Coumarins are the most abundant and main bioactive constituents present in of A. dahurica. They have a broad spectrum of pharmacological activities, such as anti-viral (Liu et al., 2021), anti-tumor (Banikazemi et al., 2021), anti-osteoporosis (Jia et al., 2016) and effects on the cardiovascular system (Najmanova et al., 2015). To date, a total of 153 coumarins have been isolated from the root and stem of A. dahurica, include 18 simple coumarins (1–18), 93 furanocoumarins (19–111), 41 coumarins glycosides (112–147), 3 other coumarins (148–150) and 3 coumarin derivatives (151–153). Among them, furanocoumarins are the most abundant coumarins, which are mainly divided into linear and angular types based on the location of the furan group. The furan ring in linear furocoumarins is connected to the 6 and 7 carbon atoms, while the substituent often occurs in the positions of C₇ and C₈ in angelic furocoumarins (Sumorek-Wiadro et al., 2020). Furanocoumarin IMP (22) is the most principal and representative active component of A. dahurica root, which has anti-inflammatory, analgesic, anti-allergic and neuroprotective activities (Deng et al., 2020). Moreover, Other furanocoumarins such as isoimperatorin (19), oxypeucedanin (20), phellopterin (26) and byakangelicin (41) are also characteristic constituents of A. dahurica root with a wide range of bioactivities (Cho et al., 2006; Kang et al., 2008; Lee, B.W. et al., 2020; Li and Wu, 2017). These furanocoumarins are charicterized by the attachment of different substituents to C₅ or C₈ in the parent nucleus of linear furocoumarins. In addition to furanocoumarins, some simple coumarins, such scopletin (3) in the root and stem of A. dahurica also exhibited anti-microbial and neuroprotective effects (Kwon et al., 1997; Luo et al., 2020), which contribute to the bioactivities of A. dahurica. The information and chemical structures of all these coumarins are listed in Supplementary Table S1 and Supplementary Figure S1.

Volatile oils are other major physiologically active compounds in A. dahurica. The components of volatile oil can be roughly divided into four categories, including terpenoids, aromatic compounds, aliphatic compounds and other compounds. Among them, terpenoids are the most common type. Numerous studies declared that the cluster of the compounds possess extensive bioactivities and act as antibacterials, antivirals and insecticides in plants (Cascaes et al., 2021). So far, approximately 121 volatile components have been identified from the root of A. dahurica. These volatile oils include terpenes (154–200), aromatics (201–212), alcohols (213–234), aldehydes (235–246), ketones (247–252), acids (253–260), esters (261–270) and alkanes (271–274). The major components of the volatile oils in A. dahurica root include α-pinene (154), myrcene (199), terpinen-4-ol (219), 1-dodecanol (221) and sabinene (160). However, the extraction yields of volatile oil are different as the plant materials came from different regions. It was reported that the extraction yield of volatile oil from A. dahurica root cultivated in yuzhou, China is 1.4% (ml/g), including α-pinene (44.91%), myrcene (8.72%), terpinen-4-ol (8.01%), 1-dodecanol (6.43%) and sabinene (3.42%). These volatile oils were confirmed to show obvious antioxidant activity (Wang D. et al., 2020). All the identified volatile oils are listed in Table 4 and their structural formulas are displayed in Supplementary Figure S2.

Biologically important alkaloids have been less distributed in A. dahurica. Approximately 13 types of alkaloids have been isolated from this plant (Table 5 and Supplementary Figure S3), including dahurines A–F (275–280), (8R,11S,12R)-Funebral (281), (8R,11S,12R)-3,4-dihydro-3-amino-4,5-dimethylfuran-2 [5H]-one-2-formyl pyrrole (282), 4″-butyl-2-formyl-5-(hydroxymethyl)-1H-pyrrole-1-butanoic acid (283), butyl 2-formyl-5-butoxymethyl-1H-pyrrole-1-butanoate (284), hemerocallisamine II (285), butyl 2-pyrrolidone-5-carboxylate (286) and corydaldine (287) (Sun et al., 2017; Qi et al., 2019).

