Traditional and modern uses of onion bulb (Allium cepaL.): a systematic review

Joaheer D. Teshika; Aumeeruddy M. Zakariyyah; Toorabally Zaynab; Gokhan Zengin; Kannan RR Rengasamy; Shunmugiah Karutha Pandian; Mahomoodally M. Fawzi

Onion, (Allium cepa L.), is one of the most consumed and grown vegetable crops in the world. Onion bulb with its characteristic flavor is the third most essential horticultural spice with a substantial commercial value. Apart from its culinary virtues, A. cepa is also used traditionally for its medicinal virtues in a plethora of indigenous cultures. Several publications have been produced in an endeavour to validate such traditional claims. Nonetheless, there is still a dearth of up-to-date, detailed compilation, and critical analysis of the traditional and ethnopharmacological propensities of A. cepa. The present review, therefore, aims to systematically review published literature on the traditional and pharmacological uses, and phytochemical composition of A. cepa. A. cepa was found to possess a panoply of bioactive compounds and numerous pharmacological properties, including antimicrobial, antioxidant, analgesic, anti-inflammatory, anti-diabetic, hypolipidemic, anti-hypertensive...

Critical Reviews in Food Science and Nutrition ISSN: 1040-8398 (Print) 1549-7852 (Online) Journal homepage: http://www.tandfonline.com/loi/bfsn20 Traditional and modern uses of onion bulb (Allium cepa L.): A systematic review Joaheer D. Teshika, Aumeeruddy M. Zakariyyah, Zaynab Toorabally, Gokhan Zengin, Kannan RR Rengasamy, Shunmugiah Karutha Pandian & Fawzi M. Mahomoodally To cite this article: Joaheer D. Teshika, Aumeeruddy M. Zakariyyah, Zaynab Toorabally, Gokhan Zengin, Kannan RR Rengasamy, Shunmugiah Karutha Pandian & Fawzi M. Mahomoodally (2018): Traditional and modern uses of onion bulb (Allium�cepa L.): A systematic review, Critical Reviews in Food Science and Nutrition To link to this article: https://doi.org/10.1080/10408398.2018.1499074 Accepted author version posted online: 24 Jul 2018. Submit your article to this journal View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=bfsn20 Traditional and modern uses of onion bulb (Allium cepa L.): A systematic review Joaheer D. Teshika1#, Aumeeruddy M. Zakariyyah1#, Toorabally Zaynab 1, Gokhan Zengin2, Kannan RR Rengasamy3*, Shunmugiah Karutha Pandian3, Mahomoodally M. Fawzi1#*. 1 Department of Health Sciences, Faculty of Science, University of Mauritius, 230 Réduit, ip t Mauritius Department of Biology, Science Faculty, Selcuk University, Campus, 42250, Konya, Turkey 3 Department of Biotechnology, Alagappa University, Karaikudi – 630003, India cr 2 us #Authors with equal contribution Ac ce pt ed M an *corresponding authors email: f.mahomoodally@uom.ac.mu; cr.ragupathi@gmail.com ABSTRACT Onion, (Allium cepa L.), is one of the most consumed and grown vegetable crops in the world. Onion bulb with its characteristic flavor is the third most essential horticultural spice with a substantial commercial value. Apart from its culinary virtues, A. cepa is also used traditionally for its medicinal virtues in a plethora of indigenous cultures. Several publications have been produced in an endeavour to validate such traditional claims. Nonetheless, there is still a dearth of up-to-date, detailed compilation, and critical analysis of ip t the traditional and ethnopharmacological propensities of A. cepa. The present review, cr therefore, aims to systematically review published literature on the traditional and pharmacological uses, and phytochemical composition of A. cepa. A. cepa was found to antimicrobial, antioxidant, analgesic, anti-inflammatory, an including us possess a panoply of bioactive compounds and numerous pharmacological properties, anti-diabetic, hypolipidemic, anti-hypertensive, and immunoprotective effects. Although a large number of M in vitro and in vivo studies have been conducted, several limitations and research gaps have ed been identified which need to be addressed in future studies. Keywords: Allium cepa; onion bulb; medicinal; traditional; pharmacological; Ac ce pt ethnopharmacology 1. Introduction The diversified genus Allium encompasses around 918 species among which Allium cepa L., commonly known as onion, is botanically classified under the Amaryllidaceae family (theplantlist.org). The word “onion” is derived from the Latin word ‘unio’ which means ‘single’ or ‘one’ because the onion plant produces only single bulb (Corzo-Martínez et al., 2007). Allium cepa was commonly known by many other conventional or alternative names such as Egyptian onion, common onion, shallot and many more. Onion is an essential spice ip t as well as commercial vegetable. Its edible portion stem, also known as a bulb, consists of an cr inner fleshy and outer dry membranous scaly leaves, and it is the primary organ of interest us (Figure 1). The shape of the bulb can be a globe, a flattened globe, sometimes with a flat top, spindle-like or almost cylindrical (Brewster, 2008). Usually, they exist in various colours an such as white, yellow, purple, red, green, and can