Chemistry, Bioactivity, and Prediction of the Quality Marker (Q-Marker) of Ferula Plants in China: A Review

The genus of Ferula belongs to the family Apiaceae, and many Ferula plants are used as traditional Chinese medicines. Ferula plants were initially identified as early as the “Newly Revised Materia Medica” written in the Tang Dynasty (AD 659), and several of them are also recognized as the traditional medicines of the Uygur, Kazakh, and Mongolian. Ferula plants are distributed in China, Russia, India, Africa, Central Asia, and other places. Currently, the chemical components derived from Ferula plants are mainly coumarins, sesquiterpenes, and volatile oils. Ferula plants can exhibit diverse pharmacological activities such as anti-allergy, analgesia, relieving cough, anticoagulation, and anti-tumor. Therefore, this article summarized the domestic research conducted on the genus Ferula, appropriately combines the research status of the foreign genus Ferula, and describes the chemical composition, biological activity, toxicity issues, and Q-marker prediction. In addition, all the related studies about the genus Ferula are summarized by analyzing the various databases such as CNKI, Wanfang data, PubChem and SciFinder.


Introduction
Ferula is a tall perennial herb which belongs to the Apiaceae family, and these plants are commonly characterized by a peculiar pungent garlic odor. There are more than 180 species of Ferula found worldwide [1] and they are mainly located in Central Asia, the Middle East, Siberia, and South Asia [2]. In China, Ferula is mainly distributed in Xinjiang, and a small number of Ferula plants are also found in Gansu, Shanxi, Inner Mongolia, and Tibet [3,4]. The genus Ferula in China primarily comprises more than twenty species, with a few representative plants shown in Figure 1.  [5]; (B). F. fukanensis [6]; (C). F. kingdon-wardii [7]; (D). F. songarica [8]; (E) F. syreitschikowii [9]; (F). F. licentiana [10]. The plants belonging to the genus Ferula (Apiaceae) have been implicated in the treatment of various ailments and have a long history of use in many traditional medicines. For instance, Nepali people use Ferula in their daily diets [11,12], and it is used locally as a traditional remedy in Saudi Arabia for the treatment of skin infections [13]. In addition, Ferula plants are widely used in India in food and as a medicine in Indian systems of medicine such as Ayurveda [14]. Interestingly, in China, Ferula plants are also used as an Uyghur medicinal herb, and have a long history of beneficial application [15]. Ferula has already been added to the Uyghur Medicine Criteria [16] and the calendar version of the Chinese Pharmacopoeia [17]. In other ethnic groups and regions of China, Ferula is often used as traditional medicines. The traditional uses of Ferula include beneficial effects against stomach pain, flatulence, intestinal parasites, indigestion, asthma, and flu [18]. For instance, the Kazakhs have used F. soongarica to treat headaches, colds and stomach aches, F. caspica can treat nervous breakdown, and F. lehmannii is used as an anti-parasitic, for anti-malnutrition and to cure cold and pain in the heart and abdomen [12,15]. A number of modern pharmacological and biological studies have indicated that Ferula has anticancer [19,20], anticarcinogenic [21], antimicrobial [22], antidiabetic [23], anti-flu [24], antiinflammatory [25,26], and cardiovascular system effects [27], as well as use against Alzheimer s disease [28,29] and in anti-neuropathic pain [30] activities.
Ferula contains a variety of chemical compounds, primarily coumarins [31], particularly sesquiterpenes coumarins [32], volatile oils [33], sulfur-containing compounds [34], and aromatic compounds [35], all of which exhibit diverse biological activities. However, the Q-marker prediction studies of Ferula are relatively scarce. Ferula plants of China are mainly distributed in Xinjiang, and it is less commonly present in other regions. Thus, in addition to the over-exploitation and collection of Ferula resources, the quality of Ferula herbs available on the market is a matter of concern due to the prevalence of counterfeits  [5]; (B). F. fukanensis [6]; (C). F. kingdon-wardii [7]; (D). F. songarica [8]; (E) F. syreitschikowii [9]; (F). F. licentiana [10]. The plants belonging to the genus Ferula (Apiaceae) have been implicated in the treatment of various ailments and have a long history of use in many traditional medicines. For instance, Nepali people use Ferula in their daily diets [11,12], and it is used locally as a traditional remedy in Saudi Arabia for the treatment of skin infections [13]. In addition, Ferula plants are widely used in India in food and as a medicine in Indian systems of medicine such as Ayurveda [14]. Interestingly, in China, Ferula plants are also used as an Uyghur medicinal herb, and have a long history of beneficial application [15]. Ferula has already been added to the Uyghur Medicine Criteria [16] and the calendar version of the Chinese Pharmacopoeia [17]. In other ethnic groups and regions of China, Ferula is often used as traditional medicines. The traditional uses of Ferula include beneficial effects against stomach pain, flatulence, intestinal parasites, indigestion, asthma, and flu [18]. For instance, the Kazakhs have used F. soongarica to treat headaches, colds and stomach aches, F. caspica can treat nervous breakdown, and F. lehmannii is used as an anti-parasitic, for anti-malnutrition and to cure cold and pain in the heart and abdomen [12,15]. A number of modern pharmacological and biological studies have indicated that Ferula has anticancer [19,20], anticarcinogenic [21], antimicrobial [22], antidiabetic [23], anti-flu [24], anti-inflammatory [25,26], and cardiovascular system effects [27], as well as use against Alzheimer's disease [28,29] and in anti-neuropathic pain [30] activities.
Ferula contains a variety of chemical compounds, primarily coumarins [31], particularly sesquiterpenes coumarins [32], volatile oils [33], sulfur-containing compounds [34], and aromatic compounds [35], all of which exhibit diverse biological activities. However, the Q-marker prediction studies of Ferula are relatively scarce. Ferula plants of China are mainly distributed in Xinjiang, and it is less commonly present in other regions. Thus, in addition to the over-exploitation and collection of Ferula resources, the quality of Ferula herbs available on the market is a matter of concern due to the prevalence of counterfeits and inferior species that are accessible to consumers. Furthermore, the genus Ferula seed plant breeding has been continuously shrinking due to the rapid land development, irrigation, highway building, leading to significant decrease in Ferula resources. Therefore, novel strategies have to be developed to protect the resources of Ferula plants.
Traditional Chinese medicines (TCMs) play an important role in China's modern health care system and have been found to be efficacious in clinical practice. However, due to the lack of criteria for the selection of quality control indicators, both the certification and efficacy of herbal medicines remain unclear [36,37]. Therefore, new approaches are needed to establish Q-markers for determining the quality standards of traditional Chinese medicines, and for identifying the appropriate chemicals present in plants to use them as potential quality indicators [38,39].
There are quite a few Q-marker studies reported for the genus Ferula. Thus, the identification of the various markers for the genus Ferula by the Q-marker method is essential for the identification of its authenticity and the conservation of the plant resources.

