Apiaceae Medicinal Plants in China: A Review of Traditional Uses, Phytochemistry, Bolting and Flowering (BF), and BF Control Methods

Apiaceae plants have been widely used in traditional Chinese medicine (TCM) for the removing dampness, relieving superficies, and dispelling cold, etc. In order to exploit potential applications as well as improve the yield and quality of Apiaceae medicinal plants (AMPs), the traditional use, modern pharmacological use, phytochemistry, effect of bolting and flowering (BF), and approaches for controlling BF were summarized. Currently, about 228 AMPs have been recorded as TCMs, with 6 medicinal parts, 79 traditional uses, 62 modern pharmacological uses, and 5 main kinds of metabolites. Three different degrees (i.e., significantly affected, affected to some extent, and not significantly affected) could be classed based on the yield and quality. Although the BF of some plants (e.g., Angelica sinensis) could be effectively controlled by standard cultivation techniques, the mechanism of BF has not yet been systemically revealed. This review will provide useful references for the reasonable exploration and high-quality production of AMPs.


Introduction
Apiaceae (syn. Umbelliferae) is one of the largest angiosperm families. It includes 300 genera (3000 species) globally and 100 genera (614 species) in China [1]. Apiaceae plants have been widely used in healthcare, nutrition, the food industry, and other fields [2]. Currently, 55 genera (230 species) of Apiaceae plants have been used as medicinal plants, and over 20 species have been widely used as traditional Chinese medicines (TCMs) [3]. Extensive studies have demonstrated that Apiaceae medicinal plants (AMPs) present a variety of pharmacological properties for the treatment of central nervous system, cardiovascular, and respiratory system diseases, amongst others [1,4]. These pharmacological activities are largely associated with metabolites such as polysaccharides, alkaloids, phenylpropanoids (simple phenylpropanoids and coumarins), flavonoids, and polyene alkynes [1,5,6].
In China, Apiaceae plants have been primarily used as traditional medicines for relaxing tendons, activating blood, relieving superficial wounds, treating colds, etc. [1,2]. For example, rhizomatous and whole plants are mainly used for the treatment of common colds, coughs, asthma, rheumatic arthralgia, ulcers, and pyogenes infections; fruits are mainly used for regulating vital energy, promoting digestion, relieving abdominal pain, and treating parasites [1,2].
The occurrence of bolting and flowering (BF) plays a critical role in the transition from vegetative growth to reproductive development in the plant life cycle [7]. However, BF        Trans-anethole, estragole, and anisaldehyde [18,19,117,118] [16,235] Note: * means the plant reported in "Pharmacopoeia of the People's Republic of China (2020)", ** means the plant roots used as medicine reported in "Pharmacopoeia of the People's Republic of China (2020)" [18].

Classification of AMPs Species
To our best knowledge, a total of 228 AMPs used as TCMs were collected from previously published studies and books (Table 1). Based on the traditionally used medicinal parts, the 228 AMPs were categorized into six classes, including 51 species (21 genera) used with the whole plants (i.e., rhizome and/or root, stem, and leaf), 184 species (44 genera) used with rhizomes and/or roots, 5 species (5 genera) used with stems, 9 species (8 genera) used with leaves, 17 species (14 genera) used with fruits, and 1 species (single genus) used with seeds.

