Ethnomedical uses, chemical constituents, and evidence-based pharmacological properties of Chenopodium ambrosioides L.: extensive overview

The Chenopodium genus is a plant family widely spread worldwide that includes various plant species reputed to possess several medicinal virtues in folk medicines. Chenopodium ambrosioides L. is among the most used plants in traditional medicines worldwide. This review aimed to highlight ethnomedicinal uses, phytochemical status, and pharmacological properties of C. ambrosioides L. The analysis of relevant data highlights various ethnomedicinal uses against human and veterinary diseases in forty countries. Most indications consisted of gastrointestinal tract dysfunctioning troubles and worms parasitemia. Around 330 chemical compounds have been identified in different plant parts, especially in its essential oil fractions (59.84%). However, only a few compounds—mainly monoterpenes and glycosides—have been isolated and characterized. Experimental pharmacological studies validated a large scale of significant health benefits. It appeared that many monoterpenes are antioxidant, insecticidal, trypanocidal, analgesic, antifungal, anti-inflammatory, anti-arthritic, acaricidal, amoebicidal, anthelmintic, anticancer, antibacterial, antidiabetic, antidiarrheal, antifertility, antifungal, anti-leishmanial, antimalarial, antipyretic, antisickling, antischistosomal, antiulcer, anxiolytic, immunomodulatory, molluscicidal, and vasorelaxant agents. Thus, the Chenopodium ambrosioides species necessitates further chemical studies to isolate and characterize new bioactive secondary metabolites and pharmacological investigations to precise the mechanisms of action before clinical trials.


Background
Ethnomedicine is part of folk medicine practiced by a given population and primarily based on the use of plant or herbal materials presented in various pharmaceutical formulations containing active ingredients [1]. Plants are sources of therapeutically and economically valuable compounds [2]. In recent decades, due to a large amount of research on phytochemistry and pharmacognosy, natural plant products have gained particular importance in treating different diseases [3]. Over 50,000 plants would possess therapeutic virtues.
More than 80% of the population in developing countries depends primarily on plant-based medicines for basic healthcare needs [4,5]. Since the early 1970s, the WHO keeps stimulating governments in developing countries to benefit from local knowledge on traditional herbal medicaments [6]. Among botanical species of great value, the Chenopodium genus occupies a vital place. This genus includes about 102 genera and 1400 annual herbaceous species with a pungent smell distributed worldwide, especially in the moderate and subtropical zone [7,8].
The species Chenopodium ambrosioides L. (Amaranthaceae), also well known as Mexican tea, Jesuit's tea or bluebush, Indian goosefoot, Spanish tea, or wormseed in English, is an annual or perennial shrub with a strong aromatic smell. It is widely distributed in West Africa, especially in Nigeria, Senegal, Ghana, and Cameroon [9].
Easy to grow, the plant grows on light (sandy), medium, heavy, acid, neutral, and alkaline soils (pH ranging from 5.2 to 8.3). It prefers moist soil but cannot be growing in the shade. It is mainly found on dry wasteland and cultivated ground. It is a cultivated and cosmopolitan species. The WHO pointed out that C. ambrosioides is among the most used plants in traditional medicines worldwide [8] widely used as an edible medicinal plant (especially leaves and seeds). Some recent review studies have reported primary data on conventional uses, phytochemicals, and pharmacological properties of C. ambrosioides [10][11][12].
We designed this review to complement that checks in a more detailed overview of medicinal uses, chemical composition, and evidence-based pharmacological properties that are missing.

Literature review method
The data presented are from full articles in English or French retrieved via Internet search with Google Scholar, PubMed/Medline, Science Direct, Scopus, the Wiley Online Library, Web of Science, and any other helpful search engines using Chenopodium ambrosioides OR Dysphania ambrosioides as the primary keywords, without time limit restriction. A total of 309 references were cited in this present review retrieved from those scientific engines.