Distribution of Ferula Plants in China
There are more than 180 species of genus Ferula in the worldwide, and more than 20 species have been recorded in China. The genus Ferula resources are mainly distributed in Xinjiang and a small number of other provinces in China (Table 1). Most Ferula plants are distributed at altitudes between 400 and 3500 m, and the distribution environment is mainly the desert and mountainous areas. However, in recent years, due to the destruction of the plant resources of the genus Ferula, wild Ferula is nearly extinct. The environment is mostly sandy and gravelly desert slopes, mostly in the mountains dominated by Artemisia spp. [47]

Sesquiterpenoids and Their Derivatives
In addition to the above-mentioned coumarins, sesquiterpenes are the second most abundant substances in Ferula plants. The sesquiterpenes of the genus Ferula are mainly carotene-type sesquiterpene parent nuclei, but carotene-type sesquiterpenes are rare in domestic Ferula plants and are mostly concentrated in foreign Ferula plants. The

Sesquiterpenoids and Their Derivatives
In addition to the above-mentioned coumarins, sesquiterpenes are the second most abundant substances in Ferula plants. The sesquiterpenes of the genus Ferula are mainly carotene-type sesquiterpene parent nuclei, but carotene-type sesquiterpenes are rare in domestic Ferula plants and are mostly concentrated in foreign Ferula plants. The researchers extracted the following sesquiterpenoids from F. ferulaeoides, F. caspica, F. fukanensis and F. jaeschkeana [67][68][69][70][71] (Table 3, Figures 5 and 6).

Volatile Oil
The volatile oils in genus Ferula are mainly terpenoids and polysulfide compounds [72]. Among the genus Ferula of China, the number of terpene components can reach more

Advances in the Bioactivity of Ferula Plants in China
With the gradual increase in domestic research in the field of biological activity of the genus Ferula, the bioactive compounds were isolated from the Ferula plant by various applied extraction techniques [87], and a number of different compounds with anti-tumor [88], anti-allergy, anticoagulation [89], bacterial inhibition [90], action in the gastrointestinal system [91], nervous system [92], cardiovascular system [93,94], and other pharmacological activities have been found in the genus Ferula [95][96][97].

