10 min for extraction and dispersive solvents and ultrasound time, respectively. Thirty-six constituents were found, including aromatic hydrocarbons, alkanes, alcohols, alkenes, aldehydes, ketones, lipids, acids, and nitrogenous compounds, were identified, all contributing to the distinctive floral aroma of E. chrysantha.³⁶

Gao et al. reported that the solid-phase extraction using tiliroside-imprinted polymers provided an efficient tool for 45`s extraction (% recovery ranged from 69.3 to 73.5%) from E. gardneri flower EtOAc extract.³⁷

Secondary Metabolites and Their Biological Activities

Coumarins

Oligocoumarins are uncommon natural compounds that have mostly been isolated from plants belonging to the Rutaceae, Thymelaeaceae, and Luguminosae families. Various studies reported the isolation of monomeric, bis-, and trimeric coumarins and their glycosides from Edgeworthia genus that were listed in Table 2. Edgeworthia species are important sources of structurally diverse and biologically active coumarins. A total of 32 coumarins, comprising both aglycones and glycosidic derivatives, were reported from various species of the Edgeworthia genus, primarily E. chrysantha and E. gardneri, reflecting the genus’s substantial phytochemical diversity. These compounds were identified from different plant parts such as stems, barks, roots, flower buds, and flowers. Twenty coumarins were separated from E. chrysantha, followed by E. gardneri, with around ten coumarins.

Kim et al. reported that E. chrysantha major constituent: 2 dose-dependently activated osteoblast proliferation and prohibited osteoclast differentiation (IC₅₀ 9.94 μM) in ovariectomized mice, suggesting E. chrysantha and 2 as a functional food to treat osteoporosis and increase bone strength (Figure 2).⁵⁷ Compounds 5, 7, and 9 obtained from E. gardneri`s methylethyl ketone extract thatdemonstrated marked polymerase-βlyase inhibition (IC₅₀ 43.0 µg/mL (122.3 µM), 32.1 µg/mL (94.8 µM), and 7.3 µg/mL (22.5 µM), respectively). Compound 5 also showed α-glucosidase and α-amylase-inhibition activity.³² Compound 9 was found to potentiate bleomycin cytotoxicity towards A-549 cells by inhibiting the repair of bleomycin-caused DNA (deoxyribonucleic acid) damage (Figure 3).⁵¹ Besides, E. chrysantha major coumarins: 2 and 9 exhibited anti-inflammatory and analgesic activities, whereas 12 (doses 100 and 200 mg/kg) showed only analgesic effects.²³ Compounds 7 and 9 showed potent activity versus α-glucosidase (IC₅₀s 49.6 and 18.7 μg/mL, respectively), having 9 was a noncompetitive inhibitor compared to acarbose (IC₅₀ 465 μg/mL).⁴² E. chrysantha metabolite, 16 remarkably raised 2-NBDG (2-[N-(7- nitrobenz-2-oxa-1,3- diazol-4-yl)amino]-2-deoxy-D-glucose) glucose uptake into 3T3-L1 adipocytes.⁴⁵ On the other hand, 5, 12, 14, and 25 were moderately active against α-glucosidase (IC₅₀ 86–780 μg/mL), suggesting E. gardneri coumarins more powerful α-glucosidase inhibitors.⁴² Additionally, 25 from E. gardneri EtOAc extract was reported as new PPARγ (Peroxisome Proliferator-Activated Receptor γ) and PPARβ (Peroxisome Proliferator-Activated Receptor β) agonist that activated PPARβ and PPARγ (Figure 4).⁵⁵

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Figure 2.

Chemical structures of coumarins (1–8) from Edgeworthia genus

Figure 2.

Chemical structures of coumarins (1–8) from Edgeworthia genus

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Figure 3.

Chemical structures of coumarins (9–15) from Edgeworthia genus

Figure 3.

Chemical structures of coumarins (9–15) from Edgeworthia genus

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Figure 4.

Chemical structures of coumarins (16–23) from Edgeworthia genus

Figure 4.

