Apium Plants: Beyond Simple Food and Phytopharmacological Applications

: Apium plants belong to the induction. The present review summarizes data on ecology, botany, cultivation, habitat, medicinal use, phytochemical composition, preclinical and clinical pharmacological e ﬃ cacy of Apium plants and provides future direction on how to take full advantage of Apium plants for the optimal beneﬁt to mankind.

its edible stalks, leaves, dried fruits, and seeds; A. graveolens var. rapaceum (root celery, turnip-rooted celery or celeriac), which is commonly used for it edible fleshy tap roots; and A. graveolens var. secalinum (smallage or leafy celery) which is common mostly in Asian countries and is used for its aromatic leaves [35]. A. graveolens is native to eastern Mediterranean, however, the wide distribution of wild ecotypes of the species makes definition of its origin uncertain [39]. It is usually a biannual plant, which is cultivated as an annual crop, however, annual cultivars also exist which are best suited for dry fruit and seed production [40].
It is very common to use celery in intercropping or mixed cropping systems, in order to increase income and diminish the negative impacts of weeds [41]. However, according to Baumann et al., celery has been proven to be very competitive with other species and more research is required regarding the proper amalgamation of species and plant densities in order to ensure marketable yield and quality [42]. Apart from chemical control, cover crops are also a useful means for weed control in celery crops and they may also improve celery yield and decrease fertilizer inputs [43]. Mulching and low tunneling of celery crops have also been suggested to increase total yield, mostly through the reduction of bolting incidences, and hence elongation of the growing period and an increase in the total number of harvests [44]. Other cultivation practices include biological amendments such as inoculation with arbuscular mycorrhizal fungi which has been proven to be beneficial for celery yield and the production of high-quality stalks [45].

Temperature and Soil Requirements
All varieties of celery, including A. graveolens, grow in climate conditions with a long, cool season and monthly mean temperatures of 15-21 • C, and therefore cultivation usually starts during autumn or early winter [36,46,47]. All varieties need abundant moisture during their growing, otherwise their roots can be small and hard. Therefore, they grow best in areas where rainfall or irrigation is assured. They are sensitive to freezing temperatures but can tolerate light frost for a short period of time. Celery plants thrive in soil with a pH of 6.0-6.6 in mineral soils and a pH of 5.5-6.0 in organic soils [36]. However, very low winter temperatures may induce bolting within the first growing year in biennial cultivars and severely affect yield and quality of end products (stalks, leaves, and roots) [46,48]. Such conditions are preferable when plants are meant for seed or dry fruit production where earliness in flowering induction is sought after [48]. Apart from the temperature, the photoperiod and plant growth stage are also important for flowering initiation [47], while according to Pressman and Negbi [49], long days after a chilling period increase bolting incidence and flower stalk elongation. Leafy types are considered more sensitive to freezing temperatures, as well as heat and water stress conditions than root celery [35,36,39]. Regarding soil requirements, they must be fertile and have good water holding properties without being prone to waterlogging. Apium nodiflorum lives partially submerged in water at an altitudinal range from sea level to 1200 m and it is found in most of North and South America, Europe, Asia, and North Africa. It is prostrate or ascending with a height of up to 1 m, perennial, and propagates by seeds and stolons. Petioles expand at the base sheathing and the stem and leaves are compact, pinnate, with toothed leaflets [50]. The native habitats of Apium repens are represented by lakeshores and shallow spring waters. It also grows in wet grasslands as its other habitat and it lives in flood-prone pastures [51,52].

Propagation
Propagation of plants is carried out by direct sowing of seeds (especially in the case of celeriac) or by transplanting after sowing in seed beds or seed trays. According to Baninasab [53], light exposure and temperatures higher than 20 • C and below 25 • C significantly increased germination rate and the percentage of germinated seeds of wild celery, indicating that soil temperature and exposure of seeds to light are crucial for plant propagation [47,48,54,55]. Seed germination may also be improved by thermal treatment (15 • C) and pre-sowing hydration of seeds followed by a slow drying process [56]. Regarding crop establishment, planting density is essential to the total yield, and distances of 15 × 20 cm and 45 × 40 cm for leafy celery and celeriac, respectively, showed the best results, regardless of the cultivar and irrigation regime [57,58].

Irrigation
Irrigation is crucial for high yields and marketability of vegetable products, especially in leafy vegetables such as stalk celery and smallage [59]. Unless precipitation covers crop needs in irrigation water, lack of water has a severe effect on the total yield and quality of celery, especially under low nitrogen rate regimes [60], while water stress conditions may increase furocumarins content in celery juices [61] and alter essential oil composition in terms of volatile compound content such as limonene and myrcene [62]. The quality of water is also essential and saline water (up to 5.83 dS/m) resulted in a yield reduction of 74% as compared with irrigation using tap water (0.25 dS/m) [63]. Moreover, salinity may affect seed germination, and NaCl concentrations higher than 100 mM may completely inhibit germination of celery cv. Ventura [64]. In contrast, according to other authors [65], celery plants (cv. Utah 52/70 R) grown in soilless hydroponic systems have proven to be tolerant to salinity levels up to 10.5 dS/m since no decrease of dry matter content was observed at this level. Moreover, Pardossi et al. reported that salinity levels up to 10 dS/m and 100 mM of NaCl, respectively, had no significant effect on the growth of celery plants grown in a nutrient film technique (NFT) hydroponic system [66]. Drip irrigation is the most common method used in celery crops, since it allows for higher water use efficiency through the application of lower irrigation volumes and more frequent irrigations that match evapotranspiration and crop stage [67], while the method has also been associated with more economical chemical weed control as compared with other irrigation systems [68]. Moreover, subsurface placement of film stripes in greenhouse environments may increase soil water content through the reduction of deep percolation, and further improve irrigation system efficiency [69].

Fertilization
Fertilization of horticultural crops is very intensive, and a careful management is needed to minimize nutrient losses through leaching. Considering the high total biomass production of celery varieties, the species is considered to be demanding in terms of nutrient requirements. According to Christiansen et al., celeriac has a shallow root system which allows for better nitrogen use efficiency in a soil layer of 0-25 cm depth, whereas, nitrogen (N) depletion is higher in larger depths (0.25-2.5 m) [70]. Although celery and celeriac are considered as moderate nitrate accumulators [71], there are significant differences in nitrogen use efficiency (NUE) between the existing cultivars and unreasonable use of N fertilizers should be avoided in order to avoid excessive nitrates contents. However, suggested rates may differ depending on growing and soil conditions. For example, according to Du et al., the application of 200 kg/ha of N and aerated irrigation of celery crops may improve yield, NUE and soil bacteria, fungi, and actinomycetes abundance [72], while Madrid et al. reported that 25% lower N rates (0.31 g/L of KNO 3 ) resulted in a similar mineral composition of celery plants, as compared with a control treatment (0.59 g/L of KNO 3 ) [73]. In a study by Min et al., the highest greenhouse-grown celery plants were reported for application rates between 120-180 kg/ha of N, while additional amounts of N (up to 300 kg/ha of N) were depleted through leaching [74]. Moreover, Kolota et al. reported that pre-plant application of 100 kg/ha of N is efficient for early celeriac production [75]. Regarding potassium (K) fertilization, the results from hydroponic studies showed that an application of 482.7 mg/L significantly increased celery yield, while the type of K was also important for quality since K 2 SO 4 increased tip-burn incidences as comparing with KCl [76]. In addition, Li et al. reported that 4-8 mmol/L of K, and 8 mmol/L of Ca and Mg were adequate for optimum growth and development of celery plants [77]. For phosphorus (P) fertilization, Li et al. suggested that application rates within the range of 124 to 248 mg/L along with medium Mg and Ca levels (192 mg/L and 320 mg/L, respectively) were sufficient to cover nutrient requirements of celery plants [77]. Celery is very sensitive to Ca deficiency which results in black heart symptoms and quality loss of the final product and can be controlled through foliar application of Ca in the form of Ca(NO 3 ) 2 or CaCl 2 [78]. The species is also susceptible to boron deficiency (brown checking and cracked stem) and toxicity which may severely affect the quality and marketability of the final product. According to Bellaloui and Brown, the sensitivity to these physiological disorders depends on the genotype which could explain the differences in the efficiency of boron translocation from roots to shoots and its further distribution to the aerial parts of the plant [79]. Other physiological disorders include pithiness and pencil stripe in celery stalks and hollow heart in celeriac roots [39].

