Dandelion (Taraxacum Genus): A Review of Chemical Constituents and Pharmacological Effects

Dandelion (Taraxacum genus) is a perennial herb belonging to the Asteraceae family. As a well-known and extensively studied genus, dandelion comprises numerous species. Some species have been widely used in both complementary and alternative medicine to clear heat, detoxify, activate blood circulation, dispel stasis, and discharge urine. Multiple pharmacological studies have highlighted its therapeutic potential, including anti-bacterial, anti-oxidant, anti-cancer, and anti-rheumatic activities. Furthermore, bioactive compounds associated with these effects include sesquiterpenoids, phenolic compounds, essential oils, saccharides, flavonoids, sphingolipids, triterpenoids, sterols, coumarins, etc. Based on recent studies about the Taraxacum genus, the present review critically evaluates the current state of dandelion utilization and summarizes the significant roles of dandelion and its constituents in different diseases. We also focus on the reported phytology, chemical composition, pharmacology, and toxicity of dandelion, along with the main possible action mechanisms behind their therapeutic activities. Meanwhile, the challenges and future directions of the Taraxacum genus are also prospected in this review, thus highlighting its pharmaceutical research and practical clinical applications.


Introduction
Dandelion (Taraxacum genus), named "Pugongying" in China, is a perennial plant belonging to the Asteraceae family. It has a complex classification, comprising over three hundred species [1]. In Asia, the Taraxacum genus is widely cultivated and also found wild in most parts of China, North Korea, Mongolia, and Russia [2]. It grows in temperate regions globally, including on lawns, on roadsides, on disturbed banks and shores of waterways, and in other areas with moist soils.
As an edible medicinal herb and vegetable, dandelion (Taraxacum genus) has long been utilized in traditional medicine, folk remedies, and substitution therapies in many countries to treat diverse diseases ( Figure 1) [3]. Taraxacum genus as a drug was first used to treat liver and spleen diseases in Arabian medicine. In the 16th century, the German botanist Fuchs discovered that Taraxacum can be used to treat gout, diarrhea, blisters, and spleen and liver diseases. It has been used as a common drug for detoxification, swelling, and lactation since the 16th century in China. Since the 19th century, several authors have relied on the existing traditional knowledge to provide scientific explanations about how Taraxacum works on diseases and their symptoms [4]. Taraxacum can be used as diuretics, antioxidants, bile agents, anti-inflammatory, analgesic, and anti-cancer agents. Corresponding studies in the 20th century revealed that Taraxacum can be used medicinally, while its inflorescences, leaves, and roots can be processed into different foods. For example, the leaves of cultivated or wild Taraxacum species can be eaten in salads, while roots are baked and used as a coffee The Chinese Pharmacopoeia (2020 edition) records over forty Chinese patent medicines containing Taraxacum genus, which can be clinically utilized for treating over fifty types of diseases. Since Taraxacum genus could clear away heat, remove toxicity, disperse swelling, dissipate binds, and induce diuresis, dandelion in clinic is commonly used to cure inflammation, stomach trouble, tumors, gynecological diseases, male urinary system diseases, etc. For example, clinical studies demonstrated that the Kangfuxiaoyan suppository containing dandelion could attenuate symptoms and improve immunity in pelvic inflammatory patients; Rupixiao granule containing dandelion possessed the beneficial activity to induce diuresis so as to mitigate edema and resolve hard lumps, which had a satisfactory effective rate for treating breast hyperplasia. Additionally, according to the ClinicalTrials.gov database resource (https://www.clinicaltrials.gov, accessed on 14 June 2023) supported by the U.S. National Library of Medicine, for the interventional clinical trials of Taraxacum genus, one clinical study (NCT00442091) has also been conducted by Odense University Hospital to explore the beneficial effect of dandelion juice on dyshidrotic hand eczema.
Therefore, a comprehensive review of the Taraxacum genus studies is necessary considering its numerous benefits. In this work, we reviewed the recent studies of the The Chinese Pharmacopoeia (2020 edition) records over forty Chinese patent medicines containing Taraxacum genus, which can be clinically utilized for treating over fifty types of diseases. Since Taraxacum genus could clear away heat, remove toxicity, disperse swelling, dissipate binds, and induce diuresis, dandelion in clinic is commonly used to cure inflammation, stomach trouble, tumors, gynecological diseases, male urinary system diseases, etc.
For example, clinical studies demonstrated that the Kangfuxiaoyan suppository containing dandelion could attenuate symptoms and improve immunity in pelvic inflammatory patients; Rupixiao granule containing dandelion possessed the beneficial activity to induce diuresis so as to mitigate edema and resolve hard lumps, which had a satisfactory effective rate for treating breast hyperplasia. Additionally, according to the ClinicalTrials.gov database resource (https://www.clinicaltrials.gov, accessed on 14 June 2023) supported by the U.S. National Library of Medicine, for the interventional clinical trials of Taraxacum genus, one clinical study (NCT00442091) has also been conducted by Odense University Hospital to explore the beneficial effect of dandelion juice on dyshidrotic hand eczema.
Therefore, a comprehensive review of the Taraxacum genus studies is necessary considering its numerous benefits. In this work, we reviewed the recent studies of the Taraxacum genus. Firstly, we introduced the dandelion herbs and described them both botanically and ethnopharmacologically. We then discussed the main chemical composition of Taraxacum genus and outlined its pharmacological effects and toxicity, as these previously have not been fully reviewed to date. Finally, we focused on the challenges and future directions of Taraxacum genus, which could elucidate their pharmaceutical research and practical clinical