Chemical structures of coumarins (16–23) from Edgeworthia genus

Flavonoids and Their Glycosides

A total of 44 flavonoids have been reported from Edgeworthia species, as documented in peer-reviewed literature and confirmed by the Dictionary of Natural Products (DNP). These flavonoids include flavones, isoflavones, and flavonols and their C- or O-glycosides were identified from Edgeworthia species, mainly from E. chrysantha and E. gardneri. E. gardneri and E. chrysantha contributed over 97% of the identified flavonoids, including tiliroside, kaempferol derivatives, rutin, isoquercetin, apigenin, quercetin, and catechins. These compounds were isolated from the flowers, stems, and twigs, with some detected in the bark, alabastrum, and whole plant extracts (Table 3; Figures 5-10). In addition, biflavonoids such as daphnodorin dimers 33–40 that feature a three-carbon ring connectivity of phenyl ring-A subunit in one moiety and C–C linkage of ring A with another moiety, were isolated (Figure 6).¹⁸ Compounds33–40 (IC₅₀s 0.4–20 µM) demonstrated significantα-glucosidase inhibitory activity, whereas 33–36 displayed powerful inhibition (IC₅₀ 1.09, 2.13, 0.41, and 0.96 µM, respectively) than 37–40 (IC₅₀ 3.14, 11.2, 4.0, and 19.0 µM, respectively), in comparison to acarbose (IC₅₀ 73.6 µM).¹⁸ Zhang et al. reported that 45 from E. gardneri demonstrated notable noncompetitive α-amylase inhibition potential (IC₅₀ 12.1 μM and Ki 9.72 μM). It suppressed intestinal α-amylase in mice with a consequent reduction in postprandial peak in the oral sucrose-tolerance test.⁵⁸ Also, E. gardneri lower-regulated the transcriptional factors related to adipogenesis as C/EBPα and PPARγ and diminished the accumulated triglyceride and lipid accumulations during the differentiation stage.⁵⁰ It raised ACC (acetyl-CoA carboxylase) and AMPK (MP-Activated Protein Kinase) phosphorylation, suggesting that the extract produced anti-adipogenic action through modulating the AMPK signaling pathway. Tiliroside (45) was identified as the main component of the extract that could contribute to the anti-obesity activity of the extract.⁵⁰ Cai et al reported that 45 separated from E. chrysantha buds exhibited potential reno-protective property (Figures 7).⁵⁹ It restored kidney functions by lowering blood urea nitrogen, serum creatinine, and renal damage markers: kidney injury molecule 1 and neutrophil gelatinase-associated lipocalin levels in acute kidney injury mice models. Additionally, it remarkably amended cisplatin-produced ferroptosis in HK2 cells through NRF2 activation. Thus, 45 boosted ferroptosis inhibition and GPX4/NRF2 pathway activation via the NRF2-KEAP1 PPI disruption.⁵⁹ Ma et al reported that 45, 47, 48, and 53 revealed notable α-glucosidase inhibitory activity (IC₅₀s 179–253 μg/mL), compared to acarbose (IC₅₀ 465 μg/mL).¹⁷ It was noted that 3`-OH, methyl ester, and free 7-OH groups raised activity.¹⁷ In the in-vivo test, 45 (dose 300 mg/kg) remarkably declined the postprandial glucose level, and did not affect fasting glucose level in normal mice.¹⁷ On the other hand, 45 prohibited the intestinal α-glucosidase and minimized fasting glucose level in the STZ-produced diabetic mice. In contrast to glibenclamide it revealed hypoglycemic efficacy in diabetic mice but not in normal mice, indicating that 45 did not directly act through insulin release.¹⁷ Further, 45, 59, 61, and 66 had α-glucosidase inhibition activities (IC₅₀s 1071.6 to 22.3 µM) and 53 showed α-amylase-inhibition (IC₅₀ 55.5 µM), suggesting coumarins and flavonoids accountable for E. gardneri activity (Figures 8-10).³² Compounds 66 and 67 (IC₅₀ 56.2 and 5.1 μg/mL, respectively) exhibited powerful α-glucosidase inhibitory activity, whereas 67 was the most active.¹⁷ A study by Zhuang et al revealed that 67 (conc > 10 μM/L) from E. gardneri flower remarkably boosted insulin secretion in MIN-6 cells through ERK1/2/Ca²⁺ signaling pathway.⁶⁰ Also, it suppressed palmitic acid-caused cell apoptosis by restoring the integrity of the damaged mitochondrial membrane, repressing caspase-3, -9, and -12 activation, and raising the Bcl-2/BAX ratio.⁶⁰

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Figure 5.

