Traditional Uses, Phytochemical Composition, Pharmacological Properties, and the Biodiscovery Potential of the Genus Cirsium

: Medicinal plants are rich in phytochemicals, which have been used as a source of raw material in medicine since ancient times. Presently they are mostly used to treat Henoch–Schonlein purpura, hemoptysis, and bleeding. The manuscript covers the classiﬁcation, traditional applications, phytochemistry, pharmacology, herbal formulations, and patents of Cirsium . The main goal of this review is to impart recent information to facilitate future comprehensive research and usthe e of Cirsium for the development of therapeutics. We investigated numerous databases PubMed, Google Scholar, Springer, Elsevier, Taylor and Francis imprints, and books on ethnopharmacology. The plants of the genus Cirsium of the family Asteraceae contain 350 species across the world. Phytochemical investigations showed that it contains ﬂavonoids, phenols, polyacetylenes, and triterpenoids. The biological potential of this plant is contributed by these secondary metabolites. Cirsium plants are an excellent and harmless agent for the cure of liver diseases; therefore, they might be a good clinical option for the development of therapeutics for hepatic infections. The phytochemical studies of different Cirsium species and their renowned pharmacological activities could be exploited for pharmaceutic product development. Furthermore, studies are required on less known Cirsium species, particularly on the elucidation of the mode of action of their activities.


Introduction
In recent years, there has been a surge in interest in natural products for the prevention and cure of many diseases such as cancer, arthritis, cardiovascular disorders, and diabetes.Plants and their natural products are reservoirs of phytoconstituents that have antimicrobial, antioxidant, anticancer, and antidiabetic properties and are used in traditional medicine [1].Plant extracts provide limitless opportunities for novel medicinal discoveries due to their unrivaled chemical variety and biocompatible nature.Many studies are being conducted to identify an alternative therapy using medicinal plants.In reality, roughly 25% of the medications on the market are derived directly or indirectly from plants [2].Many of these plants have recently been suggested for their capacity to act as a preservative and food additive, serving a dual function of culinary taste and bioactive constituent [3].
Cirsium is a genus of perennial and rarely annual prickly Asteraceae plants.It gets its name from the Greek word "khirsos," which means "swollen vein."According to the Plants of the World online collections at the Royal Botanic Gardens of Kew, there are around 450-480 recognized species in this genus [4,5].These plants are found in the northern or some time on the whole plant.Species of genus Cirsium are entitled 'common thistle', and 'field thistle' (Table 1).More precisely, they are termed 'Plume thistles' since some genera, i.e., Carduus, Silybum, and Onopordum, are frequently labeled by the term 'thistle' [16].Cirsium is considered a weed that grows anywhere, including near farmed areas.Despite their status as weeds, they have the potential for allelopathic impact and biological pest control [17].Some species are even planted in gardens owing to their aesthetic appeal [18,19].

Botanical Description of Genus Cirsium
Thistles are recognized by their demonstrative flower heads (purple, rose, pink, yellow, or white) with many tiny flowers.Flowers are radially symmetrical disc-like structures blooming at the end of the branches.Their flowers bloom from April to August [9].Plant constitutes straight stems and prickly leaves having a distinctive enlarged base of flower which are usually spiny; leaves are alternate, some species can be less or more hairy; leaf extension leading to the stems called wings, can be conspicuous (Cirsium vulgare), lacking, or inconspicuous (Figure 2).They can reproduce by pollination and also through rhizomes (Cirsium arvense) and are annual, biennial, and some are perennial in growth form [10,26].

Traditional Uses
Currently, traditional plants have emerged as a viable avenue for the discovery of novel therapeutic molecules to treat a variety of severe ailments, such as diabetes and cancer [27].More than 10 species of Cirsium are well known in Chinese medicines to cure

