1.1 Historical records

Bai Zhi (白芷) first appeared in the poem Li Sao of Qu Yuan in China's Warring States Period. Many alternate names for AD were recorded in Qu Yuan's Chu ci (楚辞), such as “Bai Zhi (白芷)”, “Fang Zhi (芳芷)”, “ Zhi (茝)”, “Bi Zhi (辟芷)”, “Yao Zhi (药芷)” and “Fang Xiao (芳虈)”. During the Warring States Period, between nobles, it was often made into a sachet. Since then, AD, as a representative of noble quality, had become the object of poetry in all dynasties (Zhang, 1986). In the pre-Qin and Han dynasties, AD was also called li (蓠), Fu Li (苻蓠), Xiao (虈), and Wan (莞) (Xu, 2013). AD was mostly used in vanilla at this time, and its medical use was not recorded in detail.

The first clear record of the medicinal use of AD was recorded in the Shennong's Classic of Material Medical (神农本草经) of the Han Dynasty, which indicates that AD had the functions of dispelling wind, stopping bleeding, and beautifying, and it is still used today. In Wei and Jin dynasties, it was recorded in Ming Yi Bie Lu (名医别录) that AD could cure wind evil, vomiting, head dizziness, and itching. It could be used to make a plaster. This book added the functions and aliases of AD. At this time, AD was still growing in the wild, and there was no cultivation. Later, in the Southern and Northern Dynasties, Tao Hongjing's Collective Notes to the Canon of Materia medica (本草经集注) described that AD leaves could be used in bathing to add fragrance. Traditional Chinese religious Daoists used it to remove corpse insects and made incense (Tao, 1994). It was written in Master Lei's Discourse on Drug Processing (雷公炮炙论) that Sang gong teng (One Chinese herbal medicine) and Iris lacteal var. chinensis (Fisch.) Koidz. (Ma Li) were commonly used as counterfeits of AD. Two works of the Tang Dynasty, Yao Xing Lun (药性论) and Ri Hua Zi Ben Cao (日华子本草) recorded that AD could remove facial scars and could be used to beautify the face (Tang, 1957). Later, empress Dowager ci xi's famous beauty secret recipe “Yurong powder (玉荣散)”, AD was its main medicine. By the Song Dynasty, AD had been widely known. Song Su recorded the detailed characteristic morphology of AD in Notes on Ben Cao Tu Jing (本草图经) (Song, 1988). Jia You Ben Cao (嘉佑本草) recorded that the first artificial cultivation of AD appeared in Shandong, China (Niu et al., 2018). Therefore, AD was more widely distributed after the Song Dynasty and gradually began to be cultivated. According to plant morphology, AD at this time should be is A. dahurica (Fish. ex Hoffm.) Benth. et Hook. f. var. formosana (Boiss.) Shan et Yuan (Chinese vernacular names: Hang bai zhi). After the Jin and Yuan dynasties, the efficacy of AD was further detailed. AD tastes aromatic, and the role of treating cold. The ability of AD to open the orifices (通窍) was first described in the Yao Yong Fa Xing (药用法象). After the Ming Dynasty, there were many records about AD. Mi Lan recorded another source of AD, Heracleum scabridum Franch (Chinese vernacular name: Dian bai zhi) in his work on Materia Medica of Southern Yunnan (滇南本草) (Lan, 1959). Later, Wang et al. (2020) thought AD should belong to H. scabridum. The Compendium of Materia Medica (本草纲目) (Tao, 1994), known as the pharmaceutical treasure trove, summarised the previous records of AD in detail, including plant morphology, efficacy, and classical prescriptions. At this time, cultivated AD gradually replaced wild AD and became the mainstream of commodity. During the Ming and Qing dynasties, Hangbaizhi became the mainstream commoditiy. According to Wang et al. (2001) AD at this time was more likely to be the Angelica dahurica var. formosana (Boissieu) Yen (Chinese vernacular name: Tai wan bai zhi). Angelica dahurica (Fisch. ex Hoffm.) Benth. et Hook. f (Chinese vernacular names: Yu bai zhi, Qi bai zhi) was recorded in the Yao Wu Chu Chan Bian (药物出产辨). Wang et al. (2004) believed that Yu bai zhi should be a variety brought back to Changge County from other places due to commodity exchanges during the Qianlong period of the Qing dynasty. After modern research and investigation, Wang et al. (2020) speculated that Yu bai zhi should be a wild AD cultivated in North China after domestication. In modern times, from the Chinese Pharmacopoeia published in 1930 to the 2020 edition of Chinese Pharmacopoeia, there was a systematic and detailed description of AD's medicinal parts, properties, identification, content determination, taste, and function. With the deepening of research, AD, a traditional Chinese medicine, has gradually been known worldwide. Table 1 briefly lists the development process of AD in China according to the changes in dynasties.