also be classified according to its pungency (Slimestad et al., 2007). When bulbing begins, photosynthate produced by the leaf blades is M transported to the leaf bases. This causes the core to swell resulting in the formation of a ed bulb. When the bulb ripens, the outer scales develop into a dry and impermeable skin, which help in preventing desiccation. Eventually, the bulb reaches maturity, and the leaf blade ce pt ceases to form on the inner bulb resulting in a hollow pseudostem. As the leaf sheath weakens, the pseudostem detaches from the leaf blades and the foliage falls (Rubatzky and Yamaguchi, 1997). Ac Onion is considered to be one among the oldest vegetables and was mentioned in several ancient scriptures (Singh, 2008). By the middle ages, it became one of the fundamentals in many cuisines in most parts of the world and therefore is always on demand throughout the year. In fact, onion is the third most essential horticultural crop after potato and tomato, with more than 170 countries commercially cultivating it globally. The current worldwide onion production is estimated to be 78.31 million tons with the average productivity of 19.79 t/ha (FAO, 2015). India ranks first with regards to the total area under onion cultivation, which is expected to be 1.09 million hectares and is the second largest onion producer with 15.88 million tons, followed by China (22.46 million tons) (FAO, 2015). In general, onion is cultivated and traded for its versatility, namely as fresh shoots for green salad onion and a bulb for consumption (cooked and raw), pickling, use in processed food, dehydration, and seed production (Brewster, 2008). In fact, its use depends highly on its pungency; for instance, slightly mild onions can be used in salad preparation while the highly pungent ip t varieties are suitable for sauces and gravies (Wiczkowski, 2011). cr With regards to its global consumption, Libyans are the one who consumes the highest amount of onion, which accounts for an average of 30 kg annually per capita followed by the us Americans (16 kg) (FAO, 2015). Apart from its culinary uses, onion has been reputed in the an indigenous knowledge of medicine for ages. Ancient Egyptians used to worship the bulb, as they believed in its spherical shape and concentric rings which represented eternity while the M Greek and Phoenicians sailors consumed it to prevent scurvy and other diseases (Swenson ed (2008). Various studies have explored the biological profile of this plant, and a profusion of ce pt literature has revealed and published on onion dealing with chemical analysis, flavor and discoloration precursors (Corzo-Martínez et al., 2007; Dong et al., 2010; Jones et al., 2004; Kato et al., 2013; Lanzotti, 2006; Rose et al., 2005; Wiczkowski, 2011). A wide range of Ac phytocompounds including phenolic acids, flavonoids (quercetin, kaempferol), anthocyanins, and organosulfur compounds have been identified in onion. However, there is currently a lack of updated compilation of available data on its traditional uses, chemical profile, and pharmacological properties. In this context, we aimed to review the pharmacological benefits as mentioned above in an attempt to preserve and promote its medicinal uses. A literature search was performed using articles published from 1990 to 2018 using databases such as PubMed, Science Direct and Google Scholar. Other sources such as books, dissertations, and online materials were also taken into consideration. The scientific name of the plant was identified according to the International Plant Name Index (www.ipni.org) and The Plant List database (theplantlist.org). The major chemicals were identified using the PubChem database. 2. Traditional uses of Allium cepa Allium cepa has been traditionally used for its remedial characteristics in the management of t various ailments. The essence of A. cepa proliferated into ancient Greece where it was used ip as a blood purifier for athletes. During the invasion of Rome, gladiators used to rub down cr onion juice to firm up the muscles. The Greek and Phoenicians sailors consumed it to prevent us scurvy. Moreover, the Greek physician, Hippocrates used to prescribe onion as a wound healer, diuretic and pneumonia fighters. In the 6th century, the onion was described as one of an the indispensable vegetable or spice and medicine in India (Kabrah, 2010). M In the present review, we found that the Asian nations, viz., India and Pakistan were among the majority to use onion for the treatment of various diseases. Overall, it was ed observed that A.cepa was most regularly used in low-developed countries. This could be ce pt probably due to the lack of medical facilities and the easy availability of traditional remedies including onion. As shown in Table 1, it can be noted that A. cepa is commonly taken raw or as a decoction for treating infectious diseases. It is also used in a wide variety of preparations Ac for internal and external use to relieve several ailments including digestive problems, skin diseases, metabolic disease, insect bites and others (Silambarassan and Ayyamar, 2015; Sharma et al., 2014; Hayta et al., 2014; Jaradat et al., 2016). 