Chemical Compounds
Traditional medicinal plants have a corresponding therapeutic effect depending on their constituent compounds [32]. Dandelion is highly regarded for its unique biological characteristics and good biological activity. Considering its excellent pharmacological properties, researchers have isolated their active ingredients over the past few decades. Its biological activity is determined by complex chemical components, mainly sesquiterpenoids, phenolic compounds, essential oils, saccharides, flavonoids, sphingolipids, triterpenoids, sterols, coumarins, etc. In vivo and in vitro studies have displayed outstanding bioactivities of dandelion, such as anti-bacterial, anti-oxidant, anti-cancer, anti-rheumatic, etc. Undoubtedly, it is the diverse phytoconstituents that provide dandelion with remarkable pharmacological properties. For example, phenolic acids such as caffeic acid, coumaric acid, dihydrosyingin, chicoric acid, vanillin, etc., in dandelion possess anti-oxidative and immunostimulant properties. The main sesquiterpene compounds in dandelion are sesquiterpene lactones, usually in the form of glycosides, such as sonchuside, cichorioside C, ixerin D, taraxafolide, and so on, which have anti-inflammatory and anti-bacterial activities. Triterpenoids and sterols in dandelion such as lupenyl acetate, α-amyin acetate, β-amyin acetate, β-sitosterol, daucosterol, etc., can alleviate cardiovascular diseases. Flavonoids in dandelion such as quercetin, chrysoeriol diosmetin, luteolin, etc., usually have anti-oxidative activity; While coumarins in dandelion such as aesculin, cichoriin, esculetin, scopoletin, etc., possess anti-inflammatory, bacteriostatic, anti-coagulant, and anti-cancer effects.

Saccharides
A recent study reported the successful extraction of a water-soluble heteropolysaccharide from T. mongolicum Hand.-Mazz comprising three monosaccharides, namely pika, arabinose, and galactose in a molar ratio of 1.0:10.7:11.9 [55]. Schütz et al.

Saccharides
A recent study reported the successful extraction of a water-soluble heteropolysaccharide from T. mongolicum Hand.-Mazz comprising three monosaccharides, namely pika, arabinose, and galactose in a molar ratio of 1.0:10.7:11.9 [55]. Schütz et al. isolated fructooligosaccharides and fructopolysaccharides from the root of T. officinale WEB. ex WIGG [56].

Flavonoids
Flavonoids are a class of natural compounds with a 2-phenylchromanthone structure and a ketone carbonyl group. The oxygen atom in the first position is basic and can form a salt with a strong acid. The hydroxy derivative has a yellow color and is called a xanthophyll or a flavonoid. Dandelion contains diverse flavonoids, which are important in plant growth, development, flowering, fruiting, and anti-bacterial defense ( Figure 4). Six flavonoids, including apigenin, luteolin, quercetin, luteolin-7-β-D-glucopyranoside, quercetin-7-β-D-glucopyranoside, and quercetin-37-O-β-D-diglucopyranoside, were obtained and identified from T. mongolicum [57]. Two new flavone glycosides, namely, isoetin- were isolated from the aerial part of T. mongolicum. The structures of these compounds were elucidated mainly by spectral analyses [58]. Shi et al. established an online rapid screening method, namely, high-performance liquid chromatography (HPLC) diode array for detection and electrospray mass spectrometry system for separation and identification of free radical scavengers in T. mongolicum methanol extract. Additionally, the detected anti-oxidant was directly separated by preparative HPLC (PHPLC) and Sephadex LH-20. The purified compound was sampled using an off-line nuclear magnetic resonance (NMR) spectrometer to obtain the corresponding spectrum. Thirty-two kinds of free radical scavenging compounds were screened, isolated, and identified, including 16 flavonoids, 10 phenylpropyl compounds, and 6 benzoic acid compounds. Among them, 17 compounds were isolated for the first time from T. mongolicum, including three new compounds [59]. Five flavonoid glycosides were isolated and purified from the gas phase of T. mongolicum (a traditional Chinese medicinal herb) using high-speed counter-current chromatography (HSCCC) [60][61][62]. Moreover, two polymethoxylated flavones were isolated from T. mongolicum in 2009 [63]. In 1996, three flavonoid glycosides, including luteolin 7-glycoside and two luteolin 7-diglucosides, were isolated from the flowers and leaves, while free luteolin was isolated from the flower tissues of T. officinale [63]. Eight flavones and eight flavonol glycosides were isolated from T. officinale WEB. ex WIGG. and identified using HPLC/electrospray ionization mass spectrometry [50]. Ten flavonoids were identified from T. formosanum and quantified with concentrations of 9.9-325.8 µg g −1 [51].
Molecules 2023, 28, x FOR PEER REVIEW 12 of 32 isolated fructooligosaccharides and fructopolysaccharides from the root of T. officinale WEB. ex WIGG [56].