Chemical structures of coumarins (24–32) from Edgeworthia genus

Figure 5.

Chemical structures of coumarins (24–32) from Edgeworthia genus

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Figure 6.

Chemical structures of flavonoids (33–40) from Edgeworthia genus

Figure 6.

Chemical structures of flavonoids (33–40) from Edgeworthia genus

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Figure 7.

Chemical structures of flavonoids (41–51) from Edgeworthia genus

Figure 7.

Chemical structures of flavonoids (41–51) from Edgeworthia genus

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Figure 8.

Chemical structures of flavonoids (52–60) from Edgeworthia genus

Figure 8.

Chemical structures of flavonoids (52–60) from Edgeworthia genus

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Figure 9.

Chemical structures of flavonoids (61–69) from Edgeworthia genus

Figure 9.

Chemical structures of flavonoids (61–69) from Edgeworthia genus

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Figure 10.

Chemical structures of flavonoids (70–76) from Edgeworthia genus

Figure 10.

Chemical structures of flavonoids (70–76) from Edgeworthia genus

Organic Acids and Esters

Chlorogenic, ferulic, caffeic, hydroxycinnamic, benzoic, salicylic, and gallic acid were identified from E. gardneri and E. chrysantha (Figure S1; Table 4). While esters such as methyl salicylate, benzyl acetate, vanillin isobutyrate, and methyl benzoate were purified from E. chrysantha and E. tomentosa flowers (Figure S2).

Aldehydes, Phenols, Lignans, Chromans, and Aromatic Alcohols

Three aldehydes were identified from E. gardneri (1 compound) and E. chrysantha (2 compounds) flowers. Phenolic glycosides (105–117), lignans (( + )-lariciresinol, neosesamin, ciwujiatone, and interiotherin C), and chromans (cnidimol B and isoophiopogonone A) were separated mainly from E. gardneri flowers, while alcohols (α-cumyl and benzyl alcohols) were identified from E. chrysantha flowers (Table 5; Figure S2). Compounds 85, 104, and 114 displayed α-glucosidase inhibitory activity (IC₅₀s 279, 486, and 957 μg/mL, respectively), in comparison to acarbose (IC₅₀ 465 μg/mL).¹⁷

Terpenoids

A total of 45 terpenoids were reported from Edgeworthia species, mainly from E. chrysantha, E. gardneri, and E. tomentosa, including monoterpenes, sesquiterpenes, and macrocyclic daphnane orthoesters (Table 6). Mcrocyclic daphnane orthoesters: 124–130 were separated by Asada et al. from E. chrysantha flower buds that belong to a 1-alkyldaphnane class possessing a C14-macrocyclic ring, which consists of an aliphatic chain at C-1 linked to the C-14,13,9-orthoester moiety (Table 5, Figure 11 and Figures S3-S5).³⁴ Additionally, 129 and 130 were detected in the flowers and stems of E. chrysantha, respectively by LC-ESI-MS/MS that were separated by Diaion HP-20/HPLC and elucidated by ESI-MS/MS fragmentation and spectral analyses.²⁴ Besides, 124–128 separated from E. chrysantha were examined for their anti-HIV-1 activity towards HIV-infected MT4 cells using the CellTiter-Glo Luminescent Cell Viability Assay.³⁴ Compounds 125, 127, and 128 demonstrated significant anti-HIV activity (EC₅₀s 29.3, 8.4, and 2.9 nM, respectively), whereas 127 and 128 exhibited more powerful anti-HIV activity than 124–126, suggesting that a cyclopentanone unit in the A-ring enhanced the activity. Also, the C-18 isobutyryloxy moiety boosted the activity (128 vs 127).³⁴ Another study by Otsuki et al. revealed that 124–130 exhibited anti-HIV activity (EC₅₀s 0.10–7.03 μM), whereas 124 (EC₅₀ 1.61 μM) and 128 (EC₅₀ 0.10 μM) displayed promising activity. It was noted that the C-12 acetyloxy moiety replacement with an OH group and the presence of C-18 2-methylbuty­loxy moiety reduced activity.²⁴

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Figure 11.