There have been four phenolic compounds identified from the ethanol extract of A. dahurica root, including angelicols A (288), angelicols B (289), (1S)-2-O-Z-Feruloyl-1-(4-hydroxyphenyl)ethane-1,2-diol (290) and (1S)-2-O-E-Feruloyl-1-(4-hydroxyphenyl)ethane-1,2-diol (291) (Shu et al., 2020a). Another phenolic compound, ferulic acid (292) was isolated from the EtOAc-soluble fraction of A. dahurica root (Kwon et al., 1997). In addition, five flavonoids, including cyanidin (293), rutin (294), catechin (295), epicatechin (296) and kaempferol (297) have been found in the water extract or ethanol extract (Pervin et al., 2014). Zhao X. Z. et al. (2007) reported a kind of new neolignan glycoside, namely 4-O-β-D-glucopyranosyl-9-O-β-D-glucopyranosyl-(7R,8S)-dehydrodiconiferyl alcohol (298) from the fresh root of A. dahurica. The information of them is shown in Table 5 and Supplementary Figure S3.

Sterols such as β-sitosterol (299) and daucosterol (300) were identified from the root of A. dahurica (Table 5 and Supplementary Figure S3) (Li and Wu, 2017). Plant sterols have been reported to reduce the circulating total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) to prevent cardiovascular disease (Chen et al., 2019). Although these compounds have been shown to be potential and safe drugs by many in vitro and in vivo studies, clinical studies are needed to prove the implications of these compounds on some specific diseases so as to develop them into notable drugs (Babu and Jayaraman, 2020).

Benzofurans are an important class of heterocyclic compounds, which are diffusely presented in natural products and synthetic materials (Khodarahmi et al., 2015). In a recent study, six benzofuran derivatives have been acquired from the root of A. dahurica (Table 5 and Supplementary Figure S3), including 3-[6,7-furano-9-hydroxy-4-(2″,3″-dihydroxy-3″-methylbutyloxy)]-phenyl propionic acid (301), 3-[6,7-furano-9-(β-D-glucopyranosyloxy)-4-(2″,3″-dihydroxy-3″-methylbutyloxy)]-phenyl propionic acid (302), 3-[6,7-furano-9-(β-Dglucopyranosyloxy)-4-(2″,3″-dihydroxy-3″- methylbutyloxy)]-phenyl propionic acid methyl ester (303), cnidioside A (304), methylcnidioside A (305) and methylpicraquassioside (306) (Matsuo et al., 2020).

Polyacetylenes are pervasively found in the family Asteraceae, Araliaceae and Apiaceae (Lin et al., 2016). Up to now, only two polyacetylenes, falcarindiol (307) and octadeca-1,9-dien-4,6-diyn-3,8,18-triol (308) have been reported from the root of A. dahurica (Table 5 and Supplementary Figure S3) (Choi et al., 2005).

A. dahurica polysaccharides have also been reported in some research publications. A latest study reported a new acidic A. dahurica polysaccharide (ADP) composed of rhamnose, mannose, glucose, galactose, arabinose, galacturonic acid and glucuronic acid with a Mw of 6.09 × 10³ Da (Dong et al., 2021). Xu et al. (2011) isolated four ADPs from the water extract of A. dahurica root and found that they have different degrees of anti-oxidant activity. Moreover, Wang et al. (2021) isolated a gluco-arabinan consisting of a trace of glucose and arabinose with a Mw of 9,950 Da by water extraction and ethanol precipitation from the root of A. dahurica.

In addition to the compounds mentioned above, adenosine (309) was also isolated from the root of A. dahurica (Table 5 and Supplementary Figure S3) (Shu et al., 2020b). Moreover, A. dahurica also contains sucrose and amino acids (Zhao and Yang, 2018).