Traditional Uses
As is shown in Table 1, distinct traditional uses of the 228 AMPs were recorded. Based on their clinical agents, a total of 79 traditional uses are enriched, with 40 species contributing to the treatment of relieving pain, 36 species to the treatment of dispelling wind; and 21 species to the treatment of eliminating dampness ( Figure 2). Moreover, the AMPs were also widely used as "ethnodrugs" for ethnic minorities in China. For example, Carum carvi was used as Tibetan medicine for the treatment of dispelling wind and eliminating dampness, as well as treating cat fever and joint pain [86]; Trachyspermum ammi [236] was used as Uygur medicine for the treatment of eliminating cold damp, dispelling coldness, and promoting digestion; Angelica acutiloba was used in Korean medicine for the treatment of strengthening the spleen, enriching blood, stopping bleeding, and promoting coronary circulation [237]; Angelica sinensis was used as medicine for the Tujia minority for the treatment of enriching the blood, treating dysmenorrheal, and relaxing the bowel [238]; and Chuanminshen violaceum was used as a geo-authentic medicine of Sichuan province for the treatment of moistening the lungs, treating phlegm, and nourishing the spleen and stomach [89].
Meanwhile, AMPs combined with other herbs have also been applied for thousands of years [239]. For example, the Decoction of Notopterygium for Rheumatism is a famous Chinese prescription and is composed of Notopterygium incisum, Angelica biserrata, Ligusticum sinense, Eryngium foetidum, and Ligusticum chuanxiong, etc.; it has been widely used for the treatment of exopathogenic wind-cold, rheumatism, headache, and pantalgia [94]. The Xinyisan that is composed of Yulania liliiflora, Actaea cimicifuga, Angelica dahurica, Eryngium foetidum, Ligusticum sinense, etc., has been widely used for the treatment of deficiency of pulmonary qi and nasal obstruction due to wind-cold pathogens and damp-heat in the lung channel [94,168]. The Shiquan Dabu Wan of Angelica sinensis that is recorded in the "Pharmacopoeia of the People's Republic of China" has been mainly used for the treatment of pallor, fatigability, and palpitations [240]. The Juanbi Tang of Notopterygium incisum and Angelica biserrata that is recorded in "Medical Words" (Qing dynasty) has been mainly used for treatment of arthralgia due to wind cold-dampness [121]. pallor, fatigability, and palpitations [240]. The Juanbi Tang of Notopterygium incisum and Angelica biserrata that is recorded in "Medical Words" (Qing dynasty) has been mainly used for treatment of arthralgia due to wind cold-dampness [121].

Modern Pharmacological Uses
Modern pharmacological research on the 228 AMPs is summarized in Table 1. Based on the pharmacological effects, a total of 62 modern uses are identified (Figure 3), with 36 species showing anti-inflammatory activity, 20 species showing antioxidant activity, and 16 species showing antitumor activity. In addition, other modern uses are also identified, such as antitumor, bacteriostatic, and analgesic. These modern pharmaceutical properties have been demonstrated to be associated with bioactive metabolites, and several metabolites have been found to be co-existent in the TCMs [241,242].

Modern Pharmacological Uses
Modern pharmacological research on the 228 AMPs is summarized in Table 1. Based on the pharmacological effects, a total of 62 modern uses are identified (Figure 3), with 36 species showing anti-inflammatory activity, 20 species showing antioxidant activity, and 16 species showing antitumor activity. In addition, other modern uses are also identified, such as antitumor, bacteriostatic, and analgesic. These modern pharmaceutical properties have been demonstrated to be associated with bioactive metabolites, and several metabolites have been found to be co-existent in the TCMs [241,242]. man lung adenocarcinoma cell line A549, human mammary carcinoma cell line MCF-7, and human colon carcinoma cell line LOVO [247]. The antioxidative activity of AMPs has been also identified; for example, the imperatorin, oxypeucedanin hydrate, and bergaptol in Angelica dahurica exhibited DPPH scavenging activity [30], hydromethanolic extracts from Pimpinella anisum exhibited free radical scavenging activity [248], and water-soluble polysaccharides in Chuanminshen violaceum scavenged DPPH, hydroxyl, and superoxide anion radicals [91].  Specifically, sesquiterpene-coumarin, such as (3 S, 5 S, 8 R, 9 S, 10 R)-kellerin, gummosin, galbanic acid, and methyl galbanate from Ferula sinkiangensis resin, showed antineuroinflammatory effects and might be a potential natural therapeutic agent for Alzheimer's disease [243]. The supercritical carbon dioxide extracts from Apium graveolens showed antibacterial effects, with the highest inhibitory activity against Bacillus cereus [244,245]. In vitro, the antitumor activity of AMPs have been identified; for example, the ferulin B and C in Ferula ferulaeoides rhizomes could restrain the multiplication of HepG2 stomach cancer cell lines, and 2,3-dihydro-7-hydroxyl-2R*, 3R*-dimethyl-2-[4,8-dimethyl-3(E),7nonadienyl]-furo [3,2-c] coumarin could restrain the proliferation of HepG2, MCF-7, and C6 cancer cell lines [107,246]. In addition, the osthole in Angelica biserrata could restrain the multiplication of human gastric cancer cell lines MKN-45 and BGC-823, human lung adenocarcinoma cell line A549, human mammary carcinoma cell line MCF-7, and human colon carcinoma cell line LOVO [247]. The antioxidative activity of AMPs has been also identified; for example, the imperatorin, oxypeucedanin hydrate, and bergaptol in Angelica dahurica exhibited DPPH scavenging activity [30], hydromethanolic extracts from Pimpinella anisum exhibited free radical scavenging activity [248], and water-soluble polysaccharides in Chuanminshen violaceum scavenged DPPH, hydroxyl, and superoxide anion radicals [91].