Harvesting
Harvestable maturity is reached when roots measure a diameter of 5-12 cm depending on the growing conditions. In areas with mild winters, roots might be left in the ground or straw mulched with leaves and harvested as needed. Roots can also be removed and stored in humid sand in a cool place [36]. Harvesting of celery (leafy or turnip-rooted types) is carried out manually, especially when successive harvesting is implemented, or mechanically for large fields when the product is meant for industrial purposes. Although the harvesting date is genotype and growing conditions dependent, early harvests may improve the quality of the end product mostly through the visual appearance (color and texture) and physicochemical composition [80], as well as through the increased content of essential oil in the leaves [81]. Late harvests may increase total yield when a single harvest is implemented, however the overall quality of celery petioles is reduced, especially in terms of tissue texture [82]. The white color of petioles is associated with high quality and increases consumers' acceptance, therefore, various cultivation practices (also known as blanching) are implemented to improve petioles color, including covering plants with pots, tie wrapping the leaves in order to cover the middle of the rosette, and hilling up with soil. Moreover, according to Han et al., the feature of white petiole is also genotype dependent and self-blanching or white stalk cultivars have been developed to cover market needs [83].

Postharvest Treatments
The postharvest process is essential for retaining the quality of the final product, especially for minimally processed food products, such as ready-to-eat fresh-cut salads. Celery is commonly marketed as fresh-cut raw leaves and stalks and additional processes are required for better quality and extended shelf-life of the products. Various postharvest treatments have been proposed to reduce the antimicrobial load and increase the shelf-life of processed celery products, including sanitization with gas plasma treatments [84], heat treatments, edible coating and chemical dipping [85][86][87], packaging [88,89], modified and controlled atmospheres [88,[90][91][92], and light exposure [93], while most of these treatments have been linked with quality changes [94]. However, preharvest treatments are also pivotal and may define the quality and the shelf-life of the final product. According to Ilić et al., early harvesting combined with washing and cool storage may significantly reduce water losses during prolonged storage of celery [95], while Rossi et al. reported that late harvesting may increase the incidence of cut-end browning in celery without postulating ethylene involvement in this process [96]. Moreover, postharvest washing and cold storage of celeriac roots may significantly decrease the content of nitrates [97]. Nitrogen fertilizer rates may also have an effect on the shelf-life of celery sticks. According to Gómez et al., reducing nitrogen rates by 25% may significantly improve sensory quality and decrease decay incidences and nitrate content [98].

Apium Plants Phytochemical Composition
The chemical composition of Apium plants is remarkable. The variability of chemical compounds and the effects, which these substances induce, have been determined with 508 published articles indexed in the PubMed databases and 966 articles indexed in the Web of Science-Core Collection (Clarivate Analytics) databases. The chemical composition of Apium plants differs depending on plant part (leaves, seeds or stalks), stage of harvesting, geographical region of production, type and method of preparation of essential oil, and growing conditions such as soil structure and climate [35,99]. The phytochemical composition of the Apium plants according to the USDA Nutrient Database/Distribution of Nutrients (raw vegetable), is presented in Table 1. The proximate composition of Apium graveolens is shown in Table 2.
The overall differences in the chemical compositions for Apium plants, both in quantitative and qualitative terms, found in the literature reside in the different ecological factors of territories (the origin of the samples and the genetic composition of the genotypes), the part of the planes taken in the study, the conditioning mode of the vegetal material, and either the method of extraction or the method of analysis used.

Traditional Medicinal Uses of Apium Plants
Since ancient times, human beings have been faced with disease and discomfort and have struggled to combat these with different approaches. Among all the treatments, herbs are continuously used for the treatment of all the ailments [114]. At the present time, herbal drugs are not in the list of mainline therapies, however, due to unwanted toxicity and side effects, herbal therapy is again gaining momentum. Herbal medicine is now an accepted medicine as a complementary and alternative therapy in combination with the main line therapies in the world The furocoumarins included celerin, psoralen, bergapten, apiumoside, apiumetin, apigravrin, osthenol, isopimpinellin, isoimperatorin, celereoside, and 5-and 8-hydroxy methoxypsoralen [105].
The overall differences in the chemical compositions for Apium plants, both in quantitative and qualitative terms, found in the literature reside in the different ecological factors of territories (the origin of the samples and the genetic composition of the genotypes), the part of the planes taken in the study, the conditioning mode of the vegetal material, and either the method of extraction or the method of analysis used.

Traditional Medicinal Uses of Apium Plants
Since ancient times, human beings have been faced with disease and discomfort and have struggled to combat these with different approaches. Among all the treatments, herbs are continuously used for the treatment of all the ailments [114]. At the present time, herbal drugs are not in the list of mainline therapies, however, due to unwanted toxicity and side effects, herbal therapy is again gaining momentum. Herbal medicine is now an accepted medicine as a complementary and alternative therapy in combination with the main line therapies in the world [114]. For this reason, the world today is focusing more and more on research in the field of herbal medicine [115][116][117].
The medicinal parts of A. graveolens used in treatment include (1) leaf of A. graveolens var. secalinum, (2) stalk of A. graveolens L. var. dulce, and (3) turnip root of A. graveolens var. rapaceum [6,107]. Celery is a plant mentioned in the traditional Arab and Islamic medicine with the name "Karafs". According to old literature, it was also called Udasaliyon in Greek [114]. The roots help treatment of liver, spleen dropsy, and jaundice diseases [123].
Celery is used against helminth, joint problems [31], stomach problems (relief of griping pains and flatulence), and spasm, as well as sedative, carminative, diuretic, urinary calculus, urinary antiseptic, kidney stones, emmenagogue, laxative, bronchitis, asthma, osteoarthritis, and arthritic pain [15,103,107,113,114]. It also relieves offensive breath and stimulates the production of semen and libido by its protective role against the sodium valproate [15,23,103,114,[124][125][126] and increases breast milk production [127]. Although no experimental investigation explores its effect on female fertility, its abundance of calcium, magnesium, potassium, and sodium might explain the gender determination [128]. Celery is used as a heart tonic to lower blood pressure [129] and total cholesterol [97] or hyperlipidemia in general [16,103,123,124]. It has important effects such as preserving gastric mucosa, lowering blood pressure, and strengthening the heart. Its root leads to an increase in calcium and a decrease in potassium in the heart tissue [124]. It also has potential benefits related to weight loss or management because it is a low-calorie vegetable [35]. It has a positive effect on the immune system because it contains some vitamins such as vitamin C and vitamin A [103]. Traditionally, Apium leptophyllum Pers. prevents tumor, anorexia, vomiting, and colic pain because of its antinephritic, antirheumatic, and carminative properties [101].
Apium plants are popular plants in modern societies as they represent a good alternative to expensive chemical drugs which have many negative effects on human health [30]. Table 3. Use of Apium plants in traditional and modern medicine [35].