Modern pharmacological studies have revealed that A. dahurica also exhibits potent anti-tumor effects in multiple cancers, including colon cancer, breast cancer and melanoma. In murine melanoma B16F10 cells, the 70% ethanol extract of A. dahurica root (100 and 200 μg/ml for 24 h) was confirmed to inhibit the growth, migration, invasion and colony formation, while stimulating cell apoptosis via reducing the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9 (Hwangbo et al., 2020). The essential oils from the root of A. dahurica (12.5 μg/ml for 24 h) could suppress the resistance of MCF-7/ADR breast cancer cells to doxorubicin with a fold reversal of 2.09 by inhibiting the expression of ATP-binding cassette subfamily B member1 (ABCB1) and decreasing lipid raft stability (Wu et al., 2016). As for colon cancer, the cell apoptosis assay illustrated anti-apoptosis effect of the ethyl acetate extract of A. dahurica root (200 and 250 μg/ml, 48 h) on colon cancer HT-29 cells through p53-independent pathway (Zheng et al., 2016b). Moreover, IMP was reported to significantly inhibited the proliferation at a dose of 150 μM for 12 h in colon cancer HCT116 cells, as well as suppressed angiogenesis and tumor growth (50 and 100 mg/kg b. w., 3 times a week, 35 days) in HCT116 xenograft mice by inhibiting hypoxia-inducible factor-1α (HIF-1α) protein synthesis through the mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (p70S6K)/eukaryotic initiation factor 4E binding protein-1 (4E-BP1) and mitogen-activated protein kinase (MAPK) signaling pathways (Mi et al., 2017). It could also significantly suppress the growth (IC₅₀ = 78 μM), and induce the apoptosis at a dose of 150 μM for 48 h in colon cancer HT-29 cells via upregulating p53 and caspase cascade (Zheng et al., 2016a). In addition, IMP enhanced anokis at doses of 0.1, 0.5 and 1 μg/ml in lung cancer H292 and A549 cells at 24 h after cell detachent and mitigated cancer cachexia at doses of 25 and 50 mg/kg b. w. for 15 days in colorectal adenocarcinoma CT26 tumor-bearing mice (Choochuay et al., 2013; Chen et al., 2020). These results suggested that IMP, the active ingredient of A. dahurica, is a new potential candidate for cancer treatment.

Although emerging evidence has demonstrated the anti-tumor effect of A. dahurica, several challenges must be overcome in the future. Firstly, the pathogenesis of tumors is complex and the research on the anti-tumor mechanism of A. dahurica is not in-depth enough. Furthermore, many studies focused on the crude extracts and could not determine the specific ingredient in A. dahurica that was responsible for its anti-tumor activity. Finally, the current studies mainly include in vivo and in vitro experiments, with a lack of clinical trial data. Future studies are necessary to reveal the anti-tumor effect of A. dahurica in clinical trial.

A. dahurica has been used historically to cure pain-associated diseases, such as headache, toothache, rheumatalgia and superciliary ridge pain. Modern molecular pharmacological approaches have demonstrated the analgesic effects of A. dahurica root by using multiple pain models and revealed that the analgesic mechanisms are complex. Transient receptor potential vanilloid type 1 (TRPV1) is a therapeutic target for treating various models of pain and is widely expressed in peripheral and central nervous systems (Iftinca et al., 2021). Recently, the researchers indicated that injected subcutaneously with IMP (2.45 mM) could effectively alleviated the acute pain induced by formalin or capsaicin in rats by inhibiting the activity of TRPV1 channel (Chen et al., 2014). Similarly, The water extract of A. dahurica root at a dose of 100 mg/kg b. w. for 2 h attenuated the acute pain induced by thermal, formalin and capsaicin in mice through the inhibition of TRPV1 channel (Guo et al., 2019). Moreover, coumarins of A. dahurica root (CAD) obviously reduced the nociceptive response at doses 30, 60 and 120 mg/kg b. w. for 4 days in formalin-induced pain models of mice. After intracerebroventricular administration of CAD at dose 6 mg/kg b. w., the latency of mice was significantly prolonged in the hotplate test. Further research suggested that the analgesic site of CAD might be in both peripheral and central nervous systems, and the mechanism might be associated with the synthesis and release of nitric oxide (NO) (Wang H.L. et al., 2009). These findings demonstrated that the extracts of A. dahurica root or individual compound may exert analgesic effect by the inhibiting TRPV1 channel and regulating NO level. The root of A. dahurica might have the potential to be effective therapeutic drug for various pains, which was consistent with its traditional use of analgesia.