Polysaccharides
Polysaccharides are the largest components of biomass and account for ca. 90% of the carbohydrates in plants [250]. Studies have demonstrated that polysaccharides in medicinal plants are indispensable bioactive compounds, presenting uniquely pharmacological effects such as immunomodulatory, hypoglycemic, antitumor, anti-diabetic, and antioxidant effects, amongst others, with few side effects or adverse drug reactions [251,252]. To date, polysaccharides in the 228 AMPs have also been identified, showing multiple pharmacological effects. For example, polysaccharides in Angelica sinensis present hematopoietic, antitumor, and liver protection effects [239,253]; polysaccharides in Angelica dahurica protect spleen lymphocytes, natural killer cells, and procoagulants [254,255]; and polysaccharides in Bupleurum chinense and Bupleurum smithii present the effect of macrophage modulation, kidney protection, and inflammatory alleviation [256][257][258].

Alkaloids
About 27,000 alkaloids presenting as water-soluble salts of organic acids, esters, and combined with tannins or sugars have been found in plants [259]. Many alkaloids are valuable medicinal agents that can be utilized to treat various diseases, including malaria, diabetes, cancer, cardiac dysfunction, blood clotting-related diseases, etc. [260][261][262]. Alkaloids in the 228 AMPs mainly exist in the Ligusticum, Apium, Conium, and Cuminum genera [249]. Pharmacological studies have demonstrated that alkaloids in Ligusticum chuanxiong show the activity of inhibiting myocardial fibrosis, protecting ischemic myocardium, and relieving cerebral ischemia-reperfusion injury [151,263,264]. A novel alkaloid 2-pentylpiperidine known as conmaculatin in Conium maculatum shows strong peripheral and central antinociceptive activity [265]. Some alkaloids have been identified to show antidepressant activity, such as berberine in Berberis aristata, strictosidine acid in Psychotria myriantha, and Anonaine in Annona cherimolia; these could be explored as an emerging therapeutic alternative for the treatment of depression.

