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Essential oil of Angelica sinensis: A review of its extraction processes, phytochemistry, pharmacological effects, potential drug delivery systems, and applications
*Corresponding author: E-mail address: 2051028@sntcm.edu.cn (X. Zhang)
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Received: ,
Accepted: ,
Abstract
Essential oils have long been integral to various traditional healing systems for their medicinal properties, frequently preferred over chemical drugs due to chemical drugs reported adverse effects. Consequently, diverse plant sources have been explored for essential oil extraction. The essential oil of Angelica sinensis (EOAS) contributes significantly to its medicinal properties and is a critical quality control marker for its assessment. EOAS finds application in personal care products, perfumery, pharmaceuticals and food additives. A comprehensive literature search was performed using databases such as PubMed, ScienceDirect, Scopus, and Bentham. Keywords such as essential oil, EOAS and A. sinensis were employed to retrieve literature detailing therapeutic mechanisms and applications of herbal preparations. This review systematically outlines the pharmacological effects of EOAS on the cardiovascular and cerebrovascular systems, central nervous system (CNS), antioxidant properties, inflammation, and sedation. It details its roles in analgesia, antimicrobial activity, and asthma management. This manuscript further summarizes the drug delivery system, potential applications, extraction process, toxicity, contraindications, and chemical composition of EOAS. It critically assesses the limitations of current research in this field. EOAS exerts pharmacological effects in cardiovascular and cerebrovascular diseases, CNS diseases, inflammation, analgesia and sedation by improving microcirculation, scavenging ROS, activating endogenous antioxidants, activating Nrf2/ARE pathways, and enhancing endogenous antioxidant enzyme activity. It exerts a multimodal analgesic effect by inhibiting TRPV1 channel desensitization and modulating μ-opioid receptor activity in detail. In terms of antibacterial, EOAS can reduce fungal lipid and alginate content and change cell membrane permeability. In addition, he lowers IL-4 levels while increasing IL-10 and stabilizing T cells to alleviate asthma symptoms. This manuscript further summarizes Potential applications for EOAS such as β-cyclodextrin inclusion complexes, liposomes, etc. This manuscript further summarizes potential applications of EOAS, such as β-cyclodextrin complexes, liposomes, and others. We cover how to remove EOAS steam distillation, organic solvent extraction, and more. In addition, adverse reactions such as gastrointestinal discomfort and strong irritation can be present in EOAS applications. Its potential applications in baked goods, food packaging, insect repellents, crop fungicides.We also cover the main chemical constituents of EOAS such as ligustrum, n-butylbenzelene, β-occiene, etc. This comprehensive review underscores the potential of EOAS as a natural and effective treatment for cardiovascular diseases, fungal infections, and inflammation. It advocates utilizing EOAS as a prospective raw material in developing new health-promoting products, such as green natural foods and food preservation packaging.
Keywords
Natural products
Extraction processes
Chemical compositions
Pharmacological effects
Applications
1. Introduction
Herbal products have emerged as pivotal sources for discovering novel drug molecules to combat serious diseases [1]. Owing to their medicinal properties, they are pivotal in disease treatment and healthcare [2]. Recent years have seen growing interest in essential oils, which are key components of herbal products. Aromatic metabolites found in certain plants, known as essential oils. Owing to their low antibiotic resistance and lack of cumulative toxicity, the food and drug administration (FDA) has classified most essential oils and their active ingredients as generally recognized as safe (GRAS) [3,4]. Essential oils have wide-ranging applications in biomedicine, food, and agriculture. Their antibacterial, anti-inflammatory, antioxidant, and immunomodulatory properties render them valuable in disease prevention and health management [5]. These green, safe characteristics position them as potential alternatives to chemical synthetic preservatives, prompting research into their use in food preservation and active packaging [6]. Studies show essential oils can serve as preservatives, nutrients, and flavor enhancers. For example, the citral-eugenol combination exerts antifungal activity via a metacaspase-dependent apoptosis induction, serviceable in preserving functional baked foods [7]. In agriculture, essential oils act as stress-resistance modulators and green pesticides [8]. Overall, essential oils hold huge potential for development in biomedicine, food, and agriculture.
Angelica sinensis is a species of the Apiaceae family [9,10], as illustrated in Figure 1. The medicinal properties of A. sinensis primarily reside in its roots [11]. Due to its widespread use in the fields of medicinal, culinary, and health products, it is popular in Asia [12]. Essential oil of Angelica sinensis (EOAS) predominantly contains Ligustilide (LIG) (45%–65%), n-Butylidenephthalide (BP) (8.25%), n-Butylphthalide (NBP) (2.06%), α-Pinene (2.18%), Spathulenol (0.9%), and β-Ocimene (3.75%), among others [13,14]. EOAS exhibits a variety of biological activities, including anti-inflammatory, antibacterial, antiviral, immunomodulatory, antitumor, and neuroprotective antioxidant properties [15]. Emerging evidence indicates that this essential oil may provide pharmacological benefits across various bodily systems, such as gastrointestinal, hepatic, renal, cutaneous, respiratory, cerebral, and nervous systems, demonstrating hypoglycemic and hypolipidemic effects. Moreover, it is commonly used for its antibacterial, analgesic, sedative, and anti-inflammatory properties [16,17]. Although EOAS demonstrates effectiveness across various diseases, particularly in cardiovascular conditions, anxiety relief, and depression, its quality remains highly variable. EOAS has broad-spectrum antibacterial activity, low toxicity, and is obviously derived. It shows great potential in food preservation, active packaging, and agriculture. In food preservation, EOAS reduces contamination and resource waste. It also enhances the freshness of baked foods and extends their shelf life [4]. Its phthalide compounds, like phenolic acid, have strong repellent activity. EOAS’s repellent effect can last up to 7 h, making it a promising candidate for native mosquito-repellent products [18]. EOAS also effectively inhibits various plant pathogenic fungi, such as Fusarium head blight (FHB) [19,20]. Compared to chemical fungicides, EOAS is more environmentally friendly and less likely to provoke resistance. However, inconsistent quality and its pungent odor can limit its direct application [21]. There are differences in the components and yield of EOAS extracted via common methods like supercritical CO₂ extraction, organic solvent extraction, and water vapor distillation [22]. Hearing the specific background and applications of each method helps select and optimize EOAS quality and extraction efficiency. EOAS can be formulated into various drug-delivery systems, including microemulsions, β-cyclodextrin inclusion complexes, liposomes, and microcapsules. These systems mitigate issues like pungent odor and susceptibility to oxidation, thereby broadening EOAS’s scope of application.
- Diagram of the flowering period of the Angelica sinensis.
In this review, the pharmacological activities of EOAS have been comprehensively examined in the cardiovascular and cerebrovascular systems, central nervous system (CNS), anxiety relief, antioxidant properties, inflammation, and sedation. Moreover, its role in analgesia, antimicrobial activity, and asthma management has been systematically summarized [23,24]. Despite the limitations of EOAS, such as rapid metabolism and short duration of action, advancements in drug delivery systems have addressed these challenges effectively [25]. In addition, we reviewed the potential applications of EOAS in baked goods and antimicrobial food packaging, as well as insect repellents and mosquito repellents for crops. Its toxicity and contraindications were understood, and the major chemical components of EOAS have been detailed. To fully realize the potential of EOAS, a deeper understanding of its active components and mechanisms of action is crucial. This review systematically summarizes EOAS’s pharmacological activities, extraction processes, drug delivery systems, potential applications, and primary chemical constituents, offering a foundational analysis to support future developments and applications of EOAS, particularly in the food industry.
2. Ingredients of EOAS
The composition and concentration of essential oil constituents vary, rendering each oil distinct in its chemical properties and therapeutic efficacy. EOAS is increasingly utilized in consumer products and pharmaceutical applications. Meanwhile, studies on its pharmacological activities, particularly antibacterial and anti-inflammatory properties, are progressing rapidly. These advancements have prompted researchers worldwide to intensify efforts in analyzing its chemical composition. A. sinensis contains a substantial amount of essential oil, approximately 0.4% [26]. Gas chromatography/mass spectrometry (GC/MS) analysis has identified around 40 compounds, accounting for 95.5% of the total essential oil content. The principal chemical components of EOAS significantly contribute to its efficacy. LIG (45%-65%) emerges as the dominant compound, followed by n-Butylidenephthalide (BP) (8.25%), n-Butylphthalide (NBP) (2.06%), α-Pinene (2.18%), Spathulenol (0.9%), and β-Ocimene (3.75%) [13]. Factors such as light, temperature, precipitation, soil conditions, harvest time, and extraction processes can influence the chemical composition and yield of EOAS, presenting challenges related to its diverse components, content standardization, and quality control.
2.1. Main chemical components
A comparative analysis of the major components of EOAS and other plants of the same genus, such as Levisticum officinale and Angelica acutiloba Kitagawa, revealed significantly higher LIG content in EOAS-21 times that of A. acutiloba Kitagawa essential oil [27]. EOAS is generally rich in neutral oils (88%), particularly LIG (55.7%), BP (8.25%), β-Ocimene (3.75%), α-Pinene (2.18%), NBP (2.06%), and β-Bisabolene (0.2%) [14]. Additionally, EOAS contains minor bioactive compounds, including phenolic oil (10%) and acidic oil (2%) [13]. This has been shown in Table 1.
| No. | Content (%) | Structural formula | Compound | Performances | Pharmacological activity | Potential applications | Reference |
|---|---|---|---|---|---|---|---|
| 1 | 55.7 | LIG |
Phthalide Yellow oily liquid Soluble in organic solvents Special odor |
Antibacterial activity Analgesic effect Anti-inflammatory Antioxidant effect Promote blood circulation Neuroprotection |
Food preservation Potential Drug for Coronary Heart Disease Potential Drug for Lung Injury Potential drug for cognitive disorders Potential drug for tumors Potential drug for inflammatory pain |
[29-34] | |
| 2 | 8.25 | BP |
Phthalide Colorless to light yellow paste Soluble in organic solvents Herbal fragrance |
Anti-angiogenic effect Anti-inflammatory Antihypertensive effect Insecticide effect Inhibition of liver cancer Anti-obesity effect |
Potential drug for atherosclerosis Treatment of diabetic retinal inflammation Potential antihypertensive drug Drugs for the treatment of peanut leukodystrophy Potential drug for anti-cancer Potential drug for obesity-suppressing |
[35-39] | |
| 3 | 3.75 | β-Ocimene |
Monoterpene Colorless to light yellow oily substance Slightly soluble in chloroform and methanol Herbal odor |
Anti-Leishmania effect Antibacterial effect Anti-inflammatory effect Anti-oxidation |
Potential drug for antiparasitic Potential drug for chronic inflammation |
[40,41] | |
| 4 | 2.18 | α-Pinene |
Monoterpene Colorless Transparent Liquid Slightly soluble in water, insoluble in most organic solvents Pine tree odor |
Antifungal effect Antioxidant effect Protect gastric mucosa and anti-ulcer Anti-cancer Bactericidal effect Insecticidal effect Antiseptic |
Potential anticoagulant Potential drug for respiratory infections Drugs to treat peptic ulcers Potential drug for Liver Cancer Potential insecticide |
[43] [44] |
|
| 5 | 2.06 | NBP |
Phthalide Yellow oily liquid Slightly soluble in water and dimethyl sulfoxide Celery flavor |
Anti-inflammatory effect Increasing serum insulin Decreasing lipid and hepatic lipid levels Scavenging oxygen free radicals Inhibiting neuronal apoptosis Inhibiting platelet aggregation Improving blood circulation |
Potential drug for cognitive Impairment Potential drug for hyperglycaemia Potential drug to treat anti-AD Drug for ischemic stroke |
[48] |
|
| 6 | 0.9 | Spathulenol |
Tricyclic sesquiterpene alcohol Pale Yellow Liquid Soluble in methanol, benzene, slightly soluble in water Fruity herbaceous odor |
Pollinator attraction | Potential drug to promote pollination | [49] | |
| 7 | 0.86 | Cedrene |
Sesquiterpene Colorless liquid Insoluble in water, soluble in organic solvents Woody fragrance |
Antioxidant Anti-inflammatory |
Surfactant Reactive Diluent Polymers and composites |
[50] | |
| 8 | 0.78 | (+)-Cuparene |
Aromatic Sesquiterpenes Colorless to yellow oily liquid Soluble in organic solvents, insoluble in water Pine aroma |
Antibacterial effect Improves microcirculation |
Potential drug for the treatment of traumatic injuries | [51] | |
| 9 | 0.2 | β-Bisabolene |
Monocyclic Sesquiterpenes Colorless oily liquid Insoluble in water, soluble in organic melts Sweet aroma |
Anticonvulsive effect Anti-cellulite activity Anti-cancer activity |
Potential drug for the treatment of convulsions Potential drug for breast cancer |
[52] | |
| 10 | 0.12 | 4-Vinylguaiacol |
Vinylphenol derivatives Colorless to light yellow oily liquid Insoluble in water, soluble in oil Strong spice aroma |
Antioxidant activity Antimicrobial activity Anticancer |
Potential antimicrobials Contact lens solutions and eye drops Potential drug for cancer |
[53-55] |
2.1.1. Ligustilide
LIG (1), a prominent member of the phthalide class, is predominantly found in A. sinensis, Ligusticum sinense, and other Apiaceae family plants [28]. Known for its numerous health benefits, LIG was first isolated by Mitsuhashi in 1960. However, it exhibits limited stability and is susceptible to chemical reactions, including dehydrogenation, oxidation, hydrolysis, and degradation. LIG exists as two isomers: (Z)-LIG and (E)-LIG, with the Z-type being more stable and found in much higher concentrations in plants than the E-type. Due to its high bioavailability and penetration capability, LIG is regarded as a promising candidate for drug development. Key pharmacokinetic data includes oral bioavailability of 53.72%, a half-life (T1/2) of 5.61 h, a blood-brain barrier coefficient of 1.25, and a drug-likeness index of 0.07 [56]. LIG exhibits a broad spectrum of therapeutic effects, including anti-inflammatory, antioxidant, anti-apoptotic, neuroprotective, and cytoprotective properties. It has shown significant efficacy in the treatment of conditions such as atherosclerosis (AS) [57], coronary heart disease [30], other cardiovascular disorders, lung injury [31], vascular dementia, cognitive impairments [32], and various cancers [33]. Its therapeutic mechanisms are closely tied to its anti-inflammatory and antioxidant actions, particularly its ability to cross the blood-brain barrier, suppress inflammatory responses, and counteract oxidative stress. LIG also improves cerebral microcirculation and enhances choline acetyltransferase (ChAT) activity. It plays a pivotal therapeutic role by inhibiting macrophage adhesion, suppressing nuclear factor kappa-B (NF-κB)-mediated chemokine production, and reducing reactive oxygen species (ROS) generation [34]. Additionally, LIG modulates the MyD88/TLR4 signaling pathway and regulates cellular autophagy and apoptosis [56].