Flavonoids
Flavonoids are a class of natural compounds with a 2-phenylchromanthone structure and a ketone carbonyl group. The oxygen atom in the first position is basic and can form a salt with a strong acid. The hydroxy derivative has a yellow color and is called a xanthophyll or a flavonoid. Dandelion contains diverse flavonoids, which are important in plant growth, development, flowering, fruiting, and anti-bacterial defense ( Figure 4). Six flavonoids, including apigenin, luteolin, quercetin, luteolin-7-β-D-glucopyranoside, quercetin-7-β-D-glucopyranoside, and quercetin-37-O-β-D-diglucopyranoside, were obtained and identified from T. mongolicum [57]. Two new flavone glycosides, namely, mongolicum. The structures of these compounds were elucidated mainly by spectral analyses [58]. Shi et al. established an online rapid screening method, namely, highperformance liquid chromatography (HPLC) diode array for detection and electrospray mass spectrometry system for separation and identification of free radical scavengers in T. mongolicum methanol extract. Additionally, the detected anti-oxidant was directly separated by preparative HPLC (PHPLC) and Sephadex LH-20. The purified compound was sampled using an off-line nuclear magnetic resonance (NMR) spectrometer to obtain the corresponding spectrum. Thirty-two kinds of free radical scavenging compounds were screened, isolated, and identified, including 16 flavonoids, 10 phenylpropyl compounds, and 6 benzoic acid compounds. Among them, 17 compounds were isolated for the first time from T. mongolicum, including three new compounds [59]. Five flavonoid glycosides were isolated and purified from the gas phase of T. mongolicum (a traditional Chinese medicinal herb) using high-speed counter-current chromatography (HSCCC) [60][61][62]. Moreover, two polymethoxylated flavones were isolated from T. mongolicum in 2009 [63]. In 1996, three flavonoid glycosides, including luteolin 7-glycoside and two luteolin 7-diglucosides, were isolated from the flowers and leaves, while free luteolin was isolated from the flower tissues of T. officinale [63]. Eight flavones and eight flavonol glycosides were isolated from T. officinale WEB. ex WIGG. and identified using HPLC/electrospray ionization mass spectrometry [50]. Ten flavonoids were identified from T. formosanum and quantified with concentrations of 9.9-325.8 μg g −1 [51].

Sphingolipids
A sphingolipid comprises a long-chain fatty acid, a sphingosine molecule or its derivative, and a polar head alcohol. The polar head group of the sphingolipid binds to the hydroxyl group of the sphingosine, while the fatty acid moiety forms an amide bond with its amino group. Two sphingolipids, namely, gynuramide II and phytolacca cerebroside, were obtained and identified from the root of T. mongolicum [57] ( Figure 5).

Triterpenoids and Sterols
Triterpenoids are substances formed by the end-to-end joining of several isoprenes with their hydroxyl groups being removed. Most triterpenoids comprise a chain of 30 carbon atoms, while few contain 27 carbon atoms. In dandelion, pentacyclic triterpenoids are the main type. A sterol, which is a general term for a group of compounds with a fluorene nucleus, has a cyclopentane polyhydrophenanthrene skeleton. There are different kinds of sterols in different parts of the dandelion. In dandelions, triterpenoids and sterols exhibit remarkable anti-oxidative and anti-inflammatory activities ( Figure 6). Six triterpenoids and sterols, such as gigantursenol A, taraxasterol, β-sitosterol, βsitosterol-3-O-β-D-glucoside, stigmasterol, and β-sigmasterol-3-O-β-D-glucoside were successfully obtained from the root of T. mongolicum [57]. Warashina et al. extracted eight new triterpenes from dandelion roots [47]. Later, three novel triterpenoids, including the lupane-, bauerane-, and euphane-type triterpenoids were isolated from the roots of T. officinale [64].

Sphingolipids
A sphingolipid comprises a long-chain fatty acid, a sphingosine molecule or its derivative, and a polar head alcohol. The polar head group of the sphingolipid binds to the hydroxyl group of the sphingosine, while the fatty acid moiety forms an amide bond with its amino group. Two sphingolipids, namely, gynuramide II and phytolacca cerebroside, were obtained and identified from the root of T. mongolicum [57] (Figure 5).

Sphingolipids
A sphingolipid comprises a long-chain fatty acid, a sphingosine molecule or its derivative, and a polar head alcohol. The polar head group of the sphingolipid binds to the hydroxyl group of the sphingosine, while the fatty acid moiety forms an amide bond with its amino group. Two sphingolipids, namely, gynuramide II and phytolacca cerebroside, were obtained and identified from the root of T. mongolicum [57] (Figure 5).

Triterpenoids and Sterols
Triterpenoids are substances formed by the end-to-end joining of several isoprenes with their hydroxyl groups being removed. Most triterpenoids comprise a chain of 30 carbon atoms, while few contain 27 carbon atoms. In dandelion, pentacyclic triterpenoids are the main type. A sterol, which is a general term for a group of compounds with a fluorene nucleus, has a cyclopentane polyhydrophenanthrene skeleton. There are different kinds of sterols in different parts of the dandelion. In dandelions, triterpenoids and sterols exhibit remarkable anti-oxidative and anti-inflammatory activities ( Figure 6). Six triterpenoids and sterols, such as gigantursenol A, taraxasterol, β-sitosterol, βsitosterol-3-O-β-D-glucoside, stigmasterol, and β-sigmasterol-3-O-β-D-glucoside were successfully obtained from the root of T. mongolicum [57]. Warashina et al. extracted eight new triterpenes from dandelion roots [47]. Later, three novel triterpenoids, including the lupane-, bauerane-, and euphane-type triterpenoids were isolated from the roots of T. officinale [64].