Traditional Uses
Currently, traditional plants have emerged as a viable avenue for the discovery of novel therapeutic molecules to treat a variety of severe ailments, such as diabetes and cancer [27].More than 10 species of Cirsium are well known in Chinese medicines to cure jaundice, hemorrhaging, gastrointestinal issues, and vascular diseases [28].Traditionally, Cirsium is also exploited as an herbal remedy for the healing of leukemia and peptic ulcers [29].In Central America and Mexico, C. mexicanum is utilized in traditional medicine for the cure of respiratory problems, hepatic infections, diarrhea, dysentery, and stomach pain [23].Moreover, Cirsium rivulare is utilized traditionally in Poland for anti-anxiety effects [30].The fruits and roots are also used to cure constipation, dyspepsia, skin problems, chest discomfort, and as a tonic by the people of the Himachal region [31].The indigenous culture of Meghalaya uses leaf extract to treat gastrointestinal ailments, primarily diarrhea, and dysentery.The Bhotiya tribal community of central Himalaya, India, uses the Cirsium the cure rheumatism [32].Cirsium arvense roots are diuretic, astringent, antiphlogistic, and hepatoprotective.Root decoction of Cirsium has been traditionally employed for treating worm infection in children.Moreover, root paste of Cirsium arvense in combination with Amaranthus spinosus is used for the treatment of indigestion.Rheumatic joint pains have long been treated using a hot brew made from Cirsium arvense.Decoction of the whole plant has been used as a curative medicine internally and externally for bleeding piles [33].It has been surveyed in Central Italy that Cirsium arvense leaf soup is used to alleviate digestive problems and stomach discomfort.Moreover, Cirsium arvense is also utilized to halt the flow of blood from wounds in an emergency [34].Extract and infusions of C. arvense leaves are a good repository of fibers, vitamins, and important minerals, and these were used by North American Indians for toothaches, tuberculosis, throat sores, and cancer sores due to their potent anti-inflammatory properties [35].Other species, such as Cirsium rivulare, have also been used traditionally for anxiety-related issues [36] and have been documented to exhibit antimitotic action [37].Moreover, in Polish medicine, C. arvense and C. oleraceum have been reported to be used as a diuretic, antiphlogistic, and astringent [38].C. rivulare, C. oleraceum, and C. vulgare have long been recognized for their anxiolytic properties in Poland's Northeastern regions [39].Aerial portions of C. chanroenicum have been reported to be utilized in Chinese medicine to cure pyrexia, detoxify, and improve blood circulation [40].In addition to it, C. japonicum has been utilized in Chinese medicine as a hypertensive, anti-hemorrhagic, and anti-hepatitis agent [25], as well as in folk medicine for the cure of malignancies such as uterine and liver cancer [41].The water extract of C. arisanense displayed a hepatoprotective effect and has been applied in Taiwanese traditional medication for hundreds of years [42].In another work, Cirsium species seeds and root decoction have been employed in Turkish traditional medicine to cure hemorrhoids.Flowers of Cirsium species ameliorated peptic ulcers, and stems are used for the cure of cough and bronchitis in Anatolia [43].Root paste of C. falconeri and C. verutum is useful for the cure of arthritis [22].Moreover, the dried powder of flowers and leaves of C. falconeri has been found to mediate protective effects against Cerebral edema in the Himalayan province of India [44].The stems and young leaves of C. setidens are edible in nature and high in calcium, proteins, and vitamin A. This species of Cirsium has been used to treat emesis, hypertension, and hematuria in Korean medicines [45].Moreover, Cirsium vulgare is persistently grown in gardens nowadays to attract birds and butterflies.Hummingbirds are attracted to the flowers of C. vulgare, and many immigrants keep hummingbirds in their botanical gardens [16].

Pharmacological Studies
Cirsium has abundant pharmacological activities due to the presence of a wide range of phytochemicals.Till date, a broad spectrum of biological properties such as antimicrobial, antioxidant, analgesic, anticancer, hepatoprotective, and anti-inflammatory have been reported from the different species of Cirsium (Table 1).

Antimicrobial Activity
A huge number of studies have been carried out on various species of Cirsium, which proves that it possesses a great number of antimicrobial properties (Table 3).Nazaruk and Jakoniuk [50] used the flowers and leaves of Cirsium rivulare to test the microbicidal potential against bacterial strains namely Klebsiella pneumoniae, Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli, Micrococcus and Staphylococcus aureus and fungus Candida albicans.It was found that all Cirsium rivulare extracts exerted antiproliferative and bactericidal activity.However, water extract from leaves of Cirsium was observed to be more active against Gram-positive bacteria [50].The antibacterial activity of five compounds, namely Tracin, 9,12,15-Octadecatrienoic acid, Luteolin, Hispidulin, and α-Tocopherol isolated from the Cirsium arvense, was tested against different bacterial strains.It was observed that Tracin, Luteolin, and Hispidulin exhibited marked protective efficacy against bacterial strains, whereas α-tocopherol showed moderate antibacterial activity.However, 9,12,15-Octadecatrienoic acid showed low bactericidal activity.In addition to it, the antifungal activity of these compounds was also monitored against six pathogenic fungi, Trichophyton longifusus, Microsporum canis, Fusarium solani, Candida glabrata, Candida albicans, and Aspergillus flavus.It was shown that all the phytocompounds had a moderate to low antifungal efficacy, except 9,12,15-Octadecatrienoic acid, which has no antifungal impact [35].In another study, flowers and leaf extracts from C. vulgare, C. rivulare, C. palustre, C. oleraceum, or C. arvense have been shown to exhibit a significant antimicrobial effect against P. aeruginosa, S. aureus, and B. subtilis.Flower extract of Cirsium species showed a more potent antimicrobial effect as compared to the leaf extract [87].Moreover, flavonoids present in C. oleraceum also displayed substantial antibacterial and antifungal effects [88].Nazaruk et al. [89] investigated the antibacterial effects of Cirsium species against bacterial strains such as S. aureus, P. aeruginosa, B. subtilis, and the fungal strain C. albicans.Among the Cirsium species studied, C. palustre had the strongest antibacterial activity [39].However, the protective potential of bioactive components extracted from C. canum was determined against the Gram-negative and positive bacteria.It was noticed that the extract and fractions of C. canum showed no effect on the growth of Gram negative bacteria.However, it showed potent inhibitory activity against the microbes S. pneumonia, S. aureus, S. epidermidis, B. subtilis, and B. cereus [63].Moreover, Strawa et al. [90] found that hexane and defatted methanol extracts of Cirsium roots have a strong bactericidal effect against Gram-positive and Gram-negative bacteria with MIC and MBC values ranging from 25 to 200 µg/mL.In another investigation, the microbicidal effect of crude extract and fractions of C. scabrum was determined against twenty-two Gram (+) and thirteen Gram (−) microbial strains.Ethyl acetate and Butanol fraction of C. scabrum showed profound effect against the S. aureus and D. hominis strains [47].Flavonoids isolated from C. japonicum demonstrated mild antibacterial activity against two strains of human skin bacilli and six strains of S. aureus [10].Ciryneol D, isolated from the C. setosum, inhibited the development of mycelium in a variety of fungi [91].

