Traditional Uses, Bioactive Compounds, and Pharmacological Investigations of <i>Calendula arvensis</i> L.: A Comprehensive Review

Khouchlaa, Aya; El Baaboua, Aicha; El Moudden, Hamza; Lakhdar, Fatima; Bakrim, Saad; El Menyiy, Naoual; Belmehdi, Omar; Harhar, Hicham; El Omari, Nasreddine; Balahbib, Abdelaali; Park, Moon Nyeo; Zengin, Gokhan; Kim, Bonglee; Bouyahya, Abdelhakim

doi:https://doi.org/10.1155/2023/2482544

Advances in Pharmacological and Pharmaceutical Sciences

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Review Article | Open Access

Volume 2023 | Article ID 2482544 | https://doi.org/10.1155/2023/2482544

Traditional Uses, Bioactive Compounds, and Pharmacological Investigations of Calendula arvensis L.: A Comprehensive Review

Aya Khouchlaa,¹Aicha El Baaboua,²Hamza El Moudden,³Fatima Lakhdar,⁴Saad Bakrim,⁵Naoual El Menyiy,⁶Omar Belmehdi,²Hicham Harhar,⁷Nasreddine El Omari,⁸Abdelaali Balahbib,⁹Moon Nyeo Park,¹⁰and Gokhan Zengin¹¹ et al.

Academic Editor: Kuldeep Singh

Received18 Jun 2022

Revised06 Oct 2022

Accepted10 Dec 2022

Published03 Jan 2023

Abstract

Calendula arvensis L. (Asteraceae) is a famous ornamental and medicinal plant widely distributed in Mediterranean countries and the southern region of Europe. This reputed species is widely used in traditional medicine in the treatment of many disorders and has various bioactivities, especially anti-inflammatory, antiviral, antimutagenic, antimicrobial, insecticidal, antioxidant, and immunomodulatory activities. The present review was conducted to provide a critical review of the comprehensive and current knowledge regarding C. arvensis species, in particular, its taxonomy and geographical distribution, botanical description, medicinal uses, phytochemical compounds, pharmacological properties, and toxicity investigations. The data collected on C. arvensis were obtained using different scientific research databases such as PubMed, SciFinder, SpringerLink, Web of Science, Science Direct, Google Scholar, Wiley Online, and Scopus. Phytochemical screening of different C. arvensis extracts and essential oils showed their richness in bioactive compounds, particularly in fatty acids, sterols, phenolics, flavonoids, saponins, tannins, alkaloids, and terpenoid compounds. The findings of this review showed that the pharmacological activities of C. arvensis confirm its importance and diversity as a traditional remedy for many diseases. This plant presents a wide range of bioactivities, namely, anti-inflammatory, antimicrobial, antitrypanosomial, antitumoral, antimutagenic, and immunomodulatory activities, as well as hemolytic properties and wound treatment. Nevertheless, pharmacokinetic validation and toxicological examinations are required to detect any possible toxicity for future clinical trials.

1. Introduction

C. arvensis, commonly known as “marigold,” is one of the important medicinal herbs belonging to the Calenduleae tribe of the Asteraceae family [1]. It is widely distributed in Mediterranean countries as a native plant [2], usually indigenous to the southern region of Europe, namely Spain, Portugal, Portugal, Turkey, Greece, Malta, and Italy [3], and also cultivated in other parts of the globe such as California and Australia [4]. It is an annual herbaceous plant reaching 100 cm in height [5] and it grows in waste grounds, vineyards, and fields [4]. Its leaves are lance-shaped and have tectorial and secretory trichomes. The inflorescence consists of a single flower head reaching 4 cm with yellow or yellow-orange capitula (blossoms are synthesized throughout the year, but the flowering peaks are between March and July) [6, 7]. Based on the polymorphism of stems, flowers, and achenes, several subspecies were assigned to C. arvensis [7], namely, C. arvensis var. parviflora, C. arvensis subsp. hydruntina, C. arvensis subsp. macroptera, and C. arvensis subsp. arvensis [8]. C. arvensis is distinguished from others by the presence of rostrate/bialate [4]. The karyological evidence on C. arvensis revealed a 2n = 44 and a genome size of 5.41 pg [4, 9]. Phytochemical screening of several essential oils (EOs) and extracts isolated from different parts of C. arvensis demonstrated the abundance of bioactive compounds in this plant. These include alkaloids, tannins, saponins, flavonoids, phenolic compounds, sterols, and fatty acids [10–13]. The phytochemical content of C. avensis flowers was characterized by a high content of linoleic acid, palmitic acid, and linolenic acid in the extract [10]. The volatile compounds identified from steam distillation extraction of C. arvensis were represented by aldehydes, esters, sulfur compounds, alkyl pyrazines, ketones (1-octen-3-one), lactones (δ-decalactone), and terpenoid compounds (α-terpineol and citronellol) [11]. In traditional herbal medicine, C. arvensis was reported to treat many disorders depending on the part used. It can be used as a cataplasm [14] and antidiabetic drug [15, 16], and also against neurological disorders, microbial affections, ENT (Ear, Nose, Throat) diseases, typhoid diseases [17], skin diseases [18], digestive disorders [19], high blood pressure [20], and rheumatic conditions [21], as well as an antispasmodic [22], antiemetic [23], antihelmintic, diaphoretic [18], and antifungal [24] agent.

In Morocco, C. arvensis is among the famous plants used in folk medicine, the flowers are the main part used in several regions to treat inflammation and infection in infusion [14, 16]. In addition, flowers and leaves are used as antidiabetic drugs in the northern regions of Morocco [15, 16, 25]. However, in the southern regions, C. arvensis is used in traditional medicine to treat neurological, microbial affection, ENT, and typhoid conditions [17], as well as in wound healing [26]. In European countries such as Spain, Italy, and Greece ethnobotanical surveys showed that the aerial part of this plant is used as an emmenagogue, aperitive [27], and ecchymotic [28], and also has an antiseptic effect [29]. Using decoction, the inflorescences have healing [30], emmenagogue, diaphoretic, diuretic, sedative, and anti-inflammatory effects [31]. In Turkey, the aerial part of C. arvensis was used as an infusion, mash, lotion, maceration, or oil to treat wounds, burns, and skin cancer, and also for skin care and athlete’s foot [32, 33]. The use of leaves and capitulum of this herbaceous plant can be used as a poultice to treat skin diseases. C. arvensis flower decoction was used for its hepatoprotective, germicide, and fungal effects [34]. In Asia, C. arvensis leaves and flowers in decoction oil form have traditional antirheumatic [21], astringent, and antispasmodic effects [35, 36], with expectorant properties, and also relieve varicose veins [35]. Moreover, these parts have anthelmintic effects and are used as a tonic and diaphoretic agents [37]. C. arvensis is an ornamental, medicinal, and industrial plant. Pharmacological investigation of C. arvensis leaf EOs and extracts has revealed a broad range of biological properties. Its phytochemical diversity has demonstrated varying levels of antimicrobial effect on various microorganisms. The antimicrobial effect of methanol/chloroform mixture extracts and aqueous extracts of C. arvensis leaves was assessed against six bacterial strains (Enterobacter aerogens, Bordetella bronchiseptica, Escherichia coli, Salmonella typhimurium, Staphylococcus aureus, and Bacillus subtilis) and five fungal strains (Aspergillus niger, Mucor spp., Aspergillus fumigatus, Fusarium solani, and Aspergillus flavus) [38–40]. Moreover, C. arvensis extract showed good antibacterial activity against Mycobacterium smegmatis with minimal inhibition concentration in the range of 13.2–62.5 μg [41]. Furthermore, C. arvensis aerial part EO showed antifungal activity against Aspergillus niger and Penicillium expansum [38] and did not show any interesting inhibitory effect against yeasts and dermatophyte strains [42]. Regarding the antiparasitic effect, the saponin substances arvensoside B and arvensoside D extracted from C. arvensis showed an impressive impact on the parasites of Trypanosoma brucei [43]. Additionally, several studies have proven that treatment with C. arvensis extracts has excellent anti-inflammatory potential by inhibiting edema formation and managing pain conditions [44, 45]. C. arvensis extracts and isolated molecules have also shown effective antioxidant activity in scavenging free radicals, as reported in several investigations [10, 46, 47]. On the other hand, various concentrations of the extracts of C. arvensis parts (leaves, stems, and flowers) using different solvents (methanol, ethyl acetate, chloroform, and hexane) recorded potent activities against the proliferation and growth of tumor cells, using a cancer cell model [10, 47, 48]. Enzymatic inhibitory effects of C. arvensis leaf and flower extracts have also been revealed and could be related to the presence of compounds derived from triterpenes and flavonoids identified in the different parts of this species [49]. Several other pharmacological activities of C. arvensis were also reported. As mentioned above, this medicinal herb could exhibit wound healing and immunomodulatory activities capable of activating lymphocytes and pronouncing blastogenesis and can be considered a potential immune booster [48].