Botanical description of Chenopodium ambrosioides
Chenopodium ambrosioides is a perennial tropical herb with a grooved, multi-branched reddish stem and a robust disagreeable scent growing that reaches up to 1 m high (Fig. 1). The leaves are oval (up to 4 cm long and 1 cm wide), sharply toothed, alternate, and a short petiole. The flowers are small and green, and the seeds are very small and green when fresh and black when dry. His inflorescence is the racemose type, presenting small flowers green colored. The sources are numerous, spherical, and have black color [8,13]. Ethnomedicinal knowledge Table 1 describes data collected from ethnopharmacological investigations from forty countries. The information includes vernacular names, parts used, local uses, formulations, voucher numbers, and references for each country. Only 64.33% of voucher numbers have been listed for plant identification and authentification.
As indicated in Fig. 2a, the leaves were the most used parts (50.26%), followed by the whole (entire) plant (11.79%), aerial parts (8.72%), roots (6.15%), flowers, and stems (5.64%), seeds (3.59%), branches (2.05%), twigs (1.54%), bark, and shoots (1.03%). Several studies supported the use of leaves as the most used part of traditional medicines worldwide. According to Moshi and al [161]., the frequent use of leaves is associated with their ease of accessibility among the aboveground parts of plants in natural ecosystems. Overall, decoction has often been found as an adequate formulation of herbal remedies as it is easy to prepare by mixing a drug with boiling water [168].
Concerning medical uses, Chenopodium ambrosioides is indicated in treating several human diseases, disorders, and injuries of different organs/systems, both in human and veterinary medicines. Veterinary indications are limited compared to humans. Seven signs have been listed for veterinary purposes, mainly including worms (parasites) and gastrointestinal disorders (pain, swelling, diarrhea) in livestock. Also, canine and backyard chickens were explicitly cited.

Toxicological studies
A subchronic toxicological investigation of leaf aqueous extract for 15 days has not produced mortality in mice. Overall, at the highest dose (500 mg/kg bw, per os), no alteration in body weight, food, and water consumption has been noted, except in some changes in organ weights and biochemical markers like albumin serum, triglycerides, and in the VLDL values [170]. In the oral acute toxicity test for 24 h, 3 g of aqueous leaf extract/kg bw increased transaminase levels and decreased urea serum level in rats. Results did not note any clinical signs of toxicity, macroscopic lesions, and change in total protein, creatinine, triglycerides, and cholesterol levels. On the other hand, in sub-chronic evaluation for 15 days, the extract significantly reduced ALT serum value at the dose of 1 g/kg bw.
Furthermore, the authors suggested congestion in the kidneys' medullar region at 1 and 3 g/kg bw [171]. Gadano et al. [172] found that preparations (aqueous decoction and infusion) of the aerial part at different concentrations (1, 10, 100, 1000 mg/ml) could provoke genetic damage by elevation of chromosomal aberrations and sister chromatid exchanges subjected to human lymphocyte cell cultures. A reduction of mitotic indexes appeared after treatment. A similar study concluded a possible strong interaction between DNA and active principles of aqueous extracts [173]. Table 2 summarizes the compounds isolated and characterized from different extracts, fractions, and plant parts. Table 3 reports compounds identified in different parts of the plant. Around 330 compounds (including their isomers) have been placed in other extracts/fractions, mainly in essential oil (59.54%). The majority of them were monoterpenes (43.16%) followed by flavonoid  [191]. Monoterpenes and sesquiterpenes are natural products and essential oils' main constituents [192,193]. Alcohols, aldehydes, esters, ethers, ketones, and phenols are made up of the six functional groups of organic compounds necessary to aromatherapists, especially in essential oils' terpenoid and nonterpenoid volatile compounds (aliphatic and aromatic hydrocarbons). Terpenes or isoprenoids are the largest single class of compounds found in these essential oils [194]. In the same vein, after monoterpenes, flavonoids glycosides were the majority in the plant (10.33%). Hydroalcoholic extraction (8.33%) and polar fraction obtained from ethanol (8.14%) have been used as the most critical sources of compounds after essential oil, according to Table 2. Flavonoids and flavonoid glycosides are usually extracted in ethanol and hydroalcoholic extracts. Weirong and al [195]. found that the best yield of extraction of the flavonoids from Opuntia milpa alta Skin was obtained with 80% ethanol at the temperature of 90°C. Overall, aqueous alcohol solutions are suitable for extracting flavonoids [196]. Among those 329 compounds, terpinene was the most cited (6.76%). Two isomers of terpinene were found, and β-terpinene (3.82%) has been the most cited than αterpinene (2.94%). However, from 37 studies on chemical composition essential oil of C. ambrosioides, as presented in the above table, α-terpinene was found to be the main constituent (40.5%) of essential oils from different countries include Brazil [197][198][199], Cameroon [200], China [201], Colombia [202], Egypt [203], India [204][205][206], Morocco [207], Nigeria [13], and Rwanda [208]. His concentration was variable according to countries and used parts. His highest concentration was 65.4% from essential leaf oil collected and analyzed from India [206]. The terpinenes, both αand γ-isomers, are natural cyclic monoterpenes naturally largely spread in the plant kingdom. They have been identified in several species. For example, in tea trees, α-terpinene is a major constituent of the essential oil tree [209]. After terpinene, ascaridole with their three isomers [cis-ascaridole/ascaridole (3.24%), isoascaridole (1.76%), and trans-ascaridole (0.88%)] was also cited (5.88%). From those 37 studies, ascaridole (specifically cis-ascaridole) was also the majority monoterpene (35.13%) in the essential oil of C. ambrosioides. For example, it was the main secondary metabolites in essential oil collected from Argentina [210,211], Benin [212], Brazil [213][214][215][216], China [188,217], France [218], Hungary [219], India [220], Mexico