At present, the number of Chinese patent medicine prescriptions of AD was 557, and the number of traditional Chinese medicine prescriptions was 1841 (https://www.da.yaozh.com, last accessed at 07/06/2022). Among them, Bai Zhi Gao and Huo Xiang Zheng Qi He Ji were the most famous and widely used prescriptions. Modern clinical studies had shown that AD combined with other chinese herbal medicines could effectively treat headache, vitiligo, psoriasis, constipation, and other diseases (https://www.da.yaozh.com, last accessed at 07/06/2022). In traditional Chinese therapies, AD was often combined with other medicinal plants such as Ligusticum chuanxiong Hort., Notopterygium incisum Ting ex H.T. Chang and Panax ginseng (https://powo.science.kew.org, last accessed at 07/09/2022). However, the possible interactions, synergistic effects, and underlying action mechanisms between the bioactive compounds present in AD and other medicinal plants remain unknown and should be further investigated. In addition, AD could be used not only as medicine but also as healthy food. AD was approved by the Chinese Health and Family Planning Commission as an herbal medicine that can be used as a health food (Yang et al., 2021). In China, more than 700 kinds of health foods containing AD had been recorded, with purported curative powers ranging from functions of removing spots from beauty, anti-fatigue, increasing immunity, regulating blood lipids, and improving sleep (https://www.da.yaozh.com, last accessed at 07/06/2022). Such products include Rain Brand Beauty Oral Liquid of Forest (Beauty Oral Liquid), Panlong Yunhai Shiliwei Capsule (Sleep improvement capsule), and Zhiwangpai Yishen Capsule (Relieving fatigue capsule).

AD is present in at least 8 provinces in China. Such as Neimenggu, Hebei, Henan, Sichuan, Anhui, Zhejiang, Fujian, and Taiwan. AD is suitable for planting in sandy loam and loam with flat terrain, deep soil layer, loose and fertile soil, and good drainage, but not in sandy land, saline-alkali land, gravel land, and low-lying land. The general geographical distribution of AD in China is shown in Fig. 1.

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Fig. 1

The general geographical distribution of AD in China.

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1.2 Botanical morphology of AD

In China, AD mainly has three cultivars, namely A. dahurica (Fish. ex Hoffm.) Benth. et Hook. f. var. formosana (Boiss.) Shan et Yuan, Angelica dahurica (Fisch. ex Hoffm.) Benth. et Hook. f and Angelica dahurica var. formosana (Boissieu) Yen (https://powo.science.kew.org, last accessed at 07/09/2022). The botanical morphology is as follows (Wang et al., 2020; Lian et al., 2019). Plant morphology (A) (B) and decoction pieces morphology (C) of AD are shown in Fig. 2.

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Fig. 2

Plant morphology (A) (B) and decoction pieces morphology (C) of AD.

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AD is a perennial tall herbaceous plant; the plant height generally grows to 1–2.5 m. The roots are cylindrical, branching, 3–5 cm in diam. The outer skin is yellowish-brown or brown, with a strong odor. Stem base 2–5 cm in diam, sometimes 7–8 cm, usually purplish, hollow, longitudinally furrowed.

Basal leaves have a pinnate split leaf, long petiole, and lower petiole with tabloid cauline margin membranous sheath. Upper stem leaves have 2 to 3 pinnate, leaves blade contour oblong or triangular, 15–30 cm long and 10–25 cm wide, petiole 15 cm long, lower membranous sheath cystic dilated, glabrous or rare, often purple. Terminal segments are oblong, ovate or linear-lanceolate, sessile, 2.5–7 cm long and 1–2.5 cm wide, margin with irregular white cartilaginous coarsely serrate, base on both sides are often unequal, Along the leaves axis down into a wing.