2.1.2. n-Butylidenephthalide
BP (2) exists as two isomers, Z-type and E-type, and predominantly occurs as a racemate. Found in plants such as L. sinense, A. sinensis, A. acutiloba, and Ligusticum jeholense, BP exhibits significant antiplatelet activity by inhibiting cyclooxygenase function. It notably enhances the susceptibility of Trichophyton species to antifungals like ketoconazole and itraconazole [58]. Furthermore, BP demonstrates potent antitumor effects against various cancer types, including colon cancer, glioblastoma multiforme, hepatocellular carcinoma, lung cancer, and prostate cancer [59]. Research indicates BP also effectively inhibits melanoma cell growth when encapsulated in polycationic liposomes. Its inhibition of angiogenesis in vascular diseases and ability to mitigate pulmonary fibrosis have been well-documented [35]. BP has also shown neuroprotective effects in preventing ischemic damage to the eye [60]. In terms of acaricidal properties, BP outperforms the control agent arbutamine across all cases. It possesses strong insecticidal activity, with an LC50 value of 1.56 mg/g against Spodoptera litura larvae and exhibits 98% inhibition of Macrophomina phaseolina at a concentration of 1 g/L [20]. Additionally, BP was effective in suppressing white serotonin in peanuts and yielded surprising results in alleviating high-fat diet-induced obesity [39].
2.1.3. β-Ocimene
β-Ocimene (3), a naturally occurring terpene, comprises two isomers: cis-β-Ocimene and trans-β-Ocimene. It is commonly found in the leaves and floral organs of various plants, such as Mentha canadensis, Ocimum basilicum, Petroselinum crispum, and Citrus japonica. β-Ocimene is widely utilized in the spice and flavor industry due to its distinctive aroma and flavor. Beyond its commercial uses, β-Ocimene exhibits promising anti-inflammatory and anticancer properties [61]. It exerts anti-inflammatory effects by inhibiting cellular NO production and suppressing the expression of pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β), and interleukin-6 (IL-6). These actions are believed to be linked to its antioxidant activity, as β-Ocimene reduces ROS levels while boosting the activity of enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST), leading to notable antioxidant effects [62,63]. Recent studies suggest that β-Ocimene may contribute to the antioxidant, antifungal, antiparasitic, anticancer, antimicrobial, and wound-healing properties of β-Ocimene-rich essential oils. These essential oils have shown cytotoxic effects against tumor cell lines, likely due to a synergistic interaction between β-Ocimene and other major components, although the exact mechanisms require further investigation [64]. Exogenous β-Ocimene has also been effective in increasing artemisinin content in Artemisia annua L. seedlings [65]. Moreover, β-Ocimene has been extensively studied in entomology and ecology, particularly as a key component of herbivore-induced plant volatiles (HIPVs). It holds potential in agriculture as a natural repellent and pheromone for attracting beneficial insects, offering significant developmental value and broad application prospects [66].
2.1.4. α-Pinene
α-Pinene (4) is predominantly found in higher plants, including Pinales and Cannabis Linn., and is primarily used to treat respiratory tract infections. Its mechanism of action involves inhibiting the expression of inflammatory proteins such as NF-κB, TNF-α, and IL-6, while also reducing ROS production. α-Pinene exhibits a wide range of biological activities, including antibacterial, antifungal, antileishmanial, anti-inflammatory, antioxidant, gastroprotective, and anticancer effects [67]. In hepatocellular carcinoma, it inhibits tumor growth by inducing cytotoxicity, causing cell cycle arrest at the G2/M phase, and promoting apoptosis [43]. Additionally, it has demonstrated significant inhibitory effects on Gram-negative bacteria, including Escherichia coli. α-Pinene also serves as a key raw material for synthesizing fragrances like rosinol, linalool, and sandalwood-type scents [67]. and is utilized in the production of daily chemicals and industrial goods. However, it is also considered an indoor air pollutant, present in building materials and household products. The metabolite α-Pinene oxide carries a potential mutagenic risk, though the carcinogenic potential of α-Pinene warrants further investigation [68].
2.1.5. n-Butylphthalide
NBP (5), found primarily in plants of the Ligusticum genus within the Apiaceae family and Apium graveolens L, has shown therapeutic effects on hypertension, hyperglycemia, dyslipidemia, and obesity. It enhances scavenging enzyme activity, inhibits lipid peroxidation, and reduces glucose levels while increasing serum insulin and lowering lipid and hepatic fat levels [47]. NBP also inhibits neuronal apoptosis, reduces cerebral infarction size, and improves circulation by inhibiting platelet aggregation and scavenging oxygen free radicals. It is primarily used in the treatment of ischemic stroke and has proven effective in treating cerebral ischemia and dementia [48,69]. NBP holds the distinction of being China’s first national Class I new drug with independent intellectual property rights for cerebrovascular disease treatment [70]. However, its low oral bioavailability limits its use, and it is often administered by injection in clinical settings. Future research aims to develop advanced NBP drug delivery systems to enhance its bioavailability.
2.1.6. Spathulenol
Spathulenol (6) is primarily derived from plants such as Eucalyptus spp., Myrcianthes myrsinoides, and Myrcia mollis. It demonstrates efficacy against inflammation, mycobacteria, tumors, and cardiac fibrosis [71]. Its anti-inflammatory effects result from reducing the sensitization of injured nerve fibers and modulating inflammatory mediators, while its analgesic properties are also attributed to its anti-inflammatory activity [72]. Spathulenol has shown cytotoxicity against human gastric cancer cells, though the exact mechanism remains unclear and may involve increased cellular phosphatidylserine exposure [73]. Additionally, spathulenol exhibits significant antioxidant activity, with an IC50 value of 85.60 μg/mL [74]. Due to its antimicrobial and anthelmintic properties, spathulenol is commonly used for insect control in the storage of crops and medicinal herbs [44].
2.1.7. Cedrene
Cedrene (7) can be derived naturally from plants like Pinus and Fraxinus chinensis Roxb. or synthesized through chemical methods such as olefin cyclization and olefin molecule dehydration [75]. Known for its antimicrobial properties, Cedrene can penetrate the skin, entering the bloodstream to enhance microcirculation and promote wound healing. It also alleviates wound itching and boosts immune function, making it a valuable compound in wound healing, astringents, and anti-itch treatments for trauma [50]. Additionally, its fresh, aromatic scent lends itself to use in perfumes, flavoring products, and the fragrance industry.
2.1.8. (+)-Cuparene
(+)-Cuparene (8) is typically sourced from natural colophony or extracted from plants like Cupressus funebris and Pinaceae Spreng. It can also be synthesized chemically. (+)-Cuparene exhibits anti-inflammatory, antioxidant, and bacteriostatic properties, benefiting conditions tied to chronic inflammation and infections [51]. It is widely used in personal care products such as dairy items, shampoo, and shower gel, imparting a cypress fragrance and delivering antioxidant effects. In agriculture, it is known to promote plant growth and development [76]. While its toxicity and safety profile are not extensively studied, (+)-Cuparene is generally regarded as safe; however, precautions should be taken to avoid direct skin contact, inhalation, and ingestion.
2.1.9. β-Bisabolene
β-Bisabolene (9), a naturally occurring active compound, is found in a variety of plant sources, including Paeonia lactiflora and essential oils like red myrrh and lemon oils. β-Bisabolene has significant commercial value due to its fragrance, resembling that of citrus and tropical fruits, and is commonly used in the formulation of edible and daily chemical flavors, such as orange, banana, grapefruit, and pear. Additionally, it holds potential as a new biofuel. β-Bisabolene is recognized for its anti-itch, anti-inflammatory, anti-obesity, and anticancer properties, with applications in breast cancer research [52]. It can also be converted into high-value industrial products, including pharmaceuticals, nutraceuticals, cosmetics, and biofuels [53]. Despite its extensive uses, the extraction of β-Bisabolene from plants presents challenges, including low yield and difficulty in isolation and purification. To address this, microbial metabolic engineering and chemical synthesis methods have been employed for its production [77].
2.1.10. 4-vinylguaiacol
4-vinylguaiacol (10) naturally occurs in the volatiles produced during corn alcohol fermentation but is predominantly available as a synthetic compound. With its distinct fermentation aroma and high olfactory recognition, it serves as a key flavor component in liquor, beer, wine, and soy sauce, contributing significantly to the sensory profile of these fermented products [78]. Beyond its flavoring capabilities, 4-vinylguaiacol has demonstrated antioxidant and anticancer properties [55]. It is also a valuable high-grade ingredient in the cosmetic, pharmaceutical, and flavoring industries. In the pharmaceutical field, it holds potential for use in ophthalmic products such as contact lens solutions and eye drops. Its widespread application as a flavoring agent in the food industry is supported by various biosynthetic production methods, including microbial fermentation, plant cell culture, and enzymatic processes [53]. The development and optimization of these methods have paved the way for the expanded use of 4-vinylguaiacol in food manufacturing.
2.2. Distribution of EOAS in different parts of Angelica sinensis
EOAS exhibit a broad spectrum of therapeutic and preventive properties, including anti-inflammatory, antimicrobial, antihypertensive, and analgesic effects. Understanding the distribution of EOAS is essential for determining their quality and medicinal efficacy. In traditional Chinese medicine, the root of A. sinensis is divided into three parts: head, body, and tail, each containing varying amounts of EOAS. Seasonal variations also affect the essential oil content in A. sinensis [26]. Therefore, the distribution of essential oils in A. sinensis is a complex process influenced by multiple factors. A comprehensive understanding of this distribution is critical for evaluating the plant’s quality and medicinal properties [15].
2.3. Compositional differences between different plant sources
EOAS refers to the essential oil derived from the roots of A. sinensis. With the global spread of traditional Chinese medicine, A. sinensis is commonly used as a blood tonic in traditional medicine in China, Japan, and Korea, though the plant sources vary between these regions, leading to differences in the content and composition of essential oils. As a result, five Angelica-like herbs have been confused and mixed to varying degrees in domestic and international markets. To clarify these distinctions, this study summarizes and analyzes the main components of the essential oils from these five plants, highlighting their similarities and differences.
Japanese Angelica, derived from the dried roots of A. acutiloba Kitagava and A. acutiloba Kitagava var. Sugiyama Hikino of the Apiaceae family, contains essential oil components such as LIG, n-Butylidenphthalide (NBP), Cnidilide, Isocnidilide, Niacin, Sedanolide, and p-Cymene [79]. Notably, the LIG content is about one-tenth that of A. sinensis, yet it exhibits anti-tumor, anti-diabetic, anti-obesity, and significant anti-inflammatory activities [80]. In contrast, Korean Angelica, sourced from the dried root of Angelica gigas Nakai, is known for its distinctive active compounds Decursin and Decursinol angelate. However, its essential oil contains lower amounts of LIG and NBP compared to A. sinensis and A. acutiloba Kitagava. The European herb Levisticum officinale Koch., native to coastal regions such as Scotland, Northern Ireland, Norway, Sweden, and Denmark, shares a similar chemical composition with A. sinensis, although the LIG content is considerably lower. Studies have identified approximately 190 compounds in L. officinale essential oil, with phthalides being the primary constituents. The major components include α-Terpinyl acetate (52.85%), β-Phellandrene (10.26%), Neocnidilide (10.12%), β-Pinene (5.10%), (Z)-β-Ocimene (3.99%), and Methyleugenol (3.16%) [81]. The essential oil from the aerial parts of L. officinale primarily contains β-Phellandrenes (42.5%) and α-Terpineol (27.9%), characterized by strong free radical scavenging activity, antifungal properties, non-phytotoxicity, and a high low-density (LD) value, making it suitable for use in food and agriculture, particularly in kiwi seed cultivation [82]. Another European species, Angelica archangelica L., often confused with A. sinensis due to its similar Latin and English names, grows in the cold temperate regions of Asia and Europe, including Russia, Germany, the Netherlands, and the Himalayas. Its essential oil predominantly contains monostearic, sesquiterpene, and macrolide compounds, significantly differing in composition from EOAS [83]. Consequently, the biological activities of A. archangelica L. may also differ in strength and function. This essential oil is commonly used in the food and pharmaceutical industries due to its distinctive aroma and is applied as a nicotine antidote and in the treatment of nervous and gastrointestinal disorders due to its excitatory effects on the nervous system. These results underscore both the correlations and differences in the chemical composition and biological activities of the five Angelica species, offering insight into their various medicinal and industrial applications.