3. Phytochemistry of Allium cepa Several phytochemical studies have been performed on A. cepa, and it was found to harbour myriad of compounds responsible for its peculiar flavour and medicinal properties. Among the different classes of phytochemicals, phenolic compounds have received much attention due to their contribution to the biological properties of medicinal plants. A study (Prakash et al., 2007) was conducted on four varieties of A. cepa (red, violet, white, green) for their respective phenolic composition through high performance liquid chromatography (HPLC). Ferulic acid, gallic acid, protocatechuic acid, quercetin, and kaempferol were identified. There were significant variations in the number of phenolic compounds in each variety, ferulic acid (13.5-116 μg/g), gallic acid (9.3-354 μg/g), protocatechuic acid (3.1-138 μg/g), ip t quercetin (14.5-5110 μg/g), and kaempferol (3.2-481 μg/g). cr Moreover, a number of flavonoids were also detected in different onion varieties: quercetin aglycon, quercetin-3,4'-diglucoside, quercetin-4'-monoglucoside, quercetin-3- us monoglucoside (Zill-e et al., 2011), quercetin 3-glycosides, delphinidin 3,5-diglycosides an (Zhang et al., 2016), quercetin 3,7,4'-triglucoside, quercetin 7,4'-diglucoside, quercetin 3,4'diglucoside, isorhamnetin 3,4'-diglucoside (Pérez-Gregorio et al., 2010) and more (see Table M 2). When compared to other species of vegetables and fruits, A. cepa has 5 to 10 times higher ed content of quercetin (300 mg kg–1) than broccoli (100 mg kg–1), apples (50 mg kg–1), and blueberries (40 mg kg–1) (Hollman and Arts, 2000). ce pt In addition, several studies have identified various anthocyanins in onion: cyanidin 3-O(3″-O-β-glucopyranosyl-6″-O-malonyl-β-glucopyranoside)-4′-O-β-glucopyranoside, cyanidin 7-O-(3″-O-β-glucopyranosyl-6″-O-malonyl-β-glucopyranoside)-4′-O-β-glucopyranoside, Ac cyanidin 3,4′-di-O-β-glucopyranoside, cyanidin 4′-O-β-glucoside, peonidin 3-O-(6″-Omalonyl-β-glucopyranoside)-5-O-β-glucopyranoside and peonidin 3-O-(6″-O-malonyl-βglucopyranoside) were present in minute amounts from pigmented parts of red onion (PérezGregorio et al., 2010). Additionally, four anthocyanins with the same novel 4-substituted aglycone, carboxypyranocyanidin, were isolated from methanolic extracts of red onion. The structures of two of them were identified as 5-carboxypyranocyanidin 3-O-(6"-O-malonyl-β- glucopyranoside and 5-carboxypyranocyanidin 3-O-β-glucopyranoside (Fossen et al., 2003). Moreover, peonidin 3′-glucoside petunidin 3′-glucoside acetate and malvidin 3′-glucoside were successfully identified by Fredotović et al. (2017). Vazquez-Armenta et al. (2014) identified dipropyl disulfide and dipropyl trisulfide as the main constituents in onion oil. A class of biologically active organo-sulfuric compounds, Salk(en)yl-L-cysteine sulfoxides (such as alliin and γ-glutamylcysteine) were dominant. Upon crushing the plant material, allicin, methiin, propiin, iso-alliin, and lipid-soluble sulfur ip t compounds (such as diallyl sulfide, diallyl disulfide) are released which are responsible for cr the smell and taste of fresh onion. The irritating lachrymatory factor which is released by us chopped onion has been presumed to be produced spontaneously following the action of the enzyme alliinase (Imai et al., 2002). Another compound from the sulfur volatiles, thiopropal an S-oxide, is a lachrymatory factor uniquely found in onions, which eventually converts to methylpentanols, another tear up factor (Thomas and Parkin, 1994). Moreover, several M radicals of disulfides (allyl, methyl, propyl) were found in red onion varieties by thin layer ed chromatography using dichloromethane extraction (Griffiths et al., 2002). Quantitative analysis showed that di- and trisulfides, such as cis- and trans-methyl-1-propenyl disulfide, ce pt methyl-2-propenyl disulfide, dipropyl disulfide, cis- and trans-propenyl propyl disulfide, methyl propyl trisulfide, and dipropyl trisulfide, were in abundance representing about 60% of sulphur-compounds. Ac Additionally, Dhumal et al. (2007) confirmed the presence of pyruvic acid, reducing, and non-reducing sugars in both red and white onion. The amount (g/100 g FW) of reducing, nonreducing, and total sugars (6.69, 9.56 and 16.1 respectively) were higher in red onion compared to that of white onion (3.17, 7.17 and 10.4, respectively). The pungency of A. cepa is measured indirectly as pyruvic acid content, which is a product of alkenyl-cysteine sulfoxide enzymatic degradation (Vavrina and Smittle, 1993; Yoo et al., 2006). Among the organic acids detected in the bulb extracts were ascorbic, citric, malic, succinic, tartaric, and oxalic acids. Furthermore, Liguori et al. (2017b) detected some aldehydes and ketones in onion landraces belonging to Bianca di Pompei cv., cultivated in Campania region (Italy). Furfuraldehyde was the most abundant in all samples, and its highest content was found in Aprilatica landrace. Propionaldehyde and 2-methyl-2-pentenal contents were different in landraces