Traditional uses and phytopharmacology of Cirsium arvense : Bioprospecting potential of a weed from temperate biome

Cirsium arvense , a noxious weed of the Asteraceae family, has potential medicinal benefits. Traditionally, it has been used to cure ulcers, mouth infections, leukemia, dentalgia, canker sores, pharyngitis, and other ailments. Alkaloids, flavonoids, tannins, and diverse phytoconstituents are associated with its therapeutic potential. This review article sheds light on C. arvense ’s taxonomy, geographical distribution, ethnomedicinal uses, and phytopharmacology. Despite its weedy nature, it has been a rich source of phytoconstituents, which is evident from its antimicrobial (against Gram positive and negative strains), antioxidant (2,2-diphenyl-1-picrylhydrazyl and others), and antiproliferative (HeLa, A43, and MCF7 cell lines) potential. Hispidulin, luteolin, and tracin, isolated from C. arvense were reported to be with antibacterial potential. Based on its bioactive components, a proposed mechanism for antibacterial action is also highlighted. A toxicity study revealed that the aerial parts of C. arvense are toxic (LC 50 of 51 µg/ml). Bioprospecting of this weed after detailed follow-up studies will help manage C. arvense in the future.

39].The infusion or extract of the whole plant is used for the cure of mouth infections by North American Indian tribals and is considered to be useful as an astringent, diuretic, and health-promoting tonic [21,27,40].
Also, root decoction is used as an anthelmintic, astringent, diuretic, tonic, and remedy against hepatic disorders and intestinal worms [23,41,42].David [41] documented the use of syrup from the roots to alleviate cough, while root juice is used to cure diabetes and jaundice and against snake bites [34,[43][44][45][46].The roots paste mixed with Amaranthus spinosus is given in case of indigestion [47].Leaf juice and tea are employed for treating tuberculosis, piles, eye pain, skin-related problems, wounds, and urogenital diseases [41,44,45,48].Subsequently, leaves paste is applied to heal boils [30].Leaves are chewed to relieve toothache and sore throat because of their anti-inflammatory properties [21,27].A mixture of the roots and leaves is used for oral disorders, toothache, diarrhea, dysentery, tuberculosis, and hepatic disorders [41,42,45,49].The tincture of the leaves and flowers has been recommended against dermatitis [50].

Culinary uses
The foliage of C. arvense and aromatic seeds are used as food [37,53] due to their significant content of vitamins, minerals, and fibers [21,27].The raw or cooked soft roots are eaten with other vegetables and used as drought food [54,55].The peeled stem is cooked like Asparagus, while the leaves are used raw or cooked [54].
in the 1600s and the southern hemisphere [20].It is often found in grasslands and riparian habitats.Even as a weed, C. arvense is known for its medicinal properties [21,22].For example, plant decoction is a remedy for epistaxis, gastrointestinal disorders, hemorrhage, hypertension, metrorrhagia, pyogenic infections, scabies, ulcers, and skin diseases [23,24].Additionally, C. arvense was reported as an antimicrobial and antioxidant agent, and its potential is attributed to the presence of flavonoids, alkaloids, steroids, and saponins [21,[25][26][27].
Previously published review articles were primarily focused on the consequences of C. arvense's spread as a perennial weed in European countries, as well as control measures [28].Further, reviews are available on medicinal properties, phytochemical and pharmacological studies of the genus Cirsium, and different species [29].So, in this review, we endeavored to study C. arvense's ethnomedicinal uses, phytochemistry, and pharmacology.The primary goal of this review is to explore C. arvense as an economically significant plant that can provide a way to bioprospect this weed and open new doors for future research in different areas.
Cirsium arvense grows in diverse habitats (ranging from moist places to grasslands, mountain slopes, flooded lands, disturbed sites, etc.) at 100-4,300 m [31].Its native range is Temperate Eurasia, Northwest Africa.It has been introduced into North America, South America, Africa, Europe, Asia, Australia, and other regions, as shown in Figure 2 [8].