Triterpenoids and Sterols
Triterpenoids are substances formed by the end-to-end joining of several isoprenes with their hydroxyl groups being removed. Most triterpenoids comprise a chain of 30 carbon atoms, while few contain 27 carbon atoms. In dandelion, pentacyclic triterpenoids are the main type. A sterol, which is a general term for a group of compounds with a fluorene nucleus, has a cyclopentane polyhydrophenanthrene skeleton. There are different kinds of sterols in different parts of the dandelion. In dandelions, triterpenoids and sterols exhibit remarkable anti-oxidative and anti-inflammatory activities ( Figure 6). Six triterpenoids and sterols, such as gigantursenol A, taraxasterol, β-sitosterol, β-sitosterol-3-O-β-D-glucoside, stigmasterol, and β-sigmasterol-3-O-β-D-glucoside were successfully obtained from the root of T. mongolicum [57]. Warashina et al. extracted eight new triterpenes from dandelion roots [47]. Later, three novel triterpenoids, including the lupane-, bauerane-, and euphane-type triterpenoids were isolated from the roots of T. officinale [64].

Pharmacological Effects
Dandelion has been reported to have multiple pharmacological effects, including anti-bacterial, anti-oxidant, anti-cancer, anti-rheumatic, etc. This section reviews recent findings on the pharmacological effects of Taraxacum (Figure 9) (Table 3).

Pharmacological Effects
Dandelion has been reported to have multiple pharmacological effects, including anti-bacterial, anti-oxidant, anti-cancer, anti-rheumatic, etc. This section reviews recent findings on the pharmacological effects of Taraxacum (Figure 9) (Table 3).  The possibility of a multifactorial drug−drug interaction existed between extracts and ciprofloxacin. Thus, the implications of concomitant dosing of the two agents should not be overlooked. [80] Extracts from leaves T. officinale In vitro It was found to be effective against all the tested Bacterial pathogens P.
[81]   The prevention of living cells from peroxyl radical-induced oxidation in the presence of dandelion flower extract suggested that the standardized extract had biological anti-oxidant activity. [93] Extracts

T. mongolicum In vitro
The extracts suppressed the damage to osteoblasts under oxidative stress and are potential anti-oxidant materials for preventing bone diseases. [94]

Methanol extracts T. mongolicum
In vivo and in vitro The extracts had significantly inhibitory activities on monoamine oxidase-A/B. [95] Ethanol extracts from the roots and leaves T. officinale In vitro; 400, 500, and 600 µg·mL −1 The extracts showed effective anti-oxidant activity correlating with total flavonoid and polyphenol contents. [96] Ethanol extracts from fruit T. officinale In vivo; 1, 5, 10, and 20 µg·mL −1 The extracts protected against SNP-induced decreases in cellular viability and increased in lipid peroxidation in the cortex, hippocampus, and striatum of rats. [97] Ethanol extracts from leaves T. officinale In vivo; 0.1, 0.5 mg·kg −1 The results clearly demonstrated the hepatoprotective effect of extracts against the toxicity induced by acetaminophen. [98] Granules of leaves and roots T. officinale In vivo; 250 g·day −1 (4 weeks) The treatment with dandelion root and leaf positively changed plasma anti-oxidant enzyme activities in cholesterol-fed rabbits. [99] Methanol extracts T. sect. Ruderalia In vitro The vegetative parts gave higher anti-oxidant activity, which could be related to its higher content in phenolic acids. [32] Extracts from flowers T. officinale In vitro; 0, 0.5, 1.0, and 2.5 µg·mL −1 The extracts possessed both anti-oxidant and cytotoxic properties which could, in part, be attributed to the presence of luteolin and luteolin 7-glucoside. [93,100] Anti-cancer  The extracts possessed potent anti-inflammatory activity in vitro and in vivo, which occurred at least partly through inhibition of pro-inflammatory signaling and mediator release. [106] Chloroform extracts T. officinale In vitro The fraction significantly suppressed production of NO, PGE2, and two pro-inflammatory cytokines (TNF-α and IL-1β) in a dose-dependent manner with 50% inhibitory concentration values of 66.51, 90.96, 114.76, and 171.06 µg·mL −1 , respectively. [107] Water extracts T. mongolicum In vitro; 10, 100, 1000 µg·mL −1 Treatment of extracts significantly inhibited NO production in LPS-stimulated MACT cells. [108] Water extracts T. mongolicum In vivo T. mongolicum could exert some of its anti-inflammatory and pharmacological effects by affecting the activity of PI3K/Akt/mTOR in LPS-induced acute lung injury in mice. [69] Organic acid T. mongolicum In vivo; 5 mg·kg −1 Organic acid could improve LPS-induced histopathological damage of tracheal tissues through the regulation of TLR4/NF-κB and TLR4/IKK/NF-κB signaling pathways and could be beneficial for the treatment of acute tracheobronchitis. Methanol extracts T. hallaisanense