3. EOAS extraction processes
EOAS, a natural anti-inflammatory and antioxidant derived from A. sinensis, typically contains a variety of compounds, including terpenes, lipids, aldehydes, and alcohols. Modern production methods for EOAS include water vapor distillation, organic solvent extraction, and supercritical CO2 extraction [28]. Due to the unique chemical properties of the plant and variations in extraction techniques, the composition and concentration of EOAS differ depending on the method used, as illustrated in Figure 2. These differences directly influence EOAS’s biological activity, pharmacological effects, and applications. Numerous studies have examined the extraction efficiency and composition of EOAS across these methods, each of which is suited to specific contexts and applications. Extraction efficiency typically follows the order of supercritical CO2 extraction (2.1%), organic solvent extraction (1.47%-3.11%), and water vapor distillation (0.8%) (Table 2) [84]. Water vapor distillation is a function of distillation time, temperature, and raw material particle size [85]. This method primarily extracts phthalides (e.g., LIG, BP) and small volatile molecules. However, high temperatures may degrade heat-sensitive components like LIG [86]. LIG exhibits anti-inflammatory, antioxidant, and analgesic properties. Supercritical CO2 extraction enhances oil yield by adjusting pressure and temperature [87]. It works at low temperatures (35-45°C) with no solvent residues and offers a broader range of extracted components [88,89]. It reduces LIG isomerization and preserves terpenes and esters (e.g., ethyl linoleate). Extracts from this method show higher LIG content and superior anti-inflammatory/antioxidant activity opposed to water vapor distillation [85]. It is suitable for high-purity essential oils in food and pharmaceuticals. Organic solvent extraction efficiency is dependent on solvent polarity and dosage [90]. This method isolates more fat-soluble components (e.g., linoleic acid), though residual solvents may pose concerns [96]. Microwave-assisted technology is influenced by microwave power and extraction time. It produces EOAS rich in bioactive compounds (e.g., LIG, terpenes) with anti-inflammatory and antioxidant properties [97]. Enzyme-assisted process performance is dependent on enzyme dosage, temperature, and time [98]. With a growing market demand for the deep processing of A. sinensis, advancements in extraction technology have allowed this ancient medicinal plant to play an increasingly important role in promoting health. Therefore, developing a simple and efficient extraction method that can achieve LIG concentrations exceeding 50% is of significant practical value.
- Flowchart of the three types of extraction processes.
| Method | Define | Extraction efficiency | Advantages | Disadvantages | Scope of application | Reference |
|---|---|---|---|---|---|---|
| Water vapor distillation | Heating is carried out by water vapor, and the volatile components are evaporated with the water vapor, which is condensed and cooled and then collected in layers | 0.8% |
Simple equipment Easy to operate No solvent residue Low cost Easy promotion Strong practicality Good stability |
Low yield High extraction temperature Long time |
The extraction of volatile and heat-sensitive plant components, Currently the most widely used | [91] |
| Organic solvent extraction | A process in which the solvent enters the cellular tissues of the herbs to extract the chemical constituents from the herbs | 1.47%-3.11% |
Large processing capacity Lower energy consumption Easy continuous operation |
Toxicity safety Long extraction time Low efficiency |
Widely used in the laboratory | [92] |
| Supercritical CO2 extraction | This method involves utilizing supercritical fluid (CO2) to separate one component (extractant) from another (plant matrix) | 1.9%-2.1% |
Non-toxic Easy solvent removal No pollution Green separation technology High efficiency |
High cost of equipment | Mostly used in the pharmaceutical, food and healthcare industries | [14,93] |
| Microwave-assisted technology | Microwave-assisted technology is a process to extract drugs according to the different absorption abilities of different substances in microwaves |
Essential oil extraction rate of A. sinensis could reach 11.2% 1.7%-3.4% |
Increasing the rate of drug extraction Accelerating the extraction of active substances Environmentally friendly |
Not yet mature Low extraction of EOAS components |
Small and large-scale applications | [36] |
| Enzyme-assisted process | This technique disrupts and degrades the cell wall, breaking down the macromolecules and releasing the bound target bioactivity from the macromolecules | EOAS yield and Z-LIG content increased by 0.31% and 5.6%, respectively. |
High specificity. Mild reaction conditions Improved extraction of active substances |
Currently less used | The technology is used to extract bioactive components from various plant sources | [94,95] |
3.1. Water vapor distillation
Water vapor distillation remains the traditional method for extracting plant essential oils. In this process, water vapor heats the plant material, causing the volatile components to evaporate alongside the vapor, which is then condensed, cooled, and collected in separate layers. This technique is particularly suited for extracting volatile, heat-sensitive plant compounds and is currently the most used method due to its simplicity, low cost, and absence of solvent residues. Additionally, it offers advantages such as ease of operation, practical application, stability, and mature technology and equipment. EOAS, widely utilized in traditional Chinese medicine, exhibits important pharmacological activities (Table 2). Its extraction via water vapor distillation is environmentally friendly, safe, and well-suited for large-scale production, making it a preferred method in various industries, including herbal preparations, health products, and cosmetics. This process also facilitates the extraction of bioactive compounds such as LIG, which are further fractionated into acidic, phenolic, and neutral components [14]. Specifically, the acidic fraction (5.88%) contains palmitic acid and trace amounts of phthalic anhydride, while the phenolic fraction (3.46%) can yield carvacrol through reduced-pressure fractional distillation. The neutral fraction (90.40%) provides angelicone and BP after further purification via silica gel chromatography. Despite these benefits, the process has drawbacks, including a low yield per batch, high extraction temperature, and prolonged operation times, with heating durations ranging from 5 to 14 hours, which reduces the yield of LIG due to its thermal sensitivity.
3.2. Organic solvent extraction
In contrast, organic solvent extraction involves solvent penetration into plant cellular tissues to dissolve chemical constituents. As shown in Table 2, this method offers large-scale processing capabilities, reduced energy consumption, and the potential for continuous operation. Organic solvent extraction has been employed to isolate EOAS from the roots of A. sinensis, utilizing solvents such as petroleum ether, n-hexane, ethyl ether, chloroform, ethanol (both 95% and pure), and mixed solvent systems like petroleum ether-95% ethanol and chloroform-n-hexane. Among these, chloroform-n-hexane extraction yielded the highest rate of 3.258% [92]. However, most organic solvents, aside from ethanol, pose toxicity concerns. Additionally, the process is characterized by extended extraction times, low efficiency, and significant solvent consumption, often resulting in residual solvent contamination [90].
3.3. Supercritical CO2 extraction
Supercritical CO2 extraction is a modern and highly efficient separation technology that has gained recognition in recent years for its environmental benefits. Often referred to as “green separation technology,” this method uses non-toxic CO2 in a supercritical state, which leaves no residue and avoids pollution, aligning with the principles of green product development. In this process, supercritical CO2 acts as a solvent, selectively dissolving certain compounds while facilitating the separation of the dispersed system and its components. When applied to A. sinensis, the root is first crushed, and EOAS is extracted through supercritical CO2 fluid extraction. Compared to water vapor distillation, supercritical CO2 extraction yields significantly higher amounts of EOAS. Its low extraction temperature and closed system preserve thermally unstable and easily oxidized components, enabling the extraction of EOAS compounds that are not typically obtained via conventional methods. This includes a range of alkanes, organic acids, and esters.
Notably, while the content of LIG in EOAS extracted through supercritical CO2 and water vapor distillation is similar, the yield from the supercritical CO2 process is double that of the latter [14]. EOAS extracted through this method can be used in medicinal, edible, and healthcare products, as well as pharmaceutical intermediates. Furthermore, this process allows for the isolation and purification of EOAS, facilitating the production of EOAS drops, injections, and soft capsules. After purification, EOAS can be incorporated into various pharmaceutical delivery systems, maximizing its utility. The technology is mature, enabling quantitative control over quality. Depending on the medicinal requirements, different parts of A. sinensis, the head, root, or tail, can be extracted individually. The EOAS obtained through supercritical CO2 extraction is characterized by high purity, pleasant flavor, and stable quality, making it highly suitable for use in food and health products (Table 2). The supercritical CO₂ extraction method has technical problems such as difficult equipment manufacturing and complex control of extraction parameters [88]. In addition, the equipment acquisition cost of this method is high. The extraction process consumes a large amount of CO₂ and maintains a high temperature and pressure environment [99]. This method requires high energy and capital consumption, which also limits the wide application of this method [100].
3.4. Microwave-assisted technology
Microwave-assisted extraction offers advantages like high efficiency, energy savings, and component retention. This method is about to become a sustainable alternative to traditional techniques [101]. Microwave-assisted extraction responds to the growing demand for environmentally friendly methods in food preservation and daily chemical product development. It avoids harmful solvents and reduces energy consumption [102]. Microwave-assisted extraction extracts bioactive compounds by leveraging differences in microwave absorption of materials (Table 2). Studies stress that microwave-assisted extraction reduces extraction time, energy use, and solvent volume while preserving bioactive components [101]. Compared with steam distillation, microwave-assisted extraction shortens processing time by 50-90% [36]. For example, ionic liquid-based microwave-assisted hydro distillation extracts EOAS in 4 h, reaching a 3.76-fold higher yield than steam distillation [97] .Microwave-assisted extraction also enhances product quality. Clove essential oil processed via microwave-assisted extraction shows higher eugenol purity and greatly improved antioxidant activity [103]. Refining key factors, including microwave power, solvent dielectric characteristics, and extraction conditions, can further improve efficiency [104]. Combining microwave-assisted extraction with ultrasound or dual-phase extraction techniques addresses scalability limitations [105]. Despite its potential, microwave-assisted extraction requires refinement. Industrial-scale equipment design and energy management systems need optimization [106]. Future research should concentrate on two key areas: developing industrial-scale microwave-assisted extraction equipment and deepening the understanding of extraction mechanisms. These efforts will expand microwave-assisted extraction applications in natural product development.
3.5. Enzyme-assisted process
In the pursuit of improving EOAS extraction efficiency, researchers have been continuously exploring various extraction processes and equipment. One promising approach is the use of biological enzymes, which offer high specificity and operate under mild reaction conditions. Enzyme-assisted extraction works by hydrolyzing or degrading the plant cell wall, thereby reducing the constraints on the solubility and diffusion of active ingredients and decreasing mass transfer resistance. This method has been applied to EOAS extraction with some success [36]. For instance, cellulase-assisted extraction increased the EOAS yield and Z-LIG content by 0.31% and 5.6%, respectively [94]. However, enzyme-assisted extraction remains underutilized in EOAS extraction, and further research is needed to optimize its application.
4. Pharmacological activities of EOAS
EOAS is recognized for its numerous health benefits, largely attributed to its LIG content. However, other compounds within EOAS also contribute to its therapeutic effects. A growing body of evidence demonstrates that EOAS possesses anti-inflammatory, antibacterial, antiviral, sporicidal, immunomodulatory, antitumor, neuroprotective, and antioxidant properties [107,108]. In cardiovascular diseases, EOAS improves blood circulation [109]. As an antioxidant, it boosts SOD activity and cuts malondialdehyde (MDA) levels to shield cells from oxidative damage [110]. For its calming effect, EOAS raises progesterone and pregnanolone levels, thus easing anxiety [57]. EOAS mainly alters cell membrane permeability to exert antibacterial properties [111]. In asthma treatment, it lowers IL-4 and raises IL-10, stabilizing T-cells to ease asthma symptoms [112]. EOAS also eases dysmenorrhea by reducing uterine muscle contractions [113]. In CNS diseases, it reduces ROS and IL-6 to relieve oxidative stress and prevent plaque instability [114]. For diabetes, EOAS enhances pancreatic function and inhibits TGF-β1 production to relieve symptoms,[115] as summarized in Figure 3. We have summarized EOAS’s specific pharmacological mechanisms in these systems in Table 3.
- Pharmacological effects of EOAS.