Nowadays, some studies revealed that A. dahurica present a wide range of anti-microbial activity. Kwon et al. first isolated eight compounds, including 5,8-di (2,3-dihydroxy-3-methylbutoxy)-psoralen (75), heraclenol (47), IMP, isoimperatorin (19), phellopterin (26), scopoletin (3), byakangelicin (41) and ferulic acid (292) from A. dahurica root and evaluated their anti-microbial activities against Bacillus subtilis, Escherichia coli, Cladosporium herbarum and Aspergillus candidus. They found that these active constituents displayed good inhibitory effects against Bacillus subtilis, Cladosporium herbarum and Aspergillus candidus with minimun inhibitory concentration (MIC) of 62.5 μg/ml (Kwon et al., 1997). In bioassays of anti-microbial activity, the ethanol extract of A. dahurica root showed an inhibition radio of 40% against Trypanosoma cruzi, and the water extract of A. dahurica exhibited notable effect of anti-Mycoplasma hominis with a 50% minimun inhibitory concentration (MIC₅₀) of 3.91 mg/ml, which could be used in treating Mycoplasma hominis infection (Schinella et al., 2002; Che et al., 2005). Moreover, the hexane extract of A. dahurica root was found to possess anti-microbial activity against staphylococcus aureus. From the hexane extract, an anti-microbial compound was isolated by bioassay-guided fractionation and identified as falcarindiol (307). In this study, falcarindiol inhibited the growth of staphylococcal strains with MICs ranged from 8 to 32 μg/ml (Lechner et al., 2004).

In addition to the anti-microbial activity, A. dahurica also presents significant antiviral effect. In recent years, coumarins from A. dahurica were reported to possess significant antiviral property. For example, Lee et al. found that four active furanocoumarins in the root of A. dahurica, including isoimperatorin (19), oxypeucedanin (20), oxypeucedanin hydrate (21) and IMP have significant antiviral activity against influenza A (H1N1 and H9N2) viruses. Among them, oxypeucedanin exhibit the most potent antiviral effect with an EC₅₀ of 5.98 ± 0.71 and 4.52 ± 0.39, respectively. Further investigation showed that oxypeucedanin exerts anti-influenza A viruses property by inhibiting the virus infection-induced apoptosis and early stage of the viral replication cycle (Lee, B.W. et al., 2020). Besides, IMP (10, 25 and 50 μM, 30 min) was capable of inhibiting human immunodeficiency virus type 1 (HIV-1) replication in both T cells and HeLa cells infected by HIV-1 via the regulation of transcription factor specificity protein1 (Sp1) (Sancho et al., 2004). As many diseases occur due to the infection of bacteria and viruses. These studies suggested that the root of A. dahurica is a rich source of natural anti-microbial and antiviral agents that can prevent and treat some diseases.

