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Chemical and Biological Potential of Ammi visnaga (L.) Lam. and Apium graveolens L.: A Review (1963-2020)

Medicinal plants have a vital role in our life, providing us with a variety of secondary metabolites with varied chemical structures and biological activities. Ammi visnaga (L.) Lam. and Apium graveolens L. are common traditional plant species that have long been used for the prevention and treatment of several health problems. Both A. visnaga and A. graveolens belong to the carrot family, Apiaceae (Umbelliferae) and showed different groups of natural compounds, such as coumarins, furanochromones, flavonoids and essential oils. In view of that, the current review describes various classes of chemical constituents identified so far from these medicinal species, together with their valued pharmacological and therapeutic effects.

They inhibit the contraction of vascular smooth muscles, causing dilatation of the peripheral and coronary vessels and stimulate coronary circulation [24,25]. Both the peripheral and coronary vasodilator properties were also found with visnagin, which has been used in angina pectoris as it leads to non-specific inhibition of the contractility of vascular smooth muscles [24,25]. Moreover, it has negative inotropic and chronotropic effects and aids in reducing peripheral vascular resistance [26]. It also causes a weak inhibition of the hydrolytic activity of phosphodiesterase (PDE) isozymes (PDE5, PDE4, PDE3, cyclic GMP activated PDE2 and PDE1). This inhibitory effect on cyclic nucleotide PDEs may be responsible for the vasodilatory action of visnagin at high concentrations [26]. The chloroform and methanol extracts (at 1 mg/mL) of A. visnaga fruits cause the contractions of the rabbit Guinea pig aorta in vitro [6]. The coronary blood flow increased in isolated Guinea pig hearts via visnadin at 60 and 120 μg/mL by 46 and 57%, respectively [6]. Visnadin (< 10 -5 M) was reported to cause inhibition of the contractions induced by the depolarization with 80 mM KCl or by CaCl2 in the KCl-depolarized aorta. Its inhibitory effects were not increased when the depolarization time was prolonged and was similar in aorta incubated in 5 or 40 mM KCl [27]. Samidin and khellol glucoside were reported to exhibit positive inotropic effects on the heart [6]. Khellin was reported to increase HDL-cholesterol in normolipidemic subjects. It also reported having vasodilator, bronchodilator and spasmolytic activities [24]. It has been developed in the treatment of angina pectoris as a bronchodilator and coronary medicine due to its peripheral and coronary function as a vasodilator [28]. Besides being such an antiasthmatic and vasodilator and also an important relaxant without influencing blood pressure [29]. The vasodilating features of A. visnaga are associated with the pyranocoumarin, visnadin and its two primary pyrones, khellin and visnagin. Khellin and visnadin have been shown to have antagonistic activity with calcium, which in turn results in vasodilating activities. It has been shown that visnadin exhibits both peripheral and coronary vasodilator activities and is also used to treat angina pectoris. It inhibits the contractions mediated by the entry of Ca2 + via L-type Ca2 + channels [27].

Prevention of kidney stone formation
Khellin is a spasmolytic agent and visnagin also may decrease peripheral vascular resistance, which may make the stone to pass through the urinary tract easily. In an in vitro cell culture experimentation, khellin and visnagin exhibited preventive activity and decreased lactate dehydrogenase enzyme. Also, khellin and visnagin illustrated preventive effects in vivo through decreasing deposition of calcium oxalate crystals [6,30].

Treatment of vitiligo
Khellin has phototherapeutic activities like as those of the psoralens without the formation of detectable DNA mutations or phototoxic effects. It has therefore been used for the treatment of vitiligo [31]. A total of 36 patients suffering from different types of vitiligo underwent 6 months of treatment with a novel gel formulation of khellin (1%), based upon a water/2-propanol/propylene glycol (WPG) ternary system, caused repigmentation in 86.1% of the treated cases, as opposed to 66.6% in the placebo group [6,31].

Antidiabetic activities
In many cultures, such as those of Palestine, Morocco and the Sefrou region, A. visnaga is considered a popular antidiabetic agent [22,[35][36]]. An aqueous sample containing A. visnaga was shown to possess a substantial hypoglycemic effect when offered to both regular and streptozotocin rats with diabetes [22,37]. In addition, a decoction formulated from the A. visnaga fruits had the potential in normoglycemic rats to minimize blood glucose levels by 51% in comparison to a hypoglycemic agent (tolbutamide) [22,38].

Anti-inflammatory activities
Visnagin decreases the expression of mRNA and the release of TNF-α, IL-1β and IFNγ. The anti-inflammatory activity of visnagin could be due to the inhibition of transcription factors, such as AP-1 and NF-KB [22,39]. Visnagin also has a neuroprotective effect that is responsible for its antiinflammatory activity [22].

Cytotoxic activities
The cytotoxicity of khellin was measured against four cancer cell lines: MCF-7 (breast cancer), MKN-45 (gastric cancer), HEp-2 (larynx cancer) and HT-29 (colorectal cancer). The findings were, however, not positive and the substance did not demonstrate any cytotoxic activity against the four cell lines at the tested concentrations [22,40]. Nevertheless, khellin exhibited mild to moderate activity against the hepatocellular carcinoma cell line [41]. An ethanolic extract of A. visnaga exhibited cytotoxic activity on cervical cancer and breast cancer cell lines [22,42]. Further research was performed into the cytotoxic activity of isolated khellin and visnagin against Hep-G2 (liver carcinoma), HCT 116 (colon carcinoma), Hela (cervical carcinoma), MCF7 (breast carcinoma) and Hep-G2 (liver carcinoma); the findings exhibited the cytotoxic activity of both khellin and visnagin against the Hep-G2 cell line [22,43].