Antioxidant Activity
Various in vitro investigations indicated that the roots, leaves, and flowers of C. arvense had a robust antioxidant effect (Table 3) [46].Hossain et al. (2016) examined ethanolic extract of C. arvense for antioxidant activity.It was observed that ethanolic extract of C. arvense showed marked antioxidant activity [52].The antioxidant potential of various extracts from C. vulgare, C. rivulare, C. palustre, C. oleraceum, and C. arvense was studied by Nazaruk [39], and the total antioxidant activity was found to be in the range of 0.98 to 2.71 m/mL [39].In another investigation, crude aqueous extracts of the Cirsium species were monitored for total antioxidant potential through the ABTS technique.It was observed that C. vulgare (2.31 m/mL), C. rivulare (2.78 m/mL), C. palustre (2.78 m/mL), C. oleraceum (2.76 m/mL), and C. arvense (2.74 m/mL) showed the remarkable antioxidant activity [89].In another study, Lee et al. [89] used the DPPH free radical test to determine the antioxidant capacity of leaves and root extracts of C. setidens.The IC 50 values for the butanolic fraction of leaves and roots were observed to be 33.53g/mL and 9.75 g/mL, respectively.The free radical scavenging potential of C. setidens was found to be more than the tocopherol and ascorbic acid [89].Moreover, it was observed that the methanolic extract of C. rivulare roots exhibited more DPPH scavenging activity in contrast to the hexane extract [90].Balanophonin, Vanillic acid, and Kaempferol-3-O-L-rhamnopyranoside purified from the C. sipyleum, C. eriophorum, and C. leucopsis showed huge antioxidant activity [95].In another study, it was found that hexane extracts of Cirsium species contain the active component Linoleic acid, which displayed a remarkable antioxidant activity [90].Chlorogenic acid was identified as the potent antioxidant compound among the different species of Cirsium in Poland [90].In another investigation, the major antioxidant components in Cirsium japonicum were found to be Luteolin and Silibinin [97].Moreover, Luteolin, apigenin, and their glucosides present in different species of Cirsium also showed antioxidant and hepatoprotective effects [98].In addition to it, major flavonoids Pectolinarin and Pectolinarigenin present in Cirsium exhibited strong antioxidant activity [58].In another study, Apigenin, Diosmetin, and Silicristin were found to be present in significant amounts in different species of Cirsium and also displayed potent DPPH radical-scavenging properties [99].

Antiproliferative Activity
The antiproliferative potential of methanolic and chloroform extracts from different parts of C. arvense was tested against C6 cells (Rat brain tumor cells), Hela cells (Mammalian uterine carcinoma), and Vero cells (African green monkey renal cells).The root extracts of C. arvense revealed maximum inhibitory activity against the proliferation of C6 cells.However, the stem extracts showed huge inhibition against the Vero and HeLa cell lines.Moreover, the phytoconstituents isolated from the C. arvense showed antiproliferative activity in the order: Arvense 1 < Stigmasterol < Linarin < Daucosterin < 5-FU [46].In addition to it, Tocospiro C, Tocospiro A, and Tocospiro B isolated from the leaves and stem of C. setosum showed inhibitory action against mammalian stomach cancer, ovarian cancer, lung adenocarcinoma (A549), hepatoma (Bel7402), and colon cancer (HCT-8) cells.Tocospiro C and B exerted maximum selective inhibition against the mammalian colon cancer cells, and IC 50 was observed to be 0.03 µM and 0.12 µM, respectively (Table 4).However, Tocospiro A revealed very low inhibitory activity against HCT-8 cells, and IC 50 was found to be 12.8 µM.All the compounds showed similar inhibition against the other cancer cell lines and displayed IC 50 > 20 µM [70].In another study, it was observed that aerial parts of C. setidens contain major phytoconstituents Tocopherol, 24-Hydroperoxycycloart-25-en-3β-ol, trans-Phytol, 9, 12, 15-Octadecatrienoic acid, Hexadecanoic acid, and Sitosterol.It was observed that maximum cytotoxicity against the mammalian cancer cell lines was exhibited by the 24-Hydroperoxycycloart-25-en-3β-ol, and ED 50 was observed to be in the range from 2.66 to 11.25 µM.The remaining phytoconstituents showed negligible cytotoxic action on the cancer cell lines [23].Similarly, the cytotoxic potential of leaf extracts of C. scabrum was monitored against the mammalian macrophage cell line.It has been noticed that methanolic, and petroleum ether fractions of C. scabrum displayed selective cytotoxic activity with the IC 50 value of 11.53 and 12.12 µg/mL, respectively [47].
In another investigation, the antiproliferative activity of essential oil purified from C. palustre and C. rivulare was determined against the adenocarcinoma cell line.It revealed moderate inhibitory action against the adenocarcinoma with an IC 50 value of 110-140 g/mL [73].Likewise, extracts of C. palustre and C. arvense showed a little cytotoxic effect on the normal skin fibroblasts in a dose-dependent manner [87].