TRADITIONAL USES OF C. ARVENSE
In light of existing literature, several studies have reported the ethnomedicinal and culinary uses of C. arvense.A brief overview of the ethnomedicinal uses of C. arvense has been depicted in Table 1.

Ethnomedicinal uses
Various ethnobotanical studies have recognized the therapeutic and health-promoting uses of the whole plant of C. arvense [32].In North America, C. arvense (whole plant) is used as a remedy against cirrhosis, lipoma, liver cancer, and gout [33,34].Further, a decoction of the plant is used for the treatment of gastrointestinal disorders, hypertension, hemorrhage, lung troubles, epistaxis, hematemesis, ulcers, scabies, metrorrhagia, pyogenic infections, and various types of skin diseases [23,24,35- O n l i n e F i r s t

PHARMACOLOGICAL PROFILE OF C. ARVENSE
The plant contains many phytoconstituents that have shown potential towards various bacterial strains, cancer cells, fungi, and also against free radicals.The validation of ethnomedicinal information by utilizing evidence-based pharmacological studies is necessary.Toxicity studies should support biological activities to assure the safety and efficacy of herbal medicine.This weed is not much explored; only a few studies, like antimicrobial, antioxidant, and antiproliferative are available in light of existing literature.

Antioxidant activity
Antioxidants are the molecules that can scavenge free radicals or reactive oxygen species (ROS) like superoxide (O   O n l i n e F i r s t in oxidative stress and multiple diseases [65].Antioxidants are crucial for inhibiting oxidative reactions and removing ROS or neutralizing harmful effects of ROS in the body [66].In this context, the crude extract from leaves, flowers, and roots of C. arvense displayed in vitro antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, superoxide anion radical, and also in ferric reducing antioxidant power assay [67].values of 92, 118, 142, 110, and 100 μg/ml, respectively [27].
On the other hand, the aqueous extract from C. arvense leaves exhibited antioxidant activity with total antioxidant status of 2.74 m/ml [68].The crude methanol extract of C. arvense inflorescence and leaves and its fractions (chloroform, diethyl ether, ethyl acetate, and n-butanol) were also evaluated for antioxidant activity.With a total antioxidant status of 1.76-2.69mM/l, all fractions demonstrated antioxidant activity.The inflorescences' butanol and leaves' ethyl acetate fractions were observed to be the most active [69].Cirsium arvense is reported to have antioxidant potential, but further studies (in vitro and in vivo) are warranted to validate this potential.

Antiproliferative activity
In vitro antiproliferative activity of different extracts (chloroform, n-hexane, aqueous methanol, and O n l i n e F i r s t and withstand antibiotics' lethal or biostatic effects [74].Efflux pump (groups of transporter proteins) hyperactivity contributes to drug resistance; it extrudes drugs from cells to the external environment and reduces the antibiotic concentration inside [75][76][77][78].Figure 4 displays antibiotic resistance mechanisms and a suggested strategy (based on existing literature) accentuating the antibacterial activity of C. arvense's phytoconstituents.
The enzymatic resistance mechanism involves a range of bacterial enzymes generated against distinct antibiotics, which cause structural modifications of antibiotics by hydrolysis or transferring functional groups, decreasing their efficiency [78].In addition, bacteria acquire resistance via porin channel impairment (outer membrane protein alteration), thereby reducing the uptake of antibiotics [76,78].The mutation in bacterial DNA and biofilm formation can also confer antimicrobial resistance [73,76,78,79].
The utilization of herbal remedies against bacterial strains resistant to antibiotics has recently grown.Many plants possess antibacterial chemicals that can work alone or with antibiotics [80].Likewise, to other medicinal plants, C. arvense aerial parts contain antibacterial compounds like hispidulin, luteolin, and tracin, which might help manage antibiotic resistance.Additionally, acacetin, apigenin, and citronellol are the active constituents observed in C. arvense, have already been reported in the literature as antimicrobials [81][82][83].Therefore, these compounds from C. arvense, alone or in combination with antibiotics, can manage drug resistance by inhibiting hyperactivity of the efflux pump, drug-inactivating enzymes, cell wall protein alteration, DNA, RNA, and protein synthesis.
The compounds hispidulin, tracin, 9,12,15-octadecatrienoic acid, α-tocopherol, and luteolin (1,000 μg/ml) from the C. arvense were screened for antimicrobial activity against bacteria (E.coli, B. subtilis, S. flexneri, S. aureus, Salmonella typhi, and P. aeruginosa) and fungi (C.albicans, C. glabrata, Trichophyton longifusus, Aspergillus flavus, Fusarium solani, and Microsporum canis).All tested compounds showed activity against tested microbial strains with IZD ranging between 9 and 34 mm.Tracin was observed to be most effective against B. subtilis.In contrast, luteolin and α-tocopherol were effective against M. canis with IZD 13-36 mm, whereas hispidulin was highly active against F. solani.Ashmita et al. [59] also observed the antimicrobial activity of compounds arvense A-B.All these studies support the antimicrobial potential C. arvense; however, most studies have only presented qualitative data, and quantitative studies with MIC are still required.