|
Pharmacological activities |
Types | Model/Cell line | Doses/Duration | Effects/Mechanism of action | Reference |
|---|---|---|---|---|---|
| Cardiovascular and cerebrovascular system | |||||
| Antiangiogenic | |||||
| In vivo | Danio rerio propagation population of a wild-type AB strain | 0.01 μg/mL | Disorders of the plexus ↑; Absence or reduction of vascularity ↑; the simian immunodeficiency virus (SIV) protein level of confusion ↑; | [116] | |
| In vitro | Human umbilical vein endothelial cells (HUVECs) | 1, 10-20, 30-40 μg/mL for 24 h | Migration of endothelial cells to denuded areas ↓; Capillary-like ability to form ↓; P38 mitogen-activated protein kinase, MAPK activated protein kinase (MAPKAPK)-2 protein levels ↑; Phosphorylation levels of mitogen-activated proteinkinase kinase 1 (ERK1)/2 protein ↓; | [116] | |
| In vitro | C57/black mice aortic ring model | 0, 20, 30, 40, 50 μg/mL for 3 days | Pseudo-capillary sprouting ↓; | [116] | |
| In vitro | HUVECs | 10, 30, 100 g/mL for 48 h | Cell viability ↓; | [117] | |
| Blood pressure | |||||
| In vitro | Vascular smooth muscle cell (VSMCs) were prepared by the explant method from thoracic aorta of male Wistar rats | LIG 0, 10, 20, 30 and 40 μg/mL for 2 days | Cell proliferation ↓; Cell cycle progression ↓; | [118] | |
| In vitro | Phenylephrine-induced aortic ring of sprague dawley (SD) rats | 4, 8, 16, 32 and 64 µg/mL for 10 min | Aortic tone ↓; | [119] | |
| Atherosclerosis | |||||
| In vitro | mouse aortic endothelial cells | LIG 10−4, 10−5 and 10−6 mol/L simultaneous stimulation with TNF-α (20 ng/mL) for 6 h | Akt protein level ↓; NF-κB protein level ↓; | [120] | |
| Central nervous system | |||||
| Brain injury | |||||
| In vivo | Vascular dementia (VaD) model of bilateral common carotid artery occlusion in rats | LIG 20 and 40 mg/kg/day, i.g., for 28 days | Catalase (CAT) protein level ↑; SOD protein level ↑; Glutathione peroxidase (GSH-PX) activities ↑; Malondialdehyde (MDA) ↓; | [23] | |
| In vivo | Fronto-cingulate-insular (FCI) A model of forebrain ischemic in male imprinting Control Regio (ICR) mice | 5, 20 mg/kg, i.p., 1 day reperfusion | Area of cerebral infarction ↓; Cerebral infarction volume ↓; MDA content ↓; SOD ↑; GSH-PX activities ↑; Bax, Caspase-3 protein levels ↓; | [114] | |
| In vivo | SD male of arterial ischemic | LIG 8, 16, 32 mg/kg, i.v., for 1 day | Infarct volume ↓; Neurons are lost ↓; Nrf2 nuclear translocation ↑; Nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) protein levels ↑; | [121] | |
| Stroke | |||||
| In vitro | Mouse embryonic neurons at 15-16 days of age | 0, 0.625, 1.25, 2.5, 5, 10 and 20 mmol/L for 2 h | Cell viability ↑; LDH protein release levels ↓; | [122] | |
| In vivo | I/R induced brain damage in male sprague dawley (MCAO) rat | 20, 40 and 80 mg/kg i.g., 0.5, 3 h before cerebral artery occlusion | Infarct volume↓; Erythropoietin (EPO) ↑; RTP801 protein levels↓; | [122] | |
| Alzheimer’s disease | |||||
| In vivo | Male specific pathogen free (SPF) Wistar rats of Aβ25–35 intracerebroventricular injection | LIG 40 mg/kg, i.g., once daily for 15 days | Hippocampal prefrontal cortex (PFC) and cornu ammonis 1 (CA1) subregion lesions ↓; Escape Latency ↓; TNF-α and NF-кB protein levels↓; | [123] | |
| In vivo | Male 10-month-old SAMP8 mice | LIG 10 or 40 mg/kg, i.g., once daily for 56 days | Cerebral cortex contraction ↓; Memory deficits Hippocampal ↓; Neurons of the hippocampus ↓; Antioxidant capacity ↑; MDA, Carbonylated proteins ↓; 8-hydroxy-desoxyguanosine ↓; Klotho and FoxO1↑; | [124] | |
| Vascular dementia | |||||
| In vivo | Bilateral common carotid artery occlusion induced in male SD rats as a model of 2VO | LIG 80 mg/kg, i.g., for 7 days | Escape Latency ↓; Swimming Distance ↑; Parietal cortex and hippocampal CA1 lesions ↓; Dendritic integrity ↑; The astrocytic activation ↓; | [125] | |
| In vivo | A model of ligated carotid arteries in male SPF Wistar rats | LIG 10 and 40 mg/kg, i.g., was started on day 13 and ended on day 40 after both common carotid arteries (2VO) | MDA level ↓; Choline acetyltransferase (ChAT) activity ↑; Acetylcholinesterase (AChE) activity ↓; Glial fibrillary acidic (GFAP) protein ↓; | [126] | |
| In vivo | Bilateral common carotid artery occlusion was induced in male SD rats as a 2VO model | LIG 80 mg/kg body weight per day, i.g., for 7 days | Escape Latency ↓; Cortical and hippocampal CA1 lesions ↓; | [127] | |
| Antioxidant | |||||
| In vitro | Undifferentiated PC12 cells with added hydrogen peroxide | LIG 0.1, 1.0, 2.5 and 5.0 g/mL for 24 h | Cell viability ↑; Reactive oxygen species (ROS) ↓; Total antioxidant capacity (TAC) ↑; Mitochondrial pathway apoptotic proteins were assayed ↓; | [128] | |
| Inflammatory | |||||
| Acute inflammation | |||||
| In vivo | Croton oil-induced ear oedema in male imprinting control regio (ICR) mice | Citral 100, 300 lg/ear were applied for 6 h | Degree of oedema ↓; | [129] | |
| In vivo | A model of transient MCAO-induced injury in SD male | LIG 8, 16, 32 mg/kg, | Loss of neurons ↓; Infarct volume ↓; | [121] | |
| In vivo | 1.0% carrageenan male Wistar rat induced acute inflammation model | EOAS 0.176 mL/kg, i.g., for 3 days | Prostaglandin E2 ↓; Histamine ↓; 5-Hydroxytryptamine ↓; Degree of swelling and tumor necrosis factor-α | [130] | |
| In vivo | 1.0% carrageenan male Wistar rat induced acute inflammation model | EOAS, 0.352, 0.176, 0.088 mL/kg/d, i.g., for 3 days | PGE2 ↓; HIS ↓; 5-HT ↓; | [131] | |
| In vivo | Male Swiss mice were maintained in a 12-h reverse photocycle | EOAS 30 mg/kg, i.g., Experiments started 40 min after administration | Time in open arm ↓; Percentage of head protection ↓; | [132] | |
| In vivo | LPS-induced SD male rats | EOAS 0.176 mL/kg for 4 days | TNF-α, IL-6 ↓; HIS, 5-HT, PGE2 and NO ↓; iNOS and COX-2 ↓; IL-10 ↑; | [133] | |
| In vivo | Male Wistar rats were injected intraperitoneally with LPS solution (100 μg/kg) to cause acute inflammation | 0.176 mL/kg/d, i.g., for 4 days | White blood cell count ↓; NE ↓; Platelet count ↓; | [134] | |
| In vivo | Sixty male Wistar rats were injected intraperitoneally with LPS solution (100 μg/kg) to cause acute inflammation | 0.0352, 0.176, 0.088 mL/kg, i.g., once daily for 3 days | Degree of oedema ↓; Histamine↓; 5-Hydroxytryptamine | [135] | |
| Myocardial infarction | |||||
| In vivo | LPS-induced 40 male Wistar rats | 0.176 mL/kg/day, i.g., one once daily for 3 days successively | Leukocyte count ↓; TNF-α ↓; IL-6 ↓; IL-8 ↓; IL-10↓; | [136] | |
| Analgesic | |||||
| In vivo | Acetic acid and formalin induced pain model in female imprinting control regio (ICR) mice | LIG 2.5, 5, 10 mg/kg, i.g., Modelling 1 h after drug administration | Twisting response ↓; Delayed licking ↓; | [113] | |
| In vitro | Uterus of non-pregnant sexually mature female Kunming strain mice | Essential oil of Shao-Fu-Zhu-Yu decoction 12.99 μg/mL | Contraction frequency ↓; Contraction amplitude ↓; | [137] | |
| In vivo | Establishment of a primary dysmenorrhea model in specific pathogen free-grade ICR female mice by combination of oestrogenic and oxytocin model | Essential oil of Siwu Decoction, p.o., 0.1, 1, 10, 40 mg/kg | Latency ↑; Number of torsions ↓; Sedimentation inhibition rate ↑; Prostaglandin F-2α↓; Prostaglandin E 2 ↑; | [138] | |
| In vitro | The uterus of sexually mature female unfertilised Kunming mice | EOAS 8.76 μg/mL | Contraction frequency ↓; Contraction amplitude ↓; Muscle hypertonicity ↓; | [139] | |
| Sedation | |||||
| Anxiety | |||||
| In vivo | Male and female SPF-rated Kunming mice | 20, 40, 80 μL, once a day, 1 h per inhalation, 7 and 14 consecutive days | Distance travelled ↑; Rest time ↑; | [140] | |
| Depression | |||||
| In vivo | Male SD rats modelling depression with chronic unpredictable mild stress (CUMS) | EOAS 1 g/kg i.g., 28 to 42 consecutive days | Weight ↑; Resting time ↓; | [141] | |
| In vivo | CUMS modelling in male SD rats | LIG, 10, 20 and 40 mg/kg, i.p., for 13 days | Rest time↓, Crossing frequency ↑; Feeding time ↑; Sucrose preference ↑; Open field test ↓; | [142] | |
| Antibacterial | |||||
| In vitro | Six plant pathogenic fungi strains, Rhizoctonia solani, Botrytis cinerea, Fusarium graminearum, Fusarium oxysporum, Sclerotinia sclerotiorum, and Magnaporthe grisea | EOAS 25, 50, 100 μg/mL for 7 days | The biosynthesis of ergosterol ↓; Lipid peroxidation ↑; Deoxynivalenol (DON) toxin by F. graminearum ↓; | [4] | |
| In vitro | Three Colletotrichum Species, Colletotrichum acutatum, Colletotrichum fragariae, Colletotrichum gloeosporioides | EOAS 4, 8 µL 2 mM for successive 4 days | Fungal hyphae ↓; Substrates ↓; Ring of inhibition ↑; | [4] | |
| In vitro | Six tested plant pathogenic fungi strains, R. solani, B. cinerea, F. graminearum, Fusarium oxysporum, S. sclerotiorum, and M. grisea | 3-BP 50, 100 µg/mL 25°C for 3 days | Inhibition rate ↑; Spore germination ↓; | [19] | |
| In vitro | C. acutatum, C. fragariae, C. gloeosporioides | EOAS 4, 8 µL | Mean fungal growth inhibition ↑; | [143] | |
| Asthma | |||||
| In vitro | Independent tracheal smooth muscle of Male guinea pigs | EOAS 10∼0.1 mL, | Circulating relaxation ↑; Muscular tension ↓; | [112] | |
| In vivo | The asthma model was developed in half male and half female SD rats using 0.5% 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid (HIS) phosphate saline solution | EOAS 4, 8, 16 mg/kg, i.g., for 28 days | Inflammation of the lungs and bronchial tubes ↓; Treg cell ↑; IL-4 ↓; | [144] | |
| In vivo | Asthma model in SD rats with 0.5% HIS | EOAS 40, 80, 160 mg/kg, i.g., once a day, for successive 42 days | Number of sneezing ↓; Nose scratching ↓; Asthma attacks ↓; Exhale peak flow ↑; IL-10 ↑; | [145] | |
| In vivo | HIS-induced asthma model in Female SD rats | 40, 80, 160 mg/kg, i.g., once a day, for successive 41 days | Number of sneezing ↓; Nose scratching ↓; Asthma attacks ↓; IL-10 ↑; Exhale peak flow ↑; Foxp3 ↑; | [146] | |
| In vivo | Ovalvalbumin replicates a BALB/c mouse model of asthma | 40, 60, 120 mg/kg, i.g., once a day, for successive 28 days | Scratch the nose ↓; Weight ↑; Tidal volume ↑; Espiratory rate ↓; Epithelial cell swelling ↓; | [147] | |
| Diabetes | |||||
| In vivo | Streptozotocin combined with a high-fat diet was used to induce a rat model of DN. | LIG 20, 80 mg/d, i.g., for 56 days | Role of Silent Information Regulator 1/nuclear factor kappa-B↓; Triglyceride↓; Low-density lipoprotein cholesterol↓; Blood urea nitrogen↓; Serum creatinine levels↓; High density lipoprotein cholesterol | [148] | |
| In vivo | Intraperitoneally-injected streptozotocin Male SD rat establishment of the diabetes | Z-LIG 10 mg/kg, i.p., for 84 consecutive days | Blood glucose levels ↓; Retinal dysfunction ↓; TNF-α ↓; | [149] | |
| In vivo | Streptozotocin constructed DM model of male SD rats. | LIG 10, 20, 40 mg/kg | Lipocalin ↑; Obesity index, ↓; Blood glucose level ↓; P-insulin content ↓; Glycosylated hemoglobin, type A1C↓; Homeostatic model assessment of Insulin resistance↓; | [115] | |
| In vitro | Tibility - derivation H9c2(2-1) rat cardiomyocyte | Z-LIG 2-100 μm for 24 h | Cell viability ↑; HG/P activity of cysteinyl asparaginase-3 ↓; Pro-apoptotic Bax ↓; Bcl-2 ↓; | [16] | |
Note: ↑, elevation/upregulation/activation; ↓, reduction/downregulation/inhibition.
In cardiovascular conditions, EOAS contributes to lower TC and p38 levels while enhancing blood circulation. As an antioxidant, it activates the Nrf-ARE pathway, reducing superoxide dismutase (SOD) levels to protect cells from oxidative damage. In its sedative role, EOAS elevates progesterone and allopregnanolone levels, effectively reducing anxiety. For its antimicrobial properties, EOAS decreases fungal lipid and alginate content, altering cell membrane permeability. In asthma treatment, it lowers IL-4 levels while raising IL-10, stabilizing T cells and alleviating asthma symptoms. EOAS also has analgesic effects by reducing uterine muscle contractions, helping to alleviate dysmenorrhea. In central nervous system (CNS) disorders, EOAS mitigates oxidative stress, preventing plaque instability by lowering ROS and IL-6 levels. For diabetes, it regulates blood glucose through NF-κB induction, improving pancreatic function and inhibiting TGF-β1 production, thus alleviating diabetic symptoms.
4.1. Cardiovascular and cerebrovascular systems
EOAS exhibits a wide range of pharmacological effects, including lowering blood pressure, protecting against ischemia-reperfusion injury, anti-inflammatory activity, anticoagulant effects, and vascular protection [109]. In treating cardiovascular and cerebrovascular diseases, LIG, NBP, and BP in EOAS are essential. LIG and NBP have anti-platelet aggregation and vasodilation effects [139,150]. BP combats thrombosis by inhibiting platelet activation actuated by ADP and collagen [151]. EOAS enhances cardiovascular health by promoting vasodilation, reducing heart rate, and lowering blood pressure. However, challenges such as strong irritation, poor stability, and difficulties in maintaining its efficacy in practical applications persist [26]. This review summarizes EOAS’s mechanisms and current status in combating cardiovascular and cerebrovascular diseases, offering insights and recommendations for developing functional EOAS-based products targeting conditions like hypertension, thrombosis, and AS.