Analgesic and Anti-Inflammatory Activity
The water extracts from the aerial portion of C. subcoriaceum and its active component pectolinarin were monitored for analgesic and anti-inflammatory activity (Table 4).It was observed that crude extract of C. subcoriaceum and pectolinarin hampered the acidinduced writhing in mice in a concentration dependent manner.The pectolinarin (ED 50 28.44 mg/kg) was observed to be more effective as an analgesic as compared to the crude extract of C. subcoriaceum (ED 50 83.18mg/kg).It has been observed that Pectolinarin showed similar protective efficacy as a standard analgesic compound, Acetylsalicylic, at a similar concentration.The water extract of C. subcoriaceum and pectolinarin hindered the edema induced by carrageenan.The ED 30 of C. subcoriaceum and pectolinarin was detected to be 25 mg/kg and 3.7 mg/kg, respectively [58].Similarly, Pectolinarigenin and Pectolinarin extracted from the aerial parts of C. chanroenicum hindered cyclooxygenase-2 mediated prostaglandin E2 synthesis and leukotrienes in LPS-treated macrophages, which resulted in lesser production of eicosanoid.Moreover, oral administration of Pectolinarigenin and Pectolinarin declined inflammation and allergy in the animal control group.Thus, these components might play some part in the anti-inflammatory properties of crude extract of C. chanroenicum.COX inhibitors are utilized as anti-inflammatory drugs, while 5-lipoxygenase inhibitors have anti-allergic action [59].In another research, the crude extract and its flavonoid Cirsimaritin caused the marked inhibition of nitric oxide and nitric oxide synthase expression in macrophage cells.It repressed the production of tumor necrosis factor-α, interleukin-6, and NO in macrophage cells induced by lipopolysaccharide.Moreover, pretreatment with Cirsimaritin caused the reduction of phosphorylation of IκBα and Akt in LPS-induced macrophage cells.Cirsimaritin decreased the induction of FOS and STAT3 (signal transducer and activator of transcription 3) signaling in macrophages which depicts its anti-inflammatory nature [102].Likewise, Silibinin purified from C. japonicum decreased the growth of human mast cells and caused a reduction in the expression of pro-inflammatory cytokines.Furthermore, Silibinin declined the phosphorylation of IκBα and NF-κB transcriptional activity in stimulated mast cells.Therefore, it can be employed for the cure of mast cells mediated allergic inflammatory ailments [103].

Hepatoprotective Activity
The hepatoprotective activity of water extract of roots and leaves of C. arisanense was monitored in mammalian hepatocellular carcinoma cell lines and mice (Table 5).Roots and leaves of C. arisanense shielded the hepatocellular carcinoma cells against tacrine-stimulated hepatotoxicity and decreased the expression of hepatitis B surface antigen.Furthermore, roots and leaves of C. arisanense ameliorated the hepatic damage in mice induced due to tacrine as they lowered the concentration of serum glutamate-pyruvate transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT).These effects of the roots of C. arisanense might be due to an enhancement in the concentration of liver glutathione [42].Likewise, the administration of butanol extract of C. setidens at 500 mg/kg caused a reduction in the hepatic damage in rats induced due to CCl 4 .Treatment of C. setidens elevated the concentration of antioxidant markers glutathione peroxidase, glutathione peroxidase, and superoxide dismutase (SOD) in the liver of rats.Histological studies substantiated the biochemical analysis, indicating that the extract of C. setidens caused a remarkable decrease in hepatic ballooning degeneration [21].Moreover, the active components Pectolinarin and Pectolinarigenin present in methanolic extracts of C. setidens leaves decreased the hepatic derangement in rats induced due to galactosamine toxicity.The concentration of SGOT, SGPT, alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) were observed to be decreased after the treatment of Pectolinarin and Pectolinarigenin, indicating the hepatoprotective potential of both of the components.Treatment with Pectolinarin and Pectolinarigenin boosted the antioxidant enzymes glutathione, glutathione transferase, glutamylcysteine synthetase, glutathione reductase, and SOD.It revealed that the hepatoprotective activity of Pectolinarin and Pectolinarigenin is attributed to the induction of the antioxidant system [60].In another investigation, the crude extracts of Cirsium normalized the levels of SGOT and SGPT in mice that had been raised by CCl 4 injection.Cirsium japonicum and Cirsii herba decreased the CCl 4 stimulated liver necrosis and restored the levels of hepatic antioxidant enzymes and malondialdehyde [104].9.6.Immunomodulatory Activity C. japonicum and its phytoconstituent Pectolinarin hindered the growth of tumors in mice and enhanced the humoral and cellular immune responses (Table 5).It boosted the complement pathway in the tumor-bearing mice and also caused the improvement in the transformation of spleen cells as well as natural killer cell activity [57].