Leaves below inflorescence simplified into leafless, abaxially dilated cystic sheaths, glabrous outside. Inflorescences terminal or lateral, 10–30 cm in diam. Peduncles 5–20 cm long, Inflorescence peduncle, rachis, and pedicel have short brown hair. The spokes of the main umbrella range from 18 to 40, with the central main umbrella sometimes reaching as high as 70. The bract morphology is usually an ovate-expanded sheath. Small bracts composed of 5 to 10, linear-lanceolate, membranous, flower white, no calyx teeth, petals obovate, ovary glabrous or short-haired, styles 2 times longer than the base of the short conical style. Fruits oblong to oval, yellowish-brown, sometimes purplish, 4–7 mm long and 4–6 mm wide, glabrous, dorsal edges flattened, thick and obtuse, sub-spongy. The rib is wider; the lateral rib is winged, narrower than the fruit body. Tubing 1 in the groove, tubing 2 in the combined surface. The flowering period is July-August and the fruiting period is August-September. In Table 2, we analyzed the differences in plant morphology of three AD base sources.

2.1 Polysaccharide

AD polysaccharides had an antioxidant effect. In the in vitro coagulation experiment, ADPS-1b, ADPS-2, ADPS-3a, and ADPS-3b were found to cause FIB (fibrinogen) coagulation to produce the anticoagulant effect. ADPS-1a had no anticoagulant effect (Wang et al., 2017). It had been reported that the content of polysaccharides in AD in Anguo of Hebei Province and Hangzhou of Zhejiang Province is relatively high (Zhou et al., 2015). In Table 3, the structural composition and related information of AD polysaccharides are in detail.

2.2 Coumarins

Coumarins in AD had many pharmacological activities, especially in the central nervous system, such as relief of pain (Pang et al., 2021). Studies had shown that 15, 18 coumarins had a strong stimulating effect on alkaline phosphatase (AP). Estrogen could promote the secretion of alkaline phosphatase in Ishikawa cells, which indicated that coumarins had a certain estrogenic effect (Piao et al., 2006). PPAR-γ was a receptor expressed in macrophages related to lipid and glucose metabolism. Compounds 52, 53, and 57 showed obvious ligand-binding activity of PPAR-γ (Matsuo et al., 2020). Some benzofuran compounds mentioned below also had this effect. The main coumarin components are shown in Table 4. Serial number: 11–63.

2.3 Alkaloids

Qi et al. (2019) isolated 12 alkaloids from AD, among which compounds 70 and 71 were isolated for the first time from plants. In addition, they detected the inhibitory effects of 12 compounds on acetylcholinesterase and found that compounds 65, 66, 67, 73 and 74 had an inhibitory effect. The alkaloids in AD had a certain inhibitory effect on the growth of cervical cancer (Hela) cells in a dose-dependent manner (Wang and Ma, 2014). AD alkaloids could effectively inhibit the reproduction of mouse U14 cervical cancer cells and reduce the content of Ki-67 (a protein similar to the change of DNA content during cell division) and mutant P53 protein (a protein expressed by mutant tumor suppressor genes) (Li et al., 2012). In summary, alkaloids, the active AD components, could be used as a prospective drug for cancer treatment. The main alkaloids isolated from AD are listed in Table 4. Serial number: 64–75.

2.4 Benzofurans

PPAR-γ was a receptor related to fat and glucose metabolism. Compounds 76, 80, and 81 showed obvious PPAR-γ ligand activity at 500 μmoL/L, and compound 76 had the strongest activity. Moreover, compound 76 could induce adipocyte differentiation, which was expected to become a leading compound for anti-obesity drugs (Matsuo et al. 2020). In Table 4, six benzofuran compounds had been identified from AD. Serial number: 76–81.

2.5 Volatile oil

The volatile oil from AD was the most abundant chemical component in AD. Modern studies had shown that the volatile oil extracted from AD had clinical application effects, such as analgesia, treatment of cold, and rheumatism. Sun et al. (2017) isolated 22 kinds of volatile oil from the ethanol extract of AD and found that volatile oil had a significant therapeutic effect on migraine in rats. It could reduce the content of NO in the serum and brain of rats, reduce the level of CGRP in plasma, and increase the level of ET. Therefore, they concluded that AD volatile oil might treat migraine in rats by regulating the level of vasoactive substances. In addition, Zhang et al. (2019) reviewed the types and contents of volatile oils from AD in six regions of China. There were 12 quinones, 48 alkenes, 6 ketones, 6 aldehydes, 14 alkanes, and 25 others. A total of 111 kinds of volatile oils were found. Alcohols had the highest content, indicating that alcohols were the main components of volatile oils from AD. The main volatile oils components are shown in Table 4. Serial number: 82–103.