Use of Apium Plants in Food Preservation
Celery, as well as many other aromatic and medicinal plants, produces a large array of phytochemicals such as terpenoids, alcoholic compounds, phenols, and essential oils, etc. [130,131] which have uses ranging from the control of metabolic disease to pathogenic microorganisms to food preservation [23,130,132,133]. The antifungal and antibacterial properties of several active constituents and essential oils of Apium plants against foodborne microorganisms can be easily served in foods that could provide alternatives to conventional and synthetic bactericides and fungicides [132,133]. Thus, the antimicrobial properties of Apium plants enable the possibility of using natural, low-cost, safe, renewable, food grade, and easily biodegradable antimicrobial agents for the preservation of several food products [130]. Consequently, they are important for providing resistance to several pathogens. Some authors have reported that the essential oil of this plant has the potential to act against various bacterial and fungal pathogens due to its composition, which is rich in antimicrobial constituents such as carvone, a-phellandrene, and limonene [130,131].
The antioxidant of celery extracts has also been evaluated both therapeutically and in food preservation [114,120,132,134]. The food industry must continually evaluate the utility of alternative strategies to meet consumer demand for "clean labels" and limit the use of chemical preservatives. The deterioration of the quality of the fats, vegetable oil, and other food systems is associated with lipid peroxidation. For example, the oxidation of lipids in vegetable oils results in chemical changes that impart off-flavor and rancid odor. The use of antioxidants is the most suitable means to stabilize oil, prevent lipid oxidation, and protect oil from free radicals inflicted damages. Mitigation of the oxidation process can be achieved using synthetic antioxidants such as tertiary butylhydroquinone (TBHQ), butylated hydroxyanisole, and butylated hydroxytoluene. An alternative to the use of those synthetic antioxidants is extracts from celery. Celery extracts have demonstrated antioxidant activity and can suitably replace the synthetic antioxidant, TBHQ in canola oil [134,135]. Indeed, essential oil of Apium plants has the potential to be used as a substitution for chemical food preservatives like tertiary butyl hydroquinone (TBHQ) and butylated hydroxytoluene (BHT) since it is considered a cancer promoter [130]. However, the method of extraction of the antioxidant compounds must be considered to ensure optimal activity while being simple and cost appropriate.
Admittedly, the greatest application of celery extract (celery powder and celery juice) has been in meat preservation. It can serve as a natural flavoring and can be used as a nitrate replacer in meat products with special significance on their antifungal, antibacterial, and food preservation properties [130,131]. Indeed, Sebranek and Bacus demonstrated that the celery juice or powder and starter culture treatment is an efficient alternative instead of direct addition of sodium nitrite into frankfurter-style cured hams and sausage [136]. The improvement of safety of "naturally cured (no-nitrite-or-nitrate-added)" meats implies a cured cooked meat model system consisting of several natural ingredients (2% salt, 10% water, 80:20 pork, and 150 or 50 ppm ingoing sodium nitrite) that closely looks like the commercial frankfurters that reduced Listeria monocytogenes inhibition (p < 0.05) in the major part of the uncured meat products (nitrite or nitrate free, with celery powder as the nitrate source) as compared with control samples conventionally produced with direct addition of sodium nitrite [137]. Sodium nitrite is included in the production of cured meat products to provide the characteristic color, flavor, and microbiological safety [138]. Studies have linked the consumption of processed meats containing nitrites to the risk of certain types of cancer [139,140]. In the last decades, the increased demand for nitrite or nitrate-free meat products led many manufacturers to use celery powder, containing a substantial amount of nitrate (celery can contain as high as 1500 ppm to 2800 ppm nitrate or greater than 2500 mg nitrate/kg) in combination with a starter culture to reduce nitrate to nitrite during this process [136,137,141,142]. Apium petroselinum essential oil demonstrated antibacterial effects on food spoilage bacteria, A. faecalis and S. dysenteriae bacteria [142]. Previous studies have also reported that the essential oils and extracts of the Apium petroselinum and A. graveolens are effective on various bacteria such as S. dysenteriae, E. coli, and S. aureus [143]. Their results suggest that the replacement of synthetic preservatives with the essential oils of these natural healthy compounds can be applied as an alternative way to increase the shelf-life of several special foods [142]. However, to prove its usefulness as a food preservative, the antimicrobial activity of A. graveolens essential oil, of known composition, needs to be assessed in specific food products. The effective antimicrobial dose of oil may exceed the sufficient level for flavoring purposes because of its unique taste and aroma [141]. Thus, the use of Apium plant oil would probably be limited in food products. Menghini et al. indicated that the essential oil of Apium nodiflorum (L.) Lag, which is used as a culinary herb, showed antimicrobial activity against Helicobacter pylori with a minimum inhibitory concentration (MIC) of 12.5 µg/mL [144]. Pseudomonas putida is one of the most important spoilage bacteria in meat and meat products. Oussalah et al. investigated the effect of several essential oils against P. putida to see their antibacterial activity. Oussalah et al. showed that oils which already had proven antimicrobial properties appeared to have little or no effect against the P. putida strain. However, the Apium plant showed antimicrobial activity at a MIC of 0.8% wt/vol. against P. putida [131].
Thus, celery powder and juice are highly compatible sources of nitrite for process meat products due to their mild flavor profile and fairly low vegetable pigment that does not impart the final product flavor [136,141,145]. Indeed, the use of celery juice or powder in processed meat products is widely known [113,119,131,133].
In addition to this, the growth of pathogenic microorganisms including Listeria monocytogenes, Clostridium botulinum, and Clostridium perfringens in processed meats containing celery juice or celery powder has been investigated. Celery juice treatments at both 100 and 200 mg/kg resulted in growth of L. monocytogenes similar to that of conventional nitrite at the same concentrations used in ham [145]. The researchers indicated that celery juice may increase the meat product pH which could have an impact on antimicrobial properties of nitrite in some products. The control of L. monocytogenes in hams made with pre-fermented celery juice has been demonstrated [146]. The use of natural curing ingredients results in hams that possess L. monocytogenes inhibitory properties similar to those in traditionally cured hams. The use of celery juice powder containing preformed nitrite in turkey bologna was shown to have similar antimicrobial properties to the chemical form of nitrite, but it lacked flavor and color [147]. The control of C. perfringens in frankfurters containing a natural source of nitrite was effective only when additional natural antimicrobial agent was used [137]. However, the addition of celery powder in processed meat should be limited to around 0.2%-0.4% of the formulation weight since high-level incorporation of celery powder may cause the development of off flavors [148]. Thus, celery powder or concentrate of celery juice was frequently mentioned as ingredients because they are a food plant and their potential contribution as a source of nitrate is very significant [139]. However, the use of celery powder alone, without nitrate reducing bacteria, is less appropriate for producing standard cured meat [143]. Moreover, it would be of interest to investigate the synergistic effects of celery powder rich in natural nitrate and volatile oil on meat preservation.
Overall, the use of celery-based products in the preservation of food will likely expand and might garner greater regulatory oversight that could prevent their use as flavoring ingredients.

Antimicrobial Activities of Apium Plants
Antibiotics have been critical in the control of microbial infections. The emerging antimicrobial resistance throughout the world [149] emphasizes the research of new treatments. Natural resources, especially plants, are potent candidates for antimicrobial uses. Medicinal plants have a critical role in fulfilling the basic health needs and introduce a new source of natural antibacterial and antifungal agents [150]. Many naturally found compounds, such as essential oils extracted from edible and medicinal plants, herbs, and spices have been shown to possess antimicrobial functionality and serve as a natural antimicrobial agent against a wide range of food spoilage and pathogen microorganisms [130], thus, they have long been traditionally used for centuries due to their antifungal and antibacterial properties. Therefore, essential oil of Apium plants can be assumed to be one of the important groups of natural sources for the development of broad-spectrum, safer and cheaper antifungal agents [151]. The main active compounds of these oils are primarily limonene, pinene, and selinene [119,130]. More particularly, phenolic constituents also have been reported to be responsible for these properties [152]. Antimicrobial properties of Apium plants have been confirmed in several in vitro studies [109,[151][152][153].
Various epidemiological studies showed that Apium plants play a significant role in the prevention of microbial growth with its antibacterial and antifungal effects [119]. Baananou et al. indicated that essential oil and aqueous extract from A. graveolens showed antibacterial activity with MIC values of 0.01-0.25 mg/mL [109]. In a study by Asif et al., the antimicrobial activity of the essential oil of this plant was determined in vitro against Helicobacter pylori and, consequently, a MIC value of 12.5 mg/mL was obtained [34]. A study by Menghini et al. also revealed the inhibitory activity of A. nodiflorum essential oil against Helicobacter pilori [143]. Maxia et al. evaluated the antifungal activity of A. nodiflorum essential oil and extracts against yeasts, dermatophytes, and Aspergillus spp [151]. According to their results, the MIC of the oil showed a variability of inhibition among all the fungi tested. Essential oil of A. nodiflorum from different origins showed significant activity against dermatophytes with MIC values ranging from 0.04 to 0.32 µg/mL. The oil for Aspergillus fumigatus and A. flavus is less effective against Aspergillus spp., especially MICs of 2.5 and 5µg/mL [151]. Maxia et al. also indicated that the occurrence of myristicin and dillapiol in essential oil could show a synergistic effect, which may explain the relatively higher antifungal activity against the same strains. These results support the potential application of A. nodiflorum essential oil in the treatment of dermatophytosis and candidosis [151]. Moderate antimicrobial activity was shown by A. graveolens (leaves) against Salmonella typhi that are resistant to most antibiotics [153].
A. graveolens essential oil showed an inhibitory activity against S. aureus and different Listeria strains, whereas, E. coli and several Salmonella species remained unaffected. The inhibitory activity was also recorded against several fungal strains with varying efficiency. However, Din et al. indicated that extracts of A. graveolens were very effective and showed good activity against E. coli, S. aureus, S. typhi, B. subtilis, and P. aeruginosa [154]. Baananou et al. showed that the essential oil of A. graveolens was strongly inhibitory against E. coli and moderately inhibitory against P. aeruginosa and S. aureus [109]. Din and colleagues performed an experiment to evaluate the antimicrobial activity of A. graveolens against several bacterial strains and fungal strains. They reported that all fractions of A. graveolens showed good activity against E. coli, S. aureus, S. typhi, B. subtilis, and P. aeruginosa. It was observed that crude ethanolic fraction of A. graveolens exhibited good activity as fraction was effective against S. typhi and B. subtilis having a MIC value of 0.96 µg/mL and 0.82 µg/mL, respectively, whereas, the same fraction was least effective against E. coli, recording MIC values of 17.7 µg/mL. Hexane and methylated spirit showed at par activity while methylated spirit was a slightly less effective inhibitor against P. aeruginosa (MIC: 11 µg/mL) [154]. A. graveolens was also evaluated against antifungal activity using different strains of fungi. The data showed that the ethanolic fraction of A. graveolens was more effective against A. flavus having a MIC value of 5 µg/mL followed by hexane fractions (MIC: 12 µg/mL). Similarly, the methylated spirit fraction also proved to be effective against relevant fungal strains followed by the methanolic fractions. It was also noted that the crude ethanolic fraction of A. graveolens revealed good activity as compared with other fractions [154].
Rani and Khullar revealed that moderate antimicrobial activity was shown by A. graveolens against multidrug-resistant Salmonella typhi [155]. Similar results were reported by Shad et al. and Edziri et al. [150,152]. Din et al. also indicated that the ethanolic fraction of A. graveolens was more effective against A. flavus, followed by hexane fractions. Similarly, the methylated spirit fraction also showed activity against relevant fungal strains followed by methanolic fractions [154]. Momin and Nair reported that the methanolic extract of A. graveolens seeds had an inhibitory effect on the growth of C. albicans and C. parapsilasis at 100 µg/mL [107]. Similarly, Edziri et al. concluded that the methanolic extract of A. graveolens had the best antifungal activity against various yeasts such as C. albicans, C. kreussei, and C. parapsilosis with MIC values that varied from 0.08 to 0.31 mg/mL [150,152]. Baananou et al. reported similar results for the antifungal activity of methanolic extract of A. graveolens against Candida serovars with MIC values ranging between 0.08 and 0.31 mg/mL and with minimum fungicidal concentration values ranging between 0.08 and 0.63 mg/mL [109].
According to the obtained results, which confirmed earlier studies by different authors, the antimicrobial activity of each extract can be varied within each other and that methanol is the best solvent for the extraction of the antimicrobial substances from Apium plants as compared with the other solvents [152,156]. Moreover, the development of fractionations of extracts should be carried out for further investigation of their possible use as food preservatives to adopt their promising potential in the food industry [152].
A. graveolens extract antimicrobial activity has been associated with numerous free hydroxyls, limonene, β-selinene, and other compounds that are able to combine with the carbohydrates and proteins in the bacterial cell wall and or the lipophilic character of these compounds, leading to either enzyme inhibition or accumulation in membranes and resulting energy depletion which is associated with their antibacterial properties [130].
In short, Apium plants show antifungal and antibacterial activities [109,151,153,154]. In many studies investigating the antimicrobial effect of essential oil or extracts of Apium plants, authors generally reported the minimum inhibitory concentration (MIC) of tested samples by using different methods. These methods varied from the agar dilution method to the disc diffusion method [130]. The MIC is defined as the lowest concentration of extract needed to prevent growth of any microorganism [153]. The results of these studies revealed some activity against specific pathogens which varied from none to moderate. It is quite difficult to interpret the obtained data because different antimicrobial tests were used (e.g., disc diffusion and broth microdilution techniques), which were previously shown to provide results that were hard to compare [155]. In addition, they determined some antioxidant activity in vitro models such as antioxidant capacity by radical scavenging activity using DPPH (α, α-diphenyl-β-picrylhydrazyl), β-carotene-linoleate, reducing power, metal chelating effects, and the phosphomolybdenum method [113]. They showed that the highest phenolic content of the extracts was established in methanol (51.09 mg/g) followed by water extract (46.40 mg/g), ethyl acetate (22.70 mg/g), and butanol extract (19.43 mg/g). In addition, they found that methanol extract had the highest free-radical scavenging capacity followed by water, ethyl acetate, and butanol extract. Their results showed that A. graveolens leaves are rich in phenolics and are a good source of antioxidants [113,119]. In another study, Yildiz et al. evaluated the total antioxidant capacity of A. graveolens leaves using CUPRAC (cupric ion reducing antioxidant capacity) and ABTS (2,2-azino-bis [3-ethyl-benzothiazoline-6-sulfonate]) methods and they also determined the phenolic compounds with high-performance liquid chromatography (HPLC) [158]. Caffeic acid, p-coumaric acid, and ferulic acid were determined as major phenolic acids, and apigenin, luteolin, and kaempferol were determined as major flavonoids [119,158].