Anticancer Activity
The main chemical components of Ferula plants that exert anti-tumor effects are ferulic acids [98], sesquiterpenoids [99], and volatile oils [100]. For instance, Wu Jing [101] found that the inhibition rate of A549 lung cancer xenografts in nude mice gradually increased with increase in dose of ferulic acid administration. The low (25 mg/L), medium (50 mg/L) and high (100 mg/L) dose groups inhibited the expression levels of both mTOR protein and mRNA in the tumor tissues of the nude mice, and decreased the expression levels of Ki-67 protein, which decreased with increasing dose, and also enhanced the ex-

Advances in the Bioactivity of Ferula Plants in China
With the gradual increase in domestic research in the field of biological activity of the genus Ferula, the bioactive compounds were isolated from the Ferula plant by various applied extraction techniques [87], and a number of different compounds with anti-tumor [88], anti-allergy, anticoagulation [89], bacterial inhibition [90], action in the gastrointestinal system [91], nervous system [92], cardiovascular system [93,94], and other pharmacological activities have been found in the genus Ferula [95][96][97].

Anticancer Activity
The main chemical components of Ferula plants that exert anti-tumor effects are ferulic acids [98], sesquiterpenoids [99], and volatile oils [100]. For instance, Wu Jing [101] found that the inhibition rate of A549 lung cancer xenografts in nude mice gradually increased with increase in dose of ferulic acid administration. The low (25 mg/L), medium (50 mg/L) and high (100 mg/L) dose groups inhibited the expression levels of both mTOR protein and mRNA in the tumor tissues of the nude mice, and decreased the expression levels of Ki-67 protein, which decreased with increasing dose, and also enhanced the expression levels of Caspase-3 protein. The investigators suggested that ferulic acid can attenuate growth of lung cancer probably by downregulating mTOR protein expression, inhibiting Ki-67 expression and promoting Caspase-3 levels. The petroleum ether, n-butanol, ethyl acetate, trichloromethane, and aqueous fractions, as well as volatile oil and 95% ethanol extract of F. ferulaeoides were screened for their pharmacological activities, among which trichloromethane and ethyl acetate fractions exhibited certain inhibitory effects on five distinct gastric cancer cell lines, whereas trichloromethane fractions showed the strongest inhibitory effect on gastric cancer cells SGC-7901 (IC 50 [104]. Moreover, experimental animal studies have revealed that in an immunocompromised nude mouse model with subcutaneous transplantation of STS-26T cells, when DAW22 was administered intraperitoneally at a daily dose of 60 mg/kg/day for 4 weeks, it significantly inhibited tumor xenografts compared to the control group. It was found by Western blotting analysis, that DAW22 inhibited phosphorylation of AKT and ERK and reduced the level of Non-phospho (Active) CTNNB1, there by resulting in an inhibitory effect on cell proliferation and suppression of tumor growth in for MPNST cell lines. These results supported the use of DAW22 as an alternative therapeutic compound to MPNST which can effectively produce anticancer effects by affecting multiple signaling pathways in tumor disease progression. 8-p-Hydroxybenzoyl tovarol (TAW) was isolated from the roots of F.dissecta, and found to inhibit the growth of human cervical cancer HeLa cells by promoting protective autophagy, and in the future, advanced molecular dynamics techniques and free energy calculations and reverse molecular docking can be used to reveal the effects of the major coumarins, sesquiterpenoids, and terpenoids in the genus Ferula on the anticancer mechanism, and there are already documented studies of other plants using similar measurement techniques [105,106].