samples. The concentration of 1,2-cyclopentanedione differed at harvest time; in ip t spring months, Aprilatica, Maggiaiola, and Giugnese onions had a higher content than those cr yielded in winter (Febbrarese and Marzatica). The butyrolactone compound was found only in onions harvested in spring periods (Aprilatica, Maggiaiola, and Giugnese). us An antifungal peptide, allicepin, was isolated by aqueous extraction, ion exchange an chromatography on DEAE- cellulose, affinity chromatography on Affi-gel blue gel, and FPLC-gel filtration on Superdex 75 (Wang and Ng, 2004). Another compound isolated from M onion bulbs is Zwiebelane A (cis-2,3-dimethyl-5,6-dithiabicyclohexane 5-oxide), which was ed found to enhance the potential fungicidal activity of the typical bactericidal antibiotic Polymyxin B (Borjihan et al., 2010). Zwiebelane A is the compound responsible for the ce pt flavour released by onion during frying. Additionally, Tverskoy et al. (1991) isolated two new phytoalexins: 5-octyl-cyclopenta-1,3-dione and 5-hexy-cyclopenta-1,3-dione from the bulbs of A. cepa which were elucidated by gel filtration, HPLC and thin layer Ac chromatography (TLC). The main chemical constituents present in A. cepa are shown in Figure 2 and their bio-functions are summarised in Table 2. 4. Pharmacological properties of A. cepa 4.1. Antimicrobial activity Allium cepa has been described as a potent antimicrobial agent to fight against infectious diseases. Many bacteria, fungi, and viruses were found to be susceptible to different solvents extracts of A. cepa (Table 3). Sulphur compounds have proven to be the principal active antimicrobial agent present in onion (Rose et al., 2005). Many studies (Liguori et al., 2017b; t Thomas and Parkin, 1994; Vazquez-Armenta et al., 2014) have reconsidered the effect of ip organosulphur-containing compounds on the growth of microorganisms. A. cepa also cr possesses other antimicrobial phenolic compounds including protocatechuic, p-coumaric, us ferulic acids, and catechol. Quercetin and kaempferol have been found as significant contributors to this activity. The effectiveness of kaempferol was greater than quercetin in an inhibiting bacterial growth of B. cereus, L. monocytogenes, and P. aeruginosa and was as M effective as quercetin in inhibiting the growth of S. aureus and M. luteus (Santas et al. (2010). Other studies also showed that quercetin oxidation products from yellow onion skin such as ed 2-(3,4-dihydroxyphenyl)-4,6-dihydroxy-2-methoxybenzofuran-3-one demonstrated selective ce pt activity against Helicobacter pylori strains while 3-(quercetin-8-yl)-2,3-epoxyflavanone showed antibacterial activity against both multi-drug resistant Staphylococcus aureus and H. pylori strains (Ramos et al., 2006). Ac Moreover, Benkeblia, 2004 observed that essential oil of three types of onion (yellow, green and, red) displayed marked antimicrobial activity against specific pathogens, including Staphylococcus aureus, Salmonella enteritidis, Aspergillus niger, Penicillium cyclopium, and Fusarium oxysporum (Benkeblia, 2004). Several researchers (Begum and Yassen, 2015; Hamza, 2015; Palaksha et al., 2013; Zohri et al. (1995) have studied the activity of onion extracts on the Gram-negative bacteria Klebsiella spp. However, contradicting results were obtained from Srinivasan et al. (2001) and Gomaa (2017) whereby there was no inhibition of K. pneumonia with onion extracts. Besides, the antibacterial activity of the red variety of A. cepa extract was found to be higher compared to yellow and white varieties (Sharma et al., 2017). In the study of Park and Chin (2010), onion extracts did not express antimicrobial activities against two pathogens (E.coli and L. monocytogenes). Ziarlarimi et al. (2011) also found that the aqueous extract of onion did not show any effect against E.coli and this corroborates with the study of Penecilla and Magno (2011) in which the hexane and ethanol extracts were also ineffective. ip t The similar result by Ponce et al. (2003) who studied antimicrobial activities of cr natural plant extracts, reported that onion oleoresin did not present inhibitory activity against L. monocytogenes in agar diffusion method. Also, they suggested that the lack of us antimicrobial activity of onion might be due to its used concentration and low purity of onion an oleoresin. Interestingly, Azu et al. (2007) found that A. cepa was effective against P. aeruginosa isolated from patients suffering from urinary tract infections indicating its M potential in the management of such condition. In vivo study of ur Rahman et al. (2017) ed showed that birds fed with onion at a rate of 2.5 g/kg of feed had a decrease of E. coli population and a significant increase of Lactobacillus spp. The result corresponded to that of ce pt Goodarzi et al. (2014) whereby broilers were fed with diets containing 10-30 g onion/kg. Interestingly, a recent study conducted by Lekshmi et al. (2012) showed how nanoparticles synthesised from onion displayed a positive effect in inhibiting Klebsiella spp. Ac Saxena et al. (2010) also reported the synthesis of