Anticancer Activity
There are numerous studies indicating the anticancerous nature of Cirsium (Table 4) and its promising therapeutic ability to prevent malignancies.The Pectolinarin and 5,7-Dihydroxy-6,4-dimethoxyflavone obtained from C. japonicum were monitored for anticancer activity in the mouse.It was observed that both of the compounds exhibited a remarkable reduction in the multiplication of tumor cells in a concentration-dependent manner [53].Similarly, the extract of Cirsium japonicum and Cirsimaritin caused a reduction in the breast cancer cells indicated by the suppression of expression of Akt, VEGF, and ERK in MDA-MB-231 cells.Furthermore, C. japonicum extract exhibited an antiproliferative effect in MCF-7 cancer cells by restricting the cell cycle in the G1 phase and also triggered cell death by influencing mitochondrial apoptotic pathways [100].Triterpenes present in Cirsium setosum revealed moderate cytotoxicity against human colon and ovarian cancer cells.[101], while 3β-Hydroxy-22-oxo-20-dandelion-30-oleic acid displayed a potent selective inhibition on the ovarian tumor cell line A2780 [110].Silybin, derived from Cirsium japonicum, hindered gastric cancer cells by reducing the production of cell cycle proteins and blocking gastric tumor cells in the G2/M phase, which ultimately resulted in apoptosis (Figure 12) [111].

Oviposition Stimulatory Activity
Treatment of roots essential oil of C. japonicum induced the oviposition in Ostrinia zealis (Table 5).It was observed that root essential oil of plants contains majorly Aplotaxene, which might serve as a stimulator of oviposition [41].In another investigation, treatment of C. japonicum extract to ovariectomized rats caused a marked decline in cholesterol, body weight, and triglyceride, as well as remarkable enhancement in estradiol and bone mineral density.Moreover, Molecular docking studies revealed that the active phytoconstituents of C. japonicum have a binding affinity with the ligand-binding sites of the estrogen receptor.It indicated the potential of C. japonicum extract in the relief of symptoms of pre-menopause and post-menopause [100].
present in Cirsium setosum revealed moderate cytotoxicity against human colon and ovarian cancer cells.[101], while 3β-Hydroxy-22-oxo-20-dandelion-30-oleic acid displayed a potent selective inhibition on the ovarian tumor cell line A2780 [110].Silybin, derived from Cirsium japonicum, hindered gastric cancer cells by reducing the production of cell cycle proteins and blocking gastric tumor cells in the G2/M phase, which ultimately resulted in apoptosis (Figure 12) [111].

Anti-Anxiety Effect
The ethanolic extract of Cirsium japonicum was screened for the anti-anxiety effect in mice.The extract of C. japonicum showed no effect on the movement of mice in the open-field test.However, it increased the exploration in the undefended center zone.Administration of plant extract also enhanced the duration of mice in the elevated plusmaze test, which pointed out that the Cirsium japonicum exhibited anti-anxiety properties.It was observed that C. japonicum's anti-anxiety effects were equivalent to those of the benzodiazepine.Further, the anti-anxiety effect of C. japonicum was confirmed by examining its effect on human neuroblastoma cells.Treatment of C. japonicum upregulated the influx of chloride ions in neuroblastoma cells in a concentration-dependent manner, which was reduced by coadministration of bicuculline [112].In another investigation, C. japonicum had an antidepressant-like impact on mice in the forced-swimming test by dramatically lowering immobility.It was observed that administration of C. japonicum did not boost the locomotor activity in the open field test.Moreover, it enhanced the influx of Cl-ions without affecting the uptake of monoamine in mammalian neuroblastoma cells.Only Luteolin, one of the active components of the C. japonicum extract, revealed similar antidepressant-like effects.Therefore, the antidepressant-like action of C. japonicum extract was believed to be due to the presence of luteolin in it [113].

Nephroprotective
Cirsium is nephroprotective in nature, as it shields the kidney from various toxins (Table 5).Pectolinarin and flavones purified from Cirsium japonicum were studied for their nephroprotective activity in diabetic rats induced by streptozotocin followed by a highcarbohydrate/high-fat diet.Both flavones exhibited antidiabetic activity in rats.However, a combination of Pectolinarin and 5,7-Dihydroxy-6,4'-dimethoxy flavone in diabetic rats was found to be more potent in the reduction of Cholesterol, Glucose, and Triglycerides.Treatment of flavones in diabetic rats caused the reversal of abnormal levels of glucose metabolism-related enzymes.It increased the concentration of adiponectin in diabetic rats, but there was no discernible impact of the flavones on the abnormal concentration of insulin or leptin and glucose transporter 4 [108].Moreover, Cirsium japonicum flavones improved adipocyte development by enhancing the levels of PPARγ.It enhanced the insulin-induced glucose intake in adipocytes, which is probably due to the more levels of adiponectin and GLUT4 [109].In another study, the glucosidase enzyme is inhibited by taraxastane-type triterpenoids derived from Cirsium setosum [110].Additionally, the leaves of Cirsium maackii and its flavonoids showed an antidiabetic effect by hampering the production of glycation end products [114].