Antibacterial Activity
Extraction studies on three distinct kinds of dry roots of F. sinkiangensis, F. lehmannii Boiss. and F. ferulaeoides revealed that the alcoholic and macerated extracts displayed antibacterial effects on Staphylococcus aureus, Bacillus subtilis, and Sporosarcina. The MIC about F. sinkiangensis root's alcoholic extracts for three bacteria were 31.25 mg/mL, 3.92 mg/mL, and 1000 mg/mL. The MIC about F. sinkiangensis root's macerated extracts for three bacteria were 1000 mg/mL, 1000 mg/mL, and 1000 mg/mL. The MIC about F. ferulaeoides root's alcoholic extracts for three bacteria were 3.91 mg/mL, 3.91 mg/mL, and 15.63 mg/mL. The MIC about F. ferulaeoides root's macerated extracts for three bacteria were 500 mg/mL, 500 mg/mL, and 1000 mg/mL. The MIC about F. ferulaeoides root's alcoholic extracts for three bacteria were 7.81 mg/mL, 3.91 mg/mL, and 15.63 mg/mL [107]. A total of 27 compounds were extracted and isolated from F. ferulaeoides, and 7 of the 27compounds were found in the plant for the first time. These 27 compounds were screened for their potential antibacterial activity, and only a few coumarins among the 27 compounds were found to affect multi-drug resistant (MDR) and methicillin-resistant Staphylococcusaureus (MRSA) bacteria, and six of them showed inhibition against tetracycline-resistant strain XU212 [108]. In addition, three new sesquiterpene derivatives were obtained from F. ferulaeoides [109] and it was observed that their minimum inhibitory concentrations (MIC) ranged from 0.5-128 µg/mL. It was found that the volatile oil of the seeds of F. olivacea exhibited an inhibitory effect on the Gram-positive bacteria such as Enterococcus faecalis and S. aureus [110,111].

Anti-Allergic, Anti-Inflammatory, and Immunosuppressive Effects
Using sodium cromoglycate (10 mg/kg) as the control group and volatile oil of F. sinkiangensis (50 mg/kg) as the experimental group, experiments were conducted to evaluate the potential effect of passive skin allergic reaction in mice, the effect of Arthus reaction in rabbits, and the antigen sensitization confrontation in the sensitized guinea pigs [112]. It was found that the F. sinkiangensis volatile oil (200 mg/kg) could significantly inhibit Ig E response to allergic reactions, and the degree of effect was similar to that of sodium cromoglycate. Ferulic acid can also reverse skin sensitization in rats and suppress the delayed hypersensitivity reactions in mice, thus indicating that ferulic acid has inhibitory effect on allergic reactions [113]. In another study, designed to examine the impact of the raw juices of F. sinkiangensis, F. conocaula, and F. feruloides, it was found that all three types of Ferula plants exhibited significant inhibitory effects on foot topography swelling (the dosing concentrations were F. sinkiangensis: 90 mg/kg, F. conocaula: 90 mg/kg, F. feruloides: 80 mg/kg)and capillary permeability (the dosing concentrations were F. sinkiangensis: 34 mg/kg, F. conocaula: 34 mg/kg, F. feruloides: 30 mg/kg) in rabbits induced by p-hornwort, and on the delayed hypersensitivity (the dosing concentrations were F. sinkiangensis: 98 mg/kg, F. conocaula: 97 mg/kg, F. feruloides: 78 mg/kg) and serum hemolysin formation (the dosing concentrations were F. sinkiangensis: 98 mg/kg, F. conocaula: 97 mg/kg, F. feruloides: 78 mg/kg) in mice induced by sheep erythrocytes or dinitrochlorobenzene [114].

Anticoagulant Effect
The extract of F. lehmannii was obtained by using 95% ethanol, and an anticoagulant assay was then performed. The experimental results revealed that F. lehmannii extract inhibited the endogenous coagulation pathway and showed an inhibitory effect on the activity of thrombinogen. The dosing concentrations were: the high-dose group (100 mg/kg), the medium-dose group (50 mg/kg), and the low-dose group (25 mf/kg) [115]. Radiatinol and scopoletin were isolated from F. dissecta, and both these compounds acted in the endogenous coagulation pathway and prolonged the prothrombin time as well as activated partial thromboplastin time at different concentrations [86].

Effects on the Cardiovascular System
Interestingly, another study showed that after ferulic acid was administered to C57 mice in the heart failure preclinical model, the mice in the heart failure administration group exhibited different degrees of improvement in cardiac left ventricular ejection fraction, end-systolic and end-diastolic internal diameter changes, collagen area percentage changes, and protein expression levels compared to the control mice. Ferulic acid could improve ventricular remodeling to some extent [116]. In addition, studies conducted with the hydroalcoholic extracted fractions and the aqueous decoction of F. sinkiangensis revealed that they could reduce the heart amplitude and enhance the heart rate in isolated frog hearts [117].