In vitro
The extracts possessed marked anti-inflammatory activity. [104]

In vitro
This compound was found to have an inhibitory activity on nitric oxide production with an IC 50 of 32.4 µM in activated RAW 264.7 cells. [36] Water extracts T. mongolicum

In vitro
The results showed no significantly cytotoxic effects on the MAC-T cells at 1-1000 µg·mL −1 of extracts. [108] Ethanol extracts T. mongolicum In vitro; 0, 50, 100, 200, and 400 mg·mL −1 It possessed the most effective hypolipidemic activity in HepG2 cells. [111] Chlorogenic acids T. antungense In vitro TaHQT1 and TaHQT2 function in the biosynthesis of 5-caffeoylquinic acid, but the genes showed tissue-specific expression patterns, suggesting a mechanism for the regulation of 5-caffeoylquinic acid production. [112]

Ethanol extracts T. mongolicum In vitro
The results demonstrated the potential estrogenic activities of the extract, providing scientific evidence supporting their use in traditional medicine. [70] Ethanol extracts T. mongolicum In vitro The extracts at 50-100 µg·mL −1 improved D-galactosamine, thioacetamide and tert-butyl hydroperoxide (t-BHP)-injured rat hepatocytes, and produced protection rates of 42.2, 34.6, and 43.8% at 100 µg·mL −1 , respectively. [71] Water-ethanol extracts from roots T. officinale In vivo; 200, 600 mg·kg −1 (10 days) Hepatic Cu/Zn SOD activity decreased in intoxicated mice and normalized in extract-treated groups. [113] Extracts T. officinale In vivo; 50 mg·kg −1 (30 days) The body weight of mice and rats was decreased after administration of extracts. [114]  The extracts which were used against histopathological changes in the kidney caused by toxication showed a corrective effect, which were supported by biochemical parameters. [115] Water extracts of leaves T. officinale In vitro; 25 mg·kg −1 (14 days) The study revealed that leaf extract could afford a significant protection against CCl4-induced hepatocellular injury. [116] Extracts of leaves T. officinale In vitro; 0.2 g·mL −1 The methylene chloride inhibited as much as 97% of proliferation of the SGT cells and only about 7% of the RAW 246.7 cells. Ethyl acetate and butanol fractions inhibited 42.03% and 24.35% proliferation of the SGT cells, respectively, and only 12% and 8% of the RAW 246.7 cells. [83] Taraxinic acid T. coreanum in vitro The induction of HL-60 cell maturation by taraxinic acid may have potential as a therapeutic approach for the treatment of leukemia. [117] Methanol extracts T. platycarpum In vitro The triterpene fraction had an effect on the proliferation of normal skin fibroblasts at a concentration of 10 or 5.0 µg·mL −1 , but some compounds showed cytotoxicity and anti-proliferative activity toward fibroblasts at the same concentration. [47] The water extracts from roots and leaves T. officinale In vivo; 50, 100, and 200 mg·kg −1 The results clearly demonstrated the antidepressant effects of extracts in animal models of behavioral despair and suggested the mechanism involved in the neuroendocrine system. [118] Methanol extracts from leaves T. officinale In vivo; 150, 300 mg·kg −1 The results revealed that leaf extracts had protective effects against CCl 4 -induced liver toxicity and damage. [119] Granules of leaves and roots T. officinale In vivo; 250 g·day −1 (4 weeks) The treatment with dandelion root and leaf positively changed lipid profiles in cholesterol-fed rabbits. [99] Ethanol extracts T. officinale In vivo; 1 g·mL −1 (1 day) It showed promising potential as a diuretic in humans. [120] Extracts from leaves T. officinale In vivo; 2 g·kg −1 (10 weeks) The extracts may represent a promising approach for the prevention of high-fat diet-induced nonalcoholic fatty liver. [121] Root extracts T. officinale In vivo; 250, 500, 750 mg·kg −1 The administration of extracts ameliorated CCl 4 induced liver damage. [122] Desacetylmatricarin T. platycarpum

In vitro
The results showed a potent inhibitory activity upon the β-hexosaminidase release from RBL-2H3 cells in a dose-dependent manner and the IC 50 was 7.5 µM. [48] Extracts T. officinale In vivo; 100 mg·kg −1 n-Butanol fraction-induced increase in gastric emptying was related to smooth muscle contraction. [123]