Cardiovascular diseases are major contributor to global mortality and result in a huge socioeconomic burden. Many studies have decleared that A. dahurica extract and its active ingredients possess obvious protective role on cardiovascular system. Lee et al. (2015) first reported that 70% methanol extract of A. dahurica root (0.03–3.0 μg/ml) markedly relaxed calcium-induced vasocontraction of aortic rings in a concentration-dependent manner. In high-fat/high-fructose diet (HFFD)-fed rats, IMP at doses of 15 and 30 mg/kg b. w. for 4 weeks significantly reduced blood pressure and heart rate values, and alleviated changes in vascular morphology by regulating the expression of adiponectin receptor 1, endothelial nitric oxide synthase (eNOS) and p47^phox (Bunbupha et al., 2021). Meanwhile, IMP displayed a potent vasodilatation role by partially affecting the level of NO in phenylephrine-induced mouse thoracic aorta (IC₅₀ = 12.2 ± 2.4 μmol/L) (Nie et al., 2009). He et al. (2007) found that IMP (1 μM–1 mM) might promote vasodilatation on arteries precontracted by agonists by regulating the calcium channel and competitively antagonizing 5-hydroxytryptamine (5-HT) recptors. Additionally, IMP could also attenuate pathological myocardial hypertrophy and cardiac fibrosis, inhibit transition to heart failure, and prevent cardiac myocyte protein synthesis and cell size induced by angiotensin II. The high dose of IMP (30 μM) was more effective than IMP (10 and 3 μM) and displayed concentration-dependently (Zhang et al., 2010). These scientific reports demonstrated that the root of A. dahurica and its active ingredients may control Ca²⁺ channel, modulate the expression of adiponectin receptor 1, eNOS and p47^phox to exert vasodilative and cardioprotective effects. IMP may be responsible for the effects of A. dahurica on cardiovascular system.

IMP might largely contribute to the neuroprotective function of A. dahurica and possess significant properties on the nervous system, such as improving memory, antidepressive-like effect and anticonvulsant (Luszczki et al., 2009; Sigurdsson and Gudbjarnason, 2013; Cao et al., 2017). For example, pretreatment with IMP (5, 10 mg/kg b. w., 14 days) exhibited significant amelioration in the mice of LPS-induced poor memory retention by upregulating the level of brain derived neurotrophic factor (BDNF) and inhibiting oxidative stress and inflammation (Chowdhury et al., 2018). In middle cerebral artery occlusion (MCAO) rats, IMP at doses of 5 and 10 mg/kg b. w. reduced the infarct volume and increased the behavior ability. Moreover, IMP (0.612 and 2.56 μM) ameliorated the damage of neural cell lines (SH-SY5Y cells) by anti-apoptosis through increasing the expression of BDNF and phosphorylated-extracellular signal-regulated kinase (p-ERK) (Wang et al., 2013). In the maximal electroshock-induced seizure (MES) test, IMP at a dose of 50 mg/kg b. w. markedly enhanced the anticonvulsant activity of lamotrigine (LTG) in mice by reducing the 50% effective dose (ED₅₀) value by 60% and increased the protective index from 4.90 to 8.96. The MES threshold for IMP administrated alone at 50 and 100 mg/kg were significantly increased by 38% and 68% at 30 min after its administration (Luszczki et al., 2007; Luszczki et al., 2008). In addition to IMP, some other compounds such as phellopterin (26) and scopoletin (3) also exhibit neuroprotective effects. Scopoletin (2, 10 and 50 mg/kg b. w.) administration for 2 weeks mitigated anxiety-like symptoms in complete Freund’s adjuvant (CFA)-induced mice by activating γ-aminobutyric acid (GABA_A) receptors and phellopterin was reported to competitively bind to central nervous system benzodiazepine receptors with IC₅₀ of 0.36 μM (Bergendorff et al., 1997; Luo et al., 2020). Alzheimer’s disease is a common neurodegenerative disease characterized by the formation of β-amyloid plaques and neurofibrillary tangles (Zhang et al., 2020). Marumoto et al. evaluated the inhibitory activities against β-secretase (BACE1) of five furanocoumarins from A. dahurica and found that IMP and byakangelicol (34) exhibit the most excellent properties with IC₅₀ of 91.8 ± 7.5 and 104.9 ± 2.4 μM (Marumoto and Miyazawa, 2010), implying their potential for the treatment of Alzheimer’s disease. However, based on the present study, due to the complexities of the nervous system, IMP is limited to achieve desired therapeutic effects. The combination of IMP with other effective compounds may be a promising direction in clinical trials.