Chemical structures of terpenoids (124–130) from Edgeworthia genus

Figure 11.

Chemical structures of terpenoids (124–130) from Edgeworthia genus

Cao et al analyzed using GC-MS the E. chrysantha flowers essential oil after extraction by diethyl ether and isolation through steam distillation. A total of 61 volatile compounds were identified, constituting 60.14% of the volatile fraction, with notable constituents including 1,1′-oxybisdecane, 7-bromomethyl-7-pentadecene, and tert-hexadecanethiol.⁶³ The GC-MS analysis of E. tomentosa flowers revealed 38 constituents, accounting for 98% of the essential oil. The major components included terpenoids, making up 36.47% of the oil, with key compounds such as carvone, carveol, and β-caryophyllene. Sesquiterpenes and monoterpenes contributed 21.63% and 14.84%, respectively. Additionally, various fatty acids and hydrocarbons, including decanal and octadecanoic acid, as well as phenolic compounds such as methyl benzoate and vanillin isobutyrate were detected.³¹ It was found that E. tomentosa essential oil demonstrated wide-spectrum antibacterial capacity versus various bacterial strains of Gram-positive and Gram-negative types with MBC and MIC values ranging between 26.0–71.0 and 7.8–62.5 μg/mL, respectively, whereas the powerful bacteriostatic efficacy was noted versus Diplococcus pneumonia.³¹ The powerful antibacterial capacity was attributed to its high monoterpene and sesquiterpene constituents; 150, 144, 138, and 149 (8.81, 6.96, 3.45, and 3.34%, respectively).³¹

Sterols, Alkaloids, and Nitrogenous Compounds

Four sterols were reported, including chrysanthosides that are sterol acylglucosides identified from E. chrysantha flower that were characterized as sitosterol-3-O-6-linoleoyl (169) and sitosterol-3-O-6-linolenoyl-β-D-glucopyranosides (168) (Table 7; Figure S6).⁴⁷ Additionally, compounds 166 and 167 were obtained from E. gardneri flowers. E. chrysantha`s flowerEtOAc extract at concentrations of 100 ppm and 10 ppm killed Oryzia latipes (Killie-fish) after 1 minutes and 28 hours, respectively, while the n-butanol extract did not affect the same fish.⁴⁷ Compounds 168 and 169 (Conc. 0.1 ppm) exhibited powerful piscicidal effectiveness, they caused death to Oryzia latipes killie-fish within 3 hr.⁴⁷ Notably, 16 alkaloids and nitrogenous compounds were reported exclusively from E. gardneri, including berberine,⁵⁶ cytisine,⁵⁶ scopolamine, swainonine,⁵⁶ gentialutine,⁵⁶ and trigonelline⁵⁶ (Table 7; Figure S7).

Fatty Acids

Additionally, 20 fatty acids were reported predominantly from E. gardneri and E. tomentosa (Table 8; Figure S8). Among them, 186 activated PPARβ and PPARγ, suggesting its PPARγ and PPARβ agonistic potential.⁵⁵

Aliphatic Aldehydes, Hydrocarbons, Esters, Alcohols, and Other Metabolites

Further, hydrocarbons (6 compounds), aldehydes (6 compounds), esters (8 compounds), alcohols (5 compounds), and other metabolites were reported from this genus (Figures S9-S11; Table 9). Interestingly, compound 241 from E. gardneri alcohol extract exhibited in vitro α-glucosidase inhibition, comparable to acarbose.⁵³