Anti-Bacterial and Anti-Oxidant Effects
Dandelion reportedly possesses excellent anti-bacterial activity. Díaz and his colleagues isolated diverse chemical compounds from T. officinale leaves, mainly triterpenoids and other unknown compounds. Subsequently, the leaves' extract could markedly inhibit Gram-positive bacteria with a minimum inhibitory concentration (MIC) of 200 g mL −1 ), thus suggesting dandelion had promising anti-bacterial potential [127]. In another experiment, the content, anti-oxidant activity, and cytotoxicity of phenols and flavonoids in three different types of dandelion methanolic extracts were investigated. The total phenolic content was 1000 mg·kg −1 , with the aboveground content being higher than the root. T. mongolicum had the highest phenolic content in the stems (76.8 mg·kg −1 ) and roots (40.0 mg·kg −1 ), followed by T. coreanum and T. officinale (p < 0.05). Furthermore, the total flavonoid content also showed a consistent trend with the total phenolic content. The anti-oxidant activity of each methanolic extract increased in a dose-dependent manner. The maximum 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activities of T. mongolicum shoot and root extracts (89.6% and 83.4%) were obtained at a concentration of 1000 mg·kg −1 . The overall experimental results proved that the total phenolic and flavonoid levels were highly correlated with anti-oxidant activity, but their content and activity varied across species [87,89]. In another study of the anti-bacterial activity of the extracts of T. mongolicum in different solvents, Gao reported that only the ethanolic extract had varying degrees of anti-bacterial activity (inhibition zone >7 mm in diameter), while the aqueous extract did not [78].
Flavonoids and coumaric acid derivatives were extracted from dandelion flowers. In the study of anti-oxidant properties, the extracts had scavenged effects on superoxide and hydroxyl radical-induced damage; meanwhile, the inhibition of hydroxyl radicals was nonspecific. The reduction in the phenolic content of the extract reduced the DPPH capacity and showed a synergistic effect with α-tocopherol. After the addition of the corresponding extract, the bacterial lipopolysaccharide (LPS) stimulated macrophage RAW264.7 cells in mice, thereby significantly reducing the NO concentration in a concentration-dependent manner. Additionally, adding a certain extract concentration significantly inhibited the peroxide radical-induced intracellular oxidation of RAW264.7 cells. The extract demonstrated a significant anti-oxidant activity in biological and chemical models. In addition, the inhibitory effect of the extract on reactive oxygen species (ROS) and NO was related to its phenolic content [93].
T. mongolicum extract inhibited four Gram-negative bacteria and two Gram-positive bacteria, especially Pseudomonas aeruginosa and Bacillus subtilis, with MIC values of 125 and 62.5 µg·mL −1 , respectively. The ethyl acetate soluble component extracted from dandelion had high anti-bacterial activity and can be used as a natural preservative in the pharmaceutical industry [79]. The relationship between osteoporosis and oxidative stress induced by ROS was also studied and food and plants with anti-oxidant effects are being increasingly focused upon to reduce the ROS-induced damage caused during bone metabolism. The anti-oxidative effect of T. mongolicum on the proliferation and the differentiation of MC3T3-E1 cells induced by hydrogen peroxide was investigated, and the total contents of polyphenols and flavonoids were 33.65 and 4.45 mg·g −1 , respectively. Under hydrogen peroxide-induced oxidative stress, dandelion extract promoted the proliferation of MC3T3-E1 cells and differentiation of osteoblasts. Hence, dandelion extract can inhibit oxidative stress-induced damage to osteoblasts and serve as a potential anti-oxidant material for preventing bone diseases [94].
With the increasing resistance of cow mastitis to bacteria and considering the safety of dairy products, anti-bacterial extracts should be used instead of antibiotics for the treatment of mastitis in dairy cows. The anti-bacterial effects of purslane and T. mongolicum aqueous and ethanolic extracts on the main pathogens of cow mastitis (Escherichia coli, Staphylococcus aureus, Streptococcus agalactiae, and Streptococcus agalactiae) were studied using disk diffusion method. The aqueous and ethanolic extracts of the two traditional Chinese medicines had different inhibitory effects on the four pathogens of cow mastitis.
The anti-bacterial activity of the two Chinese herbal extracts against E. coli was higher than that against other bacteria. The ethanolic extract had higher anti-bacterial activity against E. coli than purslane. However, the anti-bacterial activity of the T. mongolicum ethanol extract was lower than that of the aqueous extract. Hence, purslane and the T. mongolicum extract may be used for the treatment of mastitis in dairy cows [66].

Anti-Cancer Effects
A previous report investigating the use of T. mongolicum extracts for the prevention and treatment of bovine mastitis discovered that different concentrations of the extract had no noticeable cytotoxic effect on MAC-T cells, thus being the first to report that the T. mongolicum extract significantly inhibited the production of NO and pro-inflammatory cytokines in MAC-T cells. This finding has a certain clinical application value for the prevention and treatment of bovine mastitis [108]. Breast cancer is an aggressive and fatal breast disease with limited treatment options. Although T. mongolicum (a Chinese herbal medicine with anti-cancer activity) has been used for the treatment of breast abscess and breast hyperplasia since ancient times, its mechanism of action needs further scientific studies [128]. T. mongolicum extract significantly inhibited the activity of MDA-MB-231 cells by causing the G2/M phase arrest and apoptosis. The extract also significantly increased the levels of cleaved caspase-3 and PARP proteins, with the caspase inhibitor Z-VAD-FMK inhibiting T. mongolicum extract-induced apoptosis. Three ER stress-related signals were strongly induced by the T. mongolicum treatment, including increased expression of ATF4, ATF6, XBP1s, GRP78, and cleavage-related genes along with elevated phosphorylation levels of proteins, eIF-2αIRE1, and downstream molecular GRP78 impermanence. MDA-MB-231 cells transfected with CHOP siRNA significantly inhibited the T. mongolicum extract-induced apoptosis. The underlying mechanism is partially attributed to the strong activation of the active/p-eIF2α/ATF4/cut axis. In conclusion, apoptosis induced by endoplasmic reticulum stress generates the anti-cancer effect of the T. mongolicum extract, thereby suggesting that the T. mongolicum extract may be a potential treatment for triplenegative breast cancer (TNBC) [57]. However, the use of dandelion for breast cancer treatment is mainly based on anecdotal evidence and has no sufficient scientific evidence. Therefore, Oh et al. hypothesized that T. mongolicum can act as a selective estrogenic receptor modulator and hormone replacement therapy for postmenopausal women. T. mongolicum ethanol extract significantly increased the cell proliferation and estrogenic response elementdriven luciferase activity. Hence, T. mongolicum ethanol extract can induce estrogenic activity mediated by the classical estrogenic receptor pathway, thereby providing a scientific basis for its anti-cancer application in traditional medicine [70].