Anti-arthritic potential
It was reported that C. ambrosioides graft through a gel from the lyophilized aqueous extract enhanced precociously bone neoformation in rabbits radius fracture the same way as autogenous bone marrow [249]. Recently, a formulation from chitosan and plant extract (20%) showed a potent effect of bone regeneration in rats through a complete alveolar bone reparation after 30 days' treatment and bone fractures. It was also noted to improve osteoblastic activity in the treated group [250]. Leaf hydroalcoholic crude extracts significantly (p < 0.01) improved bone density by 34.5% and 34.8% at the knee and heel, respectively. Moreover, the bone architecture appeared completely preserved in collagen-induced arthritis male DBA1/J mice [251].

Amoebicidal activity
In vitro and in vivo studies of oral administration of E.O. to hamsters infected with Entamoeba histolytica concluded his efficacy. Trophozoites of parasites exposed to E.O. and metronidazole changed color compared to the control, and E.O. inhibited the growth of serval trophozoites in a dose-dependent manner [221].

Anthelmintic effect
Leaf crude aqueous and hydroalcoholic extracts, at the concentration of 0.5 mg/ml, inhibited 100% of egg hatching of Haemonchus contortus. However, the aqueous extract produced significant mortality in adult parasites, dose-dependently [255]. However, E.O. (0.2 ml of oil/kg bw) after 7 days of post-treatment was not effective in terms of reduction of parasite burden both to adults and kids goats with natural mixed-nematode (Haemonchus contortus) infections [256]. A nematicidal evaluation in vitro of different concentrations (0.6, 1.25, 2.50, 5, 10, 20, and 40 mg/ml) of aerial part hexane extract on gerbils three months of age (experimentally infected with Haemonchus contortus L3), for 24 h and 72 h post confrontation, exhibited exciting activity. Therefore, at concentrations of 20 and 40 mg/ml, it showed lethal activity of 92.8% and 96.3%, respectively. Furthermore, the authors noted a decrease of 27.1% of the parasitic burden [257].