2. Research Methodology

The data concerning distribution, botanical description, taxonomy, medicinal use, phytochemistry, and biological properties of Calendula arvensis were collected using several scientific search engines, including Wiley Online, SpringerLink, ScienceDirect, Scopus, Web of Science, PubMed, SciFinder, and Google Scholar. The data collected were then organized and classified to be explored and analyzed, and summarized in this work according to each field. For this bibliometric investigation, different keywords linked to Calendula arvensis were used, including Calendula arvensis, Calendula arvensis essential oils, Calendula arvensis extracts, and biological effects of Calendula arvensis. Regarding the phytochemical data, the IUPAC names of the identified phytochemicals were verified using the PubChem database. Bioactive compounds were designed using ChemDraw Pro 8.0 software.

3. Results and Discussion

3.1. Botanical Description

Calendula arvensis, as depicted in Figure 1, is an annual herb that can reach 100 cm in height [5]. The leaves are lance-shaped and possess secretory and tector trichomes. The inflorescence consists of a single flower head up to 4 cm with yellow or yellow-orange capitula (blossoms appear throughout the year, but flowering peaks between March and July) [6, 7]. The peripheral flowers of the capitula (ligulate) extend over several rows (verticils) and are female; central flowers (tubular) are complete but functionally male [6]. The achenes are only produced by the ligulate flowers. The pollen is echinate, tetracolporate and monadic. The shape of pollen in the equatorial view is circular to perprolate and the polar view is rectangular [50]. Thus, a complex polymorphism is related to the position of the flowers in the capitula, with three achene types (cymbiform, rostrate, and annula) (Figure 2), with a stem size of 5–60 cm and a leaf width of 5–20 mm [6]. Due to stem, flower, and achene polymorphism, different subspecies were assigned to C. arvensis [7], viz., C. arvensis var. parviflora, C. arvensis subsp. hydruntina, C. arvensis subsp. macroptera, and C. arvensis subsp. arvensis [8]. The karyological data on C. arvensis showed a 2n = 44 and a genome size of 5.41 pg [4, 9]. C. arvensis is differencied from others by the presence of bialate/rostrate [4].

3.2. Taxonomy and Geographic Distribution

C. arvensis belongs to the Calenduleae tribe of the Asteraceae family which includes about 25 annual and perennial species [1]. The genus Calendula consists of about 15 species in the Mediterranean, Saharo-Arabian, and Irano-Turanian regions [51], native to the Mediterranean countries [2] from Macaronesia to Southeast Asia [4], and generally native to the southern region of Europe, including Spain, Portugal, Turkey, Greece, Malta, and Italy [3]. The genus Calendula belongs to other parts of the globe such as California and Australia [4]. C. arvensis, a field marigold, is abundant in spring, annually, and weeds. It is found gregarious in field margins, graveyards, roadsides, wastelands, and open places [47]. It grows in waste grounds, vineyards, and fields [4].

3.3. Ethnomedicinal Use

Several ethnobotanical studies have marked the importance of C. arvensis in traditional medicine to treat many disorders. The traditional use of C. arvensis is related to the part used. Indeed, different parts of C. arvensis have traditionally been used to treat different diseases. Table 1 lists the application of C. arvensis in traditional pharmacopeia global systems.

The flowers represent the main used part in Moroccan traditional systems in several regions to heal various disorders. The population of the Targuist region (Northern Morocco) used the flowers of C. arvensis as a cataplasm against inflammation and infections [14]. The population of Rabat-Sale-Kenitra regions (Morocco) used flowers and leaves as an antidiabetic drug [15]. Also, the same use of this plant against diabetes was reported by an ethnobotanical study conducted in the Rif region (North of Morocco) [16] and in the Taza region (North-East of Morocco) [25]. Chaachouay et al. [16] reported the use of the flowers of C. arvensis in infusion, while Naceiri Mrabti et al. [25] reported the use of flowers and stems of C. arvensis in decoction. In the northwest of Morocco, the population of Oulad Daoud Zkhanine (Nador Province) used the decoction of whole plants against digestive disorders as well as for hair care [19]. Other ethnobotanical surveys, conducted in the Aguelmouss region (Khenifra Province, Morocco), have reported the importance of C. arvensis in traditional medicine, without mentioning the part used and the mode of preparation, in healing [26], and in the treatment of neurological and microbial conditions, and diseases related to ENT and typhoid [17]. These last two sections are important knowledge in the database ethnobotanical studies, which directs researchers to target a specific part in the purpose to elaborate the phytochemical screening. Thus, a standard form of ethnobotanical surveys is primordial to conserve traditional herbal remedies.

In Western Algeria, C. arvensis flowers in infusion were used for depurative, emmenagogue, and antispasmodic effects as well as for stimulating hepatic activity and bile secretion. By maceration, the leaves were used to treat internal ulcers, warts, fistulas, frostbite, calluses body, and skin lesions and to calm vomiting [60]. The flowers of the courant plant were used by the M’Zab Valley population (Algeria) to treat high blood pressure [20]. Another ethnobotanical survey in the Bissa region (north-east of the Dahra mountains in Algeria) indicated the therapeutic effects of C. arvensis leaves and roots on rheumatism [74]. In the mountains of Tlemcen (Western Algeria), this plant has been reported to exert disinfectant, anti-influenza, antitranspiration, and antihemorrhagic effects, as well as to treat hemostatic and hepatic actions [63], thus this plant is traditionally known in the Tiaret mountains (Western Algeria) as a depurative, emmenagogues, and antispasmodic [59].

The population of Alaşehir (Manisan, Turkey) and Sarigöl district (Manisa, Turkey) used the aerial part of C. arvensis as an infusion, mash, lotion, maceration, or oil to treat wounds, burns, skin cancer, and also for skin care and athlete’s foot [32, 33]. Uzun and Kaya [76] confirmed the use of leaves and capitulum of this plant by the population of Mihalgazi (Eskişehir, Turkey) as a poultice to treat skin diseases. The decoction of C. arvensis flowers was used by the Erzincan population (Turkey) as a germicidal, hepatoprotective, and fungal agent [34]. A recent ethnobotanical study conducted by Aslan et al. [24] reported the use of C. arvensis flower decoction as an antifungal by the population of Yaslıca town and Arıkök neighborhood in the Bozova district of Şanlıurfa province (Turkey). In Syria's western region (Tartus and Latakia), the aerial part of C. arvensis was used to treat varicose veins, sore eyes, wounds, sprains, stings, bites, and skin problems [72].