Other Therapeutic Effects
Treatment with C. japonicum (50-100 mg/kg/day) enhanced cognitive skills by diminishing the oxidative stress in amyloid β-peptide-induced mice, and it can be utilized as a potent agent for the cure of Alzheimer's disease (Figure 13).In addition to it, many investigators have examined the hemostatic action and mechanism of different Cirsium species.Administration of Cirsium setosum extract exhibited a substantial activity on hemostasis, blood coagulation, and hemorrhage in rats [115,116].Wang (2018) also reported the hemostatic action of nano-scale constituents in Cirsium charcoal [117].Moreover, Shikokiol A obtained from C. nipponicum roots was tested in vitro for enzyme inhibitory activities.It was observed to be a potent inhibitor of the non-heme iron-containing enzyme, i.e., lipoxygenase, in guinea pig tracheal contraction [118,119].
Chemistry 2022, 4, FOR PEER REVIEW 22 Administration of Cirsium setosum extract exhibited a substantial activity on hemostasis, blood coagulation, and hemorrhage in rats [115,116].Wang (2018) also reported the hemostatic action of nano-scale constituents in Cirsium charcoal [117].Moreover, Shikokiol A obtained from C. nipponicum roots was tested in vitro for enzyme inhibitory activities.It was observed to be a potent inhibitor of the non-heme iron-containing enzyme, i.e., lipoxygenase, in guinea pig tracheal contraction [118,119].The C. sipyleum, C. leucopsis, and C. eriophorum exhibited 16-57% inhibition against acetyl-and butyryl-cholinesterase activity [21,105].Similarly, Lee et al. [54] showed that ethanolic fraction and flavonoids of C. japonicum displayed aldose reductase inhibition activity with IC50 values of 0.21 μg/mL and 0.77 μM, respectively [54].In another study, Cirsium japonicum and its constituent apigenin caused a marked reduction in the expression of Hif-2α and decreased the levels of metalloproteinases and cyclooxygenases in chondrocytes.This study depicted the potential of Cirsium japonicum and its constituents for the development of therapeutics for hindering osteoarthritis [104].The extracts of C. japonicum hindered the adipogenesis in adipocytes by diminishing the concentration of triglycerol.The chloroform fraction of C. japonicum was observed to reveal the maximum inhibition of adipocyte differentiation.The extract downregulated the expression of lipoprotein lipase, PPARγ, adiponectin, and fatty acid synthetase intricated in adipogenesis.Therefore, C. japonicum extract can be used as an ideal candidate for the treatment of obesity [120].

Herbal Formulations and Clinical Trials
MS-10, a formulation of Cirsium and Thyme extract, was examined on 71 premeno- The C. sipyleum, C. leucopsis, and C. eriophorum exhibited 16-57% inhibition against acetyl-and butyryl-cholinesterase activity [21,105].Similarly, Lee et al. [54] showed that ethanolic fraction and flavonoids of C. japonicum displayed aldose reductase inhibition activity with IC 50 values of 0.21 µg/mL and 0.77 µM, respectively [54].In another study, Cirsium japonicum and its constituent apigenin caused a marked reduction in the expression of Hif-2α and decreased the levels of metalloproteinases and cyclooxygenases in chondrocytes.This study depicted the potential of Cirsium japonicum and its constituents for the development of therapeutics for hindering osteoarthritis [104].The extracts of C. japonicum hindered the adipogenesis in adipocytes by diminishing the concentration of triglycerol.The chloroform fraction of C. japonicum was observed to reveal the maximum inhibition of adipocyte differentiation.The extract downregulated the expression of lipoprotein lipase, PPARγ, adiponectin, and fatty acid synthetase intricated in adipogenesis.Therefore, C. japonicum extract can be used as an ideal candidate for the treatment of obesity [120].

Herbal Formulations and Clinical Trials
MS-10, a formulation of Cirsium and Thyme extract, was examined on 71 premenopausal women for 28 and 84 days in a randomized, double-blind clinical trial.Treatment of MS-10 significantly reduced the onset of menopause by 48%.Moreover, MS-10 enhanced the insulinlike growth factor-1 (IGF-1) and estrogen, which might show protective inhibitory effects on menopause and aging in women.MS-10 also promoted bone health in women by increasing bone formation and absorption indicators such as osteocalcin, alkaline phosphatase, collagen, and N-telopeptides of type I collagen.It was observed that MS-10 therapy improved the levels of cortisol and upgraded the psychological well-being index in women [121].Another herbal formulation, Fufang Zhenzhu Tiaozhi (FTZ), contains Ligustrum lucidum, Citrus medica, Coptis chinensis, Atractylodes macrocephala, Panax, Cirsium japonicum, Salvia miltiorrhiza, and Eucommia ulmoides [122].FTZ has been employed clinically for the cure of hyperlipidemia, diabetes, osteoporosis, and atherosclerosis [123,124].Zhang et al. [125] reported that the FTZ treatment lessened cardiac hypertrophy in mice through the downregulation of expression of miR-214 and upregulation of SIRT3 expression.Several studies indicated the therapeutic potential of FTZ is linked to a variety of pharmacotherapeutic activities [126,127].Moreover, various human and animal studies demonstrated that FTZ has an excellent ability to reduce total cholesterol, triglyceride in the blood.This formulation also exhibited protective action against metabolic diseases such as atherosclerosis, hyperlipidemia, and hepatic infections by modifying the concentration of glucose and lipids in the blood [128,129].Diao et al. (129) demonstrated that FTZ decreased atherosclerosis by hindering endothelial-mesenchymal transition through the β-catenin pathway.Treatment of FTZ bettered dyslipidemia and dysfunctioning of endothelial cells in the atherosclerotic mice.Moreover, FTZ administration caused the reduction of total bad cholesterol and boosted HDL.It also enhanced the levels of endothelial markers such as CD31 and cadherin and diminished the mesenchymal markers, signifying that it impeded the endothelial-mesenchymal transition.
In another study, the protective efficacy of FTZ was determined in a mouse model of Polycystic ovary syndrome (PCOS).It was found that FTZ remarkably increased the levels of adiponectin, thus modifying adipose-ovary crosstalk to decline PCOS.Moreover, the administration of FTZ decreased the disruption of the estrous cycle, cystic follicles, and insulin resistance [96].In another investigation, Yang et al. [130] described that FTZ repressed renal inflammation and fibrosis by the suppression of NF-κB and IL-17.Administration of FTZ also reduced the levels of urea, glucose, triglycerides, cholesterol, fibronectin, and collagen.Similarly, a multicenter, randomized, double-blind trial also reported the protective potential of FTZ on diabetic coronary heart disease [131].In another clinical study, flower extract of Cirsium japonicum improved the wrinkles and elasticity of the skin, and it can be preferred as an active component of antiaging cosmetics [132].