silver nanoparticles by using onion extract and demonstrated that these nanoparticles, at a concentration of 50 μg/mL, presented a complete antibacterial activity against E. and Salmonella typhimurium. Moreover, onion extracts are potent against fungal species, and its essential oil inhibits the dermatophyte fungi (Zohri et al., 1995). Aspergillus niger and Fusarium oxysporum were strongly inhibited (minimum fungicidal concentration (MFC) = 75 and 100 mg/mL, respectively) by the ethyl alcohol extract of dehydrated onion (Irkin and Korukluoglu, 2007; Irkin and Korukluoglu, 2009). Anti-fungal saponins (ceposide A and C) discovered by Lanzotti et al. (2012) were able to inhibit the growth of soil-borne pathogens (R. solani), air-borne pathogens (A. alternata, B. cenerea, Mucor spp and Phomopsis spp) and antagonistic fungi (T. atroviride and T. harzianum). High inhibitory effect against M. furfur (minimum inhibitory concentration (MIC) = 8.062 mg/ml) and C. albicans (MIC=4.522 mg/ml) were reported by Shams-Ghahfarokhi et al. (2006). Kocić-Tanackov et ip t al. (2009) stated that essential oil of A. cepa, at a concentration of 7%¸ had complete cr inhibition on the growth of two yeasts (C. tropicalis and S. cerevisiae) and this was also confirmed by the study of Kivanc and Kunduhoglu (1997). High concentration of the an and complete inhibition was observed for E. astelodami. us essential oil also weakened the growth of moulds (A. tamarii and P. griseofulvum) as well Goren et al. (2002) conducted a clinical experiment to find out if dehydrated A. cepa M could be used in the treatment of AIDS. Eight persons (from 28 to 30 years old) who were ed HIV positive started a dietary regimen comprising of 9-13 g/day of A. cepa extract. After the treatment, all the HIV positive patients experienced a total remission of clinical symptoms ce pt associated with AIDS and were able to resume their healthy lifestyle. 4.2. Other pharmacological activities of Allium cepa Ac Allium cepa has a miscellany of phytochemicals involving flavonoids, phenolic acids, and organosulfur compounds which contributes to its bioactivities. A. cepa possess a wide range of pharmacological properties including antimicrobial, antioxidant, analgesic, antiinflammatory, anti-diabetic, hypolipidemic, anti-hypertensive, and immunoprotective effects, which are displayed in Table 4. Dietary antioxidants play a crucial role in the suppression of oxidative stress, which may cause initiation and progression of several diseases, including cancer, diabetes, inflammation, and cardiovascular diseases (Razavi-Azarkhiavi et al., 2014). Recently, numerous studies have emphasized the antioxidant activity of A. cepa. Kaur et al. (2009) studied the antioxidant activity in ten cultivars of Indian onion. Red cultivars (Sel-383, N-53, Pusa red, and Sel-402) displayed higher ferric reducing antioxidant power (FRAP), cupric reducing antioxidant capacity (CUPRAC) compared to white cultivars (Pusa white flat, Pusa white round and Early grano). In the study of Lee et al. (2015), the antioxidant activity of fifteen onions of white, yellow, or red colors, based on the 2,2-diphenyl-1-picrylhydrazyl ip t (DPPH) assay. Red onions displayed the highest DPPH scavenging effect unlike white onions were less active. The DPPH assay also showed correlations with anthocyanin (r2 =0.65) and cr quercetin (r2 =0.76) contents which indicates that onions with higher levels of anthocyanin us and quercetin tend to exhibit higher antioxidant power. Abdel-Salam et al. (2014) found that an the essential oil of red onion showed stronger scavenging effect against DPPH radicals (30.81%) compared to the essential oil extract of garlic (22.04%). Gorinstein et al. (2008) M observed the phenolic content in the red onion to be higher than in white onion and garlic, ed which could explain its higher antioxidant activity compared to garlic. Ouyang et al. (2017) reported the DPPH radical-scavenging activity, FRAP radical- ce pt scavenging activity, and OH⋅ radical scavenging activity of total polyphenols from onion (IC50 = 43.24 µg/mL, 560.61 µg/mL, and 12.97 µg/mL, respectively). In addition, these polyphenols significantly inhibited xanthine oxidase activity (IC50 = 17.36 µg/mL). Ac Moreover, (Sellappan and Akoh, 2002) investigated into the total polyphenols and Trolox equivalent antioxidant capacity (TEAC) of Vidalia onion varieties: Nirvana, DPS 1032, Yellow 2025, King-Midas, and SBO 133 grown at Vidalia, Georgia, which ranged from 73.33 to 180.84 mg/100 g FW and from 0.92 to 1.56 μM TEAC/g FW, respectively. In another recent study, Ma et al. (2018) found that polysaccharide extracted from A. cepa displayed strong antioxidant activity towards 2,2′‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS) radical cations, Fe2+ chelating and superoxide anion radical scavenging. Onion extracts of different cultivars in Ontario were also found to significantly induced apoptosis, decreased the rate of proliferation, and slowed the migration of human adenocarcinoma (Caco-2) cells. Bioactive flavonoids and organosulfur compounds present in onions