Simple Phenylpropanoids
To date, limited simple phenylpropanoids have been identified from AMPs, including three phenylpropanoids (trans-isoelemicin, sarisan, and trans-isomyristicin) in the roots of Ligusticum mutellina [268]. Ferulic acid, one of the phenylpropionic acids, is an important bioactive metabolite of AMPs; it mainly exists in Angelica, Ligusticum, Ferula, and Pleurospermum genera [239,269,270]. Pharmacological studies have demonstrated that the ferulic acid in Angelica sinensis shows strong properties in inhibiting platelet aggregation, increasing coronary blood flow, and stimulating smooth muscle [271,272]; the ferulic acid in Angelica acutiloba shows antidiabetic, immunostimulant, antiinfammatory, antimicrobial, anti-arrhythmic, and antithrombotic activity [273]; and the ferulic acid in Ligusticum tenuissimum shows anti-melanogenic and anti-oxidative effects [274].
Studies have found that terpenoids possess various biological activities, including anti-inflammatory, anti-oxidative, anti-fibrosis, antitumor, anti-Alzheimer's disease, and anti-depression activities [293,294]. For example, the xiongterpene in Ligusticum chuanxiong shows insecticide effects [151], the asiaticoside in Centella asiatica shows antitumor properties [295], and the saikosaponin d in Bupleurum chinense DC. and Bupleurum scorzonerifolium show the effects of reducing blood glucose, inhibiting inflammation, and reducing insulin resistance [296].

Effect of Bolting and Flowering (BF) on Yield and Quality
Previous studies have repeatedly emphasized that BF reduces the yield and quality of plants, especially in rhizomatous medicinal plants [11]. Here, a total of 38 rhizomatous plants that have been reported in the 228 AMPs are associated with BF (Table 3). Based on the effect degree of BF on the yield and quality, 38 rhizomatous AMPs belonging to 17 genera can be categorized into 3 classes: (1) BF significantly affects the yield and quality of 14 AMPs (i.e., Angelica acutiloba, Angelica biserrata, Angelica dahurica, Angelica dahurica cv. Hangbaizhi, Angelica decursiva, Angelica polymorpha, Angelica sinensis, Daucus carota, Heracleum hemsleyanum, Heracleum rapula, Libanotis iliensis, Libanotis seseloides, Peucedanum praeruptorum, and Saposhnikovia divaricata), and their rhizomes and/or roots are wholly lignified and cannot be used for clinical application; (2) BF affects the yield of 11 AMPs (i.e., Angelica gigas, Bupleurum chinense, Bupleurum scorzonerifolium, Changium smyrnioides, Chuanminshen violaceum, Glehnia littoralis, Ligusticum chuanxiong, Ligusticum jeholense, Ligusticum sinense, Notopterygium franchetii, and Notopterygium incisum), though their rhizomes or roots can be used as medicine to some extent; (3) BF has no significant effect on the yield and quality of 13 AMPs (i.e., Angelica sylvestris, Cicuta virosa, Ferula ferulaeoides, Ferula fukanensis, Ferula lehmannii, Ferula olivacea, Ferula sinkiangensis, Ferula teterrima, Levisticum officinale, Libanotis buchtormensis, Libanotis lancifolia, Libanotis spodotrichoma, and Pimpinella candolleana), and their rhizomes or roots can be used as medicine ( Figure 6).  Figure 6). For example, for class (1) after BF, there was a 8.3-and 16.1-fold reduction of dry weight and quality marker ferulic acid content in Angelica sinensis [301] and a 1.5-and 1.5fold reduction of dry weight and quality marker isoimperatorin content in Angelica dahurica [302]. For class (2), there was a 1.34-fold reduction of saikosaponinsands, while no significant change of dry weight in Bupleurum chinense was seen [303,304]; and a 2.0-and 1.7-fold reduction of dry weigh and polysaccharide content in Changium smyrnioides [305].  For example, for class (1) after BF, there was a 8.3-and 16.1-fold reduction of dry weight and quality marker ferulic acid content in Angelica sinensis [301] and a 1.5-and 1.5-fold reduction of dry weight and quality marker isoimperatorin content in Angelica dahurica [302]. For class (2), there was a 1.34-fold reduction of saikosaponinsands, while no significant change of dry weight in Bupleurum chinense was seen [303,304]; and a 2.0-and 1.7-fold reduction of dry weigh and polysaccharide content in Changium smyrnioides [305]. For class (3), there was no reduction of the yield and quality of the 13 AMPs at the harvest stages [19]. (1) [323,324] Note: (1) BF significantly affects the yield and quality, and the rhizomes or roots cannot be used for clinical applications; (2) BF differently affects the yield, but the rhizomes or roots can be used as medicine to some extent; and (3) BF has no significant effect on the yield and quality, and their rhizomes or roots are used as medicine. * means the plant reported in "Pharmacopoeia of the People's Republic of China (2020)", ** means the plant roots used as medicine reported in "Pharmacopoeia of the People's Republic of China (2020)" [18].