2.6 Fatty acids

Liu et al. (2011) isolated 13 compounds from the ethyl acetate extract of AD by biological induction technology, including 10 fatty acids and 3 derivatives. Srchomol-ogy-2domain-containing protein tyrosine phosphatase (Shp2) was considered to be a proto-oncogene that promotes tumorigenesis. It was found that compounds 107, 108, 112, and 114 showed significant selective inhibitory activity against Shp2. HepG2 cells (A human liver cancer cell) were treated with a fatty acid mixture. Compound 108 strongly induced poly (ADP-ribose) polymerase (PARP) cleavage in a dose and time-dependent manner and increased the activities of caspase-3, caspase-8, and caspase-9 at 100 mL Promoting apoptosis of HepG2 cells. In Table 4, 13 fatty acids isolated from AD were listed. Serial number: 104–116.

2.7 Amino acids

Niu et al. (2016) determined 17 common amino acids in AD from different areas by pre-column derivatization HPLC. AD from different regions contains eight essential amino acids, such as Lysine and Phenylalanine. Chen et al. (2015) detected the content of amino acids in AD in Hunan Province. They found that the highest content of amino acids in AD was Arg, accounting for 31.12% of the total amino acids. The total essential amino acids were 27.01%, of which the highest content was Leu, accounting for 24.14%. They found that the content of amino acids in AD in Hunan is in line with the recommended intake value of WHO, and thus, it can be used as a healthy food.

11	12	13
29	34	35
40	43	44
49	50

52.R1 = Glc 53.R1=	54.R1 = Glc 55.R1=

Compound	R1	R2
56	H
57	SO3H	H

Compound	R1	R2
58	H	Glc
59	H
60	H
61	SO3H	H

62.R1 = H 63.R1 = Glc

Compound	R1	R2
14		H
15	OCH3	OH
16	OCH3
17		H
18	OH
19	OCH3
20	OCH3
21	OCH3
22	H	OH
23	OCH3	OH
24	H	OCH3
25	OCH3	OCH3
26	OCH3	H
27	H
28		OCH3
30		OCH3
31	H
32		OCH3
33	OCH3
38	H	H
39		OCH3
42	OCH3
46	OCH3
47		H
48	OCH3

Compound	R1	R2	R3
36	OCH3	OH	H
37	H	OCH3
41	H	OH
45	H	OH	H
51		OH	H

64	65	66
67	68	69
70	71

, C5
Compound	R1	R2	R3
76	C5	H	H
77	C5	Glc	H
78	C5	Glc	CH3
79	H	Glc	H
80	H	Glc	CH3
81	OCH3	Glc	CH3

Compound	n1	n2
104	7	4
105	8	4
107	6	4
108	10	4
109	16	4

106	110
111	112
113	114
115	116

3.1 Wound healing

Zhang et al. (2017) used streptozotocin to delay the healing rate of diabetic wounds in rats and then treated them with ADEE (AD ethanol extract). It was found that ADEE could promote angiogenesis and tissue formation to accelerate wound healing in rats. They also used HUVEC (human umbilical vein endothelial cells) for in vitro experiments to study the mechanism of ADEE and found that ADEE promoted angiogenesis with the increase of angiogenesis regulators, which was similar to that of VEGF (vascular endothelial growth factor). One analysis using network pharmacology and in vivo experiments proved that AD had 54 targets in diabetic wound healing, which could regulate the polarisation of macrophages M1 and M2 to produce anti-inflammatory effects to accelerate wound healing (Hu et al., 2021). In the healing experiment on diabetic trauma that AD treatment of trauma was accompanied by the expression of the HIF-1α gene and the increase of PDGF-β protein (Guo et al., 2020). Increased sebum secretion was one of the pathogenesis of acne. IMP was an effective component of AD, which could inhibit the promotion of insulin factor (IGF-1) on sebum formation and cytokine expression, and could be used to treat acne (Hwang et al., 2016). Yang et al. (2017) found that the extracts of AD and rhubarb (ARE) could increase the content of collagen fibers and myofibroblasts in the wounds of rats, thereby accelerating wound healing. They conducted experiments on rhubarb and AD extracts to treat Staphylococcus aureus infection, further confirming the function of AD in promoting wound healing (Yang et al., 2020). In patients with bedsores, it was found that AD could promote the increase of transforming growth factor (TGF-β), epidermal growth factor (EGF), and VEGF (vascular endothelial growth factor) after external application (Gong et al., 2016). AD polysaccharides played a significant noticeable effect in the coagulation process of wound healing, increasing the FIB (fibrinogen) content through endogenous or exogenous pathways to promote coagulation (Wang et al., 2021).