4.1.1. Antiangiogenic
Angiogenesis, the formation of new blood vessels from pre-existing ones, is critical in the progression of cardiovascular diseases. Abnormal angiogenesis, whether excessive, insufficient, or irregular, has been increasingly associated with pathophysiological changes in the cardiovascular system, contributing to the onset of these diseases [152]. Consequently, modulating angiogenesis through inhibitors or stimulators has become a promising approach for treating cardiovascular conditions. Early research suggests that A. sinensis exerts anti-atherosclerotic, cardioprotective, and vascular endothelial effects. EOAS demonstrates anti-angiogenic properties by inhibiting the proliferation, migration, and capillary-like formation of human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner. Similarly, BP also shows anti-angiogenic activity [116]. The underlying mechanism involves inhibiting cell proliferation through cell cycle arrest and inducing apoptosis, primarily via the activation of p38 MAPK (P38), ERK1/2, and SAPK1/2 pathways, without involvement of the SAPK/JNK and protein kinase B (Akt) pathways. Furthermore, BP suppresses endothelial cell sprouting, and both EOAS and BP display significant anti-angiogenic effects in vitro. EOAS notably impacts subintestinal vessel (SIV) angiogenesis, leading to a reduction or absence of blood vessels in the vascular plexus. LIG and BP reduce HUVEC viability in a concentration-dependent manner within the range of 40-100 µg/mL, with EOAS, either alone or in combination with LIG and BP, producing more potent effects. A strong correlation exists between the bioactivity levels and the potency of these effects [119].
4.1.2. Blood pressure
Vasodilatory activity is a key feature of natural phthalide compounds. For instance, LIG has been linked to the vasodilatory effects of A. sinensis, particularly in alleviating cold-induced vasospastic disorders. This effect is primarily due to the dose-dependent downregulation of cold-sensing proteins TRPM8 and TRPA1 in aortic smooth muscle cells [153]. LIG’s calcium antagonist-like vasodilatory properties, combined with its ability to inhibit cell proliferation, contribute to its inhibition of vasoconstriction,[118, 154,155]. making it a promising agent for hypertension management [119]. Another active component, NBP, exhibits antiplatelet, anti-vascular, anticancer, and antianginal activities. LIG, by reducing vascular resistance, enhancing blood flow, and improving microcirculation, holds potential in preventing cardiovascular diseases such as hypertension, positioning it as a critical component of EOAS in hypertension regulation [156].
4.1.3. Atherosclerosis
AS is a condition associated with abnormal lipid levels and structural changes in the arterial walls, characterized by the buildup of fats, smooth muscle cell proliferation, and connective tissue changes, leading to localized arterial wall thickening and atherosclerotic lesion formation [109]. EOAS possesses a range of pharmacological properties, including blood pressure reduction, myocardial ischemia protection, antiarrhythmic effects, inhibition of platelet aggregation, and extension of prothrombin time, making it useful for the prevention and management of hyperlipidemia and AS. LIG, specifically, has been shown to suppress Akt activation and NF-κB expression [120]. Additionally, EOAS effectively lowers serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels while positively impacting the histopathological changes associated with AS in the thoracic aorta [157].
4.1.4. Thrombosis
LIG also influences arterial thrombosis by reducing arterial clot weight in a dose-dependent manner, exhibiting significant antiplatelet aggregation effects, which contribute to its antithrombotic activity. However, LIG does not alter clotting time or coagulation parameters, suggesting that its antithrombotic effect is not directly related to the extrinsic or intrinsic coagulation pathways. Beyond its vasodilatory action, BP in EOAS also demonstrates antiplatelet activity by inhibiting the aggregation of rabbit platelets in response to collagen, arachidonic acid (AA), platelet-activating factor, and ADP [119]. Additionally, (Z)-butylidenephthalide inhibits the release of ATP from platelets [90]. Given its traditional use in Chinese medicine to nourish blood and treat ischemic diseases, LIG presents a novel and potent antithrombotic agent. Its antithrombotic effect, driven by antiplatelet rather than anticoagulant activity, highlights its potential therapeutic efficacy in managing ischemic conditions.
4.2. Central nervous system
For centuries, A. sinensis has been a cornerstone of traditional Chinese medicine, particularly in the treatment of CNS disorders. Recent research has highlighted not only the medicinal value of EOAS but also its neuroprotective properties. EOAS exerts protective effects on the nervous system by inhibiting oxidative stress, reducing inflammatory responses, and improving brain metabolism. It also reduces glutathione and glutathione peroxidase (GSH-PX) levels, helping to maintain normal neuronal function in the brain [114]. The core functional ingredients of EOAS are phthalide compounds. These compounds have a unique structure that allows them to function in the nervous and cardiovascular and cerebrovascular systems. LIG has an α, β-unsaturated lactone ring and a biennial side chain. It can improve lipid-solubility and help is past the blood-brain barrier. The α, β-unsaturated lactone ring can combine with the KEAP1 protein in glial cells, activate the Nrf2-ARE pathway, and reduce neuroinflammation mediated by NF-κB [139]. Z-LIG is a key neuroprotective component [158]. The butyl side chain of NBP improves lipid-solubility and helps cross the blood - brain barrier [159]. NBP can target and inhibit the TLR4/MyD88 signaling in microglia, reducing the release of IL-1β and TNF-α. BP has relatively weak central activity due to the lack of a conjugated system [151]. In addition, non - phthalide small molecules work together to enhance antioxidant and anti - inflammatory effects in the CNS. These include phenylalanine and mono methyl phthalate [152]. These findings suggest EOAS’s potential not only as a therapeutic agent for neurological disorders but also as an ingredient in daily soothing health products, targeting various molecular pathways, as depicted in Figure 4.
- Neuroprotective mechanisms of EOAS.
By scavenging excess ROS through SOD, GSH-Px, and CAT, EOAS reduces lipid peroxidation and exerts anti-inflammatory effects, aiding in the treatment of cerebral ischemia and brain infarction. It addresses brain injury by lowering MDA and Caspase-3 levels, balancing Bax and Bcl-2, increasing EPO, and reducing RTP801 expression to prevent stroke. EOAS can lower the risk of AD by increasing TNF-α, upregulating Klotho, inhibiting the IGF-1 pathway, and inducing FoxO1 transcription to reduce oxidative stress in the brain. Additionally, by inhibiting TNF-α and activating NF-кB, EOAS protects neurons in the PFC and CA1 regions, reducing the likelihood of brain tumors.
4.2.1. Brain injury
LIG is widely recognized for its neuroprotective and cardiovascular benefits. Studies have demonstrated that LIG enhances the activity of antioxidant enzymes, protects brain tissue cells, and reduces neuronal damage [23]. One key contributor to brain damage is the elevated production of ROS within brain tissue. Endogenous antioxidants, such as SOD, Glutathione peroxidase (GSH-PX), and Catalase (CAT), counteract ROS overproduction. Thus, boosting antioxidant activity in brain tissue aids in neuronal recovery post-injury. LIG prevents permanent cerebral ischemia in a dose-dependent manner through its potent antioxidant properties. It effectively lowers Malondialdehyde (MDA) levels while restoring GSH-PX activity [114]. Additionally, LIG downregulates the expression of protein of BCL2-Associated X (Bax) and Caspase-3, suggesting its anti-apoptotic role, which may further contribute to its anti-infarction effects. LIG also upregulates NF-E2-related factor 2 (Nrf2), which governs several cellular antioxidant mechanisms and significantly inhibits oxidative stress during stroke, enhancing endogenous antioxidant responses and providing neuroprotection [121].
LIG prolongs the activation of Nrf2 and heat shock protein 70 (HSP70) signaling pathways, which helps prevent infarction, neurological deficits, blood-brain barrier disruption, and cerebral edema. In various animal models, intragastric administration of EOAS in rats has been shown to inhibit platelet aggregation, yield antithrombotic effects, reduce neurological damage from cerebral ischemia, and provide significant neuroprotection. In summary, LIG, the main active component of EOAS, exerts profound neuroprotective effects in cerebral ischemic injury through its antioxidant and anti-apoptotic mechanisms. This evidence underscores LIG’s potential as a powerful neuroprotective drug.
4.2.2. Stroke
Stroke is a leading cause of adult disability and ranks as the third most common cause of death worldwide. Despite its widespread impact, available treatments remain limited. Oxidative stress plays a pivotal role in ischemic brain injury, with cerebral ischemia/reperfusion (I/R) generating excessive ROS in brain tissue. These ROS, including superoxide anions, hydroxyl radicals, hydrogen peroxide, and nitric oxide, directly damage biomolecules such as proteins, membrane lipids, and DNA, while also triggering apoptotic signaling pathways [160]. This cascade disrupts cellular mechanisms, leading to significant neuronal injury. Lipid peroxidation is particularly concerning due to the abundance of polyunsaturated fatty acids in neuronal membranes. Antioxidants hold promise in mitigating ROS-induced damage and protecting neurons from ischemic injury. The chemical composition of A. sinensis extract, comprising essential oil and water-soluble fractions, highlights the need to explore the therapeutic potential of its key compounds, particularly in the context of stroke [161].
LIG has demonstrated significant neuroprotective effects, reducing neurological deficits and cerebral infarction,[122]. underscoring its potential in safeguarding against brain injury. Additionally, LIG enhances cell survival and decreases lactate dehydrogenase (LDH) release in neurons, suggesting its neuroprotective benefits are likely tied to its antioxidant and anti-apoptotic mechanisms. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are critical in erythrocyte maturation and proliferation and are widely expressed across mammalian species, including humans. Erythropoietin receptors, also prevalent in the brain, are found in various cell types such as astrocytes, neurons, endothelial cells, neuroglia, and microglia. The hypoxia-inducible factor-1 (HIF-1)-mediated upregulation of VEGF has been identified as a key neuroprotective mechanism following ischemic stroke and cerebral hemorrhage. Given VEGF’s presence in the brain and its established role in neuroprotection, targeting VEGF with LIG emerges as a promising therapeutic approach. In summary, the evidence suggests LIG has considerable potential in reducing infarct size and mitigating neurological deficits, positioning it as a promising candidate for stroke prevention and treatment.
4.2.3. Alzheimer’s disease (AD)
AD is a progressive and debilitating neurological disorder characterized by the deterioration of brain regions responsible for memory and learning [162]. Research suggests that early intervention with anti-inflammatory agents can reduce the risk of developing AD, as neuroinflammation is believed to be a key contributor to its onset [163,164]. LIG has been identified for its potent anti-inflammatory properties, notably through its ability to inhibit TNF-α production and NF-кB activation. Studies have shown that LIG provides significant neuroprotection against ischemic brain damage in various stroke models, both in vivo and in vitro. Additionally, cognitive decline in most patients with AD is closely associated with structural changes in the hippocampus and prefrontal cortex (PFC), regions critical for memory and learning. Xi Kuang and colleagues [123]. demonstrated that LIG effectively prevents cognitive decline while preserving neuronal density in the brain. Neuronal alterations in the hippocampus and cerebral cortex, particularly in the PFC and internal olfactory cortex, are key drivers of cognitive deterioration in AD. LIG counters these changes by inhibiting the NF-кB signaling pathway through suppression of TNF-α. Moreover, its antioxidant properties make LIG effective in combating AD by reducing oxidative stress. Interestingly, the expression of Klotho, a protein inversely associated with AD characteristics, suggests a promising therapeutic target for age-related AD [124]. Long-term administration of LIG has been shown to prevent AD-like brain lesions and memory impairment during aging, potentially due to the upregulation of Klotho, which inhibits the insulin-like growth factor-1 (IGF-1) pathway, enhances forkhead transcription factor (FoxO1) transcriptional activity, and decreases oxidative stress in the brain. These findings highlight LIG as a promising candidate for preventing and treating cognitive decline in AD.
4.2.4. Vascular dementia
Vascular dementia, the second most common form of dementia, is often linked to attention deficit disorder and accounts for 10 to 50 percent of dementia cases. Rather than being a singular disease, it encompasses a group of disorders with varying pathologies and mechanisms. Cognitive decline and the onset of vascular dementia in the elderly are closely related to cerebral circulatory disorders. Ischemia in the brain disrupts the balance of glucose, cholinergic substances, ROS, and other metabolic substrates, which initiate and exacerbate the neuropathological processes of vascular dementia. The disease is characterized by severe, progressive cognitive deficits accompanied by significant neuropathological changes [125]. LIG is a highly lipophilic compound (logP 2.87) with a molecular weight of 190. It exhibits diverse biological activities, including smooth muscle relaxation, microcirculation enhancement, anti-asthmatic and analgesic effects, and inhibition of smooth muscle cell proliferation. Notably, LIG has been shown to cross the blood-brain barrier and exert significant effects on neurobehavioral disorders through antioxidant and anti-apoptotic mechanisms.
LIG has demonstrated positive effects on cognitive dysfunction, particularly by increasing the number of CA1 cells and alleviating neuropathological changes in the hippocampus [126]. The mechanism behind its neuroprotective effects is thought to involve the inhibition of astrocyte activation, prevention of neuronal apoptosis, and preservation of dendritic integrity [127]. Additionally, LIG reduces the immunoreactivity of glial fibrillary acidic protein (GFAP) in the dentate gyrus in a dose-dependent manner, which may promote neuronal regeneration in the ischemic hippocampus. Lipid peroxidation, a key factor in the progression of vascular dementia, damages cell membranes and leads to the production of neurotoxic secondary metabolites. The cognitive benefits of LIG are believed to be closely tied to its antioxidant activity. Oxidative stress enhances acetylcholinesterase (AChE) activity, while exogenous antioxidants like LIG prevent this enhancement by maintaining mitochondrial membrane integrity and regulating ROS efflux. Moreover, LIG may support cholinergic neuroprotection by enhancing ChAT activity. These findings suggest that LIG holds potential as a therapeutic agent for the treatment of vascular dementia and cerebrovascular insufficiency.