Effects on the Gastrointestinal Tract
It has been reported in the literature that F. sinkiangensis has been used to treat stomach disorders in Xinjiang [118]. The volatile oil and resin of F. sinkiangensis were found to be effective in three distinct gastric ulcer models, among which the volatile oil was found to be relatively better [119]. The rat model of acetic acid-injected gastric ulcer was established, and the model was tested by administering F. sinkiangensis original herbs and F. sinkiangensis prepared herbs by a folk concoction (0.048 g/mL), frying method (0.048 g/mL), a vinegar moxibustion method (0.048 g/mL), and a boiling method (0.048 g/mL). It was found that the pH value of the rat stomach increased significantly, but the area of gastric ulcer decreased markedly after the administration of F. sinkiangensis original herbs and F. sinkiangensis prepared herbs [120]. In addition, studies on the raw juices of F. feruloides and F. sinkiangensis revealed that these juices can display inhibitory effects on gastric ulcer models in rats with acetylsalicylic acid and can effectively suppress the autonomous activity of smooth muscle in isolated intestinal tubes of rabbits [121]. The compounds were isolated from the F. sinkiangensis resin and they were analyzed in anti-ulcer vivo activity experiments. It was observed that compared with the positive control group famotidine, CHCl3 extract (1.3515 g/kg) showed the best anti-ulcer activity [122].

Action on the Nervous System
A network pharmacological analysis of Ferula resulted in identification of 12 key active components against Alzheimer's disease, including Farnesiferol A, Farnesiferol B, conferol, and ferulic acid. It was predicted that Ferula can predominantly act through by modulating 14 key targets in the cholinergic synaptic signaling pathway and AD signaling pathway [123]. A bioactivity-oriented study on F. sinkiangensis showed that F. sinkiangensis significantly inhibited NO production induced by over-activated microglia and exhibited anti-neuroinflammatory effects [58]. Interestingly, a compound, Kellerin, extracted from F. sinkiangensis, was found to produce substantial effects in the rat middle cerebral artery occlusion (MCAO) model, lipopolysaccharide (LPS)-activated microglia model, mouse bilateral common carotid artery occlusion (BCCAO) model and lipopolysaccharide (LPS)-activated microglia model. Kellerin was found to markedly improve the neurological outcomes, reduce the size of cerebral infarcts and decrease brain edema in the rat MCAO model, and the dosing concentrations were: the low-dose group (3.5 mg/kg), the medium-dose group (7.0 mg/kg) and the high-dose group (14.0 mg/kg). Moreover, in the pathological conditions of focal cerebral ischemia, Kellerin could attenuate neuronal damage as well as microglial activation. In addition, in vitro study which LPS-stimulated BV2 cells, revealed that Kellerin protected the neuronal cells from injury by inhibiting microglia activation. Kellerin also reduced levels of pro-inflammatory cytokines, inhibited the NF-κB signaling pathway, and decreased ROS production as well as NADPH oxidase activity, and the [124]. Kellerin was found to alleviate the cognitive impairment, reduce neuronal loss, inhibit microglia activation, and convert microglia from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype in BCCAO mice. In addition, in another in vitro study, Kellerin was found to modulate the microglia polarization and inhibit NLRP3 and MAPK signaling pathways after LPS treatment [125].

Other Pharmacological Effects
Furthermore, studies have shown that Ferula resin can exhibit anti-pregnancy, antiimplantation and pregnancy termination effects [126,127]. It can also affect estrogen and progesterone levels in infertile mice and rabbits, thus modulating the smooth muscles of the uterus in mice and rabbits [128]. In another study, D-galactosamine/lipopolysaccharide acute liver injury model was established, and by comparing the D-galactosamine/ lipopolysaccharide model group, the biphenyldiglyceride group and the high-, mediumand low-dose ferulic acid groups, it was observed that all the three ferulic acid groups could significantly decrease the activity of enzymes AST and ALT in mouse hepatocytes, increase the activity of antioxidant enzyme SOD as well as peroxidase GSH-Px in mice, and decrease the MDA content, thereby suggesting that ferulic acid exhibited a protective effect on acute liver injury [129]. The petroleum ether, ethyl acetate, n-butanol and methanol fractions of F. sinkiangensis displayed no substantial effect on the lipase activity, whereas the ethyl acetate, n-butanol and methanol fractions lowered total cholesterol in HepG-2 cells and triglycerides in non-alcoholic fatty liver model cells. Thus, it was hypothesized that F. sinkiangensis has certain lipid-regulating effects [130]. Four coumarin-like compounds were extracted from F. moschata showed anti-HIV activity [131].