In European countries, several authors have reported the traditional use of C. arvensis to treat different illnesses. In Spain, C. arvensis aerial part was used as an emmenagogue and aperitive by the population of the Canary Islands [27]. In the same country, the inflorescence (in the form of a liniment) was effective against ecchymotic [28]. Gras et al. [29] showed that the aerial part of the C. arvensis bath exhibited an ocular antiseptic effect. As a poultice or infusion, the flowers of this plant were used in the villages of Lotzorai and Escolca (Sardinia, Italy) as antispasmodic and to treat burns [22]. In decoction, the inflorescences have a healing effect [30] as well as an emmenagogue, diaphoretic, diuretic, sedative, and anti-inflammatory effects [31]. In 2016, the population of the Mainarde Mountains (central-southern Apennine, Italy) used C. arvensis after maceration or as an ointment against burns, sunburn, chilblains, joint pain, and stings [62]. The flowers of C. arvensis have been used by the population of Bosnia and Herzegovina against lung and liver cancer, and skin disorders [73]. Another ethnobotanical study conducted in Greece, [61] showed that the flowers, stems, and leaves of C. arvensis were used to treat swollen areas, acne, and diaper rash.

In Pakistan, the traditional use of C. arvensis was confirmed by several ethnobotanical studies (Table 1). As a poultice, this species was consumed by the population of Tehsil Barawal, Upper Dir, Khyber Pakhtunkhwa (Pakistan) as a tonic and inflammatory agent against eye troubles and oral sores [53]. The flowers of C. arvensis were used by the population of Attock district (Pakistan) to strengthen eyesight, heart diseases and to heal the skin [55]. The same effects were confirmed by Rehman et al. [52] and Jan et al. [69] in the Khattak tribe population of Chonthra Karak (Pakistan) and by the Kohistan Valley population, Khyber Pakhtoonkhwa (Pakistan). Another ethnobotanical study of this plant in the tribal communities of North-West Frontier Province (Pakistan) indicated that the leaves of C. arvensis were used for wound healing [36, 54]. Khan et al. [70] confirmed the use of C. arvensis as a wound healer by the population of the Sawans Valley Mianwali, Punjab (Pakistan). This plant's flowers and leaves were used as stimulant, antispasmodic, astringent, healing wounds and injuries [67], as well as in the treatment of scrofula, diaphoretic, anthelmintic, discharge of mucus, and helminthic [64–66]. Other ethnobotanical studies showed that C. arvensis leaves and flowers in decoction oil form have traditional effects as antirheumatic (Tehsil Razzar District Swabi, Pakistan) [21], astringent, and antispasmodic [35, 36], with expectorant properties, and also to relieve varicose veins [35]. Ali et al. [37] showed that the Malam Jabba Valley population of Swat (Pakistan) used the leaves and flowers of C. arvensis as an anthelmintic, tonic, and diaphoretic agents. Other ethnobotanical studies at Madyan Valley in district Swat (Pakistan) Malam Jabba, Swat (Pakistan), the Jatlan Azad Jammu, Kashmir region (Pakistan), and the Azad Jammu And Kashmir state (Pakistan) confirmed the anthelmintic, tonic, and diaphoretic actions of C. arvensis [18, 23, 56, 57]. Leaves and flowers of C. arvensis have been known to be used in traditional pharmacopeia by the population of the Karak, Talash Valley of Lower Dir (Pakistan) and Khyber Pakhtunkhwa district (Pakistan) against toothache [58, 71, 78]. The leaves and shoots of C. arvensis were used by the population of Chagharzai Valley, district Buner (Pakistan) against skin diseases [75]. Recently, this plant's stems and leaves were used against diabetes in the South-West of Pakistan [77]. In 2020, the population of the Gujranwala region, Punjab (Pakistan) used the leaves and flowers as extract preparation mode to treat severe pains [68].

3.4. Phytochemistry

Medicinal plants secrete different chemical compounds as secondary metabolites, including terpenoids, flavonoids, phenolic acids, alkaloids, and others. These bioactive compounds exhibited several biotactical activities such as antimicrobial, anticancer, antidiabetic, anti-inflammatory, and antioxidant effects [79–83].

C. arvensis secondary metabolites were the subject of multiple works. Almost the majority of them have been on the aerial parts. Phytochemical screening of different C. arvensis extracts and essential oils showed their richness in biomolecules. These are most often fatty acids, sterols, phenolics, flavonoids, saponins, tannins, alkaloids, and terpenoid compounds (Table 2 and Figures 3–7).

(a)

(b)

Pizza and de Tommasi [84] isolated and determined the structure of four triterpenoid saponins from methanolic extract of C. arvensis aerial parts, these four compounds are 3-O-(β-D-galactopyranosyl-(1⟶3)-β-D-glucopyranosyl) oleanolic acid-28-O-β-D-glucopyranoside(1) (98 mg/2.2 g of MeOH extract); 3β-O-(β-D-galactopyranosyl-(1⟶3)-β-D-glucopyranosyl) oleanolic acid (2) (30 mg/2.2 g of MeOH extract); 3β-O-(β-D-galactopyranosyl-(1⟶3)-β-D-glucopyranosyluronic acid) oleanolic acid-28-O- β-D-glucopyranoside(3) (15 mg/2.2 g of MeOH extract) and 3β-O-(β-D-galactopyranosyl-(1⟶3)-β-D-glucopyranosyluronic acid) oleanolic acid (4) (10 mg/2.2 g of MeOH extract). A similar study was elaborated on the same saponin separation pathway in order to identify four compounds 4-O-(β-D-fucopyranosyl)-4-alloaromadendrole (5), and three derivatives of arvoside B. In addition, De Tommasi et al. [87] have isolated the same compounds and two other saponins which are 3-O-{β-D-ga1actopyranosyl-(1⟶3)(β-D-glucopyranosyl-(1⟶4))-β-D-glucopyranosyl}oleanolic acid (28⟶1)-β-D-glucopyranosyl ester (6) and 3-O-{β-D-ga1actopyranosyl-(1⟶3)(β-D-glucopyranosyl-(1⟶4))-β-D-glucopyranosyl}oleanolic acid (7) from the aerial parts of C. arvensi [87].

On the other hand, two new triterpenoid glycosides from C. arvensis aerial parts were identified as arvensoside A (8) and B (9) by FAB, FAB-MIKE mass spectrometry, and ¹³C NMR spectroscopy.

The study by Vidal-Ollivier et al. on C. arvensis was based on the chemical and physicochemical evidence to isolate four compounds, (8), (9), calenduloside C (10), and D (11) from fresh-aerial parts of C. arvensis, two saponosides of these four compounds showed anti-inflammatory activities.

De Tommasi et al. [87] reported several compounds, after analysis of chloroform extracts of C. arvensis aerial parts, compounds (1), (2), (3), (4), and 4-O-(β-D-fucopyranosyl)-4-alloaromadendrole (12), the two new alloaromadendrolglycosides were identified, such as 4-O-(β-D-fucopyranosyl)-4-alloaromadendrol-2″-methylpropanoyl esters (13) and 4-O-(β-D-fucopyranosyl)-4-alloaromadendrol-2″-methyl-2″-butenoyl esters (14).