have been reported to affect signal transduction pathway, leading to cell cycle arrest in the G1 and G2/M (Manohar et al., 2017). The ethyl acetate extract of onion also could induce ip t apoptosis of human breast cancer MDA-MB-231 cells and reduce intercellular lipid cr accumulation of 3T3-L1 adipocytes via the inhibition intracellular animal fatty acid synthase (FAS) activity (Wang et al., 2012). Also, the methanol extract of onion displayed inhibition us of two kinds of human lung cancer cell lines (NCI-H522, NCI-H596) with IC50 values of 1.04 an and 0.79 mg/mL, respectively (Rho and Han, 2000). Onion oil also showed marked suppression of HL-60 human promyelocytic leukemia cells proliferation; the suppression was M almost identical with those obtained by the positive controls, all-trans-retinoic acid or ed dimethyl sulfoxide. Also, the combination of onion oil with all-trans-retinoic acid showed higher effect than either alone (Seki et al., 2000). Moreover, at a concentration of 100 µg/ml, ce pt the methanol extract of white, yellow, and red onion peel displayed an inhibition of 78.43, 81.90, and 96.52%, respectively, against human breast cancer cell (MCF-7) and an inhibition of 71.58, 77.93, and 98.47%, respectively, on human prostate cancer cell (LNCaP) (Jeong et Ac al., 2009). Onion extracts also dose-dependently inhibited the proliferation of four human tumorigenic cell lines such as HT-29 (colon), MCF-7 (breast), DU-145 (prostate) and HepG2 (liver) (Shon and Park, 2006). Furthermore, Lee et al. (2012) investigated the effect of red onion in rats and found that rat consuming red onion experienced an increase in the plasma superoxide dismutase activity and the glutathione peroxidase activity. Interestingly, it was also found that liver malondialdehyde levels were significantly decreased. Pretreatment with A. cepa also protected against doxorubicin-induced hepatotoxicity in rats due to its antioxidant properties (Mete et al., 2016). The ethyl acetate fraction from onion also showed excellent enhancing effects on spatial cognitive function and learning and memory functions and also protected against trimethyltin-induced cognitive dysfunction in mice (Park et al., 2015). Another study (Hyun et al., 2013) demonstrated that onion extract prevented brain edema, blood-brain barrier hyperpermeability, and tight junction proteins disruption, possibly through its ip t antioxidant effects in mice. The study revealed that onion could be helpful in preventing cr blood-brain barrier function during brain ischemia. Besides, it was observed that A. cepa was also effective in reducing liver oxidative us stress by preventing the decrease in antioxidant parameters such as superoxide dismutase, an catalase, catalase, in glutathione peroxidase in diabetic rabbits (Ogunmodede et al., 2012). The level of free radicals was decreased in plasma and tissues of alloxan-diabetic rats after M treating them with onion extract (El-Demerdash et al., 2005) and this result was in agreement ed with the study of Baynes and Thorpe (1999), Kumari and Augusti (2002), and Campos et al. (2003). ce pt Besides, onion also displayed hypoglycemic effect. For instance, many experimental studies on animals showed that the hypoglycemic effects of A. cepa are attributed to its sulfur-containing compounds such as S-methlycysteine sulfoxide (SMCS) and S- Ac allylcysteinesulpoxide which can directly act on the pancreas and increase insulin levels in the blood (Akash et al., 2014). SMCS from onion showed a gradual decrease in urine sugar (Kumari and Augusti (2002). On top of that, intake of essential oil of onion in streptozotocininduced diabetic albino rats caused a significant decrease in serum lipids, lipid peroxide formation, blood glucose and increase in serum insulin (El-Soud and Khalil, 2010). In another experiment conducted by Kumari and Augusti (2002), they found that SMCS isolated from onion improved diabetic condition significantly in rats, viz. maintenance of body weight and control of blood sugar. Ur ur Rahman et al. (2017) also elucidated that dietary supplementation of onion increase the weight gain and feed consumption of broilers chicken, producing a positive effect on performance, gut microflora, and intestinal histomorphology (Goodarzi et al., 2014). Moreover, consumption of fresh onion juice had both spermatogenesis and antiprotozoal effects in Toxoplasma gondii infected rats (Gharadaghi et al., 2012; Khaki et ip t al., 2011). Zhou et al. (2017) also found that the essential oil of A. cepa displayed an cr acetylcholinesterase inhibition of 41.46% at 100 µg/ml. Additionally, Nasri et al. (2012) tested for the analgesic effect of fresh onion juice in chronic pain model with a hot plate and us acute pain in mice by formalin test. They also investigated its anti-inflammatory properties an using carrageenan-induced paw edema in rats. As results, fresh onion juice was able to decrease the hind paw thickness significantly compared to the control group and also M demonstrated better results than the standard treatment, diclofenac with a 10 mg/kg dosage. ed The