Hair loss
The topical use of A. visnaga was tested for hair loss. A lotion consisting of visnadin and other components leading to enhancement in local microcirculatory flow [22,44].

Antimutagenic effects
In Salmonella typhimurium T98, khellin exhibited inhibitory effects of the mutagenicity of two promutagens benzo[a]pyrenes, 2-aminofluorene and 2-aminoanthracene, while visnagin illustrated a greater toxic effect. The total extract of the fruits of A. visnaga displayed a higher inhibition ability against 2aminoanthracene, 1-nitropyrene and daunomycin than khellin alone. This was attributed to the presence of additional inhibitors such as coumarins or due to the synergistic effect of different compounds [22,45].

Both larvicidal and insecticidal features of A. visnaga have been investigated and the khellin toxicity was examined against
Oncopeltus fasciatus (Hemiptera) and Aedes aegypti (Diptera) larvae, where high activity was observed [22,48]. Khellin and visnagin may therefore be used for the production of new botanical acaricides [49]. A. visnaga fruit ethanolic extract caused inhibition of the lipid content in the haemolymph of nymphs and adults [50], while A. visnaga nbutanolic extract caused inhibition to glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) activity in the haemolymph [51].

A. graveolens
A. graveolens (Apiaceae) is widely distributed in Italy, Sweden, Egypt, Algeria and Ethiopia [53]. It consists of three varieties that are classified according to the part of the plant consumed [54]; A. graveolens var. dulce; commonly known as celery, A. graveolens var. rapaceum; commonly known as celeriac or root celery and A. graveolens var. secalinum; commonly known as smallage or leaf celery. Celery is an important source of minerals, vitamins and amino acids. It has many different uses such as sedative, stimulant, carminative, laxative, antispasmodic, anthelmintic, diuretic, urinary antiseptic, emmenagogue and aphrodisiac [53,55].

Phytochemical review
A. graveolens contained various classes of secondary metabolites, noticed from the isolated groups of compounds including; flavonoids, coumarins, furanocoumarins, isobenzofurans, sesquiterpenes, phthalides and miscellaneous [55]. A comprehensive list of the previously isolated compounds from A. graveolens is presented in (Table 2 and Figure 2).

Anticancer activities
Celery seed oil (CSO) is a source of anticancer phytochemicals. When, CSO (300 mg/kg, p.o.) was given to rats for four weeks after DENA-induced hepatocellular carcinoma (diethyl nitrosamine) (HCC), its increased caspase-3 expression and decreased PCNA expression, suggesting both apoptotic and antiproliferative activity, respectively. CSO uses anti-proliferative, anti-inflammatory and proapoptotic pathways to exert its anticancer effect [53].

Antibacterial activities
The essential oil of celery displayed strong inhibitory activities against E. coli and moderate inhibition against S. aureus and P. aeruginosa [77].

Antiulcerogenic activities
Evaluation of the antiulcerogenic activity in rats was done by using the HCl/EtOH method. Inhibition of gastric lesions by extracts of A. graveolens was dose-dependent for both seeds and aerial parts by (51-95%) and (53-76%), respectively. The methanolic and aqueous extracts at 300 mg/kg caused inhibition of gastric lesions, which was similar to that induced by omeprazole (94%) [77].

Hypolipidemic effects
Ethanol seed extract of A. graveolens showed a decrease of serum total cholesterol, low-density lipoprotein cholesterol, triglycerides and significant increase in high-density lipoprotein cholesterol in the treated groups. The oral administration of ethanol seed extract of A. graveolens showed good hypolipidemic effects. The results agreed to the traditional use of A. graveolens in the treatment of hyperlipidemia [78].

Antihypertensive effects
Administration of the methanolic, hexanoic and aqueousethanolic celery seeds extracts was used to demonstrate their effects on blood pressure and heart rate using spironolactone as a guide. The findings showed that in hypertensive rats, they decreased blood pressure and increased heart rate, but they had no effect on normotensive rats. At 300 mg/kg, each celery seed extract resulted in a decrease in blood pressure of 38, 24 and 23 mmHg and an increase in heart rate of 60, 25 and 27 beats/min, respectively [79].

Conclusion
Several classes of secondary metabolites isolated from different parts of A. visnaga including furanochromones, furanocoumarins, pyranocoumarins, flavonoids and essential oil, where flavonoids and essential oil are the most common investigated classes, while others need more attention from the researchers. Fruits and aerial parts were investigated. Therefore, other parts need further investigation.      Also, many biological studies have been conducted on A. visnaga and resulted in having antimicrobial, antidiabetic, antiinflammatory, cytotoxic, antimutagenic, immunostimulatory, larvicidal, insecticidal, herbicidal and cardiovascular effects. Also, it causes the prevention of kidney stone formation and it has a role in the treatment of vitiligo. On the other hand, A. graveolens is rich in many compounds as flavonoids, coumarins, furanocoumarins, isobenzofurans, sesquiterpenes, phthalides and miscellaneous. Coumarins, isobenzofurans and flavonoids are the most commonly investigated. Leaves and seeds were investigated. Therefore, other parts need further investigation. As well, the effectiveness of A. graveolens has been proven as anticancer, antibacterial, antiulcerogenic, hypolipidemic and antihypertensive effects.