Antioxidant Activities of Apium Plants
The antioxidant activity of A. graveolens was investigated by Din et al. [154]. They also indicated that the total phenolic content was higher in methanolic fraction (63.46 mg GAE/g) followed by ethanol (36.60 GAE/g), and hexane fractions (34.86 mg GAE/g). Similarly, the flavonoid content was high in methanolic extract (56.95 quercetin/g). In addition, they showed antioxidant activity with FRAP assay with 12.48 mM FeSO 4 equivalent/L in methanolic fraction [150,154]. The DPPH radical scavenging capacity of the essential oil from the A. graveolens leaves was investigated and the results indicated that the essential oil from A. graveolens has potential as a natural antioxidant, and thus inhibited the oxidation process [159]. In another study, eleven cultivars of celery were analyzed for their antioxidant activities. Among these eleven cultivars, Shengjie celery had the highest antioxidant activity, whereas, Tropica had the lowest. An extremely significant positive correlation between the antioxidant activity and the contents of total flavonoids, total phenolic acids, or total phenolics was observed in this study. The A. graveolens species displayed high antioxidant capacity and high free-radical scavenging activities [134].
Kolarovic et al. investigated the antioxidant activity of celery in rats treated with doxorubicin and also the effect of the celery itself, and its combination with doxorubicin was determined by its antioxidant status [160]. The n-butanol extract from A. graveolens seed at 60 mg/kg ameliorate lipid peroxidation and its antioxidant properties improved antioxidant enzymes in streptozotocin-induced diabetic rats after 21 days of treatment [26].