Toxicological Studies
Acute toxicity experiments were conducted on the volatile oils of F. feruloides and F. teterrima, and the findings revealed that the LD50 of the volatile oil of F. feruloides was 10.24 g/kg and the LD50 of the volatile oil of F. teterrima was 491.61 mg/kg. After analyzing the volatile oils of both, it was found that the volatile oil of F. teterrima contained more polysulfides, accounting for 60% of the volatile oil, but no polysulfides were detected in the volatile oil of F. feruloides. Polysulfide can cause irritation and possess a garlic-like odor, so it was presumed that polysulfide was more likely to be a toxic component in F. teterrima [132]. However, the acute toxicity studies with polysulfide has not been reported previously in the literature. It was found that goats fed with F. fukanensis (2.5 g/kg) for 15 days showed obvious signs of toxicity, such as loss of appetite, anorexia, diarrhea, vitamin K-dependent reduction in coagulation factors, the toxic component of which may be possibly coumarins, but no obvious symptoms were found in these animals, such as impaired liver and platelet function [133]. Acute toxicity tests were conducted on F. sinkiangensis and F. fukanensis [134], and the LD50 values were calculated by Kou's method. The LD50 values of F. sinkiangensis volatile oil aqueous suspension and F. fukanensi volatile oil aqueous suspension were found to be 2.82 g/kg and 1.55 g/kg; and the LD50 values of F. sinkiangensis volatile oil emulsion and F. fukanensi volatile oil emulsion were separately 0.39 g/kg and 0.41 g/kg −1 . After analyzing ten batches of F. sinkiangensis test samples [135], two of them were observed to contain different ferulic acid contents. No. 1 F. sinkiangensis with (0.775 ± 1.44) mg/g and No. 5 F. sinkiangensis with (0.279 ± 1.63) mg/g, were selected and subjected to the toxicity studies by SRB method. The proliferation rates of No. 1 F. sinkiangensis and No. 5 F. sinkiangensis on the rat renal NRK cells was found to gradually increase with increasing drug concentrations, with IC50 values of No. 1 F. sinkiangensis at 60.60 mg/Land No. 5 F. sinkiangensis at 39.90 mg/L. The comparison of the IC50 values showed that the cytotoxicity of No. 1 F. sinkiangensis was significnatly less than that of No. 5 F. sinkiangensis, but the ferulic acid content of No. 1 F. sinkiangensis was significantly higher than that of No. 5 F. sinkiangensis, thus indicating that the toxicity of F. sinkiangensis may be possibly related to its chemical composition.

Quality Marker (Q-Marker) Prediction Analysis
With the depletion of the domestic Ferula plant resources, the phenomenon of substandard and uneven quality of Ferula plants in the market needs to be urgently solved. Thus, the quality markers (Q-marker) [136] need be established for the effective protection of the domestic Ferula plant resources. At present, the Chinese Pharmacopoeia 2020 edition stipulates that the sources of medicinal Ferula plant is the resin of F. sinkiangensis and F. fukanensi and requires that their quality marker is ferulic acid. However, ferulic acid is widely present in different plants such as Angelica sinensis [137], Ligusticum chuanxiong [138], Cimicifugafoetida L. [139], Ligusticum [140] and Fructus Toosendan [141]. It is also an important active component of many traditional Chinese medicines [142]. A large amount of sesquiterpene coumarins are found in Ferula plants, and they may be used as unique chemical components which can effectively help to identify Ferula plants by the Q-marker method.

Q-Marker Prediction Analysis by Kinship and Chemical Composition Specificity of Ferula Plants
The global distribution of Ferula plants is widespread in Central Asia, Iran and Pakistan. It has been reported that during the course of foreign research on the chemical composition of Ferula plants, it was observed that genus Ferula contained a large number of sesquiterpene coumarins with umbelliferous lactones as the parent nucleus [143], and Ferulenol was the most abundant and the first isolated coumarin from Ferula [144]. Although various sesquiterpenes and coumarins are widely distributed in the Apiaceae family, they constitute the characteristic chemical constituents of genus Ferula, and can be used as important evidence of the affinities of Ferula plants. They could also form a sound basis for the chemical taxonomy of genus Ferula [145], such as Farnesiferol A, Farnesiferol B, Farnesiferol C, and DAW22, because sesquiterpene coumarins are widespread in different plants of the genus Ferula. Additionally, the pharmacopoeia mentions ferulic acid as potentially another characteristic chemical constituent of the genus Ferula.