Antibacterial activities
From MIC of 4.29 to 34.37 mg/ml, leaf ethyl acetate fraction inhibited several strains, which showed effectiveness against Enterococcus faecalis, Paenibacillus apiarus, Paenibacillus thiaminolyticus, Pseudomonas aeruginosa, and Staphylococcus aureus (They exhibited the lowest values of MIC). However, chloroform fraction was the most active against Mycobacterium species include M. avium (MIC = 625 μg/ml) and M. smegmatis (MIC= 156.25 μg/ml ) [238]. Oliveira-Tintino et al. [245] obtained essential oil from C. ambrosioides, and αterpinene has potentialized norfloxacin and ethidium bromide against it Staphylococcus aureus by significative reduction of their MIC through inhibition of efflux pumps. These results are under a previous study where the essential oil significantly decreased MIC of tetracycline and ethidium bromide against the same strain and the exact mechanism [244]. The fruit methanol extract showed antibacterial potential against three strains, including Enterococcus faecalis, Escherichia coli, and Salmonella typhimurium with MIC values (μg/ml) of 4375, 1094, and 137, respectively. As a standard drug, Chloramphenicol produced the best effect MIC values against those strains (MIC = 6 μg/ml ) [258]. Hydroethanolic leaf extract showed a weak antimycobacterial activity on Mycobacterium tuberculosis subsp. tuberculosis Mycobacterium tuberculosis; Strain H37Ra with a MIC of 5,000 μg/ml. However, the leaf extract of Solanum torvum showed the best effect (MIC= 156.3 μg/ml ) [259]. However, a previous study from South Africa confirmed the antibacterial activity of the acetone extract against Mycobacterium tuberculosis. In fact, with a MIC value of 0.1 mg/ml [260]. Essential oils inhibited Gram-positive (Listeria monocytogenes) growth and Gram-negative bacteria [199]. Pharmacological screening of medicinal plants from South African used against common skin pathogens reported the efficacy of dichloromethanemethanol extract on Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Brevibacillus agri, Propionibacterium acnes, and Trichophyton mentagrophytes with MIC values of 0.80, 0.50, 0.25, 0.50, 0.40, and 0.25 mg/ml respectively. These MIC values were close to those obtained from standards drugs, including methicin and gentamycin resistants to Staphylococcus aureus (0.25 and 0.50 mg/ml ) [261].

Anticancer property
Leaf hydroalcoholic extract (5 mg/kg) inhibited the development of ascitic and solid tumor Ehrlich tumors in Swiss mice, on cells implanted on the left footpad, and in the peritoneal cavity. It also extended the life expectancy of tumor-bearing mice [262]. Furthermore, Cruz et al. [263] reported his antitumor effect on macrophage and lymphoid organ cellularity models by increasing nitric oxide production and the number of cells in the peritoneal cavity spleen and lymph node. Also, the activity of the macrophages increased. Leaf and fruit methanol extract produced contradictory results than other plant extracts on the enterocyte cell line Caco-2 demonstrated. Thus, fruit extract was the most cytotoxic with CC 50 = 45 ± 7 μg/ml; however, leaf extract was the least cytotoxic with IC 50 = 563 ± 66 μg/ml [258]. However, essential oils from the ethanol extract exhibited a potent anticancer property on RAJI cells. That effect was similar to that obtained with doxorubicin (as a standard) with IC 50 of 1 mg/ml and 13.2 mg/ml, respectively. Furthermore, the fractions extracted effectively affected myeloid leukemia cells compared to positive control with 34 and 47 mg/ml values, respectively [215]. EO showed antitumor properties on human liver cancer SMMC-7721 cells by inhibiting cell proliferation, stopping cell division in the Go/G1 phase, and inducing caspase-dependent apoptosis [264].

Antidiabetic effect
Crude leaves extract (100-300 mg/kg bw) significantly reduced blood glucose levels in low-dose STZ-treated and high-fat diet-fed mice after 2 weeks of treatment [265]. At a 20 μg/ml concentration, root hexane extract showed an antidiabetic potential by the high level of αamylase inhibition (50.24 ± 0.9% ) [266].