The structures of the new substances were established by high-field¹H-NMR spectroscopy on the aerial part extracts of Italian C. arvensis which provided four new sesquiterpene glycosides, namely, 3α,7β-dihydroxy-5β,6β-epoxyeudesm-4(15)-ene-11-(O-β-D-fucopyranoside-2′,4′-diangelate-3′-acetate) (15); 3α,7β-dihydroxy-5β,6β-epoxyeudesm-4(15)-ene-11-(O-β-D-fucopyranoside-2′,4′-diangelate-3′-isobutyrate) (16); 3α,7β-dihydroxy-5β,6β-epoxyeudesm-4(15)-ene-11-(O-β-D-fucopyranoside-2′,4′-diangelate-3′-methylbutyrate) (17), and 3α,7β-dihydroxy-15-acetoxyeudesm-4(5)-ene-11-(O-β-D-fucopyranoside-2′,4′-diangelate-3′-acetate) (18), in addition to three known compounds [12].

Phytochemical determination of the aqueous and methanolic extracts detected their richness in phenolics and flavonoids. The total phenolic contents ranged from 47.89 ± 2.34 to 50.26 ± 0.18 mg GAE/g DW for the aqueous and methanolic extracts, respectively. The total flavonoid contents were 74.93 ± 1.50 and 174.93 ± 5.21 mg RE/g DW for the aqueous and methanolic extracts, respectively [47].

Phytochemical analyses of C. arvensis flower ethyl acetate extract identified phenols (354 μg/mL) and flavonoids (270 μg/mL), and the GC-MS analysis revealed a high content of linoleic acid (19) (14.12%), palmitic acid (20) (20.28%), and linolenic acid (21) (59.12%) in the extract. Stearic (22), palmitoleic (23), and oleic (24) acids were present in small amounts [10].

The phytochemical content of C. avensis leaves from Pakistan was studied by Akhtar et al. [49]. Qualitative analysis of phytochemicals showed that this plant contains several secondary metabolites such as alkaloids, saponins, tannins, and terpenoids. For the quantitative analysis of phytochemicals, the total phenolic content of the samples ranged from 20.2 to 85.6 mg/g DW in methanol/chloroform extracts and from 5.5 to 62.1 mg GAE/g DW in aqueous extracts. The total flavonoid content ranged from 2.9 to 44.5 mg QE/g DW of the sample for the methanol/chloroform extracts and from 2.4 to 37.1 mg QE/g DW for the aqueous extracts [38]. The C. arvensis flower methanol extract was the richest in flavonoids (74.14 ± 3.09 mg QE/g extract) and phenolics (118.18 ± 10.29 mg GAE/g extract) [49].

Phytochemical screening of all extracts (distilled water, 50% aqueous/ethanol, ethanol, chloroform, and petroleum ether) was carried out and showed the presence of proteins, alkaloids, terpenoids, and flavonoids. Petroleum ether extract has been shown to be rich in flavonoids, and the ethanolic extract contained alkaloids, flavonoids, and proteins. Additionally, two phytochemical groups’ flavonoids and terpenoids were revealed in the aqueous/ethanolic extract, and the chloroform extract showed the presence of terpenoids, alkaloids, and proteins. Finally, these substances were not identified in the aqueous extract [48].

Four saponins were isolated from the dried aerial parts of C. arvensis by Elias and Meo [89] and the identification was carried out by mass spectrometry, FAB, ¹H- and ¹³C-NMR, and two-dimensional NMR studies. These compounds were (2), (3); 3-O-(β-D-glucopyranosyl-(1⟶2)- β-D-galactopyranosyl-(1⟶3)-β-D-glucopyranosyl) oleanolic acid (25); and 3-O-(β-D-glucopyranosyl-(1⟶2)- β-D-galactopyranosyl-(1⟶3)-β-D-glucopyranosyl) oleanolic acid-28-O- β-D-glucopyranoside(26) [89].

C. arvensis hexane extracts were analyzed by GC–MS allowing the identification of 34 compounds, namely a 1,2-saturated pyrrolizidine alkaloid derivative (27) (0.57 mg/g of the dry plant), sesquiterpene 8,14-cedranoxide (28) (0.70 mg/g of the dry plant), and (21) (0.78 mg/g of the dry plant) the only ones detected in this species were the three main compounds of their hexane extract. However, carbohydrates were the most abundant, together accounting for approximately 30.7%, followed by terpenoids and carboxylic acids with 27.9% and 27.4%, respectively [42].

Overall, UPLC-MS analysis identified 26 compounds in the studied methanolic extract of C. arvensis. This extract is clearly enriched with quercetin derivatives and caffeic acid. In the methanolic extract, saponins and hydroxybenzoic acids were also determined. Quantitatively, C. arvensis methanol extract was dominated by flavonoids (53.5%) while hydroxycinnamic and hydroxybenzoic acids shared approximately 20%. In this extract, the main compounds were the 5-O-caffeoylquinic acid (29) (0.221 ± 0.016 mg/100 mg extract), protocatechuic acid pentoside (30) (0.366 ± 0.073 mg/100 mg extract), and quercetin (31) (0.534 ± 0.042 mg/100 mg extract) [42].

Sixty-six constituents were detected in C. arvensis flower extract. Volatile compounds have been subdivided into seven chemical classes, namely terpenes (36 compounds), sesquiterpenes (32 compounds), ketones (4 compounds), esters (25 compounds), aliphatic hydrocarbons (4 compounds), aldehydes (8 compounds), and alcohols (7 compounds). The most abundant terpene compounds in C. arvensis were α-thujene(32) (788 μg/100 g flower) followed by α-pinene(33) (268 μg/100 g flower). Regarding the number of compounds, sesquiterpenes were the second most abundant chemical class in this plant, with 28 constituents identified. However, seven of them have only been tentatively determined as sesquiterpene-like molecules. the main sesquiterpene was α-caryophyllene(34) (118 μg/100 g flower), followed by δ-cadinene(35) (31.5 μg/100 g flower) and β-caryophyllene(36) (26.4 μg/100 g flower) and finally γ-muurolene(37) (22.6 μg/100 g flower) [91]. Nevertheless, C. arvensis water/acetone extract exhibited the lowest amount of all the bioactive compounds studied, with total flavonoids of 0.35 ± 0.10 mg QE/g DW, hydrolyzable tannin of 3.7 ± 1.8 mg TAE/g DW, and total monomeric anthocyanin of 0.07 ± 0.01 mg Cy 3-glu/g DW [91].

The total contents of phenolic and flavonoid compounds in the methanolic extracts of C. arvensis were, respectively, 14.49 + 0.38 and 5.26 + 0.36 mg/g and in the aqueous extract of 15.12 + 0.40 and 5.31 + 0.36 mg/g [92]. The total content of phenolic compounds in C. arvensis methanolic and aqueous extracts was 12.3 and 16.8 mg GAE/g DW, respectively [97].