Q-Marker Prediction Analysis by Chemical Composition Validity
As an emerging method to evaluate and control the quality of Chinese herbal medicine Q-markers is essential to predict both the effectiveness and safety of Chinese herbal medicines. Therefore, Q-marker analysis of Chinese herbal medicines should be combined with the effectiveness of the target herbal medicines to facilitate better research on the effectiveness of Chinese herbal medicines [146,147]. Because of the presence of the different coumarin sesquiterpenoids in large quantities in the genus Ferula, most studies on the chemical composition effectiveness and safety of Ferula resources have primarily focused on these compounds, which are expected to become quality markers of Ferula plants.

Q-Marker Prediction Analysis by Traditional Drug Properties
The medicinal properties of Ferula plants have been recorded as Ku (bitter), Xing (pungent) and Wen (warm), as well as Guipi and Weijing (benefit for the spleen and stomach) in the Chinese Pharmacopoeia Edition (2020). The chemical compositions of the various bitter medicines in Chinese medicine are mainly alkaloids, glycosides, terpenoids and other bitter substances [148,149]. Terpenes have a bitter taste primarily due to their chemical structure with chelating structures such as lactones, endo-acetals, endo-hydrogen bonds and glycosidic groups [150]. The sesquiterpene coumarins, which are found in relatively large quantities in the genus Ferula, are based on 7-hydroxyumbelliferolactone as the parent nucleus. A number of prior studies have shown that terpenes and volatile oils are found in ample quantities in herbs with the Xing (pungent) taste [151], whereas coumarin sesquiterpenes are similarly abundant in the genus Ferula. In addition, the main chemical components of genus Ferula, such as Farnesiferol A, Farnesiferol B, Farnesiferol C and DAW22, are all coumarin sesquiterpenoids.

Predictive Analysis by the Q-Marker of Traditional Efficacy
The effects of Ferula plants have been recorded in the Chinese Pharmacopoeia 2020 edition and found to be useful as digesting aid, relief of symptoms, dispersal of agglomerates as well as insecticide. They are also used for the treatment of excessive meat consumption, leading to stagnation and masses in the abdomen, and treating bruises, intestinal parasites and the abdominal pain [17]. Their effects are reported in the Xinxiubencao as an insecticide, deodorization, in elimination of intra-abdominal masses, relief of blood stasis, septicemia and pus, and alleviation of symptoms of poisoning [152]. Ferula plants have been also used to treat tuberculosis, eliminate lumps that have accumulated in the abdomen, cure cold, and treat malaria, which are effective against acute gastroenteritis as well as other intestinal diseases. They have a pain-relieving effect on the chest and stomach in addition to pain [153] and similar records have been found in other ethnomedicinal books [154]. Moreover, during the course of modern pharmacological research, the pharmacological effects of Ferula plants are similar to those recorded in ancient books, such as anti-allergy, action on the gastrointestinal tract, anti-bacterial as well as antiseptic effects, anticoagulant effects, and effects related to the cardiovascular system. The CHCl3 extracted fraction of F. sinkiangensis resin can exhibit significant anti-gastric ulcer activity, and the sesquiterpene coumarins contained in this fraction were mainly Farnesiferol B and Farnesiferol C. In addition, prior studies have shown that the raw juices of F. sinkiangensis and F. feruloides have certain effects on gastrointestinal smooth muscle inhibition and anti-experimental gastric ulcer, whereas the chemical compositions of these three types mainly consist of the sesquiterpenes, Farnesiferol A [58], Farnesiferol B, Farnesiferol C. Interestingly, in vivo studies have shown that Farnesiferol B can protect the kidney from I/R-induced damage by reducing oxidative stress and inflammation. In vitro, Farnesiferol B was reported to improve macrophage migration by activating TGR5 [155]. Furthermore, DAW22 was shown in the literature to inhibit five human MPNST cancer cell lines and C6 glioma cells to varying degrees. Overall, ferulic acid possesses numerous pharmacological activities, mainly related to anticancer, anti-bacterial, anti-inflammatory, antioxidant, anti-thrombotic actions, and can also exhibit hypolipidemic effects [156,157].