Approaches to Control BF
Generally, most Apiaceae plants are "low-temperature and long-day" perennial herbs; in other words, the plants must experience vernalization (i.e., an extended period of cool weather at 0 to 10 • C) and long days (>12 h daylight) to induce BF. Examples include Angelica sinensis [325], Daucus carota [326], and Coriandrum sativum [327]. Table 4 shows the approaches to inhibit BF of 24 AMPs. For example, the bolting rate of Angelica sinensis can be significantly decreased by planting the green stem cultivar (Mingui 2) instead of the purple stem cultivar (Mingui 1) [328], selecting smaller seedlings (i.e., root-shoulder diameter <0.55 cm) instead of larger seedlings [329,330], storing the seedlings at freezing temperature (i.e., <0 • C) during the overwinter stage [325], shading the plants under sunshade (i.e., >40%) during growth stage [331], and providing the plants with good growth conditions (e.g., plant intensity, nutrient and water balance) [332]. The bolting rate of Angelica dahurica can be significantly decreased through planting pure breeds [333], selecting immature seeds for seeding [308], increasing potassic fertilizer while decreasing nitrogen and phosphorus fertilizers [334], and planting using standard techniques [335]. The bolting rate of Saposhnikovia divaricata can also be significantly decreased by controlling the sunshade [336], sowing date [337], and planting density [338], and preventing excessive growth [336]. Seed quality and seed maturity degree [308,333] Soil selection to avoid continuous cropping and fertile sticky soil, density of planted seedlings, and seeding time [333,335,340] Rational application of fertilizer, and appropriate N, P, and K fertilizer [308,333,341] Seven types of reproductive conversion genes, and constans-like genes [342,343] (1) 4/11 ** Angelica dahurica cv. Hangbaizhi Seed quality and seed maturity degree [308,333] Soil selection to avoid continuous cropping and fertile sticky soil, density of planted seedlings, and seeding time [333,335,340] Rational application of fertilizer, and appropriate N, P, and K fertilizer [308,333,341] Seven types of reproductive conversion genes, and constans-like genes [342,343] (  To inhibit the occurrence of BF in AMPs, several measures can be used, including breeding new cultivars, controlling the seedling age and size to delay the transition from vegetative growth to flowering, storing seedlings at freezing temperatures to avoid vernalization, growing the plants under sunshade to avoid long-day photoperiodism, and planting with standard techniques to reduce pests and diseases (Figure 7). creased by controlling the sunshade [336], sowing date [337], and planting density [338], and preventing excessive growth [336].
To inhibit the occurrence of BF in AMPs, several measures can be used, including breeding new cultivars, controlling the seedling age and size to delay the transition from vegetative growth to flowering, storing seedlings at freezing temperatures to avoid vernalization, growing the plants under sunshade to avoid long-day photoperiodism, and planting with standard techniques to reduce pests and diseases (Figure 7).