Anti-Inflammatory Effects
Inflammation plays an important role in the pathogenesis of acute tracheobronchitis. The main component of T. mongolicum Hand.-Mazz-an organic acid, has good antiinflammatory activity. Furthermore, organic acids can improve the regulation of the TLR4/NF-κB (TLR4/IKK/NF-κB) signaling pathway in LPS-mediated histopathological damage, which may provide a basis for the treatment of acute tracheobronchitis [72,73].
T. mongolicum is widely used in the Eastern Hemisphere. Since T. mongolicum has a high mineral content, it causes potential problems with the absorption of quinolones. Since a previous study reported the occurrence of multifactorial drug interactions between T. mongolicum and ciprofloxacin, the effects of their simultaneous use should not be ignored. Ciprofloxacin is a fluoroquinolone antibiotic that has good anti-bacterial activity against Gram-positive, Gram-negative, and mycobacteria. However, its oral absorption greatly diminished the effect of simultaneous administration of metal-containing cations. This phenomenon has been extensively studied for antacids, mineral supplements, and dairy products. However, information about this interaction is not yet available in mineral-rich herbal and health foods. Drug-drug interactions may occur between ciprofloxacin and a mineral-rich anti-inflammatory/anti-bacterial herb, T. mongolicum Hand-Mazz. Traditionally, T. mongolian dried plants are used for the treatment of lice, ulcers, mastitis, lymphadenitis, inflamed eyes, sore throat, lung and breast abscesses, acute appendicitis, jaundice, and urinary tract infections. Furthermore, this herb exerts a bactericidal effect on multiple pathogens, and its water extract has MIC values ranging from 1:10 to 1:640. In addition, the in vitro antifungal, anti-leptospiral, and antiviral effects of the herbs have been proven. Chemical testing of T. mongolicum indicates the presence of triterpenoids (such as tartaric alcohol and tartaric acid), inulin, pectin, asparagine, and phenolic compounds. A comprehensive pharmacokinetic assessment of the rat was performed and demonstrated the potential of drug-drug interactions between T. mongolicum and ciprofloxacin [80].
Different solvent extracts of T. officinale were successfully prepared by Jeon et al. in a carrageenan-induced balloon model [104]. The ethanolic extract inhibited the production of exudates and significantly reduced the NO and leukocyte levels in the exudate. The extract also inhibited acetic acid-induced vascular permeability in a dose-dependent manner in acetic acid-induced abdominal peristalsis in mice. In summary, medicinal dandelion has anti-angiogenic, anti-inflammatory, and anti-nociceptive properties by inhibiting NO production and cyclooxygenase-2 (COX-2) expression and/or its anti-oxidant activity.
Mouse macrophages (RAW 264.7) were used to study the anti-inflammatory effects and mechanism of the methanolic extract of T. officinale leaves on LPS induction. The methanolic extract and its components inhibited LPS-induced production of NO, proinflammatory cytokines, and prostaglandin (PG) E 2 in a dose-dependent manner. However, the chloroform soluble fraction significantly inhibited the production of NO, PG E 2 , and two pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)) in a dose-dependent manner, with MIC values of 66.51, 90.96, 114.76, and 171.06 µg·mL −1 , respectively. Hence, the anti-inflammatory effects of leaf extract may be due to the downregulation of NO, PG, E 2 , and pro-inflammatory cytokines along with the inactivation of the MAP kinase signaling pathway, thereby reducing the expression of inducible NO synthase (iNOS) and COX-2 [107]. Therefore, in the anti-inflammatory mechanism study, the aqueous extract of T. mongolicum exerted certain protective effects on acute lung injury-induced inflammation in mice [69].