Q-Marker Predictive Analysis by Chemical Composition Measurability
The chemical compositions of Chinese medicines are complex, and therefore the chemical measurability of the subject is reported to be an essential element in the Q-marker study [158]. Thus, based on the previous summary study on the specificity and close linkage of the chemical compositions as well as effectiveness of the domestic plants of the genus Ferula, the sesquiterpene coumarins and ferulic acid were further identified as the quality markers of Ferula plants by measuring their chemical compositions. The contents of ferulic acid were determined by HPLC on the different parts of F. sinkiangensis and the roots and leaves of F. fukanensis, and the content of ferulic acid was found to be in the following descending order: gum > root > leaf > stem [159,160], and the content of ferulic acid was also determined by HPLC on the anti-ulcer extract of F. sinkiangensis [161]. In addition, the determination of Farnesiferol A, Farnesiferol C and ferulic acid in the ethyl acetate fraction of F. sinkiangensis was performed by HPLC [162]. The UPLC method was used to estimate the content of DAW22 in F. feruloides. It was observed that the methanolic extract of F. feruloides contained more DAW22, and DAW22 was most abundant in F. feruloides harvested in the first half of May [163].

Conclusions
Although the genus Ferula is widespread and diverse throughout the world, its distribution in China is concentrated mainly in Xinjiang and is less diverse. Ferula is native to Central Asia and Middle East, and especially found in eastern Iran and Afghanistan, and is exported to be present worldwide. Nevertheless, Ferula is not native to China, and it has been around for a long time but has become a traditional Chinese herb and ethnic medicine. It plays a vital role in the traditional Chinese medical system.
The document analysis of the China's Ferula resources revealed that there are several studies describing the chemical compositions and biological activities of Ferula plants. Ferula are mainly composed of coumarins, particularly sesquiterpenes coumarins, volatile oils, sulfur-containing compounds, and aromatic compounds. Interestingly, beneficial pharmacological activity of Ferula is not only traditionally used, but its various components have been reported to possess anticancer, anti-diabetic, antibacterial, anti-flu, anti-inflammatory and other effects.
The documented benefits of Ferula include the elimination of lumps, deworming, antibacterial and other traditional uses. In addition, some traditional uses of Ferula are closely related to the modern research and have clinical relevance. For example, modern phytochemical and pharmacological studies have revealed that DAW22 could target the main components in the MPNST tumorigenic pathways: namely, suppress the phosphorylation of AKT and ERK, and reduce the levels of non-phospho (active) CTNNB1. Moreover, other studies have reported that farnesylate A can facilitate the anticancer drugs to exert substantial cytotoxic effects by inhibiting P-glycoprotein. Another study showed that both Farnesiferol B and Farnesiferol C displayed the best inhibitory effects on P-gp pump efflux and they could be considered as lead scaffolds for further structure modifications. Currently, anticancer activity of F. ferulaeoides is being investigated by the author and his colleagues.
Because of the availability of a wide variety of TCM, their quality standards are not uniform, thereby resulting in the gradual increase in defective medicines, which can adversely the efficacy of TCM. Faced with this challenge, in 2016, Academician Changxiao Liu proposed the concept of the Q-marker. A Q-marker can better identify the various characteristic compounds present in TCM and can be used sequentially as a criterion to evaluate their quality and to better identify their authenticity, thus providing quality assurance for the development of TCM. Additionally, it was found that there were only a few selected studies related to Q-markers of domestic Ferula. Q-marker studies can be of great help to the breeding, conservation and utilization of the domestic Ferula. However, it was observed that the few studies on the Q-markers of domestic Ferula were not conducive to the research development of domestic Ferula spp. in the context of mixed quality.
Moreover, there are only few toxicological studies on the genus Ferula in China. Toxicological studies could be of great help in the clinical analysis of the active components in the domestic Ferula plants, and hence toxicological studies about the chemical composition of domestic Ferula plants should also be strengthened in the future.
Eventually, Ferula plants have a long history of use in China, but Ferula plant resources have suffered great damage due to human activities in recent years, resulting in acute shortage of plant resources and protective measures are urgently needed. However, regarding the rich background of biological activities of Ferula, it appears that there are still a large number of unaccomplished investigations that need to be conducted in the future. Examples include research on the biological characteristics and genetic variation mechanisms of the genus Ferula, for better germplasm conservation and utilization; research on the medicinal value and pharmacological mechanisms of action of the genus Ferula, to explore its application prospects and value in the field of medicine; research on the cultivation and production techniques of Ferula spp. to improve its yield and quality and to meet market demand; analysis and research on the distribution status of the resources and ecological impact of the genus Abies, and the development of conservation strategies to effectively protect and manage these precious plant resources.