Bioactivities of Edgeworthia Plant Extracts

Edgeworthia gardneri flowers were reported to exhibit significant anti-hyperglycemic, antioxidant, and α-glucosidase inhibitory capacities.^11,32 Ma et al demonstrated that E. gardneri flowers extract exhibited potent α-glucosidase inhibitory activity (IC₅₀ 267.0 μg/mL) than acarbose (IC₅₀ 465 μg/mL).¹⁷ Similarly, Gao et al assessed the in-vitro PPARγ/β dual agonist activity of different E. gardneri flower extracts, fractions, and metabolites. It was noted that n-BuOH, n-hexane, and EtOAc extracts remarkably activated PPARβ and PPARγ, respectively, with EtOAc extract showing the highest activity.⁵⁵ In addition, the extract promoted insulin secretion comparable to quercetin, however, it demonstrated more notable anti-apoptotic potential than quercetin.⁶⁰ Further,the flower water extract demonstrated inhibition of lipo-toxicity, as well as it notably enhanced glucose uptake and consumption in palmitate-treated HepG2 cells.⁶¹ Also, it increased glycogen content, suppressed endogenous glucose production, and lessened intracellular TG content in PA-treated HepG2 cells. These effects were related to GSK3β/IRS-1/FoxO1 signaling pathway regulation and promoted GLUT4 and GLUT2 transporters translocation.⁶¹ A study by Chengfei et al reported that E. gardneri extract upregulated AMPK and LPL mRNA expression, while downregulated SREBP1c, PPARγ, and Fas mRNA expression. This led to alleviate lipid and glucose metabolism disorders in KKAy mice through LPL/PPARγ regulation and Fas/AMPK/SREBP1c pathway activation.¹⁵ In-vivo, E. gardneri flower H₂O extract (3 g/kg/day) noticeably reduced blood glucose level by 30.0%.⁵⁶ Furthermore, it improved lipid metabolism, insulin sensitivity, and the function and morphology of adipose tissues, pancreas, and liver in diabetic mice and modulated the gut microbiota. Thus, this extract modulated gut microbiota constitution and enhanced short-chain fatty acid contents, suggesting its potential to improve lipid and glucose metabolic disturbances through gut microbiota reshaping in diabetic mice.⁵⁶ Additionally, the flower hexane extract improved the impaired β-cells by activating AKT, reducing caspase-3 gene transcription level and ROS generation, and suppressing FOXO1and JNK activation STZ (streptozotocin)-high-fat diet diabetic mice model.¹⁶ Cardioprotective capacity of E. gardneri flowers were also reported. A 30% ethanol fraction of E. gardneri flowers remarkably weakened myocardial infarct size, improved cardiac function, and attenuated post-infarction adverse cardiac remodeling and inflammation in rats.²⁰ Its cardioprotective potential was due to repressing the activation of ERK, p38 MAPK, and NF-kB signaling pathways, counteracting inflammatory injury to the ischemic heart. Hence, E. gardneri has the potential to manage ischemic cardiovascular illness and attenuate endothelial inflammation.²⁰ Similarly, E. gardneri flower 60%EtOH extract was reported to combat ischemia/reperfusion-produced inflammation and its associated cardiac injury in rats by prohibiting endothelium activation via lessening NF-κB, c-JNK, extracellular-regulated protein kinase, and p38 mitogen-activated protein kinase signaling pathways.¹⁹ Additionally, E. gardneri`s methylethyl ketone extract exhibited notable polymerase βlyase inhibition activity in an in-vitro assay employing purified human polymerase β enzyme, where inhibition was assessed by monitoring the incorporation of radiolabeled nucleotides into synthetic DNA substrates, indicating its potential for DNA repair modulation.³²