Anticancer Activities of Apium Plants
Cancer is an important health issue throughout the world. Due to the side effects of anticancer drugs, scientists have started to focus on natural products. The discovery of anticancer natural products of plant origin such as vinblastine, vincristine, and podophyllotoxins prompted the research community to explore plant-derived natural products such as flavonoids, terpenes, alkaloids, etc. due to their diverse pharmacological properties including cancer chemopreventive effects. Other Apium species also yield similar effects. For example, in a study performed on flavonoidal fractions of A. leptophyllum fruits, it was shown that the fractions had chemopreventive potential on 7,12-dimethylbenz[a]anthracene (DMBA) induced carcinogenesis in mice. DMBA is a polycyclic aromatic hydrocarbon, which acts as a procarcinogen and is an ultimate carcinogen after metabolic activation. The activity of the plant might be due to the modulation of cutaneous lipid peroxidation or enhancement of total antioxidant capacity. Flavonoid fractions were also found to be effective in suppressing skin tumor growth at a dose of 20 mg/kg [100].
Combinations of plants with other plant-based natural products are also seen in the literature. For example, A. graveolens is known to be present in the herbal-marine mixture called HESA along with Carum carvi, Penaeus latisculatus, and other marine products, which are used to improve the quality of life in colon and breast cancer patients in the Near East [161]. Chemoprevention is one of the strategies that can revert or delay the response of carcinogens. Dietary factors contribute to about a third of potentially preventive cancers, long known as preventive effects of plant-based products on tumorigenesis and other chronic diseases [162]. Plants provide important and valuable compounds against this terrifying disease, and therefore using them against cancer and also consuming certain food plants would be beneficial in our fight against cancer.
Several works concerning the in vitro anticancer studies of Apium plants are present in the literature, in particular, those regarding both the plant species directly and some compounds previously extracted from Apium species. Among the anticancer activity studies on the total species, those concerning A. graveolens L. are the most important and well known. Nevertheless, other similar works are present about A. graveolens var. rapaceum (Mill.) Poir. (unresolved name) and A. nodiflorum (L.) Lag.
With respect to A. graveolens, its seeds have widely demonstrated its in vitro efficacy as potent anticancer agents. In particular, its crude extracts in n-hexane, ethanol, and water showed a concentration-dependent effect on the growth inhibition (GI) of rhabdomyosarcoma cell lines with the n-hexane extract as the most efficient one. In fact, the GI percentage for this extract was 68.70% and 81.71% for the concentration of 100 and 200 µg/mL, respectively. Indeed, the GI values for the ethanolic extract and the aqueous extract at the same concentrations were lower, i.e., 59.23% and 63.09% for the former and 56.64% and 61.33% for the latter. An important result from this study was that the power of inhibiting the cell growth started only at concentrations higher than 100 µg/mL. In fact, at lower concentrations, the effects for all three extracts were minimal. On the other hand, all the crude extracts showed a very slight or no effect on the growth inhibition of murine L20B cells, not even reaching GI values of 10% in most cases. All these calculations were made by using cultures containing only the RPMI-1640 medium as a control [163].
Less notable results were observed in three other works. The first one by Octaviani et al. studied the effect of the ethanol extract on the LNCaP prostate cancer cell lines with GI values less than 50% [164]. The second one, by Mencherini and coworkers, studied the effect of the 1:1 ethanol-water extract on J774.A1 (murine monocyte/macrophage) and HEK-293 (human epithelial kidney) cell lines and gave no inhibition [27]. Lastly, the third one, by Brahmi et al., studied the effect of the H 2 O:MeOH extract at only the concentration of 12.5 mg/mL on the SK-N-BE(2)-C (human bone marrow neuroblastoma) and HepG2 (human hepatoblastoma) cell lines against Trolox ® used as an antioxidant standard [165].
Indeed, an extremely positive result was achieved by Gao et al. [166] who were the first to discover that the supercritical CO 2 extract of the seeds also possess a very high inhibition on the growth of cultured BGC-823 cells (human gastric cancer). An untreated BGC-823 cell was used as a positive control. The mechanism of the action of this inhibition passes through a concentration-and time-dependent cellular apoptosis via a mitochondria-mediated pathway which represents a total new scenario with respect to the usual pathway as described later for other types of cancer cell lines [166].
With regards to A. graveolens var. rapaceum, only a partial study has been done. In fact, the data in the literature report only on the anticancer activities of four compounds isolated from the dichloromethane extract of the roots of this species, whereas, no test has ever been performed on the extract obtained from the other plant organs. However, these compounds which belong to the polyacetylenes class showed only modest activity against the investigated cell lines, i.e., CEM-C7H2 (leukemia), U937 (lymphoma), RPMI (lymphoma), and HRT-18 (myeloma) as compared with the positive control, 14-hydroxyhypocretenolide-α-d-glucopyranoside-4 ,14 -hydroxyhypocretenoate. In fact, the general IC 50 values of these compounds ranged from 30 to above 100 µM as compared with the values of the control which were between 2.59 and 19.2 µM. The only exception was falcarindiol which was shown to be more efficient against CEM-C7H2 having 3.50 µM as an IC 50 value which was comparable with respect to the control (2.59 µM) [167].
With regards to A. nodiflorum (L.) Lag., Maggi et al. collected three different exemplars of this species and studied the anticancer activities of the methanolic extracts of their essential oil against three different cell lines, i.e., A375 (human malignant melanoma), MDA-MB 231 (human breast adenocarcinoma), and HCT116 (human colon carcinoma). In all the experiments, which were repeated three times each, the extracts proved to be effective with IC 50 values ranging from 3.16 to 17.72 µg/mL. Cisplatin was used as a positive control and was more effective with IC 50 values which were between 0.48 and 2.79 µg/mL. Thus, A. nodiflorum may represent a new possible species to be used against some types of cancer in cases that are not particularly acute [168].
Apium plants have antioxidative and anti-inflammatory properties, which play a vital role in the inhibition of tumor initiation, promotion, and progression [100]. Some of the compounds in the seed of the Apium plant have collaborations in the molecular mechanisms and pathways of cellular targets that are considered to have a significant effect on the treatment of human cancers with its anti-inflammatory and analgesic effects [119]. Kolarovic et al. reported on the potential activity of parsley for its anticancer property. In their study, they revealed that the flavonoid apigenin expressed strong antioxidant effects by increasing the activities of antioxidant enzymes and, as a result of this activity, decreased the oxidative damage to the tissues [159]. Moreover, there is a lack of information about peptides from plants of Apium. Previously, it had been shown that an antioxidative peptide was already isolated and purified from A. graveolens. This purified peptide could possess synergistic antioxidant potential with the other antioxidants, thus, leading to anticancer activity in the fraction of celery extracts [169].
In many in vivo studies, it was shown that perillyl alcohol causes regression of tumors of the pancreas, liver, and breast. Celery seed was injected in wistar rats in the laboratory and had an inhibitive effect on liver carcinoma. A protective effect on the gastric mucosa and it is anti-gastric ulcer was also discovered [119]. A. graveolens extract induces apoptosis via Bax and p-53 proteins in the LNCaP human prostate cancer cell line [170].
Zidorn et al. investigated the potential activity of four polyacetylenes against leukemia, lymphoma, and myeloma cell lines. All the polyacetylenes with falcarinol showed at least moderate toxicity to all cell lines. Falcarinol was the most active compound of Apium plants and showed significant cytotoxicity against acute lymphoblastic leukemia cell line CEM-C7H2 [157]. Young et al. reported that the polyacetylene falcarinol also showed protective activity against chemically-induced colon cancer development in rats. These compounds of Apium plants had a biphasic effect on CaCo-2 cells, with antiproliferative effects at high doses [171]. In addition, the biphasic responses of bioactive polyacetylenes, falcarinol, and falcarindiol on the stress responses in primary myotube cultures were also reported. Preincubation with low concentrations of both polyacetylenes prior to H 2 O 2 exposure induced a cytoprotective effect, whereas, higher concentrations had adverse effects [171].
In previous studies, Peng et al. reported that phthalides, such as sedanolide and 3-n-butylphthalide, have been shown to possess anticarcinogenic and neuroprotective properties. According to the findings, 3-n-butylphthalide inhibits platelet aggregation, reduces neuron apoptosis, improves mitochondrial function, and decreases oxidative damage. These compounds are officially approved for the treatment of stroke patients in China [172]. The efficiency of the protection is very high and quite fast, and also leads to restoration of normal levels of glutathione, ascorbic acid, and glycogen, as well as no increase of the levels of SGOT, SGPT, ALP (liver marker enzymes) and total bilirubin. In this case, one group of seven rats was used as a control, and received only the vehicle for administration, i.e., corn oil. The same protective effect has been observed with the same experimental conditions against other hepatotoxicants [152,168], thus providing this species effective as hepatoprotective. In both these cases, a group of rats was used as control and received the vehicle for administration only.
Moreover, in 2011, Salman et al. discovered that the daily consumption of the fresh leaves and stalks of A. graveolens in rabbits that were affected with tumor and already treated with doxorubicin, was able to diminish the severe side effects linked to the assumption of this drug [173]. In fact, doxorubicin (an anthracycline antibiotic) exhibits a high anticancer activity against a broad series of cancer types, i.e., ovarian, breast, lung, uterine, cervical, and soft tissue cancers [174,175] but is also known to have important toxicities, even causing cardiac, hepatic, and hematological damage [176,177]. This interaction was seen at a concentration of 7.5 mg/kg/day per 14 days after comparison with data obtained from the control group that received only 5 mL/kg of 0.9% NaCl solution intraperitoneally four times in 14 days and it was observed to be very effective, acting through an antioxidant pathway [173].
A. graveolens is also one of the three ingredients of HESA-A, an herbal-marine mixture of plant species. This mixture has been shown to have a high antitumor effect on human patients with end-stage metastatic colon cancer after six months of therapy with a great contribution due to A. graveolens itself. In fact, HESA-A is able to completely inhibit the growth of cells at the highest concentration of 5.4 mg/mL, whereas, at minor concentrations its effect is somewhat lower. Nevertheless, this mixture does not affect non tumoral cells and acts by following an apoptotic mechanism [178].
Indeed, the methanolic extract of the fruits of A. leptophyllum (Pers.) F.Muell. ex Benth. (now synonym of Cyclospermum leptophyllum (Pers.) Sprague) have been proven to have a good chemopreventive effect in a dose-dependent manner starting from a concentration of 20 mg/Kg, on DMBA-induced skin cancer cells of Swiss mice. The effect was observed against a control group, and was carried on by the flavonoid components through antioxidant action, and consequently, the normalization of the lipid peroxidation status was observed [100].

Anti-Inflammatory Effects of Apium Plants
Anti-inflammatory activity studies on Apium plants started early. For example, ethanolic extracts of the seeds showed an anti-inflammatory effect against chronic inflammation induced by cotton pellet granuloma. The extract also induced a dose-dependent analgesic protective effect against both thermal stimuli and the writhing syndrome indicating central and peripheral action. These data support the traditional use of these plants for pain and inflammation condition effects [179].
In more recent studies, compounds isolated from Apium plants were tested for their anti-inflammatory effect. It was demonstrated that luteolin, a naturally occurring flavone, which has various biological activities, exhibited significant anti-inflammation activity in both acute and chronic inflammatory models. In addition, downregulation of inducible COX-2 expression was an important factor regarding the mechanism underlying its anti-inflammatory activity [175]. In another study, apiin was isolated from the leaves and both apiin and celery extract inhibited in vitro NO release and iNOS expression significantly and in a concentration dependent manner. It is well known that NO production is elevated in inflammatory diseases, and therefore we conclude that the plant has topical anti-inflammatory capability to ameliorate inflammation or other conditions where enhanced expression of iNOS could be observed [9]. The extract can be used alone for its anti-inflammatory effect since aqueous extracts of celery stems have been found to have anti-inflammatory activity in the rat carrageenan foot paw edema model and in mouse ear histamine vascular inflammation [179].
As a result, the plant is demonstrated to have components that possess potent anti-inflammatory effects [180,181]. The anti-inflammatory activity of phytochemicals presents in food merits further study to help those suffering chronic inflammation to ameliorate their inflammatory conditions by offering a proper selection of food [182]. Ovodova et al. studied the anti-inflammatory activity of purified pectin from A. graveolens var. Dulce, after oral administration to mice. The findings showed that extracts prevented LPS-induced inflammation. The anti-inflammatory activity of apium pectin suggests a potential health benefit of celery as an alternative for preventing inflammation [183]. Anti-nociceptive and anti-inflammatory effects of A. graveolens have been studied previously [154].