Furthermore, from the aerial parts of C. arvensis (butanolic and ethyl acetate extracts), a novel triterpene saponin, called arvensoside C (38), has been isolated along with four other known (8), (9), (11), and glycoside C (39). Three known flavonol glycosides, namely quercetin 3-O-β-D-galactopyranoside(40), quercetin3-O-β-D-glucopyranoside(41), and isorhamnetin 3-O-β-D-glucopyranoside(42) have also been characterized. Their structures have been elucidated by 1D and 2D NMR experiments, including HSQC, DQF-COZY, 1D-TOCSY, and HMBC spectroscopy [93]. Similar studies were reported on the isolation and purification of (9) and arvensoside D (43) [43]; [95]. GC-MS analysis of chloroform extracts of C. arvensis samples from Portugal showed that the most abundant compound was β-sitosterol(44) [94]. The phytochemical composition of Algerian C. arvensis aerial part EOs and hydrosol extract was studied by GC/MS and GC-FID. However, the hydrosol extract and the essential oil were rich in sesquiterpene compounds (81.8%) in which the oxygenated compounds were superior to hydrocarbons with 53.4% and 28.4%, respectively. The major compounds were γ-curcumene(45) (5.4%), (E,Z)-farnesol (46) (6.5%), τ-cadinol(47) (7.5%), zingiberenol 2 (48) (8.3%), eremoligenol (49) (9.5%), (E)-phytol (50) (10.8%), β-curcumene(51) (12.5%), and zingiberenol 1 (52) (19.1%) [88].

Volatile compounds from the steam distillation extraction of C. arvensis were analyzed by GC/MS. The compounds detected were represented by aldehydes ((E,E)-2,4-octadienal (53), (E)-2-nonenal (54)) and 5-methyl-2-furanaldehyde (55), esters (ethyl butyrate (56), ethyl hexanoate (57)), phenethyl acetate (58), sulfur compounds (2-methyl-3-furanthiol (59) and methional (60)), alkyl pyrazines (2,6-dimethyl-3-ethyl pyrazine (61)), ketones (1-octen-3-one (62)), lactones (δ-decalactone(63)), and terpenoid compounds (α-terpineol(64) and citronellol (65)) [11]. Paolini et al. [7] elucidated the C. arvensis EO chemical composition by the combination of GC/MS and GC. Consequently, this oil had a high content of sesquiterpenes (87.3 g/100 g of oil) containing a high variety of phytochemical classes in low concentrations. The major sesquiterpenes were α-cadinol(66) (12.4 g/100 g of oil) and compound (35) (15.1 g/100 g of oil). The minor compounds identified were α-muurolene(67) (4.9 g/100 g of oil), cubebol (68) (3.7 g/100 g of oil), cubenol (69) (3.5 g/100 g of oil), cubeban-11-ol (70) (3.2 g/100 g of oil), germacradien-11-ol (71) (3.2 g/100 g of oil), 1-epi-cubenol(72) (3.8 g/100 g of oil), 4-epi-cubebol(73) (4.5 g/100 g of oil), guaiol (74) (1.5 g/100 g of oil), ledol (75) (1.9 g/100 g of oil), α-bisabolol(76) (1.7 g/100 g of oil), calamenene (cis and/or trans) (77) (4.7 g/100 g of oil), presilphiperfolane-9α-ol(78) (4.6 g/100 g of oil), τ-muurolol(79) (1.2 g/100 g of oil), eremophila-1(10),7-diene (80) (1.9 g/100 g of oil), and compound (37) (0.1 g/100 g of oil) [7].

Servi et al. [96] also determined the EO components of the C. arvensis aerial part by GC-MS analyses. Thirty-six components were identified. The major compounds were ledene (81) (5.1%), (72) (5.4%), (68) (7.2%), (69) (7.7%), (66) (8.5%), (72) (10.7%), and (35) (14.8%) compounds [96].

The GC-MS and GC-FID analysis of C. arvensis EO extracted by microwave distillation (MD) and hydrodistillation (HD) revealed a total of 44 and 45 components, representing more than 84.8% and 88.3% of the oil composition, respectively. Monoterpene compounds (HD: 26.3% and MD: 24.3%) and sesquiterpenes (HD: 30.5% and MD: 23.4%) were found to be the major group of volatile compounds. The main terpene compounds of C. arvensis EOs were β-pinene (82) (HD, 1.8% and MD, 2.4%), viridiflorene (83) (HD, 2.5% and MD, 1.7%), 7-epi-silphiperfol-5-ene (84) (HD, 2.6% and MD, 3.7%), (Z)-sesquilavandulol (85) (HD, 4.8% and MD, 0.0%), δ-amorphene (86) (HD, 0.0% and MD, 8.0%), (Z)-α-santalol (87) (HD, 8.2% and MD, 7.4%), (33) (HD, 11.9% and MD, 12.3%), and α-selinene (88) (HD, 16.0% and MD, 0.0%) [41].

3.5. Pharmacological Properties

Calendula arvensis is an important medicinal, industrial, and ornamental plant with different bioactivities described in the bibliography, especially as anti-inflammatory [44, 45], antiviral [87, 98], insecticidal [99], antitrypanosomial [43], anticholinesterase [49], antimutagenic [89], immunomodulator [48], hemolytic [100], and wound healing [101] agent (Figure 8).

3.5.1. Antimicrobial Activity

C. arvensis is one of the most interesting medicinal plants, its diverse chemical composition displays a varying degree of antimicrobial activity on different microorganisms. Jamal et al. [40] showed that C. arvensis leaf extract exhibits an important inhibition on some microorganisms including pathogens using the agar diffusion method and the tube dilution method to define the minimum inhibitory concentration (MIC). The study showed that the potential of C. arvensis as a source of antibacterial agents can be utilized in the healthcare delivery process. Indeed, C. arvensis chloroform and petroleum ether extract exhibited, respectively, an inhibition at MIC = 2 μg/mL against Klebsiella pneumoniae and Escherichia coli. The greatest inhibition zone is produced by the chloroform extract at 512 mg/mL against E. coli. C. arvensis leaf extract was found to have better antibacterial activity in petroleum ether with a zone of inhibition of 1.9 cm.

Likewise, the study of Jamal et al. [40] showed that the organic extracts of C. arvensis flowers have an important antibacterial potency evaluated by the agar well diffusion method and by the microtitration technique. Except for Acinetobacter baumannii, Proteus mirabilis, and Listeria monocytogenes, the methanol extract of C. arvensis flowers had remarkable activity against the bacteria studied (Gram-positive and Gram-negative). C. arvensis flower hexanolic extract inhibited all bacteria except Acinetobacter baumannii, Streptococcus agalactiae, and Staphylococcus aureus MRSA. The MIC value of the methanol extract was between 12.5 and 25 μg/mL and the MIC value of the hexanolic extract was between 6.25 and 12.5 μg/mL. Therefore, the hexane extract was more potent than the methanol extract. The hexanolic extracts of C. arvensis flowers obtained by soxhlet extraction were bacteriostatic for all the bacteria studied (E. coli MDR, E. coli, E. coli ATCC, E. coli enteropathogenes, Salmonella braenderup, Salmonella aequatoria, and Salmonella blockley), while aqueous and methanolic extracts obtained by maceration in cold water showed bactericidal activity. Moreover, the extracts studied did not show any activity on Candida species with the exception of the methanolic extract, which inhibited Candida famata and Candida tropicalis with inhibition diameters of 20 and 14 mm, respectively [47]. Zoufan et al. [39] showed the antibacterial effect of ethanolic and methanolic extracts of whole C. arvensis examined by the disc diffusion method is greatest against P. aeruginosa, S. aureus, and E. coli.

However, the antimicrobial effect of chloroform/methanol mixture extracts and aqueous extracts of C. arvensis leaves, assessed against six bacterial (Escherichia coli, Salmonella typhimurium, Staphylococcus aureus, Bacillus subtilis, Bordetella bronchiseptica, and Enterobacter aerogens) and five fungal strains (Aspergillus niger, Mucor spp., Aspergillus fumigatus, Fusarium solani, and Aspergillus flavus) using the disc diffusion method, showed no activity against the different strains tested [38].