Mechanistic insights into antibacterial potential
Antibiotic resistance has grown to be a serious global concern.Drug-resistant infections are mainly brought on by the improper use and overuse of antibiotics [72].Antibacterial drugs disrupt bacterial membranes and inhibit DNA, RNA, and protein synthesis [73].Bacterial strains are constantly devising new mechanisms through many processes to adapt O n l i n e F i r s t (LC 50 0.44 µg/ml) [71].More in vitro, in vivo, and clinical studies are required to assess the toxicity of this weed, as it is critical to focus research on the plant's safety and efficacy to use it adequately.

BIOPROSPECTING OF C. ARVENSE
Cirsium arvense is a widespread weed, but its potential for bioprospecting was not explicitly addressed.Despite being seen as an invasive plant in agricultural fields, C. arvense extracts have strong antioxidant properties, making them a viable source of antioxidants [67].Its antimicrobial activity has also been investigated; tracin, hispidulin, and luteolin have antibacterial and antifungal effects [58].Iranian C. arvense extracts displayed antibacterial efficacy against various bacterial strains [40].Cirsium arvense was employed to generate silver nanoparticles with a high biological value and better E. coli inhibition activity [84].Diverse phytoconstituents were responsible for the synthesis and biological activity of plant-mediated nanoparticles, as evidenced by several reports [85][86][87][88][89].Therefore, C. arvense's varied phytocomposition can be used in the future.However, in Tasmania, C. arvense root and foliage extracts prevented the germination and growth of several plant species, which may make it difficult for pasture and crop species to establish in C. arvense-infested environments [90].Although its weeding potential may restrict its uses, but the biological potential of this opens up a new avenue for bioprospecting.

CONCLUSION AND FUTURE PERSPECTIVES
Cirsium arvense is a globally distributed weed that grows in various habitats.Ethnomedicinally, the plant is employed against gastrointestinal ailments, hypertension, bleeding, metrorrhagia, scabies, pyogenic infections, ulcers, and skin infections.Kaempferol-3-O-β-D-glucopyranoside, quercetin-3-O-β-D-glucopyranoside, hispidulin-7-O-β-D-glucopyranoside, luteolin-5-O-β-D-glucopyranoside, caffeic acid, chlorogenic acid, enicin, rutin, stigmasterol, and acacetin represent diverse phytocomposition of this weed.The current review study highlighted antioxidant, antibacterial, and antiproliferative activities.The major limitation of the antimicrobial studies is that researchers did not reported MIC, as IZD evaluation is only a preliminary study.Cirsium arvense extracts' antiproliferative ability against HeLa, A43, and MCF7 cell lines was evaluated, but vast research is still necessary.Although C. arvense has been utilized in various ethnomedicines, its pharmacological potential has yet to be thoroughly investigated, especially its toxicity (LC 50 51 µg/ml).
radical ( • OH), hydrogen peroxide (H 2 O2 ), and others.ROS are produced in a cell due to biochemical reactions and can adversely affect nucleic acids, lipids, and proteins, resulting