Both aqueous extracts of E. chrysantha and E. gardneri (dose 200 mg/kg/orally) lowered blood glucose in diabetic mice during an oral glucose tolerance test.¹² E. chrysantha barks and roots chloroform fractions exhibited notable anti-inflammation and analgesic properties, additionally 75% EtOH and chloroform fractions lessened LPS-stimulated NO formation in RAW264.7 cells.²³ Notably, E. chrysantha extract demonstrated potent α-glucosidase inhibitory (IC₅₀ 21.4 μg/mL) potential than acarbose (IC₅₀ 73.6 µM).¹⁸ Furthermore, E. chrysantha flower buds MeOH extract was found to show notable anti-HIV (EC₅₀ 4.1 μg/mL) potential.³⁴ A study by Kim et al. revealed that E. chrysantha twigs and leaves extractreduced osteoclastic marker blood levels in ovariectomized mice and maintained the trabecular bone structure and volume.⁵⁷ In another in-vitro study by the same group, E. chrysantha stem extract prohibited RANKL-caused RAW 264.7 cells osteoclast differentiation and boosted MC3T3-E1 cells differentiation to osteoblast-like cells.⁴³. The extract also reduced elevated bone resorption biomarkers; tartrate-resistant acid phosphatase and pyridinoline (48.1 and 25.6 %, respectively), while preventing bone loss mediated by ovariectomy in mice.⁴³

Acute Toxicity

A study by Hu et al revealed that 75% EtOH extract of E. chrysantha bark and roots, along with various fractions, showed no acute toxicity at doses up to 5 g/kg. After 7 days of observation, the mice maintained normal body weight, and no common side effects such as mild diarrhea, weight loss, or depression were observed.²³ Although the tested Edgeworthia extracts were reported to be safe, these findings are based on limited experimental data. Thus, comprehensive toxicity evaluations are warranted to confirm safety profiles and to support potential pharmacological applications.

Discussion

Edgeworthia species chemically characterized by structurally varied coumarins. Among the 32 coumarins reported from various species of the Edgeworthia genus, daphnoretin is most frequently reported coumarin, documented in 16 different studies. It was isolated from E. chrysantha and E. gardneri collected from different regions including Japan, China, India, Bhutan, and Korea, suggesting it as chemotaxonomic marker of E. chrysantha and E. gardneri. Glycosylated and dimeric coumarins such as 2 and 12 were also commonly found. Additionally, rare oligocoumarin 1 and its glycoside 4 and the unique coumarins 18 and 19 were identified exclusively in E. chrysantha and E. gardneri, respectively, indicating unique biosynthetic pathways of these species. These unique biosynthetic pathways of these species are suggested based on their phytochemical profiling, which revealed the production of rare coumarins and unusual flavonoids that are uncommon in related genera. Edgeworthia species, especially E. chrysantha and E. gardneri demonstrated various bioactivities, due in great part to their constituents particularly coumarins and flavonoids. Compound 2 exhibited notable anti-osteoporotic action by encouraging osteoblast proliferation and prohibiting osteoclast differentiation, suggesting its potential use in maintaining bone health. Compounds 5, 7, and 9 demonstrated substantial suppression of polymerase-β lyase, while compound 9 increased bleomycin’s cytotoxicity through inhibition of DNA repair. Further, compound 9 had powerful α-glucosidase inhibitory activity, compound 16 improved glucose absorption in adipocytes, and compound 25 acted as a dual PPARγ/PPARβ agonist.

Besides, E. chrysantha and E. gardneri are abundant in structurally varied flavonoids that are renowned for their substantial bioactivities. Particularly, biflavonoids such as daphnodorin dimers demonstrated marked α-glucosidase inhibition. Compound 45 revealed multiple bioactivities. Its dual suppression of α-amylase and α-glucosidase, as well as its modulation of lipid metabolism and glucose uptake pathways. Also, compounds 67 had powerful α-glucosidase inhibitory activity and boosted insulin secretion. These findings reinforce Edgeworthia plants potential as a candidate for metabolic syndrome interventions.

E. chrysantha, E. gardneri, and E. tomentosa yielded different types of terpenoids such as macrocyclic daphnane orthoesters, monoterpenes, sesquiterpenes, and their oxygenated derivatives, highlighting the diverse biosynthetic capacity of these species. Among them, 127 and 128 showed nanomolar anti-HIV efficacy, suggesting their promise as antiviral agents. The structural features of daphnane orthoesters such as the cyclopentanone moiety and the C-18 isobutyryloxy substitution enhanced the bioactivity. E. chrysantha and E. tomentosa essential oils were rich in sesquiterpenes and monoterpenes with broad-spectrum antibacterial properties. E. chrysantha’s sterol acylglucosides exhibited remarkable piscicidal activity, while E. gardneri’s alkaloids displayed species-specific bioactivity. Compounds 186 and 241 demonstrated dual activation of PPARβ/γ and α-glucosidase inhibition, further confirming metabolic regulatory and antidiabetic potential of this genus.