Cardiovascular Effects of Apium Plants
Extracts prepared from the celery plant, or compounds isolated from different parts of the plant, have been studied extensively for a long period for their effects on the cardiovascular system. We can sum these studies up as follows: Increased blood pressure (BP) is one of the important risk factors for coronary heart disease, which is the largest cause of mortality in industrial countries. Hypertension has been termed the silent killer, and if it is untreated, silently damages the blood vessels, heart, brain, and kidneys. Thus, hypertensive patients have increased risk of silent ischemia and unrecognized myocardial infarction. Therefore, regulating blood pressure is of outmost importance among cardiovascular problems [184]. Moghadam et al. conducted a study that confirmed that celery seeds possess a hypotensive effect and this effect was attributable to some hydrophobic constituents, for example, n-butylphthalide (NBP) in this plant [184].

Central Nervous System Related Effects
Celery plant is known to possess various effects on the central nervous system, and therefore it can be used in the prevention and treatment of various CNS disorders. According to our literature search, celery plant can be used in the following disorders: Alzheimer's disease is the most common form of senile dementia, characterized by progressive memory loss. L-3-n-butylphthalide, a pure compound extracted from the seeds of the celery plant, significantly improved microcirculation in pial arterioles, reduced the area of cerebral infarct and inhibited platelet aggregation, improved mitochondrial function and decreased oxidative damage, reduced neural apoptosis and inhibited increases in intracellular calcium levels and the inflammatory response in experimental ischemic animal models. It was also found to alleviate the learning and memory deficits induced by cerebral hypoperfusion in rats. As a result, this compound appears to be promising as a multitarget drug for the prevention and treatment of Alzheimer's disease [185]. This activity of the compound DL-3-n-butylphthalide (NBP) was also confirmed in a study by Wang et al., who suggested that NBP alleviates oxidative stress, implicating its potential use in Alzheimer's disease and other forms of dementia [186].
However, not a desired effect, celery plant may lead to some drug interactions that can lead to unwanted results. Celery contains phytoestrogens and these compounds are structurally similar to estrogen making them a commonly utilized herbal supplement for the management of low estrogen states such as menopause. In addition, phytoestrogens also interact with many of the same enzymes as endogenous estrogen including CYP450. Celery also possesses high inhibitory activity directed toward CYP450-2D6, and thus it may change the pharmacokinetics of active substances that are metabolized by these enzymes. For example, in a case report, celery extract usage was believed to lead to the alteration of pharmacokinetics of venlafaxine; the drug was not sufficiently metabolized, and therefore resulted in symptoms of mania [187]. Khalid et al. also reported that the plant might lead to the alteration of the pharmacokinetics, resulting in elevated levels of the venflaxine drug and causing symptoms of mania [187].
A. graveolens extracts have neuroprotective effects in in vitro models and seeds have also been helpful to regulate the nervous system by a combination of effects. It stimulates the sex drive and also produces sedative effects. According to Boonruamkaew et al., methanolic extract of the whole plant was shown to possess antidepressant-like effects in the forced swimming and tail suspension tests. It also had a cognitive-enhancing effect on the Morris water maze and object recognition tests. The plant mediated a potent antidepressant-like effect which involved biochemical changes reducing the MAO-A neurotransmitter system, cognitive-enhancing effects associated with decreased AChE activity, antioxidant pathway related to a decrease of the MDA level, and inhibition percentage of the O 2 − while increasing GPx activity [188]. It has been shown that celery seed extract can be used to regulate the nervous system [30].

Diabetes Mellitus and Dyslipidemia
Diabetes is a major manifestation of endocrine and metabolism disorders and hyperglycemia and, unfortunately, results in secondary diseases and long-term complications such as nephropathy, neuropathy, retinopathy, and diabetic foot syndrome. In a study by Taskhakori-Sabzevar et al., administration of hexane extract of the seeds of celery significantly reduced water intake and glucose, and cholesterol and triglyceride levels in STZ-induced diabetic rats; it also increased serum insulin, and HDL as compared to the negative diabetic rats [189]. In another study, it was reported that the administration of celery leaf infusion showed significant effect on decreasing the level of blood glucose in rats [190]. However, in another study, the seed extract showed mild antihyperglycemic and antihyperlipidemic effects. The results of these studies are considered important because drugs available for the treatment of diabetes and high blood lipids are associated with side effects, and therefore scientists are focusing on the effectiveness of herbal treatments since they lack side effects [191].
In another study, it has been shown that celery leaf extracts of suspension produce an antipyretic effect. In addition, it has been reported that Apium plants produce hepatoprotective, hypocholesterolemic, and anti-inflammatory activities. Aqueous celery extract was also used to decrease total cholesterol level in rats for 8 weeks. On the other hand, aqueous extract of Apium graveolens (400 mg/kg) significantly decreased the body weight in obese rats in 40 days as compared to an obesity-induced group [16]. In another study, cafeteria-fed rats were fed daily with 400 mg/kg aqueous extract of A. graveolens for 40 days, and the researchers found that glucose, cholesterol, LDL, VLDL, and triglyceride amounts significantly decreased and the HDL cholesterol levels were increased [192].

Hepatoprotective Effect of Apium Plants
In the Indian medical system, A. graveolens seeds were used for the treatment of liver disorders. Singh et al. investigated the antihepatotoxic effect of methanolic extracts of the seeds of the plant [157,173]. Celery plant petroleum ether and methanol extracts of the seeds showed hepatoprotective activity in paracetamol and thioacetamide intoxicated rats. The stimulation of hepatic regeneration resulted in their livers becoming more resistant to damage and toxins. As well, the protective effect of the methanolic extract was further confirmed by histopathological examination [16]. In another and more recent study, seeds of the plant were successively extracted to exhaustion with petroleum ether, acetone, and methanol using the cold percolation method. This methanolic extract showed maximum antihepatotoxic activity against CCL 4 -induced hepatotoxicity, which could be related to the methanol soluble particles such as flavone and diterpene. The activity was comparable to that of the standard drug silymarin [157].
The plant can also be used against hepatotoxicity induced by other drugs, as well. For example, carboplatin is an antineoplastic agent with a potent effect, and thus it is being used in the treatment of ovarian cancer recurring following previous chemotherapy and in some other types of carcinogenic developments. However, the substance is reported to lead to renal and hepatic major organ toxicity and also result in peripheral neurotoxicity. Since the seeds of the celery plant are known to be used as hepatoprotective in Turkey, Özbek et al. tested the seeds for their hepatoprotective activity and demonstrated that the administration of carboplatin alone to rats for five consecutive days led to liver damage, however, when carboplatin was combined with the fixed oil obtained from the seeds of the plant, it was observed that liver toxicity could be partially prevented [193].
Acetaminophen is another toxic substance that can manifest harmful effects on humans. In a study performed on a fish species, it was found that for the short-term treatment of efficient flavonoids (rutin, quercetin, and luteolin) rich celery extract could act in multiple ways to preserve the normal functioning of a fish species named Pangasitus sutchi. These mechanisms may involve chelating or scavenging the APAP-generated oxyradicals, protecting antioxidant enzymes, preserving hepatocyte structure, promoting antioxidant levels, maintaining normal carbohydrate and lipid metabolism and hepatic ions. Although this study was performed on fish, the authors suggested that flavonoid-rich celery should be included in the diet of humans in case of APAP toxicity [194].
In addition to its direct effect on liver health, the plant can also be used in liver problems associated with other conditions. For example, in a study performed on the livers of rats with adjuvant-induced arthritis in which enzymatic antioxidants are decreased and production of ROS that appear to contribute to oxidative stress in the liver increased, methanolic extract of the whole plant reduced oxidative stress by causing a decrease in the superoxide anion and total peroxide and an increase in the activities of glutathione peroxidase and superoxide dismutase. It was suggested that A. graveolens represents a potential beneficial agent for the reduction of liver destruction in arthritis [195].

Renal Disorders
Hyperuricemia is a predisposing factor for gout since excessive production of uric acid leads to deposition of monosodium uric acid crystals in soft tissues and joints which are associated with gout and is also thought to be associated with a number of clinical disorders including endothelial dysfunction, atherosclerosis, hypertension, coronary artery disease, diabetes, dyslipidemia, and chronic kidney disease. The plant contains furocoumarins (apigravin, celerin, and umbelliferon), flavonoids (apigenin, apiin, kaempferol, and luteolin), phenolic compounds (caffeic acid, p-coumaric acid, and ferulic acid), and tannins. Celery essential oil has also been shown to have a series of phthalide derivatives. Antigout activity has been described for phthalide derivatives, phenolic compounds, and tannins. Apigenin, at a dose of 25 mg/kg, also significantly decreased serum uric acid and inhibited liver XO activity by 38.4% in hyperuricemia mice. Luteolin, another major component of celery also reversibly inhibits XO in a comparative manner, by interacting with the primary amino acid residues located within the active site pocket of XO. Therefore, the plant is probably promising in the treatment of hyperuricemia [196].
In another study, it was observed that ethanol and aqueous extracts of the plant showed improvement in the excretion of urinary sodium even after gentamycin induced renal toxicity, and potassium excretion was found to be increased in all treatment groups as compared to a control. The plant has a significant diuretic activity and could be used for this purpose [197]. It has been shown that celery seed extract can help to improve digestion and kidney function [30].