Several research publications reported the hepatoprotective activities of some active ingredients from A. dahurica. For example, Oh et al. isolated and identified six furocoumarins, including IMP, isoimperatorin (19), byakangelicol (34), oxypeucedanin (20), byakangelicin (41), and aviprin (78) from the methanol extract of A. dahurica root and validated their cytotoxic effect on tacrine-induced Hep G2 cells. Subsequently, IMP and byakangelicin displayed superior hepatoprotective activities with EC₅₀ values of 36.6 ± 0.98 and 47.9 ± 4.6 μM, respectively. Byakangelicol and oxypeucedanin exhibited moderate hepatoprotective effects with EC₅₀ values of 112.7 ± 5.35 and 286.7 ± 6.36 μM, respectively (Oh et al., 2002). Meanwhile, IMP at a dose of 100 mg/kg b. w. for 5 days was able to ameliorate acetaminophen overdose-induced acute liver injury in rats as evidenced by the reduced mortality, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum and centrilobular hepatic necrosis via stimulating the sirtuin 1 (SIRT1)-farnesoid X receptor (FXR) pathway (Gao et al., 2020). Furthermore, Oral administration of byakangelicin (100 mg/kg b. w., 4 weeks) in mice significantly improved carbon tetrachloride-induced liver fibrosis and damage by inhibiting the deposition of collagen and α-SMA, and decreasing the levels of ALT and AST in serum, which was more effective than that of silibinin. In 4-HNE–induced HepG2 cells, byakangelicin (20 and 40 μmol/L, 24 h) inhibited activation and proliferation of hepatic stellate cells, and prevented the apoptosis of hepatocyte through apoptosis signal regulating kinase-1 (ASK-1)/c-Jun N-terminal kinase (JNK) pathway (Li et al., 2020). The above mentioned results indicated that furocoumarins in A. dahurica exhibited obvious hepatoprotective activity and may be responsible for the hepatoprotective activity of A. dahurica. However, the molecular mechanism and clinical safety of some coumarins are not clear enough, which hinders the development of coumarins as hepatoprotective drugs. Future research should focus on the precise molecular mechanisms of furocoumarins in A. dahurica.

A. dahurica was extensively used as a traditional Chinese medicine in treating skin-associated diseases. In recent years, several studies revealed that A. dahurica has excellent activity on diabetes-induced skin ulcer (Guo et al., 2020; Chao et al., 2021; Hu et al., 2021). Guo et al. (2020) indicated that 10 days treatment with A. dahurica at 1.8 g/kg b. w. significantly promoted would healing and angiogenesis by activating phosphatidylinositide 3-kinase/protein kinase B (PI3K/AKT) and HIF-1α/platelet-derived growth factor-β (PDGF-β) pathways in db/db mice. Moreover, the 70% ethanol extract of A. dahurica root (2.5 mg/ml, 3 days) was reported to improve the adhesion of melanocytes to fibronectin and stimulate the migration of melanoctes to treat vitiligo (Zhang et al., 2005). Hwang et al. (2016) found that the root of A. dahurica methanol extract (50 μg/ml) and IMP (10, 20 and 40 μM, 2 days) markedly inhibited the insulin-like growth factor-1 (IGF-1)-induced sebum production by suppressing the phosphorylation of Akt and the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) and sterol response element-binding protein-1 (SREBP-1) in sebocytes, suggesting that they have the potential to be used in the treatment of acne. In addition, IMP and isoimperatorin (19) from A. dahurica root can inhibit melanogenesis by preventing tyrosinase synthesis in B16 melanoma cells and might have the potential to be exploit as a novel whitening agents in cosmetics (Cho et al., 2006). Collectively, the investigations mentioned above could partly support the claim about the traditional use of A. dahurica root for the treatment of skin diseases. The root of A. dahurica is commonly used to treat various skin diseases, such as scabies, carbuncle, sore and pruitus in China and other traditional medicinal systems in Asia, these indications may be promising for future clinical trials.