3.2 Antitumor activity

Tumor has always been a difficult problem in modern medical treatment. The traditional treatment is based on radiotherapy and chemotherapy, but the side effects are large, and low cure rate. Patients need to suffer great pain during the treatment. With the modern medical research of traditional Chinese medicine, it has been found that many components in traditional Chinese medicine have great help in the treatment of cancer. Modern medical experiments have proved that AD extracts have a good effect in treating cancer.

Some experiments found that the organic solvent extract of AD had a good therapeutic effect on cancer and stimulated the activation of the caspase pathway. Still, the specific components had not been shown (Zheng et al., 2016; Liu et al., 2011). Some later studies found that IMP was a chemical component of AD, which had been proved to be a very effective antitumor substance. Advanced liver cancer would resist cytotoxic drugs, resulting in little drug effect. IMP could act on the Mcl-1 target (An anti-apoptotic factor), inhibit its expression, make BAK express in mitochondria, and promote mitochondrial oligomerization to induce apoptosis of cancer cells (Li et al., 2014). In Choochuay's experiment, it was also shown that IMP could act on Mcl-1 targets and inhibit the metastasis and growth of lung cancer cells, promoting apoptosis of cancer cells (Choochuay et al., 2013). IMP could inhibit the synthesis of hypoxia-inducible factor protein (Mi et al., 2017); it showed an inhibitory effect on human colon cancer cells through caspase joint reaction (Zheng et al., 2016) and had a remarkable curative effect on skeletal muscle atrophy characterized by cancer (Chen et al., 2020). In addition, Oxypeucedanin (12) could inhibit liver cancer cells' G2/M division cycle, which was related to the regulation of p53 in cancer cells (Park et al., 2020). In summary, the mitochondrial pathway is an important way for the apoptosis of IMP.

In addition, it was found in previous studies that coumarin compounds extracted from AD could promote the apoptosis of various cancer cells (Liu et al., 2011; Luo et al., 2011; Kim et al., 2007). A polysaccharide extracted from AD could significantly increase the content of spleen lymphocytes and NK cells in tumor mice and improve the apoptosis rate of tumor cells at G1 (Dong et al., 2021). Bai et al. (2021) found that iso-imperatorin extracted from AD could significantly increase the apoptosis rate of female cervical cancer (Hela) cells. The apoptosis mechanism promotes the expression of apoptotic proteins in cervical cancer cells through mitochondrial and external apoptotic pathways. AD extract activated the mitochondrial apoptosis pathway of mouse melanoma cells, increased the intracellular reactive oxygen species content and Bax/Bcl-2 expression, induced apoptosis of cancer cells but also reduced the activities of metalloproteinases (MMP-2, 9, and 4) reduced the colony and migration rate of melanoma cells (Hwangbo et al., 2020). The molecular mechanism is concisely shown in Fig. 3.

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Fig. 3

The component molecular mechanism of AD in anticancer.

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Mcl-1: myeloid cell leukaemia 1, Bax: Bcl-2-Associated X, Bcl-2: B-cell lymphoma-2, BAK: Bcl-2-associated protein X, P53: tumor suppressor gene.

3.3 Neurological diseases

Modern research showed that AD extracts had the effects of alleviating pain, treating Alzheimer's disease, and depression (Nong, 2016). In traditional Chinese medicine, prescriptions composed of AD were widely used in analgesic treatment, such as migraine. In 2007, Dr. Yuan published an article on the analgesic effect of Yuan Hu Zhi Tong Formula, a prescription composed of AD and Corydalis Rhizoma, and found that it had an obvious analgesic effect and was dose-dependent. Still, the mechanism was not clear (Yuan et al., 2004). Later, in the study of Liao et al. (2010) it was pointed out that Cou (total coumarin) and VO (volatile oil) of AD could enhance the content of di-ThP (an effective component of tetrahydropalmatine alkaloids, with obvious analgesic effect) in mouse plasma. Mi et al. (2020) used network pharmacology to analyze the analgesic mechanism of YB (Yuanhu-Baizhi herbal pair). A total of 78 target genes were screened and then folded with pain-related genes. Finally, 34 related genes, 10 Hub genes and 23 important related compounds were obtained, indicating that YB was closely related to the central nervous system. AD and Ligusticum chuanxiong Hort. were common drug components for migraine treatment. DL (Duliang Soft Capsule) was a traditional Chinese medicine prescription composed of Chuanxiong and AD. In the experiment, it was found that DL extract could reduce the pain response of rats, reduce the content of CGRP, NO, and DA in rat plasma, and increase the content of ET and 5-HT (Hou et al., 2017). Tou feng yu pill (TFY) was a traditional Chinese medicine prescription composed of AD, Chuanxiong, and camellia. it was found that after oral administration of TFY extract, it could effectively reduce the pain reaction of mice caused by acetic acid and formalin, reduce the contents of CGRP, NO and dopamine in rats, improve the contents of endothelin, 5-HT and norepinephrine, effectively resist vasospasm, improve the cerebral blood flow of normal rabbits, and reduce the cerebral vascular resistance index (Li et al., 2011). Studies by Feng et al. (2018) had shown that the analgesic process of AD total coumarin extracts was also consistent with the above process. Auraptenol (43) was an effective analgesic substance in AD. Auraptenol (43) could significantly improve the foot withdrawal threshold of mice, and the receptor was mainly 5-HT mediated 1A (Wang et al., 2013). Chen and his colleagues found that IMP, the AD extract, could regulate pain by activating the TRPV1 channel but could not change the heat rejection threshold of animals (Chen et al., 2014).