Reproductive Issues
Reproductive problems are important health issues since they might lead to infertility both in men and in women. Functional foods or nutraceuticals can provide a beneficial alternative in this aspect. Celery plant is also known for its beneficial effects on the reproductive system and when we performed a literature search, we saw that studies were mainly focused on male fertility. In one study, the plant was reported to be listed among the plants that are being used in gynecological disorders in the Ottoman period [198].
Infertility is one of the most common health problems in the world, which involves approximately 15% of couples. Infertility can be present in both genders, but about 50% of infertility is associated with the male factor. Decreased sperm count and motility and deformity of sperm are the most important factors of male infertility. Plasma membrane of sperm is susceptible to oxidative damage due to large amounts of unsaturated fatty acids, finally leading to decreased motility and viability of sperm [23]. The plant may have a direct effect on the male reproductive system, or it may exert a protective effect against various drugs or environmental chemicals.
In a study on the hydroalcoholic extract of celery leaf, it was observed that the extract could increase spermatogenesis in rats, and this effect was more pronounced in higher doses [23]. Similarly, the aqueous extract of the leaves was observed to improve the spermatogenesis process and could be useful for some sperm fertility parameters [126]. In another study, hydroalcoholic extract of the plant was shown to boost spermatogenesis and, as indicated by this study, celery can have a protective effect against substances that cause damage to the testicular structure and spermatogenesis [199].
As for the protective effects of celery, in a study that demonstrated the protective effect of celery seeds against sodium valproate (VPA) used in the treatment of epilepsy, bipolar psychiatric disorders, and migraine, the plant was shown to have a potent protective effect against VPA-induced testicular damage and oxidative stress in rats. The drug is known to disturb the reproductive endocrine function and reduce the quality of semen in epilepsy patients. The protective effect of the plant may be due to its antioxidant property and detoxification capacity [125].
Phthalates, which are used in plastics to impart flexibility to rigid polymers, are also environmental toxic substances that humans are exposed. DEHP (di-(2-ethylhexyl) phthalate) is normally used for the production of storage containers, bags, and waterproof clothing and because it is not covalently bound to the vinyl polymer matrix, it can easily be released from these products into foods, beverages or directly into body fluids. In a study performed on celery oil, it was demonstrated that the oil alleviated testicular damage induced by DEHP and this protective effect can be attributed to its antioxidant properties and the androgenic activities of apigenin, limonene. Celery oil can also decrease the oxidative stress in the testis, protect maturation of spermatozoa, and improve sperm function [200]. In another study performed with the plant, based on the hypothesis that DEHP is rapidly metabolized to mono-(2-ethlyhexyl) phthalate after ingestion which is more toxic for Leydig cells and Sertoli cells as compared with DEHP, administration of the celery oil partially prevented the decrease in body and testicular weights and enhanced epididymal sperm count and serum hormone levels [201]. Apigenin, as the important flavonoid in celery, is a potent antiplatelet agent, and thus a vascular relaxant effect in animals has been demonstrated [202]. It has been shown that ethanol extracts of celery leaves increase spermatogenesis and also improves fertility of rats. In addition, it has been shown that aqueous extract of celery significantly reduced the fat in the blood serum of mice [203]. A. graveolens leaves extract were used to examine mice to increase sertoli cells and primary spermatocytes, as well as the improvement of spermatogenesis. However, another study, indicated that the hydroalcoholic extract from A. graveolens leaf (150 mg/kg) diminishes FSH level and exerts dependent adverse effect on pituitary in mice [204].

Osteoarthritis
Osteoarthritis is a major cause of joint pain and disability, resulting in great socioeconomic costs worldwide. A bioactive coumarin called isofraxidin was isolated from A. graveolens and it was found that in vivo treatment of isofraxidin not only prevented calcification and erosion of cartilage, as well as the thickening of subchondral bone, but also reduced serum levels of inflammatory cytokines in the mouse osteoarthritis model. Therefore, it can be concluded that isofraxidin has potential in the treatment of osteoarthritis [205].

Osteoporosis
Methanol extract of fresh roots of the plant was tested against osteoporosis in ovariectomized rats since this animal model has similar pathophysiological mechanism of bone deterioration that is seen especially in women after menopause. Osteoporosis is a systemic disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and, consequently, increased fracture risk. Osteoporosis affects an estimated 75 million people in Europe, USA, and Japan and it is the underlying cause for more than 8.9 million fractures annually. The most common type of osteoporosis is associated with estrogen deficiency in postmenopausal women, and it leads to acceleration of bone resorption and rapid bone loss. Treatment with the extract significantly decreased pain thresholds as compared to control animals. The extract also enhanced BMS (bone mineral density) and improved bone quality. Therefore, it possesses the potential of an effective drug for prevention of possible fracture-induced pain by increasing bone mass density. After supplementation of the extract for a period of 4 weeks in ovariectomized rats pronounced beneficial effects were observed and Apium was demonstrated to have the potential as an effective and safe supplementation for retarding osteoporosis development [206].

Diarrhea
Diarrhea is one of the most important worldwide health issues, particularly affecting people of all ages and resulting in electrolyte loss, dehydration, shock, and sometimes death. Another Apium species, A. leptophyllum, is traditionally being used in the treatment of diarrhea due to its strong antifungal, antibacterial, and anti-inflammatory properties. Flavonoid fraction of the fruits was shown to exhibit marked reduction in the frequency of diarrhea, the weight and volume of intestinal contents, as well as intestinal transit. In addition, the antidiarrheal effect may be due to the reduction of gastrointestinal motility, inhibition of the synthesis of prostaglandin, and intestinal muscle contraction, all of which are due to the flavonoids that the plant contains [106].

Hyperthyroid
Hydroalcoholic extract of the leaves of the celery plant is beneficial in the balancing of hyperthyroid. Since abnormalities in the synthesis and release of thyroid hormones may lead to direct or indirect diseases, the plant may be beneficial in increasing the quality of life of humans [207].

Dandruff
Finally, the plant also has a cosmeceutical effect with its usage against dandruff. Dandruff, in acute or chronic form, is a benign but unsightly scalp disorder affecting 40%-50% of the world adult population, men being two to six times more affected than women. From a preliminary screening, compounds improving barrier permeability functions were identified from marine microorganisms and plants. Some of them belong to the family of phthalides, small compounds widely present in plants and fungi. Senkyunolide-A (SENKY) was extracted from the seeds of the plant and it was concluded that it could be of interest for promoting scalp homeostasis. It reinforced its barrier function and reduced irritation in promoting detoxification and anti-inflammation pathways. When it was applied on the scalp, it significantly reduced the formation of dandruff and soothed the scalp [208].