Patents
A formulation comprising Cirsium japonicum extract as a potent agent for the induction of melanogenesis: The melanogenesis-stimulating formulation includes Cirsium japonicum extract as an active component, and this composition can be safely utilized for the prevention and treatment of vitiligo, white hair, or hypopigmentation [133].
A process for the cure of fatty liver: A method was designed for the preparation of hepatoprotective formulation from the extract of Cirsium (Table 6) [134].
A method for the enhancement of Lipolysis: The extracts of Cirsium showed huge lipolysis when orally administrated or dermatologically apply through local administration.It pointed out the potential of Cirsium in the control and treatment of obesity [135].
Anti-acne formulation: A composition was prepared from Quercus robur, Sesamum indicum, Houttuynia cordata, Cirsium japonicum, and Thuja orientalis as potent agents for the cure of acne.This composition revealed maximum antibacterial activity against C. acnes [136].Enhancer and moisturizer of Ceramide production: Composition containing Cirsium japonicum singly or in combination with Chenopodium hybridum, Melia toosendan, Indigofera tinctoria, Catalpa ovata, and Tagetes erecta showed an excellent capacity for the enhancement of ceramide [137].

Pharmacokinetics
Pharmacokinetics serves a critical role in preclinical drug development, screening of toxicity of the drug, and optimization of the concentration of the drug.It is measured as an effective way of detecting the potential active constituents and explaining the mode of action of plants or drug formulations.So far, there are very few scientific investigations in the literature on the pharmacokinetic behavior of Cirsium.A liquid chromatography-mass spectrometry (LC-MS) technique was employed to monitor the different flavonoids of C. setosum in rat plasma.It was observed that Rutin, Acacetin, Naringin, Wogonin, and Quercetin were the long-acting constituents of the C. setosum, with more elimination time and bioavailability [138].
Similarly, Zhang et al. [139] detected twenty-seven flavonoids in the blood, bile, and urine of rats after the administration of Cirsium japonicum through the UPLC-MS.In another study, after treatment with the extract of Cirsium japonicum in rats, the maximum concentration of Linarin, Pectolinarigenin, Hispidulin, Pectolinarin, Diosmetin, Acacetin, and Apigenin in plasma was observed to be 86 ng/mL, 6 ng/mL, 32 ng/mL, 876 ng/mL, 37 ng/mL, 19 ng/mL and 148 ng/mL, respectively.Pectolinarin, Linarin, Pectolinarigenin, Hispidulin, Diosmetin, and Acacetin were absorbed rapidly and reached their maximum concentration in plasma in five minutes (Table 7).However, Apigenin was absorbed slowly and reached its maximum concentration after 360 min of its administration [140].

Toxicology
A systemic safety study of Cirsium extract is required for the expansion of novel pharmaceuticals or drugs.Oral administration of C. setidens extract in rats for 28 days at the dose of 1.25, 2.5, and 5 g/kg body weight did not exhibit significant toxicological alterations such as mortality, hematology, and biochemical parameters.Treatment of C. setidens extract revealed normal histological architecture of the liver, heart, spleen, and kidney, which indicated the wide safety index of the plant extract [141].Similarly, treatment with extract of C. japonicum at the concentration of 2 g/kg body weight for 15 days revealed no marked toxic effects and mutagenicity [142].