Other Effects
Baek examined the methanolic extract of T. mongolicum and its fraction for their scavenging effects on DPPH and superoxide radicals and also their hepatoprotective effects on tacrine-induced cytotoxicity in the human hepatoma cell line, HepG2 cells. The extract had free radical scavenging and hepatoprotective effects [129]. The novel homogenous polysaccharide DPSW-A was obtained from T. mongolicum and its derivative demonstrated limited anti-coagulant function [55]. Furthermore, the newly isolated compound 1β,3βdihydroxy-eudesman-11(13)-en-6α from T. mongolicum inhibited the NO production, with an IC 50 of 38.9 µM [36].
In the study of its hypolipidemic action and mechanism, T. mongolicum was extracted separately with water, 50% ethanol, and 95% ethanol. The 50% ethanolic extract was the most effective among the 13 extracts. Prolonged administration of the 50% ethanolic extract significantly reduced the body weight of rats and the serum levels of triglyceride LDL-C and total cholesterol. Hence, T. mongolicum helps in lowering blood lipid levels [68]. Moreover, the T. mongolicum methanol extract strongly inhibited monoamine oxidase. Therefore, the extract can potentially affect diseases, such as depression, dementia, and Alzheimer's disease [95].
Skin whitening is becoming popular among people. Melanin is an important factor that determines skin color. In the study of melanin synthesis inhibition by T. mongolicum extract, reverse-transcriptase polymerase chain reaction and Western blot were used to analyze the protein and mRNA levels of tyrosinase-related protein (TRP)-1, TRP-2, tyrosinase, MITF, ERK, and PKA, and it was found to inhibit melanin synthesis [110].
To verify the antiviral effect of T. mongolicum on the hepatitis B virus, researchers found that 50-100 g·mL −1 T. mongolicum extract could protect the rat hepatocytes as com-pared with D-galactosamine (D-GalN), thioacetamide (TAA), and t-butyl hydroperoxide (t-BHP). The protective effect of 100 g·mL −1 T. mongolicum extract on rat hepatocytes was enhanced. Furthermore, the T. mongolicum extract significantly inhibited DNA replication at 1-100 g·mL −1 , and reduced the levels of HBsAg and HBeAg at 25-100 g·mL −1 , with inhibition rates of 91.39% and 91.72% at 100 g·mL −1 , respectively. The T. mongolicum extract significantly inhibited DNA replication at 25-100 g·mL −1 , thus exerting a strong antiviral effect on HBV. The protective effect of T. mongolicum extract on hepatocytes may be achieved by inhibiting oxidative stress. However, the antiviral properties of the T. mongolicum extract may help block protein synthesis and DNA replication. The main components of the T. mongolicum extract were quantitatively analyzed to provide a scientific basis for its use in the treatment of hepatitis [71].

Toxicity
When a plant or a compound isolated from a plant has no significant toxicity or side effects, its potential therapeutic effect should be studied further. This is particularly important for dandelion [130]. In daily life, the recommended dosage of dandelion is 10-15 g [1]. In 1974, Râcz-Kotilla et al. [114] studied the diuretic effect of a 4% aqueous extract of dandelion. Firstly, they performed acute toxicity tests on different parts of dandelion and fluid extracts of grass (DL 50 = 27.2 g·kg −1 body weight). In the diuretic experiment, the aqueous extract of dandelion was administered at a dose of 8 g·kg −1 body weight for one month, and the body weight of the mice and rats were found to be reduced by~30%. In the study of the protective effect of renal oxidative damage caused by CCl 4 , the oral administration of 100, 250, 300, 500, and 750 mg·kg −1 dandelion aqueous extract for the duration of the test was considered safe. In addition, the corresponding lesions in mice showed a good prognosis, thus indicating that these dosages are within the normal range [115,122,131]. In terms of cytotoxicity, HepG2, HeLa, HL60, and Vero E6 cells had different IC 50 values (0.015 ± 0.001, 0.023 ± 0.002, >0.25) [92].

Conclusions and Future Prospects
As a well-known complementary and alternative medicine, the whole dandelion herb, including its roots, stem, leaf, flower, and seed is rich in diverse bioactive ingredients including sesquiterpenes, phenolic compounds, phytosterols, triterpenes, etc. However, previous studies have mainly focused on extracting and identifying active ingredient structures from different kinds of dandelion. At present, most research focuses on studying the biological activity of partial extracts such as the root extracts, while the research on the biological activity of other effective active ingredients of dandelion are relatively fewer. Moreover, the pharmacological research of the effective active ingredients of dandelion mostly focuses on the basic pharmacological mechanism, and the form of mechanism research is relatively simple. For example, in order to clarify the specific anti-cancer mechanism of dandelion, more advanced strategies including network pharmacology, molecular pharmacology, and metabolomics methods can be flexibly used to comprehensively demonstrate the multitarget anti-cancer action mechanism of dandelion, which will provide new insights for further accurate search, and confirmation and optimization of the relationship between the active ingredient of dandelion and the target. Additionally, most of the current studies focus on in vitro cell experiments, and the research results lack clinical applicability. In the future, a large number of in vivo animal models are needed to deeply study the pharmacological mechanisms and targets of active ingredients of dandelion, so that they can realize clinical application as soon as possible and offer new ideas and methods for precise treatment.
To be more specific, T. mongolicum, T. borealisinense, T. coreanum Nakai, and T. officinale are the most frequently utilized species for complementary and alternative medicine. Additionally, in terms of pharmacological effects, dandelion could exert potent anti-bacterial, anti-oxidant, anti-cancer, and anti-rheumatic activities. Moreover, the extracts from different parts all displayed excellent aforementioned activities, which provided strong evidence regarding the use of the traditional medicinal herb as an anti-bacterial drug. However, the anti-bacterial effect differed between the different types of dandelion. Although dandelion is a traditional medicinal plant used for different treatments, its mechanism of action and its corresponding biological activity and safety should be further studied. Furthermore, when dandelion is clinically applied, in-depth research and investigation should be conducted regarding its distribution and metabolism. Therefore, we believe that with further developments in science and technology, novel drug technologies can be combined with traditional therapeutic medicinal plants, such as dandelion, to achieve better treatment outcomes.