Antidiarrheal activity
The percentage of 43.4 ± 6.5 and 48.7 ± 11.6, respectively, methanolic and aqueous extracts (300 mg/kg) from the aerial parts (green variety) showed suitable antisecretory property on intestinal secretion response in the rat jejunal loops model. That effect was better than that obtained from loperamide, as a standard drug (43.3 ± 13.1%) [267]. Previously, a similar study of the methanol extract from aerial parts at the same concentration showed an inhibition rate of 40.4 ± 1.0% on charcoalgum acacia-induced hyperperistalsis in rats. That effect was also better than that obtained from loperamide as a standard drug, with a percentage of inhibition of 34.0 ± 3.7 [268].

Antifeedant activity
EO showed high contact toxicity against the DBM, Plutella xylostella. His fumigant toxicity was more pronounced to the second-instar than third-and fourthinstar larvae. Either contact or fumigant toxicities, EO showed the best results compared to α-terpinene and pcymene [269].

Antifertility effect
The leaf methanolic extract produced an antifertility effect temporally in male rats (but reversible). It was mainly observed weak spermatozoa in a vaginal smear in female rats and reduced pups born after 60 days of treatment, dose-dependently. Thus, females' fertility rate was 83%, 66%, and 50%, respectively, in groups treated with 50, 100, and 150 mg/kg of plant extracts. After the cessation of treatment, the hormonal status becomes normal in male rats [270].

Antifungal potential
At the concentration of 0.1%, essential of from leaf methanol extract inhibited in range of 90 and 100% Aspergillus flavus, Aspergillus glaucus, Aspergillus niger, Aspergillus ochraceous, Colletotrichum gloespor-ioides, Colletotrichum musae, and Fusarium semitectum [216]. It also exhibited the highest antifungal effect on Colletotrichum acutatum, C. fragariae, and C. gloeosporioides compared to essential oils Zanthoxylum armatum and Juniperus communis. It inhibited growth zones at 80 and 160 μg/spot, from 6.5 to 8.0 mm and 11.0 to 14.5 mm. At the dose of 160 μg/spot, that effect on all three fungal species was closed to that produced by the reference (captan ) [232]. At the concentration of 500 μg/ml, EO inhibited all two aflatoxigenic strains of A. flavus and the production of aflatoxin B1 production at 10 μg/ml [271]. In the same way, EO was toxic and inhibited the mycelial growth of all fungi, including Aspergillus flavus, A. niger, A. ochraceus, and A. terreus. His fungitoxicity was more effective than those obtained from aluminum phosphide and ethylene dibromide, taken as standards fumigants [220]. Previously, after 72 h of exposition, 176.5 μl EO/l has inhibited at 97.3% (mycelial inhibition) Fusarium oxysporum [202]. At the concentration of 200 μg/ml, leaf hexane extract inhibited the complete growth of Candida kruse [272]. Moreover, with GM-MIC = 7.82 μg/ml, EO demonstrated a strong effect against C. krusei [273]. However, the EO from aerial parts has been sensible on Candida glabrata and C. guilliermondi [200]. Brahim et al. [207] demonstrated a complete synergic action of EO's combination from aerial parts with conventional drugs, especially fluconazole against microbial strains like Candida parapsilosis C. krusei and C. glabrata. The MIC of fluconazole was decreased by 8-16fold. On the other hand, leaf, stem, root, and inflorescence methanol extracts showed a significant effect against Macrophomina phaseolina, with the best result obtained from leaf extract [274].

Anti-inflammatory property
Leaf and stem ethanol extract (300 and 500 mg/kg bw) significantly inhibited paw edema and edema induced by carrageenan (56%), prostaglandin-E2 (55%), bradykinin (62%), and BK (60%) in mice [184]. Leaf crude hydroalcoholic extract produced anti-inflammatory and antinociceptive properties in the chronicity of osteoarthritis conditions. In fact, after the tenth day of treatment with different doses of the section, it was observed a decrease of knee edema, intensities of allodynia, synovial inflammation, and other symptoms related to pain [275]. Inhalation of ethanolic extract (nebulized extract) improved lung inflammation by modulating the pulmonary inflammatory response induced following the ischemiareperfusion method of the mesenteric artery in rats [276]. Topical treatment of leaf and stem ethanol extracts enhanced the cutaneous wound healing caused by wound-induced experimentally in mice. Overall, the extracts repaired tissue, and improved lesion size on days 7, 14, and 19 after injury induction, recovering from the injured area [184].