4.3. Antioxidant
The antioxidant activity of essential oils is primarily linked to phenolic and terpenoid compounds. For example, ferulic acid neutralizes free radicals (e.g., DPPH) by donating hydrogen from its phenolic hydroxyl groups. Its conjugated system stabilizes oxidative intermediates, suppressing lipid peroxidation chain reactions [165]. EOAS exerts antioxidant effects through its key components, LIG and NBP. These compounds activate the Nrf2 pathway. LIG’s α, β-unsaturated lactone ring contains conjugated double bonds. These bonds stabilize free radical intermediates through electron delocalization. This directly neutralizes superoxide anions and hydroxyl radicals [166]. Key constituents like LIG and NBP demonstrate potent free radical scavenging and antioxidant activities In aerobic organisms, natural antioxidant defense systems safeguard against oxygen toxicity through enzymatic and non-enzymatic pathways [128]. Among these, SOD plays a critical role by catalyzing the conversion of O2 into hydrogen peroxide, thereby mitigating OH formation. Additionally, Z-LIG in EOAS indirectly mitigates oxidative damage. It inhibits inflammation-related enzymes (e.g., COX-2) and modulates the NF-κB signaling pathway [98]. Ferulate derived from Pinus sylvestris acts as a potent GST inhibitor, reducing lipid peroxidation and neutralizing free radicals produced from linoleic acid hydroperoxides [128]. Preventing oxidative stress-induced cellular damage is crucial in cancer prevention. Lipid peroxidation, often considered a toxic process related to oxidative stress, is implicated in various pathological reactions. The antioxidant properties of EOAS have been shown to be concentration-dependent. In China and Taiwan, essential oils have long been employed to improve physical well-being and prevent diseases, with their beneficial effects partly attributed to their ability to counteract free radical-induced damage by reducing lipid peroxide levels [167]. LIG’s antioxidant potential is further demonstrated by its capacity to decrease LDH leakage, elevate SOD activity, and reduce MDA levels [110], as shown in Figure 5.
- Schematic diagram of EOAS-mediated antioxidant mechanisms.
EOAS mitigates oxidative stress through three synergistic pathways. The key components (LIG and NBP) stabilize free radical intermediates by conjugating double bonds. EOAS enhances SOD activity and inhibits GST to lower MDA. Anti-inflammatory synergy, EOAS inhibits COX-2 and NF-κB signaling and attenuates inflammation-induced ROS.
4.4. Inflammatory
Inflammation is a pathological process characterized by an imbalance between pro- and anti-inflammatory factors [168]. It serves as the body’s defense mechanism against injury and often manifests with redness, swelling, heat, pain, leukocytosis, and organ or tissue dysfunction. In recent years, herbal medicines and their active constituents have garnered significant attention as potential sources for novel anti-inflammatory therapies, offering an alternative to non-steroidal and corticosteroid-based treatments [17]. These herbal medicines are abundant in essential oils, which contain a wealth of bioactive compounds [129]. Owing to their small molecular size, high lipid solubility, and rapid absorption, essential oils exert anti-inflammatory effects through multiple pathways and mechanisms [169].
EOAS inhibits pro-inflammatory cytokines (NF-κB, IL-6, IL-8). EOAS reduces PGE2 levels by down regulating COX-2 activity. EOAS disrupts AA metabolism. Reduces acute inflammation and decreases vascular leakage through tissue protection.
4.4.1. Acute inflammation
EOAS, a key component in herbal medicine, demonstrates anti-inflammatory properties by regulating the secretion of inflammatory cytokines such as TNF-α, IL-1β, IL-6, IL-8, and IL-4, while also influencing the expression of anti-inflammatory (IL-10), as shown in Figure 6. Additionally, EOAS modulates inflammatory mediators, including histamine (HIS), 5-hydroxy tryptamine (5-HT), prostaglandin E2 (PGE2), and NO, and affects the activity of inflammation-related enzymes like inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). It is involved in metabolic pathways related to histidine, fatty acids, AA, steroid hormones, tryptophan, and energy. Metabolic abnormalities associated with inflammation are closely linked to these metabolites. EOAS alleviates inflammation by reducing HIS and 5-HT levels, restoring the TCA cycle by lowering succinic acid, and diminishing the release of inflammatory mediators such as NO and PGE2, as well as cytokines like TNF-α and IL-1β. Research by Jian Li et al. revealed EOAS’s protective effects on inflammation and the liver, as it inhibits the release of PGE2, HIS, 5-HT, and TNF-α [130,131]. Furthermore, EOAS increases glycine levels while reducing succinate, glutamine (Gln), pyruvate, and AA expression [130], and downregulates COX-2 and iNOS activity [132], suppressing pro-inflammatory factors and enhancing anti-inflammatory cytokines such as IL-10. NBP, a key EOAS constituent, inhibits AA metabolism, contributing to its anti-inflammatory action. As lipid metabolism disorders are strongly associated with inflammation, EOAS also influences steroid hormone activity, cholesterol metabolism, and tryptophan degradation pathways, all of which are closely related to inflammatory processes [133]. Moreover, EOAS has demonstrated potential in treating acute lung injury induced by endotoxins [170]. With its potent anti-inflammatory effects and minimal side effects, EOAS holds promise for applications in pharmaceuticals, cosmetic additives, drug delivery systems, and natural functional nutrients. Although it offers a promising natural medicine option [135], further research on its efficacy and safety is essential. Additionally, EOAS’s ease of use and fast-acting nature position it as a viable raw material for analgesics, health products, and treatments for dysmenorrhea.
- Map of EOAS anti-inflammatory mechanisms through multi-targeting.
4.4.2. Myocardial infarction
Myocardial infarction, or acute myocardial infarction (AMI), is a sudden and life-threatening condition, predominantly affecting the elderly, characterized by intense chest pressure, pain, or constriction near the heart. AMI is associated with high rates of disability and mortality. Elevated levels of inflammatory factors such as IL-6, MMP-1, and MMP-3 are commonly found in atherosclerotic plaques, which are pivotal in the initiation and progression of myocardial infarction [171]. EOAS, known for its anti-inflammatory, lipid-regulating, anti-platelet aggregation, and anti-atherosclerotic properties, contains alkyl phthalates as its primary components, with LIG being the most abundant. LIG is often used as a quality biomarker for EOAS. Both EOAS and LIG influence the metabolites of anti-inflammatory pathways, including glycine, glutamate, malate, succinate, AA, glycerol, galactose, and glucose, playing a key role in energy and amino acid metabolism [136]. LIG modulates the transactivation activity of NF-кB, while glycine reduces TNF-α levels, stimulates IL-10 expression in monocytes, and inhibits transcription factor activation, as well as the production of free radicals and inflammatory cytokines. These insights suggest that EOAS may hold therapeutic potential in managing myocardial infarction-related injuries. EOAS has demonstrated significant anti-inflammatory effects by regulating the Krebs cycle, improving glucose levels, and restoring fatty acid metabolism to achieve its anti-inflammatory function. Furthermore, EOAS effectively lowered the levels of TNF-α, IL-6, IL-8, and IL-1β, while preventing a decline in plasma glycine concentration. These findings underscore EOAS’s efficacy in treating inflammation-related myocardial infarction.
4.5. Analgesic
Primary dysmenorrhea, a prevalent issue among adolescent females, is primarily driven by elevated prostaglandin (PG) levels and increased endometrial production during menstruation, occurring in the absence of pathological abnormalities in the reproductive organs. EOAS has been shown to effectively relieve pain by raising the pain threshold and providing significant analgesic effects. It also reduces the frequency and intensity of uterine smooth muscle contractions, exhibiting a marked antispasmodic effect. This inhibition of smooth muscle contractions is easily observed and comparable to that of clinically prescribed analgesics and antispasmodics. EOAS’s key components, such as LIG and NBP, have demonstrated clinical success in promoting blood circulation, providing analgesia and sedation, and addressing gynecological issues like anemia and menstrual disorders. LIG, an active constituent of A. sinensis, exhibits a non-specific antispasmodic effect and helps alleviate primary symptoms by inhibiting acetylcholine, HIS, and barium sulfate, all of which induce smooth muscle contractions. LIG also inhibits spontaneous uterine contractions during both early and late menstruation in a concentration-dependent manner, positioning it as a regulator of uterine contractions in the female reproductive system [113]. By acting on the myometrium, LIG reduces neurogenic and inflammatory pain and inhibits prostaglandin synthesis, offering anti-inflammatory and analgesic activity in both acute and chronic stages of inflammation [137]. Consequently, LIG shows promise in preventing and treating primary dysmenorrhea and other pain syndromes. “Siwu Decoction,” a traditional Chinese herbal formula containing EOAS as a main ingredient, includes phthalates in its essential oil, which further inhibit uterine contractions and support its therapeutic potential. Research indicates that this essential oil has notable analgesic properties, making it a promising treatment for dysmenorrhea and menstrual disorders. It effectively reduces central and peripheral pain, demonstrating potential anti-inflammatory and analgesic effects across both acute and chronic inflammation stages. The essential oil derived from the traditional Chinese herbal formula “Siwu Decoction,” with A. sinensis as the primary component, has demonstrated a pronounced analgesic effect in the treatment of dysmenorrhea [138]. Additionally, NBP, another key bioactive ingredient in EOAS, inhibits uterine contractions, contributing to its therapeutic efficacy [139]. Thus, EOAS holds significant potential for treating menstrual disorders and dysmenorrhea, expanding its applicability in both depth and breadth. Figure 7 highlights the molecular targets influenced by EOAS, illustrating its analgesic effects.
- Analgesic mechanism of EOAS.
EOAS reduces calcium ion concentration, leading to a significant decrease in both the amplitude and frequency of uterine smooth muscle contractions. Additionally, EOAS effectively alleviates neurogenic pain and inhibits the synthesis of prostaglandins. It also decreases levels of TNF-α and IL-6, thereby mitigating inflammation and achieving analgesic effects.
4.6. Sedation
Certain natural sedatives are recognized for enhancing sleep quality by promoting relaxation of both the mind and body, leading to deeper, more restorative sleep. Among these, EOAS stands out for its ability to alleviate stress, anxiety, and depression, and serves as a potential adjunctive therapy for insomnia [172]. Widely utilized in daily health care, EOAS is commonly employed to ease anxiety and soothe emotions, often in combination with other essential oils [166,173]. However, the underlying mechanisms of its sedative effects remain to be fully elucidated.
4.6.1. Anxiety
LIG, a key component of EOAS, has demonstrated significant benefits in mitigating psychological stress-induced physiological changes within the CNS. Exhibiting a stronger sedative effect than succinate, LIG has been shown to restore sleep duration in mice subjected to social isolation and stress that activates the central noradrenergic system [174]. This effect may be linked to LIG’s protective influence on glutamate-injured PC12 cells, which involves inhibiting intracellular calcium ion efflux and blocking the release of Cytc from mitochondria into the cytosol [132]. These results suggest that EOAS has notable anxiolytic properties, making it an appealing option for anxiety relief in daily healthcare. By promoting mental and physical relaxation, EOAS offers a calming effect, particularly beneficial in the context of high-pressure, fast-paced modern lifestyles, helping to alleviate emotional tension.
4.6.2. Depression
Depression accounts for 7.5% of global years lived with disability and is one of the most prevalent mental health disorders, recognized as a leading cause of non-fatal health loss [175,176]. The effectiveness of commonly prescribed antidepressants is often questioned due to their extensive side effects, including sedation, apathy, cognitive impairment, and sleep disturbances [177]. This underscores the urgent need for more effective and tolerable treatments. Traditional Chinese medicine, particularly A. sinensis, has been used for treating gynecological disorders and has also shown antidepressant properties [141,178]. Aromatic compounds are increasingly being employed to alleviate depression symptoms with fewer adverse effects. LIG, the primary active ingredient in both A. sinensis and EOAS, is noted for its potent antidepressant effects. Its volatility and ability to cross the blood-brain barrier enable intravenous administration for direct action on the brain [173]. In depression, specific brain regions, such as the hippocampus and PFC, often exhibit functional abnormalities. These areas are integral to various functions, including memory, mood regulation, and self-referential processing. In a rat model of CUMS, LIG treatment significantly elevated levels of progesterone and its metabolites in both the hippocampus and PFC [142]. Progesterone, a selective endogenous modulator of the gamma amino butyric acid (GABA) A receptor activity, enhances the expression of receptor subunits α2, α3, and α4, contributing to antidepressant effects. Reduced levels of progesterone may be involved in the pathophysiology of depression. The increased neurosteroid levels following LIG administration suggest that its antidepressant effects are closely linked to the regulation of these neurosteroids. Kun Zhang’s research, utilizing network pharmacology, molecular docking, and molecular dynamics simulations, further revealed that LIG’s antidepressant action is related to the PI3K/Akt and MAPK signaling pathways. LIG shows strong binding affinities to ESR1, MAPK14, and Akt1, indicating potential mechanisms through which it exerts its therapeutic effects in depression [179].
4.7. Antibacterial effect
The antimicrobial activity of essential oils is closely linked to the structural features of their chemical components. Phenols, terpenes, alcohols, and aldehydes are key antifungal compounds. For example, eugenol shows a MIC of 0.5 mg/mL against Aspergillus niger, with its hydroxyl group position directly influencing membrane penetration [180]. Alcohol increases membrane permeability by inserting hydroxyl groups into cell membranes, inducing ROS accumulation [181]. Geraniol nanoemulsions disrupt Botrytis cinerea cell membranes, increasing K⁺ Leakage by 50% [182]. Cinnamaldehyde inhibits chitin synthase genes (CHS2/CHS5), reducing chitin content in fungal cell walls and causing cell rupture [183]. Key factors influencing antimicrobial activity include chemical composition ratios and microbial cell structures. For instance, carvacrol and thymol content in oregano essential oil correlates positively with inhibition rates [184]. Gram-positive bacteria, with thinner cell walls, are more susceptible to hydrophobic essential oils [185]. Fungal cell walls contain chitin and β-glucan, requiring essential oils to disrupt both cell walls (via chitin synthase inhibition) and membranes (via ergosterol synthesis suppression).