AD polysaccharide (ADP) could increase the expression of CD86 and MHC-II in dendritic cells (DC), increase the contents of IL-12, IL-1β, and TNF-α, and significantly enhance the activation of allogeneic T cells in DC, Increase DC cell viability. Phosphorylation of ERK, JNK, and P38 MAPKs increased after ADP binds to TLR4. This suggests that ADP enhances the immunity of DC cells by activating the ERK/JNK pathway (Kim et al., 2013). In the study of AD in the treatment of Parkinson's disease (PD), it was found that the mixed extracts of peony bark, AD, and Bupleurum could significantly improve the decrease of OXPHOS complex 1 activity caused by tyrosinase inhibition and mitochondrial damage, and increase mitochondrial membrane potential and reactive oxygen species levels, promote apoptosis of damaged brain cells (Jeong et al., 2018). In the PD mouse model, oral AD extracts could increase dopamine content. In vitro and in vivo experiments, the extract could improve AKT phosphorylation and mitochondrial gene expression under the insulin signaling pathway, and could significantly improve the decrease of cell viability caused by 6-OHDA, stimulate the activity of antioxidant enzymes to inhibit cell apoptosis, inhibit the movement disorder caused by 6-OHDA, and reduce the nerve transfer between dopamine neurons. This indicated that AD exerted a therapeutic effect on PD by restoring neural cell vitality and increasing dopamine content (Eo et al., 2019). Bax and caspase were the key apoptosis factors of brain cell apoptosis induced by cerebral ischemia. A study showed that IMP could reduce the number of SH-SY5Y cells apoptosis induced by OGD-R (oxygen-glucose deprivation/reperfusion) and inhibit the expression of apoptosis factors (Wang et al., 2013). Cao et al. (2017) established a rat model of depression by prenatal stress and observed the role of IMP in treating depression. It was found that IMP could increase sucrose intake in offspring rats and restore the decrease of 5-HT caused by depression. In addition, Gu et al. (2014) found that auraptenol (43) in AD could shorten the resting time of tail suspension and swimming model mice, which proved that the antidepressant effect was related to the activation of 5-HT. In addition, IMP could improve the cognitive impairment and hippocampal neuronal damage caused by vascular dementia in rats, improve synaptic Structure, increase SAZ (synaptic active zone) length and PSD (postsynaptic density) thickness, and inhibit neuronal apoptosis by regulating Bax and caspase-3 (Huang et al., 2021). The molecular mechanisms are shown in Fig. 4.

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Fig. 4

The component molecular mechanism of AD in Nerve.

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CGRP: calcitonin gene-related to peptide, DA: dopamine, ET: endothelin, 5-HT: 5-hydroxytryptamine, NE: norepinephrine, TRPV 1: proteins form calcium channels that transmit pain to the central nervous system.

3.4 Anti-inflammatory

Inflammation is the body's immune response to the external invasion, usually manifested as swelling, fever, and pain. Cytokines secreted by immune cells (also known as inflammatory factors), such as TNF-α, TGF-β, IL-1β, IL-6, and COX-2, are important mediators for inflammatory response.