Nanoformulations of Cirsium
Shin et al. [143] examined the C. setidens-derived selenium nanoformulations for their protective potential against oxidative stress.The nanoparticles of C. setidens extract unveiled zeta potential of −27.4 mV with a particle size of 117.8 nm.It was noticed that nanoformulation of C. setidens extract displayed more antioxidant and antibacterial activities as compared to the alone C. setidens extract.In addition to it, nanoformulation of C. setidens was observed to be harmless to normal fibroblast cell lines.However, they showed marked cytotoxic effects against A549 mammalian lung cancer cells through rupturing the mitochondrial membrane and nucleus [143].Moreover, C. arvense-derived silver nanoparticles showed robust protective activity against Escherichia coli [144,145].In another investigation, Cirsium vulgare-derived cobalt oxide nanoparticles augmented the electrocatalytic action for the monitoring of cysteine [146].Moreover, C. japonicum extract served as a reducing and stabilizing agent for the synthesis of nontoxic silver nanoparticles.These silver nanoparticles showed 98% degradation of bromo phenyl blue in twelve minutes, which indicated the robust reductive potential of silver nanoparticles in the water cleansing and altering some organic harmful compounds to harmless components.In another investigation, Cirsium arvense derived copper nanoparticles (CA-CuNP) were examined for antibacterial and photocatalytic properties.CA-CuNP showed the photocatalytic potential and caused the complete degradation of Rhodamine B in thirty minutes.CA-CuNP exhibited microbicidal potential by hindering the growth rate of S. aureus and E. coli and displayed zone of inhibition 18 mm and 21 mm respectively [147,148].In addition to it, water extract of Cirsium setosum carbonisata (CSC) was used for the synthesis of carbon dots (CD), which were spherical and even in size and unveiled a little noxiousness against macrophage cells.Moreover, tail and liver bleeding experiments showed a lower bleeding time in CSC-CD-treated mice in contrast to normal saline-treated mice.It was noticed that CSC-CD can enhance the extrinsic blood coagulation pathway and stimulate the fibrinogen proteins, which are projected towards the hemostatic effect of CSC-CD [149].

Conclusions and Future Perspectives
The Cirsium genus has been given a lot of attention due to its widespread usage in traditional medicine.The chemical compounds extracted from the Cirsium genus include mostly flavonoids, phenylpropanoids, and triterpenoids, which contribute to the multiple medicinal properties.From a phytochemical standpoint, a wide range of chemical structures have been identified from Cirsium species of varying distribution, which can result in a variety of biological effects.The current review suggests a wide range of potential applications of Cirsium in the field of pharmaceuticals, cosmetics, and health foods.Pharmacological studies revealed that Cirsium species have several biological activities, such as hepatoprotective, antibacterial, antioxidant, antitumor, and anti-inflammatory, which tends to untangle the various traditional applications of the Cirsium genus.The phytochemical studies of different Cirsium species and their renowned pharmacological activities could be exploited for pharmaceutic product development in the future.Furthermore, studies are required on less known Cirsium species, particularly on the elucidation of the mode of action of their biological activities.Further investigations should be carried out on pharmacodynamics, pharmacokinetics, and quality control system for Cirsium, which is critical for broadening its medicinal potential in the future.Moreover, the toxic and safe profile of Cirsium has not been well investigated; thus, further research is needed in this domain.

Figure 1 .
Figure 1.The botanical classification of the genus Cirsium.

Figure 1 .
Figure 1.The botanical classification of the genus Cirsium.

7 Figure 3 .
Figure 3. Commonly found flavonoids in different species of Cirsium.

Figure 3 .
Figure 3. Commonly found flavonoids in different species of Cirsium.

Figure 5 .
Figure 5. Major flavone glucoside detected in different species of Cirsium.

Figure 5 .
Figure 5. Major flavone glucoside detected in different species of Cirsium.Figure 5. Major flavone glucoside detected in different species of Cirsium.

Figure 5 .
Figure 5. Major flavone glucoside detected in different species of Cirsium.Figure 5. Major flavone glucoside detected in different species of Cirsium.

Figure 7 .
Figure 7. Terpenoids found in different species of Cirsium.

Figure 8 .
Figure 8. Major sterols identified in different species of Cirsium.

Figure 9 .
Figure 9. Major phenolic acids found in different species of Cirsium.

Figure 8 .
Figure 8. Major sterols identified in different species of Cirsium.

Figure 9 .
Figure 9. Major phenolic acids found in different species of Cirsium.

Figure 9 .
Figure 9. Major phenolic acids found in different species of Cirsium.

Figure 12 .
Figure 12.Mode of action of Silybin against gastric cancer.Figure 12. Mode of action of Silybin against gastric cancer.

Figure 12 .
Figure 12.Mode of action of Silybin against gastric cancer.Figure 12. Mode of action of Silybin against gastric cancer.

Figure 13 .
Figure 13.Mode of action of Cirsium species against Alzheimer's disease.

Figure 13 .
Figure 13.Mode of action of Cirsium species against Alzheimer's disease.

Table 1 .
Distribution and pharmacological potential of some species of Cirsium.

Table 1 .
Distribution and pharmacological potential of some species of Cirsium.

Table 2 .
Major phytoconstituents present in various species of Cirsium.

Table 2 .
Major phytoconstituents present in various species of Cirsium.

Table 3 .
Antimicrobial and antioxidant potential of different Cirsium species.

Table 4 .
Anticancer and anti-inflammatory activities of Cirsium species.

Table 5 .
Other pharmacological activities of Cirsium species.

Table 6 .
Details of patents of Cirsium.

Table 7 .
Pharmacokinetic information of Cirsium in vivo.