Anti-leishmanial effect
In vitro study of EO against both Leishmania amazonensis and L. donovani showed complete inhibition of growth of promastigotes and intracellular amastigotes. Otherwise, in vivo investigation, in BALB/c mice infected with L. amazonensis, 30 mg/Kg of EO notably decreased the size of the lesions caused by the disease [277]. Besides, in this condition, EO prevented lesion development of parasite burden compared to pure compounds including ascaridole, carvacrol, and caryophyllene oxide for 14 days of evaluation. Moreover, statistically, EO was more effective than a standard drug (glucantime) [231]. Aqueous extract from the aerial part (100 μg/ml) exhibited a growth inhibition by 87.4% of Leishmania amazonensis collected from patients [278].

Antimalarial potential
After 3 days of treatment, leaf crude hydroalcoholic extract (5 mg/kg/day) extended the life expectancy of BALB/c mice infected with Plasmodium berghei at the end of the 21st-day evaluation. Furthermore, the extract enhanced the parasitemia evaluated by flow cytometry 3 days after infection. On the other hand, plant extract significantly (1.9-to 4.3-fold) interacted with total proteins of erythrocytes infected by P. falciparum, compared to a standard drug (chloroquine). Moreover, at the dose of 25.4 μg/ml (LC 50 ), plant extract completely prevented Plasmodium falciparum's growth [279].

Anti-nociceptive
The results demonstrated that the oral administration of the extract at the dose of 500 mg/kg bw inhibited at 77.39% of neurogenic and 95.06% degrees of inflammation in Algogen-induced nociception male Swiss mice by administering prostaglandin-E2, formalin, capsaicin, and bradykinin. Furthermore, phlogistic substances produced nociceptive responses that were significantly improved 68%, 53%, and 32%, respectively, for prostaglandin-E2, capsaicin, and bradykinin. However, the inhibition of pain induced by the extract's formalin response was comparable to that obtained by indomethacin, taken as standard [184]. Crude alkaloid extract showed a protective effect against writhings induced by acetic acid in mice [280].

Antipyretic effect
At the dose of 40 mg/kg, aqueous bark extract showed a significant (p < 0.0001) antipyretic effect by reduction of body temperature in mice from 36.3 to 31.0°C [281].

Antioxidant activity
Leaf aqueous crude extract at a 250 μg/ml concentration showed the highest superoxide scavenging radicals and hydroxyl properties with the maximum percentage at 44.35% (more remarkable than that produced by BHA 37.46%) and 51.80% (against 54.23% obtained by BHT), respectively. Furthermore, at the same concentration, intracellular ROS, SOD, nitric oxide production, and CAT concentrations were significantly higher in splenocytes than in control [223]. Aqueous infusion and ethanolic extract showed a protective effect against lipid oxidation from raw pork meat and their products by reducing significantly (p < 0.05) compared to control values [242]. Essential oils from leaf extract produced the antioxidant effect by capturing the DPPH radical [199]. On the other hand, C. ambrosioides elevated antioxidant enzyme activities in response to Cu-toxicity [282].
Antisickling potential 1.0 and 0.1 mg/ml of the root, leaf, and bark aqueous and methanol extracts exhibited a significant (p < 0.05) anti-sickling effect by inhibiting sodium metabisulphite-induced sickling of HbSS erythrocytes. The best percentage of inhibition (64%) was obtained after 30 min of incubation in aqueous and methanol extract at 0.1 mg/ml. The high dose (10.0 mg/ml) provoked erythrocytes' lysis [283].