Bioactivities of Phytochemicals Identified in Apium spp.
The various activities observed for the extracts are strongly supported by the presence of peculiar phytochemical constituents in both volatile fraction and polar compounds (Figure 2). Sahoo et al. designed an in vivo study to investigate the chemopreventive potential of flavonoid fractions of Apium plants (FFAP) on Swiss mice. The co-administration of FFAP with DMBA-treated groups provided significant (p ≤ 0.001) prevention against skin papilloma and lipid peroxidation statue was normalized as compared to a carcinogenic control. Thus, they suggested that FFAP had chemopreventive potential on DMBA-induced carcinogenesis in mice, which may be due to the modulation of cutaneous lipid peroxidation or enhancement of total antioxidant capacity [95]. Sahoo et al. indicated that FFAP is effective on the enzyme activities of the liver as well as lipid peroxidation, thus, it can possess chemopreventive activity. FFAP was effective in suppressing skin tumor growth especially when a dose of 20 mg/kg was treated, which was probably attributed to anti-lipid peroxidative or antioxidant potential during DMBA tumor induction [100].  Gao et al. investigated the antitumor effects of A. graveolens extract (AGE) and related mechanisms of apoptosis in human gastric cancer BGC-823 cells [166]. In the study by Gao et al. it was shown that, AGE had an antiproliferation effect on human gastric cancer BGC-823 cells in a dose-and time-dependent manner [166]. The apoptotic rate significantly increased after uptake of AGE with morphological changes typical of apoptosis. The findings indicated that AGE could significantly inhibit the growth and induce apoptosis via the bcl-2 family related mitochondria-mediated pathway of human gastric cancer cell line BGC-823 in vitro. Thus, it would seem to be worth to investigate AGE as a novel natural therapeutic alternative, and the induction of apoptosis by AGE in other cancer cell lines can be the current subject of on-going investigations. [166].
In addition, 3-n-butylphthalide (3), was investigated for its neuroprotective potentialities in rat hippocampal neurons and human neuroblastoma SH-SY5Y cells. The results indicated it was an anti-cerebral ischemia agent, and it proved to have therapeutic effects on learning and memory deficits induced by intracerebroventricular infusion and chronic cerebral hypoperfusion. It was shown that 3-n-butylphthalide (3) markedly reversed the number of apoptotic cells amyloid-β-induced and, in addition, it significantly decreased the hyperphosphorylation of tau protein [172].
Perillyl alcohol (p-mentha-1,8-dien-7-ol) (4), a limonene-type monoterpenoid consisting of a cyclohexene ring substituted by a hydroxymethyl and a prop-1-en-2-yl group at positions 1 and 4, respectively. It is another constituent of A. graveolens seed-oil and other essential oils such as those obtained from lavendin, peppermint, spearmint, and cherries. It has been proven to interact with several modulators of cell growth and differentiation. The observed activities included the induction of differentiation, cell cycle arrest in the G1 phase, and apoptosis [212,213]. The effectiveness of this monoterpenoid alcohol as an anticancer agent has been tested in a phase II clinical trial for the treatment of patients with metastatic breast cancer refractory to chemotherapy [214]. It showed a modulation in the regulation of the phosphorylation for several cellular factors in human tumor cells, namely, PKB/Akt, 4E-BP1 and eIF4E/eIF4G [212]. Perillic acid (4-isopropenylcyclohex-1-enecarboxylic acid) (5), one metabolite strictly related to perillyl alcohol, showed also antiproliferative activity on non-small cell lung cancer cells (NSCLC, A549, and H520). As well as perillyl alcohol (4), perillic acid (5) by increasing expression of bax, p21. and caspase-3 activity, exerted a dose-dependent cytotoxicity. Dose-dependent sensitization to cisplatin and radiation in cells exposed to these compounds was also observed. Therefore, their use in combination therapy might have a chemotherapeutic value [213].
There are also more widespread phytoconstituents in celery and in other common foods [222] with interesting bioactivities such as is the case of flavonoids and coumarins. Their mechanism of action is generally due to the antioxidant potentialities, such as in the case of coumarins which prevent the formation of free radicals, hence the damaging of cells. This decreases the mutations incidence thus lowering the potential for cells to become cancerous.

Clinical Effectiveness of Apium Plants in Human
Nowadays, because of their lower side effects and higher effectiveness, medical plants are preferred for the treatment of various illness such as cancer, hypertension, hyperlipidemia, diabetes, cardiovascular, inflammatory diseases, and bronchitis, etc. When we search the literature, we see that numerous clinical studies have been performed on different parts of Apium plants and on the bioactive compounds that have been isolated from the species. We also note that these studies have mostly been conducted on A. graveolens species, but sometimes, other Apium species have been examined. Generally, Apium plants can prevent cardiovascular diseases, jaundice, liver and lien diseases, urinary tract obstruction, gout, and rheumatic disorders [160].

Kidney Inflammation
It has been reported that Apium plants have a reducing effect on kidney inflammation [23]. In addition to the positive effect in most cases, a high amount of celery may show a negative effect, especially in a human meal in pregnant women. In one study, the effects of abortion and periods on (bad) pregnant women were investigated. According to the results, the researchers recommended that pregnant women should not eat more celery in their meal, because its high doses can stimulate the uterus [23]. In addition, a study on the effect of creating eczema and allergies in babies during the pregnancy period when their mother ate high amounts of celery was conducted. For this research, they added celery to the meal of pregnant mothers and carried out the allergy test on the babies. The results have shown that a high amount celery in their (mothers') meal may increase the risk of complications [23].

Gastric Disorders
A. graveolens is known to be used by Unani and Ayurvedic medical practitioners for stomach and kidney disorders. Thus, a study was performed to examine the gastroprotective activity of the methanol extract of the plant and it was demonstrated that the extract was able to inhibit the formation of ulcers induced by different experimental models and it also decreased basal gastric acid secretion. This gastric antiulcer capacity of celery extract could be attributed to its antioxidant properties, resulting in a reduction of the lipid peroxidation and elevation of NP-SH content, in addition to improving the mucus coating of the stomach. These results suggest that the plant might be promising in the prevention of gastric disorders [230]. Functional dyspepsia (FD) is the most common gastrointestinal disorder, accounting for almost 50% of all patients visiting gastrointestinal specialty centers. Celery plant is known to be effective in the digestive system due to its inhibitory effects on gastric ulcers and inflammation. Azimi et al. investigated, in a randomized double-blind trial, a traditional remedy, 500 mg capsules prepared from A. graveolens and Trachyspermum copticom (AT), and treated patients with functional dyspepsia (FD) in eight weeks [231]. At the end of week four, they determined that the frequency of the symptoms began to decrease and there were significant differences in the frequency of symptoms of functional dyspepsia, and therefore until eight weeks, the frequency of symptoms continued to decrease. The research claimed that the remedy of AT was effective in reducing the frequency of this symptom [231]. The author found that AT was more effective than omeprazole in improving FD symptoms such as postprandial distress syndrome and epigastric pain syndrome [231]. These studies demonstrate that the traditional use of the plant in gastric problems is justified and consuming celery plant may provide additional benefits [114]. However, the study was limited by a small sample size and short follow up period, and therefore cannot be generalizable to all FD patients.

Central Nervous System Related Effects
The roots of the plant are reported to be a tonic for brain and is being used in Unani medicine. Aqueous extract of the roots was examined for their various effects on the central nervous system and it was found to be effective in Petit-mal epilepsy [17].
Multiple sclerosis is an inflammatory demyelinating disease with no confirmed treatment, and therefore patients tend to use complementary and alternative medicines. On the basis of the anecdotal evidence found in traditional Iranian medicine, MS 14 is a natural (herbal-marine) product voluntarily used by MS patients. It may have some benefits both on the quality of life and on the symptoms of the patients. This product contains 90% Penaeus latisculatus (king prawn), 5% A. graveolens, and 5% Hypericum perforatum. The drug not only halted the progression of the disease, but also attenuated the inflammation in the central nervous system, indicating that this herbal-marine compound has anti-inflammatory effects [232]. The effectiveness of this Iranian herbal-marine compound combination was further confirmed by another study by Ahmadi et al. in 2010 and the authors concluded that the combination might also be effective in the treatment of other neurodegenerative disorders with the same mechanisms [233].

Hyperlipidemic Effect
Dietary fat is one of the most important environmental factors associated with the incidence of cardiovascular disease. Plant polyphenols exert cardiovascular benefits by altering concentrations of blood lipid components and a high intake can significantly reduce the risk of mortality from cardiovascular disease. Epidemiological data suggested that foods containing fibers have strong protective effects against major disease risks including cancer, diabetes, cardiovascular diseases, and Alzheimer's disease. Animal and human intervention studies have shown that celery inhibits platelet activation, favorably alters eicosanoid synthesis, suppresses production of proinflammatory cytokines and lipoxygenase activity, stimulates nitric oxide production, and improves endothelial function [234].
Extracts prepared from the seeds of the plant also demonstrated beneficial effects. In a study where the effects of chloroform and aqueous basic fraction of the seeds were examined, it was found that the extract inhibited total cholesterol triglycerides, low-density lipoproteins level, and significantly increased high-density lipoprotein level [235]. Ethanolic extract of the plant was also shown to lower triglyceride levels via inhibition of hepatic cholesterol biosynthesis, increasing fecal bile acid excretion, enhancing plasma lecithin, cholesterol acyltransferase activity, and reduction of lipid absorption in the intestine [236].

Conclusions and Future Perspectives
This paper reviewed data on phytochemical composition, distribution, and habitat-cultivation conditions and various pharmacological properties or health effects of Apium plants. The medicinal activities of this herb have been previously proven by numerous studies carried out in vitro and in vivo. Therefore, Apium plants are considered as important medicinal plants all over the world. As a conclusion, all in vivo and in vitro studies have shown that Apium plants have been used to treat many diseases such as cardiovascular disorder, jaundice, liver lien diseases, urinary tract obstruction, gout, and rheumatic disorders in traditional medicine for long time, because leaves, root, seed, and stalk parts of this plant contain many bioactive compounds such as polyphenols, flavonoids, limonene, selinene, coumarin glycosides, vitamin A, and vitamin C.
Overall, numerous information has been gathered concerning celery. If clinical validation is needed, such as that of the spermatogenesis stimulation and protection, most of the clinical studies were poorly designed and involved small sample sizes and short follow up periods. Therefore, commensurable clinical data, including toxicology, are required to support its usefulness.
Author Contributions: All authors contributed equally to this work; B.S., B.Ö., P.V.T.F., W.C.C., N.M., and J.S.-R., critically reviewed the manuscript; all the authors read and approved the final manuscript.
Funding: This research received no external funding.