anti-inflammatory effect was attributed to the fact that onion extract can prevent the formation of leukotrienes and thromboxanes by the inhibition of COX and LOX pathways 5. Toxicity ce pt which is usually responsible for its anti-apoptotic effect (Alpsoy et al., 2013). Ac The exploration of medicinal plants and other natural products has increased drastically due to the belief that natural products tend to be safer with minimal to no side effects. Even though plants have many pharmacological benefits; some of them may be toxic or generate adverse effects to human (Celik, 2012). Concerning the toxicity of A. cepa, Votto et al. (2010) reported that at a concentration of 2 mg/ml, onion extracts (aqueous, methanolic, and ethyl acetate) exhibited significant DNA damage in Lucena MDR human erythroleukemic and its K562 parental cell line. In K562 cells, an increase of apoptosis was found whereas in Lucena cells there was an increase in necrosis. This damage was attributed to the compound quercetin and propyl disulfide present in onion. Genotoxic effects of organosulfur compounds were recorded in the micronucleus test on mammalian cells (L5178YTkþ/_ cells) after propyl propane thiosulfinate exposure at the highest concentration tested (17.25 mM). Additionally, in the comet assay, propyl propane thiosulfinate caused DNA damage in Caco2 cells at a high concentration (280 mM), but it did not induce oxidative DNA damage (Mellado-García et al., 2016). Moreover, the toxic effects of aqueous onion extract were ip t investigated in lung and liver tissues of rats. Administration of high doses of onion (500 cr mg/kg) showed histological changes and even resulted in 25% rate of mortality in the us treatment group (Thomson et al., 1998). Cattle fed with onion also reported clinical signs such as dehydration, ataxia, pale mucous membranes, brown-coloured urine, a distinct odour an of onions and tachycardia. When the blood samples from acutely affected animals were tested, a decrease in packed cell volume and evidence of haemolysis was seen (Parton, 2000). M Knight et al. (2000) also observed that lambs fed with onions developed clinical signs of ed onion toxicity, but none of them died from the toxic effects. ce pt 6. Limitations and recommendation During the preparation of literature search, a disparity in the contemporary knowledge of the ethnopharmacology of A. cepa was noticed, which demands more emphasis in future studies. Ac Despite being used traditional in many regions, mostly Asian and African countries, there was a lack of specific information regarding the dosage, variety of onion used, and the detailed method of preparation. Therefore, it is essential to perform more detailed ethnomedicinal studies in these regions. Furthermore, based on the result from Tables 3 and 4, it was found that out of fifty studies reviewed, only two were conducted in vivo. This implies that further research should be carried out in in vivo models. Also, it was found that some studies have not provided a consistent result. For example, for the antimicrobial activity, there was variation in the dimension of inhibition against the same strain of tested microorganisms. These variations could be attributed to different samples of A. cepa collected from different regions whereby they differ concerning soil, climatic conditions, and agricultural and processing techniques. This could also be due to the different extraction techniques used. In some studies, the varieties used for A. cepa were not mentioned, and thus it was difficult to compare the results. Consequently, future research should prioritize these gaps and strive to study factors responsible for alterations based on phytochemical ip t composition and bioactive properties. Moreover, it was observed that in many studies the cr conventional extraction method, maceration, was used. It can be suggested that other modern extraction methods such as ultrasound- assisted extraction, microwave-assisted, and us supercritical fluid extraction can be further examined to achieve higher yield at lower cost. an Last but not least, pharmacological data amassed on A. cepa should be further explored for potential applications in various fields besides drug discovery, such as food development, ed 7. Conclusion M food preservation, livestock feed, biofarming, and other biotechnological applications. ce pt The current review imparts to revise and provide an updated compilation of studies focused on A. cepa. It should be taken into account that there have been other reviews aimed to compile the medicinal aspects of A. cepa with limited emphasis laid on the Ac ethnopharmacological uses of this crop. Nevertheless, this work can be considered as an initiative to incorporate scientific shreds of evidence based on the ethnopharmacology of A. cepa. There was also an attempt made to critically assessed and broaden the knowledge of the traditionally used plant for its superfluous medicinal properties, bioactive composition, and pharmacological aspects. A. cepa can be regarded as a source of critical phytopharmaceutical agents with