Anti-schistosomal activity
A treatment (methanol extracts of Chenopodium ambrosioides, Sesbania sesban, and mefloquine) of Schistosoma mansoni in infected male Swiss Albino mice 3 weeks after infection significantly decreased worm burden around 95.5% and overall enhanced biochemical markers after sacrifice [284]. However, oral administration of methanol extract (1250 mg/kg/day) for 7 days after infection of Schistosoma mansoni in mice reduced to 53.7% (10 against 22.3 worms) the rates of worm load/ mouse. On the other hand, biochemical and parasitological parameters such as serum total protein, and albumin values, and activities of AlT, AsT, AkP, and AcP were improved in animals [285]. In vitro EO from leaves (25 and 12.5 μg/ml) demonstrated a notable schistosomicidal effect producing 100% of mortality of adult Schistosoma mansoni within 24 and 72 h [237].

Anti-ulcer property
In Helicobacter pylori-infected mice, volatile oil (49.32 mg/kg daily) showed an excellent eradication rate which was comparable to that produced by references such as lansoprazole (12.33 [281].

Immunomodulatory activity
Rodrigues et al. [240] found leaf hydroalcoholic extract recently elevated the number of B lymphocytes and splenocytes during the young worms and the pulmonary phases in Swiss mice infected with 50 cercariae Schistosoma mansoni after 60 days postinfection. Furthermore, it also increased the total number of macrophages, peritoneal cells, and neutrophils during the adult worm phase. The number of macrophages remained unchanged. However, during the cutaneous, lung, young worm, and adult worm phases, the extract reduced cytokines IFN-γ, TNF-α, IL-4, and the liver area granulomas.

Insecticidal effect
Leaf powder (200 g per 100 kg beans) applied on Acanthoscelides obtectus, and Zabrotes subfasciatus inhibited their growth totally [287]. Leaf ethanolic extraction at a concentration of 5% reduced the number of adult Bemisia tabaci 72 h after application by spraying [288]. After 14 days of exposure, aerial parts powder (5 g/kg) caused 100% mortality in adults, Trogoderma granarium, and Tribolium castaneum [203]. Insecticidal investigation from EO collected in Egypt showed an attractive potential against Culex pipiens larvae with a low EC 50 value of 0.750 ppm [289]. Administrated alone, the essential oil from leaf extract of C. ambrosioides has shown high toxicity to darkling beetle Alphitobius diaperinus adults after 24 h of exposure, compared to a standard insecticide (cypermethrin). His effectiveness was 50 times more than that of cypermethrin. Moreover, their combination at 11.79 μg/cm 2 showed high inhibition of Alphitobius diaperinus with LC 50 of 603.36 μg/ cm 2 [210]. Furthermore, ethanol extract at a concentration of 6% significantly inhibited (p < 0.05) Bemisia tabaci, a pest of many crops (93%) [290]. Bossou et al. [212] found that after 24 h of exposition, essential oil from leafy stem exhibited inhibition on A. arabiensis (LC 50 = 17.5 ppm and LC 90 = 33.2 ppm) and A. aegypti (LC 50 = 9.1 ppm and LC 90 = 14.3 ppm).

Relaxant property
Leaf aqueous, methanol and ethyl acetate extracts showed a relaxant effect on thoracic aortic rings isolated from Wistar rats inhibiting vasoconstriction induced by phenylephrine, dose-dependently manner. Methanol extract appeared most potent at the dose of 1 mg/ml, producing 68.7 ± 8.9% of relaxation [292]. At the concentration of 1000 μg/ml, EO from leaves, the tracheal smooth muscle isolated from rats was wholly relaxed due to a contraction caused by potassium, acetylcholine, serotonin, and barium in the presence of a high potassium concentration [197].