Modern studies had shown that inducible NO synthase (INOS) production can lead to an excessive increase of NO, a key factor in inducing inflammation. Methanol extract of AD inhibited NO synthesis in macrophages and reduced the expression of INOS by reducing the phosphorylation of ERK1/2 (Kang et al., 2008). Coumarins in AD showed inhibitory effects on NO synthesis (Yang et al., 2017; Wei et al., 2016). COX-2 gene was a key factor in subsequent inflammation and could be induced and expressed by various proinflammatory factors. The COX-2/PGE2 pathway was a classic proinflammatory pathway, and COX-2 was a major enzyme in the synthesis of PG. Iso-imperatorin isolated from AD could reduce the expression of COX-2 (Moon et al., 2008). Subsequent studies had found that furanocoumarins in AD could inhibit PGE production by inhibiting COX-2 and mPGES (Hong et al., 2008). Studies by Moon et al. (2012) showed that oral administration of AD extract (100 mg/kg) for 14 days decreased the levels of TNF-α, IL-1β, IL-6, INOS, COX-2, reactive oxygen species (ROS), etc. Lee et al. (2011) also found that AD ethanol extract could reduce the number of inflammatory factors in cells, reduce the mucus production and immunoglobulin (IGE) in airway inflammation model cells, in order to reduce excessive cellular immune response. In addition, they showed that AD ethanol extraction reduced airway inflammation by stimulating the expression of HO-1, TARC/CCL17, and MDC/CCL22. AD extract could inhibit the expression of TARC and MDC, preventing TH2 cell aggregation (Lee et al., 2012). AD volatile oil components could alleviate ear swelling and foot swelling in inflammatory model mice and reduce ankle synovial hyperplasia, excessive inflammatory cells, cartilage damage symptoms, and reduce plasma NO, TNF-α, PGE₂, and NOS levels. NF-κB was responsible for the transcription of many pro-inflammatory factors and chemokines genes (Wang et al., 2016). The expression of NF-κB was related to TNF-α-induced IKKα/β phosphorylation, IκB phosphorylation, degradation, and NF-κB p65 nuclear translocation. One study showed that IMP inhibited NF-κB expression by inhibiting TNF-α, down-regulated the expression of inflammatory genes induced by lipopolysaccharide, and produced anti-inflammatory effects (Wang et al., 2017). Lee et al. (2017) also found the inhibitory effect of AD on NF-κB. In addition, AD could reduce the contents of IL-1β, IL-6, IL-8, and IFN-γ (interferon-gamma) in gingival tissue cells and inhibit the expression of the genes related to the above four inflammatory factors and the synthesis of COX-2 and INOS in mouse macrophages (RAW264.7). In the colitis mouse model experiment, IMP promoted the synthesis and expression of PXR, thereby inhibiting the activity of NF-κB (Liu et al., 2018). AD, rhubarb extract showed an inhibitory effect on mastitis in dairy cows, reduced mastitis indicators: LDH (lactate dehydrogenase), TNF-α, IL-6, IL-8 content, the body would not easily develop drug resistance (Yang et al., 2019). Another study showed that AD and rhubarb extracts had therapeutic effects on inflammation caused by Staphylococcus aureus (Yang et al., 2020). Byakangelicin (16) was an extract from AD roots. In vitro cell experiments showed that Byakangelicin (16) inhibited the production of INOS, COX-2, TNF-α, and IL-6 induced by IL-1β. In vivo experiments showed that Byakangelicin (16) had a protective effect on osteoarthritis in mice. Byakangelicin (16) had a good prospect in the treatment of osteoarthritis (Zhang et al., 2020). An experiment on airway inflammation showed that IMP could inhibit the activation of Mast cells and inhibit the phosphorylation of CAMK II and ERK. CAMK II was the upstream protein of ERK, which could guide the phosphorylation of ERK. MRGPRX2 was the inducer of airway inflammation. Experiments showed that CAMK II was involved in MRGPRX2-mediated LAD2 (Human Laboratory of Allergic Disease 2) cells activation and IMP was the antagonist of MRGPRX2. It had a therapeutic effect on airway inflammation through CAMK II/ERK pathway (Wang et al., 2021). The molecular mechanisms are shown in Fig. 5.

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Fig. 5

The anti-inflammatory molecular mechanism of AD.

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INOS: Inducible nitric oxide synthase, TNF-α: Tumor necrosis factor, TGF-β: Transforming growth factor-β, IL: Interleukin, COX-2: cycloxygenase-2, ROS: reactive oxygen species, TNF-α: tumor necrosis factor-α, NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells, PXR: pregnane X receptor, CAMK Ⅱ: Ca²⁺/calmodulin-dependent kinase Ⅱ, ERK: extracellular regulated protein kinases, MRGPRX2: Mas-related G protein-coupled receptor X2.