The antifungal activities of C. arvensis aerial part EOs and hydrosol extract were investigated against two phytopathogenic fungi; Penicillium expansum and Aspergillus niger using the agar well diffusion method. The obtained results in vitro showed that C. arvensis aerial part EO has an antifungal activity at high concentrations, while the hydrosol extract induced the best inhibition against A. niger and P. expansum. The essential oil (60 mg/L) completely inhibited the growth of P. expansum with an important inhibitory activity against A. niger (86.6%). At a concentration of 30 mg/L, the hydrosol extract exerted a strong inhibition (100%) against both fungi.

Furthermore, the treatments of pears with C. arvensis L. aerial part hydrosol extract and EO showed a very marked protective activity on the severity of the infection caused by P. expansum. Against rot induced by P. expansum, the hydrosol extract (0.02 mg/L) showed a high protective effect (100%) for up to 7 days. At the highest EO concentration (0.2 mg/L), protective effects of 100% and 40% were observed up to the 7^th and 9^th day, respectively, and this was sufficient to reduce the disease severity [88]. According to Faustino et al. [42], methanol extracts of the C. arvensis sample did not show any interesting antimicrobial activity against Aspergillus, yeasts, and dermatophytes strains tested, and a weak activity was recorded against Microsporum canis and Trichophyton rubrum with both MLC and MIC of 400 μg/mL. Izzo et al. [102] showed that among the 68 extracts tested for their antibacterial action against eight Gram-negative and Gram-positive bacteria, C. arvensis ethanolic extracts possessed activity against only two Gram-positive microorganisms (Staphylococcus aureus and Bacillus subtilis), while they were completely inactive on other bacteria.

The aqueous extracts of C. arvensis foliar tissues were examined for their activity against F. oxysporum f.sp. lycopersici isolated from tomato roots using the agar diffusion method. The toxicity of C. arvensis extracts against the fungus was pronounced at 4 days of incubation, with an inhibition diameter of 43.8 mm compared to the control (60 mm), reaching 75.5 mm at 16 days of incubation [103].

Likewise, the antibacterial effect of C. arvensis L., aerial part EO obtained by HD using a Clevenger-type apparatus was investigated against E. coli, P. aeruginosa, Bacillus cereus, and S. aureus using broth microdilution. According to the results obtained, C. arvensis EO (8 mg/mL) showed weak inhibitory action against B. cereus and E. coli. While it showed no antibacterial effect against P. aeruginosa and S. aureus [96].

The antimicrobial activities of EOs obtained by HD and MD, as well as methanolic, ether, and hexane extracts of C. arvensis were quantitatively studied in respective broths against nine microorganisms (S. cerevisiae, C. albicans, M. smegmatis, B. cereus, S. aureus, E. faecalis, P. aeruginosa, Y. pseudotuberculosis, and E. coli) using double dilution and the MIC values (μg/mL) were defined. This study indicates that only the EO, obtained by HD, and the methanolic extract showed moderate effects against B. cereus and S. aureus with MIC of the order of 105–210 μg, respectively. Interestingly, all extracts displayed good antituberculosis effects against M. smegmatis with MIC between 13.2 and 62.5 μg [41]. According to Kim [104], C. arvensis extract had excellent antibacterial activity, and after 12 hours of culture, it inhibited the growth of B. subtilis, E. coli, and C. albicans by 40, 7, 35.2, and 27.5%, respectively. Moreover, the growth inhibitory effect against the positive bacteria, B. subtilis, was the highest.

3.5.2. Antiparasitic Activity

The spectral and chemical studies on triterpenoid and sesquiterpene bioactive chemotypes of C. arvensis showed a significant inhibitory effect against vesicular stomatitis and rhinovirus multiplication in cell cultures, in which glycosides 1 and 2 were most effective [87, 98]. Besides, arvensoside B and arvensoside D saponins extracted from C. arvensis also possess an impressive impact on Trypanosoma brucei brucei at a MIC value of 50 and 100 μg/mL, respectively [43].

Lemna minor, Artimia salina (Brine shrimps) larvae, Callosobruchus analis, and other parasites were tested for their susceptibility towards the methanolic extract of C. arvensis [99]. The insecticidal potential of C. arvensis pronounced a variable degree of susceptibility of strains and tested doses, in which Callosobruchus analis was the most sensitive insect with LD₅₀ of 0.51 mg/mL. A moderate level of cytotoxicity was found with a LD₅₀ value of 9.23 μg/mL against brine shrimp larvae with a mortality percentage of 40, 60, and 67% at 10, 100, and 1000 μg/mL, respectively [99]. Nonetheless, low toxicity (% inhibition ≤40%) at 10 and 100 μg/mL and moderate effect (% inhibition = 40–50%) at 1000 μg/mL were observed against Lemna minor [99].

3.5.3. Anti-Inflammatory Activity

Some studies have shown that C. arvensis extracts exhibit anti-inflammatory effects. Indeed, Mascolo and collaborators showed that the injection of 100 mg/kg BW of C. arvensis extracts in rats induces an interesting anti-inflammatory effect by inhibiting 32% (2.68 ± 0.8) of edema formation [45]. In the same way, Abudunia et al. [44] demonstrated significant anti‐inflammatory results of C. arvensis extracts, in which flowers extracted by hexane solution had the best edema reduction yield of rat paw edema, with 51.08, 71.33, 63.38, and 67.33%, induced by carrageenan and experimental trauma, respectively. These outcomes indicated the contributory effects of using C. arvensis flower extracts in the management of inflammatory and painful conditions [44].

3.5.4. Antioxidant Activities of Calendula arvensis

As mentioned in previous sections, C. arvensis is an important industrial and medicinal plant with various biological activities. To estimate, in vitro, the antioxidant effects of C. arvensis flower extracts, four different methods (DPPH, FRAP, and β-carotene bleaching test) were used. The methanolic, hexanolic, and organic extracts were obtained by soxhlet extraction, while the aqueous extracts were obtained by maceration. Both aqueous and methanolic extracts have free radical scavenging effects. However, the free radical scavenging effect of the methanolic extract appears to be closer to 332 mg/mL gallic acid. At all concentrations, the extracts were ranked according to their free radical scavenging potency in the following order; methanol extract > aqueous extract > hexanol extract. The EC₅₀ of the methanolic and aqueous extracts are, respectively, 20.9 and 33.2 mg/mL. The reducing power using the ferric-reducing antioxidant power (FRAP) method, showed that C. arvensis flower extracts show significant differences in the following order; methanol extract > aqueous extract > hexanol extract. The reducing ability of C. arvensis methanol extract was the most potent among the three extracts (203.96 mg AAE/g Ext). Similarly, all flower extracts inhibit β-carotene bleaching by scavenging free radicals derived from linoleic acid. The methanol extract inhibits β-carotene at a rate comparable to BHT [47]. Abutaha et al. [10] showed that the 1 mg/mL of C. arvensis flower ethyl acetate extract (CAF EtOAC) extracted using a Soxhlet extractor present a percentage of scavenging activity (DPPH%) moderate at 50%.