Trypanocidal effect
The leaf dichloromethane extract showed remarkable activity (IC 50 = 17.1 μg/ml) against Trypanosoma brucei brucei among 30 Ethiopian medicinal plants [295]. Table 4 shows that the antioxidant effect was among the most pharmacological investigated tools of compounds isolated from C. ambrosioides. Most of them were focused on flavonoids, including their glycosides (75%, 3 of 4 studies). The best described pharmacological potential of flavonoids and their glycosides is their antioxidant capacity, depending on functional groups' arrangement about the nuclear structure. There are three main antioxidant mechanisms of action: upregulation or protection of antioxidant defenses, scavenging of reactive oxygen species, and suppressing their formation through both enzyme inhibition and chelation of trace elements involved in a free radical generation [296]. By the way, other compounds isolated from the plant showed several activities include antioxidant, trypanocidal, analgesic, antifungal, anti-inflammatory, anticancer, antihypertensive, antimalarial, cytotoxic, myorelaxant, and sedative. αterpinene isolated from different plants (Umbelliferae labiatae, Ferula hermonis, Acinos rotundifolius, Hyssopus cuspidatus, and Salvia officinalis) showed antimicrobial activities against so many strains [297]. Kaempferol and its glycosides have demonstrated an antihypertensive potential in most cases. For example, kaempferol 3-Oalpha-L-rhamnoside has shown antihypertensive effect in both standard and hypertensive rats prolonged diuretic effect by decreasing Ca 2+ (through his elimination) and increasing of urinary excretion of Cl − and Na + [298]. On the other hand, scutellarein synthesized from scutellarin produced in vivo a more substantial antioxidant effect by scavenging capacities toward DPPH, • O.H., ABTS +• , free radicals [299]. Caryophyllene oxide has shown anticancer property MG-63 human osteosarcoma cells via various mechanisms [300]. Moreover, Fidyt et al. [301] supported the cytotoxicity of β-caryophyllene oxide, characterized from different plant resources, on cancer cell lines (human cervical adenocarcinoma, ovarian, lung, gastric, stomach, and leukemia cancer cells). pcymene extracted from the essential oil of Origanum acutidens presented lower antifungal activity on the mycelial growth of various phytopathogenic fungi [302].

Bioactivity of the isolated compounds
Insecticidal and antioxidant evaluations were the main pharmacological properties of the compounds isolated from different parts of Chenopodium ambrosioides. The main class of secondary metabolites is represented by monoterpenes, the most represented phytochemical found in Tables 2 and 3. Monoterpenes and sesquiterpenes are secondary metabolites of essential oils, which possess significant biological functions among repellant potential [193]. Among natural compounds involved in chemical defense against insects, terpenoids appeared to have a significant insecticidal potential [303] which produce different mechanisms, by attracting pollinators or by deterring herbivores, monoterpenes and sesquiterpenes play a vital role in the relations between organisms on one side and their environment on the other side [304]. Monoterpenes isolated from C. ambrosioides (Ascaridole, isoascaridole, and p-cymene) have shown significant bioactivities, particularly insecticidal against adults Blattella germanica and Sitophilus zeamais [188,217].

Clinical trials
A clinical investigation in 72 patients examined for parasitic intestinal infections, after 8 days of treatment, the plant extract inhibited Ancylostoma duodenale and Trichuris trichiura completely, against 50 Ascaris lumbricoides [305]. Similarly, a clinical trial study in Peru on efficacy comparison between a C. ambrosioides juice and Albendazole for 15 days of treatment in 60 children concluded reducing Ascaris lumbricoides burden and complete disappearance of Ascaris eggs in feces. That juice produced the best eradication rate of parasites than albendazole, 59.5%, and 58.3%, respectively. Moreover, it was also 100% effective against Hymenolepsis nana [306].

Conclusions
Research concerning medicinal herbs' multiple properties in different areas includes Phytomedicine use, Phytochemistry, Pharmacology, and Toxicology, are summarized. These researches arouse more and more interest. Scientific investigations of Chenopodium ambrosioides have proved their importance in those areas. Different parts of the plant possess potential as a possible source of interesting bioactive compounds likely to treat several human and animal diseases. Further investigations are necessary to promote this plant due to its possibilities therapeutically exploitable. Future research needs to establish a relationship between phytochemical composition, pharmacological and toxicological aspects and investigate deeply and strictly controlled clinical studies for users' safety and efficacy.