The antimicrobial properties of EOAS are notably potent,[111]. with its metabolic activity having a significant impact on protein expression in fungi, particularly in biosynthetic processes. EOAS primarily disrupts the cytoplasmic, nuclear, and mitochondrial regions, which are critical for proteolytic metabolism and the cell cycle. Key mechanisms include the degradation of RNA through the ubiquitin-proteasome pathway (UPP) and the activation of the MAPK signaling pathway [19]. EOAS demonstrates significant antifungal efficacy in food and agricultural applications. This activity is driven by Cluster+, which activates the MAPK and UPP pathways to induce apoptosis. Apoptosis, a protein degradation process occurring in both the nucleus and cytoplasm, exhibits moderate dependency on these pathways [4]. The cell membrane serves as a primary target for EOAS’s antifungal activity. EOAS disrupts fungal cell membranes, causing damage to organelles and leakage of cellular contents [111]. It decreases lipid and alginate content while increasing membrane permeability. Mycelia treated with EOAS exhibit various deformations, reduced membrane integrity, and decreased viability. EOAS disrupts the steroid biosynthesis pathway, leading to a marked decrease in nonsteroid compounds such as ergosterol, 11-deoxycortisol, and 21-deoxycortisol. These steroids are critical for maintaining membrane fluidity, structural integrity, and diverse cellular functions [186]. Lanosterol, a key precursor in the ergosterol biosynthesis pathway, experiences abnormal metabolism under EOAS treatment, potentially leading to fungal membrane dysfunction or cell death [187]. Moreover, the NBP component of EOAS has shown efficacy in inhibiting Fusarium graminearum [188]. EOAS also suppresses steroid production in Penicillium root rot and downregulates the expression of key genes involved in steroid biosynthesis. Colletotrichum corda, a type of infectious fungus affecting leaf and fruit crops worldwide, is similarly inhibited by EOAS. EOAS exerts antimicrobial activity primarily through its major component, LIG [189]. EOAS and LIG show stronger antibacterial effects than antifungal effects [29]. This may result from differences in cell wall composition: bacterial walls contain peptidoglycan, while fungal walls contain chitin (a polysaccharide polymer). Peptidoglycan’s lower molecular weight allows EOAS and LIG to penetrate and disrupt bacterial walls more easily. Additionally, EOAS is most effective against Gram-positive bacteria than Gram-negative bacteria [29]. The outer membrane of Gram-negative bacteria restricts hydrophobic substance diffusion through lipopolysaccharides, reducing EOAS’s cell wall damage. Given these strong antifungal properties, EOAS presents numerous advantages as an agrochemical,[143]. as shown in Figure 8. Its effectiveness in combating plant pathogenic fungi highlights its potential as a robust antifungal agent in the food and agricultural industries, revealing both its mechanisms of action and its broad applicability in controlling fungal infections in crops.
- Schematic diagram of the antimicrobial mechanism of EOAS.
EOAS increases membrane permeability, resulting in leakage of K⁺, Ca2⁺ plasma. EOAS reduces ATP production by blocking key enzymes in the tricarboxylic acid cycle. EOAS inhibits chitin synthesis and accelerates cell wall disintegration. The MAPK pathway is activated through the apoptotic signaling pathway.
4.8. Asthma
EOAS has shown remarkable efficacy in treating bronchial asthma and Chronic Obstructive Pulmonary Disease (COPD) with minimal adverse effects, largely attributed to its components, LIG and NBP. It inhibits HIS and acetylcholine-induced contraction of airway smooth muscles, while also affecting diastolic airway smooth muscle, thereby alleviating constriction [112]. One of the key pathological mechanisms of asthma involves the hypofunction of Treg cells, which leads to excessive proliferation of effector T-cells. The forkhead box protein P3 (Foxp3), exclusively expressed in Treg cells, serves as a critical regulator of CD4+CD25+ Treg cell activity. A deficiency in Foxp3 impairs the function of these Treg cells [144]. Tr1 cells play a role by inducing Treg cells and releasing IL-10, which in turn inhibits the hyperactivation of effector T cells, including Th2 and Th17, essential for controlling immune overreaction in patients with asthma. EOAS has been demonstrated to increase CD4+ CD25+ Treg cells in a dose-dependent manner, effectively reversing asthma symptoms [190]. Beyond dose-related efficacy in asthma management, EOAS reduces IL-4 expression in the lungs, correcting T-cell immunoreactivity dysregulation in asthma. One potential mechanism involves enhancing the expression of IL-10 and Foxp3, thereby improving Treg cell function, which is typically impaired in patients with asthma [146]. Additionally, EOAS improves lung function, enhances histology, and suppresses the overexpression of IL-17 and RORγt. It also modulates Th17 cell immunoreactivity, reducing asthmatic responses [145]. Furthermore, EOAS exhibits specific properties that alleviate asthma and suppress coughing, significantly improving common clinical symptoms such as phlegm, cough, and wheezing, while also mitigating itching and asthma attack episodes [147].
4.9. Diabetes
In studies involving diabetic rats, LIG therapy significantly reduced lipid accumulation and insulin resistance [148]. LIG also showed effectiveness in treating retinal dysfunction in diabetic rats by cleaving Caspase-3, downregulating BAX, and upregulating b-cell lymphoma-2 (Bcl-2) expression, which helped to mitigate retinal cell apoptosis [149]. Moreover, LIG provided renal protection in diabetic individuals by lowering TC, triglycerides (TG), LDL-C, blood urea nitrogen (BUN), and serum creatinine (Scr) levels, while raising high density lipoprotein cholesterol (HDL-C) levels [115,191]. LIG was also effective in alleviating symptoms associated with diabetic cardiomyopathy and diabetes mellitus [16].
5. Toxicity and contraindications to use
EOAS exhibits low oral toxicity, though gastrointestinal distress and renal degeneration have been reported following excessive oral administration. It is classified within the low toxicity range. Adverse reactions are primarily attributed to LIG, a phthalide component, whose lipophilic nature enables it to cross the blood-brain barrier, potentially affecting the CNS, reproductive system, and respiratory system [192,193]. Acute toxicity studies in mice revealed that the LD50 values for intravenous, oral, and abdominal administration were 0.175, 1.25, and 0.1 g/kg, respectively [90]. Regarding dermal toxicity, EOAS is classified as having minimal toxicity, with moderate skin irritation and mild, reversible eye irritation. Some patients may experience skin turgor. EOAS also poses a risk of inducing photosensitivity, leading to redness, swelling, and slight skin elevation upon sensitization [194]. Concentrations of EOAS up to 10 μg/mL have been shown to exert toxic effects on the viability of human dermal fibroblasts. This suggests that EOAS should be diluted and used at concentrations between 2 μg/mL and 5 μg/mL applications. EOAS concentrations up to 10 μg/mL have demonstrated to have a toxic effect on the viability of human dermal fibroblasts. This indicates that EOAS should be diluted and applied at concentrations ranging from 2 μg/mL to 5 μg/mL. At 2-5 μg/mL, EOAS has been proven to reduce inflammation and treat acne [195]. In addition, EOAS can scavenge DPPH free radicals and completed ferrous ions, delaying skin aging [196,197]. It is thought to be a natural skincare ingredient with makeup-enhancing properties [198]. EOAS is primarily used to invigorate and promote blood circulation [199]. However, it should not be combined with anticoagulants like heparin, warfarin, or aspirin due to the increased risk of bleeding, nor with antihypertensive medications. Its use during menstruation may exacerbate bleeding. EOAS contains several furano lactones that support liver drainage, stimulate liver function, and alleviate liver burden. Although its main components, LIG and NBP, are known for their pain-relieving, anti-inflammatory, and vasodilatory effects, both compounds can exhibit hepatotoxicity [200]. Overall, EOAS demonstrates good safety and reliability when used appropriately. It holds promise for a range of daily applications, such as skincare, outdoor mosquito repellent, stress relief, and cosmetic use, highlighting its social benefits and significant economic potential [8,132,201,202].
6. Potential drug delivery systems of EOAS
Drug delivery systems have been widely employed to overcome the limitations of low bioavailability and poor aqueous solubility of EOAS [203], enabling the effective use of its pharmacological properties at reduced doses, as detailed in Table 4 and Figure 9. The development of advanced drug delivery systems offers substantial potential for utilizing EOAS as a therapeutic class.
- Potential drug delivery systems of EOAS.
EOAS faces challenges such as low bioavailability and poor water solubility. Microemulsions can enhance its bioavailability, particularly in treatments for acute lung injury and other diseases. β-cyclodextrin inclusion complexes significantly improve its water solubility. Liposomes increase EOAS stability and are primarily applied in therapeutic contexts. Microcapsules enhance the body’s absorption of EOAS. Injections, by reducing EOAS oxidation, are mainly employed in the treatment of acute conditions. Colon-targeted pellets, with their targeting capabilities, extend the release duration of EOAS.
6.1. Microemulsion
EOAS-based formulations show considerable promise for addressing menstrual issues and dysmenorrhea. The “Whole Angelica” microemulsion, which combines EOAS with an aqueous extract of A. sinensis, demonstrated favorable physical and chemical properties in both in vitro and in vivo assessments, alongside notable therapeutic efficacy. This formulation significantly improved the stability and bioavailability of the active pharmaceutical ingredient (API), outperforming concentrated tablets in promoting blood circulation and enhancing oral bioavailability [204]. Additionally, the root of L. sinense has been found to possess anti-inflammatory, antioxidant, and neuroprotective properties, while also enhancing cerebral blood flow and vascular flexibility. Its essential oil, primarily composed of compounds such as butyl phthalic acid and glycyrrhizin, has demonstrated considerable antipyretic, analgesic, and anti-inflammatory effects, making it a potential candidate for treating acute lung injury. Microemulsions containing essential oils from L. sinense and A. sinensis significantly increased the bioavailability of these oils, with peak concentration (Cmax) values approximately 4.2 times higher and an average area under the curve (AUC(0-t)) approximately 2.11 times greater than those of the essential oils alone. This improved bioavailability suggests that essential oil microemulsions enhance solubility and bypass first-pass metabolism, making them highly suitable for quickly achieving therapeutic blood concentrations in acute clinical conditions [205]. Further studies comparing the effects of essential oils and their microemulsions on LPS-induced lung injury in mice revealed that microemulsions provided superior protection. They more effectively inhibited inflammatory markers and reduced lung indices, with mice showing significantly extended survival times after acute lung injury [206]. The inclusion of CA-VO in a microemulsion system substantially improved its oral bioavailability and enhanced its protective effects against acute lung injury through efficient oral delivery [205]. These findings indicate that essential oil microemulsions may hold considerable potential for treating acute lung damage.
| Pharmacological activities | Types | Model/Cell line | Doses/Duration | Effects/Mechanism of action | Reference |
|---|---|---|---|---|---|
| Potential drug delivery systems of EOAS | |||||
| Microemulsion | |||||
| In vivo | SPF male Swiss mice | 10 g/kg administered twice daily, i.g., for a total of three doses | Lung index ↓; TNF-α ↓; IL-6 ↓; IL-1β ↓; NO ↓; iNOS ↓; COX-2 ↓; | [205] | |
| In vivo | SD rats | 14 g/kg, p.o., Blood samples were collected at 0.083, 0.17, 0.25, 0.5, 1, 2, 3, 4, 6 and 8 h. | Time to peak (Tmax) ↓; Cmax ↑; AUC ↑; | [205] | |
| In vitro | RAW264.7 murine macrophages | 2.47 mg/mL for 24 h | IL-6 ↓; TNF-α ↓; NO ↓; | [205] | |
| Microcapsule | |||||
| In vivo | Male SD rats | 100 mg/kg 0.5, 1, 2, 3, 4, 6, 10, 12 h blood sampling | Tmax ↑; AUC ↑; CL ↓; K10 ↓; K12 ↓; K21 ↓; | [207] | |
| Colon-targeted Pellet | |||||
| In vivo | 3% DSS KM male mouse ulcerative colitis model | Pellet 1.67 g/kg, i.g., for 7 consecutive days | Diarrhoea ↓; Blood in stool ↓; Congestion ↓; Swelling ↓; | [208] | |
| Potential applications | |||||
| Insect repellent | |||||
| In vivo | Aedes aegypti | 0.1 mL of 25% EOAS, smear | Full protection time ↑; | [18] | |
| Crop fungicide and repellent | |||||
| In vivo | Tribolium castaneum, Lasioderma serricorne | 3-BP 3.15 nL/cm2 at 2 and 4 h | Contact toxicity ↑; Percentage repellency ↑; | [20] | |
Note: ↑, elevation/upregulation/activation; ↓, reduction/downregulation/inhibition;
6.2. β-cyclodextrin inclusion
The volatile and easily degradable nature of EOAS in drug delivery systems presents challenges in preparation and storage. As a result, it is crucial to develop strategies that protect EOAS from oxidative degradation while enhancing its purity. A commonly used method is cyclodextrin inclusion, which significantly improves the stability of both solid formulations and essential oils [203]. Studies have shown that applying this technique to the essential oils of herbal medicines not only increases their solubility and stability but also transforms liquid drugs into powders, prevents the evaporation of volatile components, reduces toxicity, minimizes irritation, and masks undesirable odors [209,210]. The encapsulation of EOAS with β-cyclodextrin has proven especially effective in enhancing its stability, providing a simple and efficient basis for qualitative analysis of the encapsulated compounds [211]. This technique not only preserves the chemical integrity of EOAS but also significantly increases the solubility of its constituents. Comparatively, β-encapsulated EOAS displayed an oil content approximately 20 times higher than its unencapsulated counterpart. Additionally, under controlled conditions, 98.86% of the encapsulated EOAS was released after 50 h at 50°C, indicating an almost complete release of the essential oil. The solubilization period of up to 12 h and consistent Rf values of the solubilized components further support the sustained-release capability of the encapsulated formulation [203].
In vitro experiments revealed that the transdermal and cumulative transmittance of LIG was notably lower than that of free EOAS, with reductions of approximately 22% and 12%, respectively. This suggests that encapsulated EOAS significantly impairs transdermal absorption, likely due to the non-polar cavity structure of cyclodextrins, which hinders the release of essential oils into the aqueous environment and limits their ability to penetrate the skin surface [212]. Although cyclodextrins are commonly used to stabilize and increase the solubility of herbal essential oils, this encapsulation technique may reduce the effectiveness of topical formulations by inhibiting transdermal absorption and penetration. Given these limitations, further research is needed to explore alternative modes of administration for cyclodextrin-encapsulated essential oils.