In order to discover novel sources of antioxidants, aqueous and methanol/chloroform extracts of C. arvensis were investigated using several methods, namely, 2,2 diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay, total antioxidant capacity (TAC), and reducing power (RP). The results showed that the antioxidant activity varies greatly not only between the extracts but also between the assays used. The reducing power values ranged from 12 Vit C equivalent mg/g DW in aqueous extracts to 100 Vit C equivalent mg/g DW in the methanol/chloroform extracts. The samples tested presented several TAC values, expressed as the number of ascorbic acid equivalents, from 19 mg vit. C equivalent/g DW in the methanol/chloroform extracts at 25 mg vit. C equivalent/g DW in aqueous extract. It was noticed that the aqueous extracts of C. arvensis had the highest percentage of scavenging, i.e., 48.7% and 8.7% for the methanol/chloroform extracts [38].

Belabbes et al. [88] showed that C. arvensis EO had the ability to reduce DPPH radical (IC₅₀ = 76.2 mg/L), and more interestingly, C. arvensis hydrosol extract indicated the highest DPPH quenching activity (IC₅₀ = 25.1 mg/L). It was found that the antioxidant activity of C. arvensis EO is proportional to the concentration. However, by the β-carotene bleaching test, the hydrosol extract (IC₅₀ = 32.4 mg/L) displayed the highest potency, while the EO showed the lowest (IC₅₀ = 100.1 mg/L). The BR antioxidant activity of C. arvensis methanolic extracts was determined as 0.024 μg/mL. The activities at pH = 7.4 (TEAC method, mM Trolox eq.) show a great variability determined as 0.46 mM Trolox. By the DPPH method in methanolic solution, the results also show a great variability determined as 80.9 μg/mL [31].

Ercetin et al. [49] examined the antioxidant activity of the water, methanol, ethyl acetate, acetone, dichloromethane, and n-hexane extracts of C. arvensis L., leaves and flowers using FRAP, ferric ion-chelating capacity, and DPPH assays at 250, 500, and 1000 μg/mL. By the FRAP assay, the studied extracts had a rather weak effect, while the C. arvensis flower methanol extract displayed the highest absorbance determined as 0.479 at 1000 μg/L. Moreover, the best scavenging activity was obtained by C. arvensis flower methanol extract (52.25 ± 1.34%), which was the only extract with an activity greater than 50%. Therefore, the studied extracts showed a relatively higher ferric ion-chelating activity compared to other tests. At 1000 μg/L, the leaves (53.36 ± 1.23%) and flowers (53.25 ± 0.15%) of C. arvensis ethyl acetate extracts were found to be the best in assays.

The influence of C. arvensis flower methanolic and aqueous extracts at concentrations of 0.10 to 0.90 mg/mL, scavenged all types of radicals studied depending on the concentration applied. For both C. arvensis extracts, all the concentrations selected had an antioxidant potential lower than that of the control. At the concentration of 0.90 mg/mL, the aqueous extract scavenged approximately 60% of DPPH radicals, while at concentrations below 0.45 mg/mL no significant scavenging activity (SA) was observed compared to the control. For hydroxyl radical scavenging activity, both C. arvensis extracts showed high scavenging activity, while the addition of 0.45 mg/mL aqueous extract clearly scavenged the hydroxyl radical, with a scavenging activity of 34.74%. The elimination of the hydroxyl radical (SA 80–90%) was obtained with 0.9 mg/mL of the methanolic or aqueous extract. In addition, the highest antioxidant effect of C. arvensis aqueous extract (0.90 mg/mL) against peroxyl radical exhibited significantly lower activity (antioxidant activity, 69.28%). High concentrations of the methanolic and aqueous extracts were more effective in reducing the peroxyl radical [92].

Likewise, C. arvensis flowers showed effective antioxidant activity on linoleic acid and DPPH radical oxidation. This herb showed a DPPH radical scavenging activity of 409.4 μg/mL as SC₅₀ and an inhibitory activity of 61.1% on linoleic acid oxidation [46].

According to Messina et al. [105], six extracts of C. arvensis obtained by various solvents (distilled water, acetone 70%, ethanol 80%, and hexane) and by supercritical fluid extraction (SFE) showed a protective effect against superoxide anions, hydroxyl radicals, scavenging hydrogen peroxide, and oxidative damage. It was observed that the supercritical fluid extracts of C. arvensis presented a very remarkable antioxidant effect compared to the ethanol 80% extract (DPPH and reducing power method), in comparison to a synthetic antioxidant.

The relative levels of antioxidant activity of methanolic and aqueous extracts of C. arvensis of Jordanian origin were determined using the ABTS ⁺ method. There was a low variation in the total antioxidant capacity of the extracts. The total antioxidant capacity ranged from 42 to 48.4 μmol TE/g DW for the methanolic and aqueous extracts, respectively [97]. Kim [104] showed that the DPPH scavenging activity of C. arvensis extract samples at concentrations of 10, 50, and 100 μg/mL showed almost the same radical scavenging activity as the control (ascorbic acid) (88.9, 91.2, and 91.3%). Lee et al. [106] showed that with high DPPH free radical scavenging activity, the possibility of using C. arvensis flower extracts as a natural antioxidant was high. The DPPH free radical scavenging activity was 66.99% and 77.63% in the hot water and 80% MeOH extracts, respectively.

3.5.5. Anticancer Activity

C. arvensis extracts have been shown to be a promising source of cytotoxic compounds. The effects of C. arvensis flower extracts from villages around the Rabat-Khemisset region (Morocco) were assessed on the growth of myeloid cancer cells using MTT assay and it was shown that methanol and hexane extracts (obtained by soxhlet) and aqueous extracts (obtained by maceration) exhibited important antimyeloid cancer activity (IC₅₀ = 31 mg/mL). Consequently, both methanolic and aqueous extracts have been shown to be effective candidates as cytotoxic agents. Indeed, their efficacy was more pronounced compared to the hexanolic extract. At the concentration of 100 mg/mL at 24 h, it was also deduced that methanolic extract shows a maximum inhibition of 89%, testifying that this extract is a very important antimyeloid cancer agent [47].

At different concentrations, the effect of C. arvensis part (leaves, stems, and flowers) extracts obtained by a Soxhlet extractor using various solvents (methanol, ethyl acetate, chloroform, and hexane) against MDA-MB-231 and MCF-7 cells were estimated. Among all extracts, the flower ethyl acetate (CAF EtOAC) extract showed the highest activity, it inhibited cell growth in a concentration-dependent manner. This extract displayed IC₅₀ values of 70 and 78 μg/mL in MCF-7 and MDA MB-231 cells, respectively. However, the flower hexane extract presented a moderate cytotoxic effect, but the methanol and chloroform extracts showed no activity [10].

The study of Attard and Cuschieri [48] indicated that the petroleum ether extract of C. arvensis aerial part is relatively nontoxic to peripheral lymphocytes, suggesting its use as an immune stimulant. In fact, all the extracts studied presented a concentration-dependent effect. Phytohemagglutinin (PHA) (SC₅₀ < 0.001 μg/mL) and the petroleum ether extract (SC₅₀ 0.089 μg/mL) of C. arvensis obtained by maceration demonstrated an increase in proliferation compared to the other extracts (IC₅₀ > 10 μg/mL). However, the most active extract of C. arvensis was the petroleum ether extract. In contrast, it has been reported that C. arvensis extract is a safe natural product, as at least it did not induce any cytotoxicity at 100 μg/mL. The cytotoxicity of this extract was 0, 0.1, 0.3, 15.1, and 28.0% at increasing concentrations of 10, 100, 250, and 500 μg/mL, respectively [104].

Quetin-Leclercq et al. [95], showed that the saponins isolated from C. arvensis are very active against certain cancer cells (human HeLa tumor cells, Flow 2002 noncancer human cells, mouse 313 noncancer fibroblasts, and mouse B16 melanoma cells) as much as the reference compound, strychnopentamine. At concentrations of 10 μg/mL and above, they exhibited some degree of cytotoxicity, while the concentration of 50 μg/mL was the most potent.