3.5 Antioxidant activity

Antioxidation refers to the inhibition of free radicals. cancer and aging were related to many free radicals. DPPH, ABTS, and ROS were commonly used antioxidant indicators. Modern research showed that some components in AD had the free radical scavenging effect. One experiment showed that the antioxidant index of fermented AD on DPPH, ABTS, and FRAP models was significantly higher than that of unfermented AD, fermentation enhanced the antioxidant activity of AD (Zhou et al., 2019). Mehanz et al. (2013) found that the scavenging capacity of AD aqueous extract on DPPH and ABTS was 0.32 and 0.20 mg/mL, respectively, and that of ethanol extract was 0.24 and 0.13 mg/mL, respectively. The ethanol extract had a better antioxidant effect than the aqueous extract. Phenolic compounds in AD had significant antioxidant activity, and these phenolics were easily soluble in organic solvents. Phenolic compounds in AD could inhibit the peroxidation of linoleic acid, showing the same activity as superoxide dismutase and protecting DNA. A study of IMP on spontaneously hypertensive rats (SHR) showed that the urinary 8-iso-PGF-2α and urinary protein contents in rats were lower than those in the control group after IMP administration. It also inhibited the NADPH, AKT, and MAPK pathways. The experiment showed that IMP protected renal injury caused by hypertension through an antioxidant effect (Cao et al, 2014). Excessive reactive oxygen species (ROS) content could cause oxidative stress and damage human DNA and protein. One study found that the Coumarin mixture in AD could significantly reduce the ROS content and protect the cells from oxidative damage caused by H₂O₂ (Kang et al., 2019). AD was best preserved at 70 °C, at which the phenolics content is high. The antioxidant activity of the extract obtained at 70 °C was higher than that of the freeze-dried extract (Liang et al., 2018). These results showed that the active substances obtained from AD had obvious antioxidant activity.

3.6 Antibacterial and antiviral activities

AD extract could inhibit the reproduction of Staphylococcus aureus (minimum inhibitory concentration, 8–32 mg/ml) (Lechner et al., 2004). Another study showed that AD and rhubarb extracts could accelerate the healing of wounds caused by Staphylococcus aureus (Yang et al., 2020). Lee et al. (2020) isolated five known furanocoumarins from AD: iso-imperatorin (13), oxypeucedanin (12), oxypeucedanin hydrate (13), and imperatorin (11). Oxypeucedanin (12) had significant inhibitory effects on the cytopathogenic effect induced by H1N2 and H9N2. In vitro experiments had shown that within 1–2 h, the CPE of infected cells treated with oxypeucedanin (12) decreased by 80–90%, but after 3 h, the effect decreased sharply. The viral NA and NP contents in cells decreased to below 20% after 2 h. They concluded that oxypeucedanin (12) might have antiviral effects at the early stage of viral replication but not directly interact with the proteins.

3.7 Other activities

Through experimental studies, IMP could increase the content of cells in low diploidy during cell division, promote the activation of the Caspase-3 pathway, and induce apoptosis in HL-60 cells. This indicated that IMP could induce apoptosis of human promyelocytic leukemia (HL-60) cells, resulting in DNA fracture and changes in nuclear morphology (Pae et al. 2002). Eun et al. (2005) found that oxypeucedanin (12) could inhibit the Hkv1.5 channel, which caused a rapid decrease in the cardiac action potential duration (APD) in cardiac cells, and the effect was voltage-dependent. The experiment had shown that Oxypeucedanin (12) was a potential antiarrhythmic drug for atrial fibrillation. GPR119 was a receptor involved in insulin secretion and glucagon peptide-1 (GLP-1) release. It was found that AD extract had a therapeutic effect on diabetes. AD extract could activate GPR119 in cells, cAMP, GLP-1, and significantly increase insulin content in cells. In vivo experiments showed that AD extract could improve mice's glucose tolerance and insulin secretion (Park et al., 2016). The methanol extract of AD could inhibit vasocontraction of aortic rings induced by PE or KCl, and prevent extracellular Ca²⁺ from flowing into cells through ROCC and VDCC pathways. These results suggested that the ADE has a vasorelaxant effect and the vasorelaxant activity was mediated by an endothelium-independent pathway that includes the blockade of extracellular calcium influx through the receptor-operated Ca²⁺ channel and voltage-dependent calcium channel pathways. It indicated that AD could be used as a potential drug for hypertension (Lee et al., 2015).