Class
No./No. in Table 1 Plant Species Measure Ⅰ (Seeding)

Measure Ⅱ (Cultivation)
Measure Ⅲ (Abiotic) Measure Ⅳ (Molecular Biology) Seedling diameter [339] Density of planted seedlings [339] Paclobutrazol Seed quality and seed maturity degree [308,333] Soil selection to avoid continuous cropping and fertile sticky soil, density of planted seedlings, and seeding time [333,335,340] Rational application of fertilizer, and appropriate N, P, and K fertilizer [308,333,341] Seven types of reproductive conversion genes, and constanslike genes [342,343] (1) 4/11 ** Angelica dahurica cv. Hangbaizhi Seed quality and seed maturity degree [308,333] Soil selection to avoid continuous cropping and fertile sticky soil, density of planted seedlings, and seeding time [333,335,340] Rational application of fertilizer, and appropriate N, P, and K fertilizer [308,333,341] Seven types of reproductive conversion genes, and constanslike genes [342,343]

The Mechanism of BF Inducing the Rhizome Lignification
Extensive experiments have demonstrated that BF induces the lignification of fleshy rhizomes and enhances the degradation of metabolites [11,13,328]. Studies on anatomical structures reveal that the ratio of secondary phloem to secondary xylem respectively changes from 2:1 to 1:10 and 2/5-1/2 to 1/2-3/4 for the rhizomes of Angelica sinensis and Angelica dahurica before and after BF; meanwhile, the number of secretory cells producing essential oils significantly decreased [368,369]. Studies have found that the Early Bolting In Short Day (EBS) acts as a negative transcriptional regulator, preventing premature flowering of Arabidopsis thaliana, and co-enrichment of a subset of EBS-associated genes with H3K4me3, H3K27me3, and Polycomb repressor complex 2 has been observed [370]; a potential genetic resource for radish late-bolting breeding with introgression of the RsVRN1In-536 insertion allele into the early-bolting genotype could contribute to delayed bolting time of Raphanus sativus [371]; and peroxidases (PRXs) involved in lignin monomer biosynthesis were found to be down-regulated in Peucedanum praeruptorum at the bolting stage [372].

Conclusions and Future Aspects
In this review, we summarized the history of AMPs as TCMs, the classification of AMPs species, their traditional use, modern pharmacological use, and phytochemistry; the effect of BF on yield and quality, approaches to control BF, and the mechanisms of BF, inducing rhizome lignification. Although ca. 228 AMPs, 79 traditional uses, 62 modern uses, and 5 main kinds of metabolites have been recorded, the potential properties remain to be exploited. Although BF significantly reduces the yield and quality of AMPs, effective measures to inhibit BF have not been applied in the field, and the mechanisms of BF have not been systemically revealed for most AMPs. Thus, in order to effectively control the BF of AMPs to improve their quality and yield, on the one hand, standard cultivation techniques of AMPs should be applied; on the other hand, new cultivars should be developed by modern biotechnology such as the CRISPR/Cas9 system. Although lignin biosynthesis has been depicted, studies on the mechanism of BF inducing rhizome lignification are still limited. To date, the mechanism of BF affecting Angelica sinensis has been revealed, with the expression level of genes (e.g., PAL1, 4CLs, HCT, CAD1, and LACs) significantly upregulated at the stem-node forming and elongating stage compared with the stem-node pre-differentiation stage, leading to the reduction of accumulation of secondary metabolites (i.e., ferulic acid and flavonoids) [13].

Conclusions and Future Aspects
In this review, we summarized the history of AMPs as TCMs, the classification of AMPs species, their traditional use, modern pharmacological use, and phytochemistry; the effect of BF on yield and quality, approaches to control BF, and the mechanisms of BF, inducing rhizome lignification. Although ca. 228 AMPs, 79 traditional uses, 62 modern uses, and 5 main kinds of metabolites have been recorded, the potential properties remain to be exploited. Although BF significantly reduces the yield and quality of AMPs, effective measures to inhibit BF have not been applied in the field, and the mechanisms of BF have not been systemically revealed for most AMPs. Thus, in order to effectively control the BF of AMPs to improve their quality and yield, on the one hand, standard cultivation techniques of AMPs should be applied; on the other hand, new cultivars should be developed by modern biotechnology such as the CRISPR/Cas9 system.

Conflicts of Interest:
The authors declare no conflict of interest.