6.3. Liposome
The dried root of A. sinensis is commonly used to create sterilized aqueous solutions for intramuscular or acupoint injections, primarily to promote blood circulation and relieve pain. A. sinensis injections are widely employed in clinical settings [213]. However, during production and storage, essential oils and other active compounds are significantly lost. The development of liposome formulations offers an effective solution to this issue [214]. Liposomes, ultra-small spherical drug delivery systems, encapsulate drugs within a thin lipid film, reducing immune responses and toxicity while enhancing drug stability and extending release times [215]. Research has shown that EOAS liposomes, produced through film dispersion technology, markedly improve the stability of EOAS, amplifying its analgesic and antispasmodic effects [216]. Additionally, this formulation enhances EOAS’s ability to cross the blood-brain barrier, offering a novel method for preparing A. sinensis for intravenous injection. Furthermore, liposomes formulated from BP, the principal component of EOAS, have demonstrated the ability to inhibit melanoma cell growth by inducing both endogenous and exogenous apoptotic pathways. These BP-based liposomes increased the anti-fibroblast activity of melanoma cells by 3.35 to 3.7 times, indicating significant potential for developing therapeutic drugs targeting melanoma [217].
6.4. Microcapsule
Due to EOAS’s limited oxidative stability, its use in pharmaceutical applications has been constrained. To address this, researchers explored oxidation-resistant gelatin-chitosan microcapsules. Various formulation factors, such as pH, gelatin concentration, and core/wall ratio, were systematically analyzed in relation to yield, encapsulation efficiency, antioxidant capacity, drug release rate within 1 h, and the time required for 85% drug release [218]. The study found that the antioxidant rate of the microcapsules was nearly eight times higher than that of EOAS alone. Moreover, microencapsulation significantly prolonged EOAS’s retention in the body, leading to improved drug absorption and a 2.62-fold increase in the relative bioavailability of orally administered drugs [207].
6.5. Injection
The active ingredient in EOAS, particularly its essential oil, is essential for its physiological effects [210]. “Foshousan,” an herbal remedy containing L. sinense and A. sinensis, features LIG as the primary chemical component of both EOAS and the essential oil of L. sinense [219]. However, LIG is chemically unstable, with 58% degrading when exposed to sunlight at 25°C for 15 days, and about 15% deteriorating even in darkness at 4°C over the same period [220]. Injectable forms are generally preferred for acute and severe illnesses, whereas oral doses are more commonly used for daily treatments due to absorption challenges [221]. To enhance the chemical stability of LIG, research was conducted to identify factors influencing its stability and to develop a suitable carrier. The degradation of LIG is influenced by oxidation, hydrolysis, and photodegradation, which can be mitigated by adding appropriate amounts of VC, using co-solvents, adjusting pH levels, and storing the drug in the dark. A semi-aqueous carrier composed of 1.5% Tween-80, 0.3% VC, 20% PG, and 80% water was found to effectively prolong LIG stability and delay its degradation [222].
6.6. Colon-targeted Pellet
A colonic localized drug delivery system offers several advantages, including increased drug concentration in the colon, making it particularly effective for treating conditions such as colitis, ulcerative colitis, and other colonic diseases. This approach allows for reduced drug dosages and minimizes side effects [223]. The EOAS colon-targeted Pellet significantly improved the concentration of EOAS in the colon. In vivo rat trials demonstrated a notable increase in the cumulative colonic release rate, prolonged release duration, and delayed, targeted drug delivery [224]. Additional in vivo trials on mice further revealed the Pellet’s efficacy in treating ulcerative colitis, highlighting its potential for managing this condition [208].
7. Potential applications
With sustained economic growth and improvements in living standards, there is a growing trend toward natural and green concepts. The demand for natural health products continues to rise, offering broad market potential. EOAS has been successfully used in clinical treatments and as an auxiliary therapy for various diseases, with significant effects and positive prognoses. Despite its limited current use, EOAS shows great potential for future development in areas such as natural antiseptics, weight loss products, mosquito repellents, and crop protection, due to its antibacterial and insect-repellent properties. As research on EOAS progresses and the “back to nature” concept gains traction, EOAS and its active ingredients are expected to find broader applications as raw materials in food,[4]. mosquito repellents,[225]. and insect-repellent products [19], opening new market prospects.
7.1. Food Applications
7.1.1 Baked Food
The bakery food sector prioritizes safety and nutrition, with a particular focus on preventing mold growth, which poses significant risks to human health. Moldy foods are not only highly toxic but also teratogenic, making them a serious food safety concern, especially in economically disadvantaged regions. Common preservation methods for baked goods include aseptic packaging, irradiation, modified storage environments, and the use of preservative acids. However, the use of organic acids like sorbic acid, benzoic acid, and propionic acid has been restricted in several countries due to their harmful effects on human health. In contrast, essential oils, derived from plants, are abundant, environmentally friendly, and safe for human consumption, attracting attention for their potential in food preservation. EOAS, in particular, has been shown to inhibit the growth of food-borne pathogens such as Penicillium, Aspergillus, E. coli, and Staphylococcus aureus. When added to baked goods, EOAS extends shelf life and prevents colony formation on products like chapattis without affecting their flavor, texture, appearance, or sensory qualities, offering a natural alternative to synthetic preservatives [4].
Essential oils effectively combat common spoilage microorganisms in baked goods, such as Penicillium roqueforti and Aspergillus niger, by targeting multiple pathways, reducing the risk of drug resistance [4,226]. Microencapsulated essential oil sachets are one of the keys strategy for antifungal preservation in baked goods [227]. This technology controls essential oil release rates for sustained antimicrobial action and minimizes flavor interference with food. Another approach involves integrating essential oils into packaging materials (e.g., coatings or blends) to create antimicrobial films [4]. Synergistic essential oil combinations (e.g., citral-eugenol) disrupt cell membranes and induce apoptosis, achieving equivalent antifungal effects with 30% lower doses than single-component essential oils [7]. This reduces cost and avoids off-flavors from excessive single components. Essential oils align with current trends in “plastic reduction” and “clean-label” demands due to their natural, efficient, and sustainable advantages [228]. Future research should concentrate on essential oil-food matrix interactions, scalable production of controlled-release carriers, and formulation optimization to advance industrial applications.
7.1.2. Food packaging
With growing concerns about environmental sustainability and food safety, the use of naturally sourced substances in food packaging is poised to become a major research focus in the future. Traditional packaging materials, particularly plastics, face significant challenges, including environmental pollution and suboptimal food preservation effects [229]. In contrast, essential oils are gaining attention in various industries—cosmetics, medicine, medicinal teas, medical dressings, and packaging materials—due to their exceptional biological activities. EOAS, in particular, stands out for its antioxidant properties, antibacterial activity, and low toxicity, making it a promising alternative to chemical additives. As a novel active ingredient in gelatin-based packaging materials, EOAS offers the dual benefits of reducing environmental pollution and resource waste associated with traditional plastic packaging, while simultaneously enhancing food preservation quality and extending shelf life. Recent studies have demonstrated that incorporating essential oils significantly improves the hydrophilic properties of gelatin nanofibers. Additionally, the antioxidant and antibacterial properties of these nanofibers are notably enhanced with increasing concentrations of Angelica essential oil [230]. Cytotoxicity tests confirmed that EOAS-infused gelatin nanofibers are non-toxic, and these nanofibers, produced via electrospinning, exhibit excellent hydrophobicity, antioxidant capacity, and bacteriostatic activity, positioning them as a material with broad application potential. This innovation not only expands the use of plant-based essential oils but also provides a new approach to improving the functionality of food packaging materials, aligning with the goals of sustainability and safety.
7.2. Insect repellent
The effectiveness of EOAS as a mosquito repellent has been well documented, with a reported protection time of 7.0 h (ranging from 6.0 to 7.5 h). This effectiveness is largely due to the sharp aromatic properties of the essential oils, which, upon evaporation, can penetrate the trachea of insects, causing discomfort or asphyxiation and thus driving them away from the treated area [231]. The key to mosquito repellent is that the components in EOAS include components such as phthalates, NBP, and LIG. These phytochemicals, either individually or in combination, have the potential to form plant-based products with anti-mosquito properties [208]. Phthalates, in particular, are versatile compounds that function as insecticides, herbicides, nematicides, and acaricides, and possess antibacterial and antifungal properties [232]. Human baiting experiments evaluated 33 plant extract products for their insect-repelling abilities, particularly against Aedes aegypti, the primary vector for dengue fever (Table 4). Results indicated that products derived from A. sinensis had the highest potential for repelling insects [18]. However, the use of EOAS is not without drawbacks. It may cause localized skin irritations, such as mild itching, redness, irritation, or swelling. Moreover, its application has been limited due to issues such as low yield (0.02%), a strong odor, and skin irritation [193]. These factors, coupled with concerns about potential health risks associated with direct skin contact, have hindered its widespread use. To optimize the commercial viability of EOAS as an insect repellent, further research is needed to mitigate skin irritation and enhance the product’s stability. Additionally, conducting toxicological studies and investigating how various environmental and laboratory conditions affect mosquito species are key steps. These efforts will be essential in refining the formulation and ensuring the effectiveness of EOAS as a safe, natural insect repellent for broader applications.
7.3. Crop fungicide and repellent
Plant pathogenic fungi represent a serious threat to agricultural productivity and economic efficiency by causing extensive damage to crops. One notable example is Fusarium spp., the fungus responsible for FHB, which can significantly impair wheat growth [233]. Essential oils offer numerous benefits for crop protection, including broad-spectrum antifungal properties, low environmental persistence, minimal toxicity to humans and animals, and natural safety [234]. These attributes make essential oil-based biopesticides a favorable alternative, as their high volatility leads to minimal harmful residue, thereby reducing the risk of soil and groundwater contamination [235]. As a result, essential oils can serve as low-risk insecticides. Within essential oils, compounds such as LIG, Senkyunolide, NBP, and 3-BPH collectively account for 67.5% of EOAS content. These, along with six other compounds, have demonstrated fungicidal effects against a variety of phytopathogenic fungi, including Rhizoctonia solani, Sclerotinia sclerotiorum, Fusarium graminearum, Botrytis cinerea, Fusarium oxysporum, and Magnaporthe grisea (Table 4). Among these, 3-BPH showed the strongest inhibitory activity against F. oxysporum, indicating its potential as a phytofungicide for managing fungal infestations in plants [19]. Additionally, BP displayed significant contact toxicity and repellent properties against F. oxysporum, suggesting its potential use as a natural insecticide or repellent for agricultural and food products. These findings underscore the potential of essential oils and their components in reducing the impact of plant pathogenic fungi on agricultural systems, offering a promising and eco-friendly approach to crop protection [20].
8. Conclusions
The principal components of EOAS were phthalide LIG (45%-65%) and NBP (8.25%). These components work by regulating microcirculation, inhibiting oxidative stress, and other mechanisms. EOAS has demonstrated multi-target pharmacological activity in the fields of cardiovascular diseases, CNS diseases, analgesia and antimicrobial. Among the many extraction methods, the supercritical CO₂ extraction method has the advantages of high efficiency and component retention. When it comes to food preservation, insect repellents and fungicides, EOAS has a bright future. However, its application is limited by problems such as unstable quality and pungent odor. EOAS has low toxicity, but elevated concentrations may cause skin irritation and should be used sparingly.
Future research should be focused on clarifying the synergistic mechanism of ingredients and optimizing the industrial extraction process to improve yield and component standardization. Long-term toxicological evaluation and clinical efficacy verification of EOAS should also be performed. EOAS has significant application potential in natural food preservatives, environmentally friendly pesticides, and functional pharmaceutical preparations. In the future, it is necessary to further explore the development of innovative EOAS-based formulations. Promote its transformation from traditional medicinal use to industrial application in multiple fields. This will serve as a scientific basis for the development of green and natural products.
Acknowledgment
This project has been supported by the National Key Research and Development Program of China (2021YFD1601004, 2023YFD1600402, 2023YFD1600403); Shaanxi Provincial Key Research and Development Program Project (2024CY-JJQ-36); Xi’an Science and Technology Plan Project (20231H-JSJ0-0007); Inner Mongolia Autonomous Region Science and Technology Program (2022YFSH0001); Qin Chuangyuan Traditional Chinese Medicine Industry Innovation Cluster Project (L2024-QCY-ZYYJJQ-X41); Science and Technology Programmer of xian New Area (DJK-2023-004); Shaanxi Provincial Traditional Chinese Medicine Science and Technology Innovation Team (TZKN-CXTD-03); Shaanxi Provincial Department of Science and Technology Project (2024 ZC-YYDP-110); Shaanxi Province Xianyang City Science and Technology Bureau Project (L2024-QCY-ZYYJJQ-X28); Shaanxi Provincial Administration of Traditional Chinese Medicine (ZYJXG-Y23005); National-Level High-Caliber Talent Innovation and Entrepreneurship Project; Key Technological Innovation Team for Industrialization of Aromatic Traditional Chinese Medicine Engineering Research Center of Traditional Chinese Shaanxi Medicine Aromatic Industry, Universities of Shaanxi Province; Key Discipline of High Level Traditional Chinese Medicine in Shaanxi Province, Traditional Chinese Medicine Processing.
CRediT authorship contribution statement:
Xiaofei Zhang conceived the idea and designed the structure of this review. Xiaoxiao Ge, Junbo Zou, Dongyan Guo and Jing Sun searched and analyzed the literature results. Xiaoxiao Ge and Xiaofei Zhang drafted the manuscript. Yajun Shi, Qin Chen, Chongbo Zhao, Fei Luan and Ming Yang designed and prepared all figures. Xiaoxiao Ge, Jing Shao, and Xiaofei Zhang finished the tables. Xiaofei Zhang reviewed and revised the manuscript. All authors have read and approved the published version of the manuscript.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Declaration of generative AI and AI-assisted technologies in the writing process
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
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