According to Ullah et al. [107], the toxic potential of the methanol crude extract of C. arvensis whole plant was evaluated by a Lemna minor bioassay. It was observed that C. arvensis exhibits dose-dependent toxicity towards Lemna minor, with low toxicity (% inhibition ≤40%) at 10 and 100 μg/mL, and moderate activity (% inhibition = 40–50%) at 1000 μg/mL. A moderate level of cytotoxicity was found to have an LD₅₀ value of 9.23 μg/mL for saltwater shrimp larvae. Zihlif et al. [108] found that the C. arvensis ethanol extract has a potential antiangiogenic activity. A selectivity was demonstrated against the proliferation of endothelial cells, indicating a direct inhibitory power on the tumor angiogenesis key step. The activity of this extract shows more than 50% growth inhibition. After 72 h at 50 μg/mL, an important antiproliferative activity was also shown against the MCF7 cell line. The extract reduced the growth of these cells to less than 30%. While it showed weak antiangiogenic activity on PFL cell proliferation at 50 μg/mL. Interestingly, it showed potent activity against HUVEC cell proliferation with IC₅₀ = 28.7 μg/mL.

3.5.6. Enzyme Inhibitory Activity

The investigation of the enzymatic inhibitory effects in different solutions (distilled water, methanol, ethyl acetate, acetone, dichloromethane, and n-hexane) of C. arvensis leaf and flower extracts, collected from the vicinity of Bodrum town in the province of Mugla (Turkey), against butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) was performed by Ercetin et al. [49]. Their outcomes highlighted the high efficiency of C. arvensis flower ethyl acetate extract in AChE inhibition assay (31.24 ± 1.29%) compared to C. officinalis extracts. This effect has been attributed to the presence of compounds derived from flavonoids and triterpenes (tannins, malic and salicylic acid, mucilages, etc.) found in the flower methanolic extract of this specie [49].

3.5.7. Antimutagenic Activity

Elias and Meo [89] used the microsuspension technique of the Salmonella/microsomal assay (Ames test) to investigate the antimutagenic potential of natural saponins isolated from the dried aerial parts of C. arvensis. Their preliminary findings demonstrated that the saponins were not toxic for the tested strains of Salmonella typhimurium (TA 100, TA 98, and TA 97) for doses up to 400 μg. The use of benzo[a]pyrene (BaP) and a mutagenic urine concentrate from a healthy smoker (consumed 40 cigarettes per day), showed that the four products (D, C, B, and A) of the studied plant exert an antimutagenic effect against 1 μg of BaP and 5 μL of smoker’s urine [89]. Probable antimutagenic mechanisms of saponins have been reported to be the modification of cell surface activity and cell membrane structure [89]. In their research paper, a group of Australian chemists concluded that the saponin arvensoside B sugar units (chemically named 1⟶3-Galactopyranosyl-D-glucopyranosyl-3-O-oleanolic acid) strongly influence the hemolytic activity of oleanolic acid disaccharides [100]. Not only that but also the linkage positions 3 or 4 either arvensoside B or its analog, calenduloside found in C. officinalis are structural requirements for high potency [100].

3.5.8. Immunomodulatory Activity

The immunomodulatory activity of various Maltese plant extracts (i.e., Carlina involucrata Poir, Galactites tomentosa Moench, Leontodon tuberosus L, Glebionis coronaria L. Tzvelev, Aster squamatus (Sprengel) Hieron, Reichardia picroides L. Roth, Sonchus oleraceus L, Calendula arvensis L, Inula crithmoides L, and Dittrichia viscosa L. Greuter) of the Asteraceae family was performed on human peripheral T-lymphocytesin vitro using macerated dried aerial parts in different solvents [48]. The authors observed marked effects in lymphocytes treated with extracts, but only C. arvensis petroleum ether extract was able to activate the lymphocytes and pronounce blastogenesis similar to that of PHA, which can be used as a potential immune booster [48].

3.5.9. Wound Healing Activity

The local application of a mixture of H. perforatum and C. arvensis EOs in the epithelial reconstruction of surgical wounds in childbirth with cesarean section in Italy on a group of 24 patients induced a wound size reduction of 37.6 ± 9.9% versus a reduction of 15.83 ± 4.64% in the control group [101]. The above-mentioned results are very encouraging to shed more light on C. arvensis for further investigations on the extraction methods according to the different plant parts, isolation of the main biomolecules, and the elucidation of their mechanism of action.

4. Conclusion and Perspectives

In this paper, the sources and main pharmacological characteristics of C. arvensis have been investigated and presented. The analysis of several published studies revealed that this natural compound has significant biological properties, especially its wide range of use in folk medicine by several ethnic groups around the world as a poultice, antidiabetic, antispasmodic, antiemetic, antihelmintic, antirheumatic, diaphoretic, and also as a treatment against neurological disorders, microbial disease, ENT and typhoid diseases, skin diseases, digestive disorders, and high blood pressure. Additionally, all C. arvensis flower extracts exhibit an inhibitory effect against most fungi and bacteria species. In addition, due to the phytochemical constituents of C. arvensis, including polyphenols, flavonoids, terpenoids, tannins, and alkaloids, and also from its antimicrobial, antioxidant, and anti-inflammatory properties, this medicinal plant can be considered an interesting bioactive compound to explore different molecular and cellular pathways in cancer prevention. However, a greater comprehension of its pharmacokinetics and pharmacodynamics is warranted for its incorporation as a drug in cancer therapy and other pathologies. In this context, the assessment of its safety potential is also required, through a more in-depth toxicological survey.

Abbreviations

μmol TE/g DW:	μmol of Trolox equivalent per gram of dry weight
ABTS:	2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)
BHT:	Butylohydroxytoluene
DPPH:	2,2 Diphenyl-1-picrylhydrazyl
EC50:	Median effective concentration
ENT:	Ear, nose, and throat
FAB:	Fast atom bombardment
FRAP:	Ferric-reducing antioxidant power
GC/MS:	Gas chromatography/mass spectrometry
GC-FID:	Gas chromatography coupled with flame-ionization detection
HD:	Hydrodistillation
LD50:	Median lethal dose
MD:	Microwave distillation
mg CAE/g DW:	mg of chlorogenic acid equivalent per gram of dry weight
mg GAE/g DW:	mg of gallic acid equivalent per gram of dry weight
mg QE/g DW:	mg of quercetin equivalent per gram of dry weight
mg RE/g DW:	mg of rutin equivalent per gram of dry weight
mg TAE/g DW:	mg of tannic acid equivalent per gram of dry weight
MIC:	Minimum inhibitory concentration
MIKE:	Mass-analyzed ion kinetic energy
MLC:	Minimal lethal concentration
MTT:	3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
NMR:	Nuclear magnetic resonance
PHA:	Phytohemagglutinin
RP:	Reducing power
SA:	Scavenging activity
SC50:	Median stimulatory concentration
SFE:	Supercritical fluid extraction
TAC:	Total antioxidant capacity
TEAC:	Trolox equivalent antioxidant capacity
UPLC–MS:	Ultraperformance liquid chromatography–MS.

Data Availability

The data used to support the findings of this study are included in the article.

Conflicts of Interest

The authors declare that they have no conflicts of interest in this study.

Authors’ Contributions

Aya Khouchlaa and Abdelhakim Bouyahya contributed equally to this work.

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Copyright © 2023 Aya Khouchlaa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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