The published pharmacological properties, especially for Edgeworthia gardneri and E. chrysantha underline their promising therapeutic potential and correlate with their traditional uses. For example, PPARγ/β dual agonist, α-glucosidase inhibitory, lipid-lowering, cardioprotective, and antioxidant properties support E. gardneri flowers usage to treat hyperlipidemia, diabetes, hypertension, obesity, and cardiovascular conditions. Similarly, its use of stem and root to cure buboes is also aligned with its anti-inflammatory capacity. E. chrysantha has long been used to treat eye conditions, muscle soreness, rheumatism, bruises, and fractures that align with its anti-inflammatory and analgesic activities. These correlations validate Edgeworthia species ethnopharmacological relevance and encourage further research into the therapeutic applications of these plants. However, the reported in-vivo doses in this work are linked to specific experimental conditions and animal models used in the reported studies. Therefore, careful consideration of safety verification and clinical validation are required to translate these doses to human applications.

The Edgeworthia extracts and chemical constituents’ antibacterial activity has been reported against both Gram-positive and Gram-negative bacteria, including S. aureus, B. subtilis, and E. coli, with inhibition zones and MIC values, indicating moderate to strong potency. Such activity suggests possibility for further development as antibacterial agents for infections or as natural preservatives. Similarly, the piscicidal activity, suggests that secondary metabolites produced from Edgeworthia may be used to control pests. However, further studies on safety, toxicity, and mechanism of action are required.

Conclusion

Medicinal plants and their constituents have a crucial role in the prevention and treatment of several illnesses. The current work summarized the reported investigations of Edgeworthia species and their biological activities. A total of 243 compounds were identified, including flavonoids, coumarins, terpenoids, phenolics, alkaloids, lignans, organic acids, sterols, fatty acids, and chromans. Flavonoids, terpenoids, and coumarins represent the major identified metabolites (Figure 12). These compounds were separated mainly from E. chrysantha and E. gardneri obtained from different countries: China, Japan, Korea, India, and Bhutan, whereas E. chrysantha is the most studied species (Figure 13). Additionally, these compounds were separated from different plant parts, including roots, stems, barks, flower buds, and whole plants, whereas most of them were obtained from the flowers of these plants.

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Figure 12.

Number of compounds reported from different classes isolated from Edgeworthia species

Figure 12.

Number of compounds reported from different classes isolated from Edgeworthia species

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Figure 13.

Number of compounds reported from Edgeworthia plants

Figure 13.

Number of compounds reported from Edgeworthia plants

Some of them possess unique structural features such as such as the daphnane-type diterpenoid orthoester moiety, specific prenylation patterns in flavonoids, and glycosylation profiles in coumarins that can remarkably influence membrane permeability, lipophilicity, membrane permeability, and receptor-binding affinity, thereby affecting their selectivity, potency, and overall pharmacological properties.

Flavonoids, terpenoids, and coumarins represent key bioactive metabolites that might directly or indirectly contribute to the highlighted bioactivities and justify the plants’ traditional uses in various cultures. Additionally, the reported data in this work revealed notable connectivity among folk uses and the validated bioactivities of these plants. These findings highlight the therapeutic potential of Edgeworthia species, underscoring the need for structure–activity relationship studies to guide the development of new therapeutic agents.

Despite the considerable number of reported works on this genus, there are limited or lacking studies that focus on derivatization, biosynthetic pathways, possible mechanisms, and the relationship between the bioactivity and these metabolites` structures. Also, attempts to investigate the unstudied species and evaluate the bioactivities of the untested constituents are required. Clinical trials and safety verification of these plants and their constituents are warranted before their pharmacological utilization for drug discovery. Therefore, these areas should be the focus of future work on this genus.

Competing Interests

The authors declare no conflicts of interest.

Ethical Approval

Not applicable.

Supplementary Files

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