potential applications in emerging fields of interest. Acknowledgements The author KRRR thank the DST-SERB, New Delhi for financial support in the form of postdoctoral fellowship (File. No. PDF/2017/001166/LS). The authors KRRR and SKP sincerely acknowledge the computational and bioinformatics facility provided by the Alagappa University Bioinformatics Infrastructure Facility (funded by DBT, GOI; File No. BT/BI/25/012/2012,BIF). The authors also thankfully acknowledge DST-FIST (Grant No. SR/FST/LSI-639/2015(C)), UGC-SAP (Grant No. F.5-1/2018/DRS-II(SAP-II)) and DST- Ac ce pt ed M an us cr ip t PURSE (Grant No. SR/PURSE Phase 2/38 (G)) for providing instrumentation facilities. References Abdel-Salam, A., Shahenda, M. E., and Jehan, B. A. (2014). Antimicrobial and antioxidant activities of red onion, garlic and leek in sausage. African Journal of Microbiology Research. 8: 2574-2582. Adeleye, I., Onubogu, C., Ayolabi, C., Isawumi, A., and Nshiogu, M. (2008). 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Table 1: Traditional uses of Allium cepa for medicinal purpose Region Ailments References Raw Cardiovascular diseases Ingestion Adjuvants (Silambarasan and Ayyanar, 2015) NI Hemorrhoids and lower gastrointestinal bleeding (Pandikumar et al., 2011) The juice of its bulb is given 3 times a day for a month Stone disease (antilithic) (Agarwal and Varma, 2015) NI Cut wounds Rheumatism, headache (Ayyanar and Ignacimuthu, 2011) Bulb extracts mixed with Mentha leaves extract is taken orally for a week Epilepsy ip t India Mode of preparation/dosage cr (Semwal et al., 2010) us Inhalation Skin allergy NI Stomach pain, blocked nose, sinusitis, phinitis M an Paste is applied externally on skin allergy. (Deb et al., 2015) Rhizome juice of Allium cepa is applied on the eyes to get relief from eye diseases (three dropsthrice a day for 24 days) Eye diseases Eat raw bulbs Fever (Pradhan and Badola, 2008) NI Alopecia (Hair loss) (Hajare, 2015) Bulbs juice and oil Hypoglycemic, hypolipidemic, stomachic, bacteriostatic, anthelmintic, rubefacient, Antiinflammatory, antiseptic. For pulmonary infection, For urinary retention, Abscesses, Cough & aphrodisiac, ear infection, demulcent, mouth ulcers. (Jaradat, 2005) About 20–30 ml of the bulb juice are to be given five times a day Diarrhea (Jaradat et al., 2016) ed Menstrual disorders (Oligomenorrhea) ce pt Palestine (Sharma et al., 2014) Half teaspoon of bulb extract is taken orally with honey early morning on an empty stomach for two weeks Ac Contine nt ASIA (Bhatia et al., 2015) (Ayyanar and Ignacimuthu, 2005) (Kala, 2005) NI Stimulant, diuretic, aphrodisiac, expectorant (Aziz S and Sharma SC, 2016) NI Anti-bacterial, dysentery cure, stung cure, bruise and pimples (Ishtiaq et al., 2015) Decoction, Juice, Infusion, Vegetable, Paste Carminative, cough, fever, flu, constipation, jaundice (Ahmed et al., 2014) One tea spoon of bulb juice thrice a day. High blood sugar (Mushtaq et al., 2009) Infusion Cicatrizant, rheumatism, asthma, cancer, diuretic, fungal infection, headache, hypertension, rheumatism, Sprain, edema, bruise (Hayta et al., 2014) us cr Turkey ip t Pakistan Gastrointestinal diseases, renal colic, menstrual pain, analgesic, bronchitis Jordan Fresh bulbs or bulb juice are taken orally Diabetes, loss of appetite, coughing, liver diseases and prostate cancer Russia and Central Asia Galenical Mauritius Decoction (Dogan and Ugulu, 2013) (Alzweiri et al., 2011) M an Crushed + salt (Sargın et al., 2013) Nigeria Rwanda Uganda (Mamedov et al., 2005) ed ce pt Ac AFRIC A Skin diseases Type 1 diabetes Type 2 diabetes (Mootoosamy and Mahomoodally, 2014) High level of cholesterol Renal failure Hearing loss Erectile dysfunction Cataract Maceration Decoction Decoction Hypertension Reduce flatulence Liver disease Chewing, cooking, oral in water and in food Sexual Impotence and Erectile Dysfunction (Gbolade, 2012) (Mukazayire et al., 2011) (Kamatenesi-Mugisha and Oryem-Origa, 2005) Kenya Bulb pounded and sap applied. Snake bites (Antivenin) (Owuor and Kisangau, 2006) Serbia Decoction Tonic, colds, coughs (Jarić et al., 2015) Cataplasm Injuries, swelling, hematomas, cuts, toothache, draining pus from infected areas. Inflammations and infections of the urogenital tract, cystitis Italy Decoction or eaten raw Eaten raw Topic use by rubbing Stimulating milk production, antispasmodic antiseptic, blood purifying, diuretic, hypotensive, wounds , cold , insect bites, greasy skin, warts, sting nephritis, ear pain, urinary diseases Spain Infusion decoction raw crushed Skin diseases, sinusitis, flu, cold, bronchitis, pneumonia, asthma, sore throat, teeth disorders, high blood pressure. Anti-catarrhal EUROP E t ip cr us an NI Whitlows, pimples, wounds and grazes, to healing skin infections, boils Balkan Peninsula Heated and externally applied as a poultice France Decoction Brazil M Middle Navarra ed Wound healing (Menendez-Baceta et al., 2014) (González et al., 2010) (Cavero et al., 2011) (Jarić et al., 2018) (Boulogne et al., 2011) Maceration, infusion Diabetes, asthma, bronchitis, expectorant, flu, cough, cough with catarrh (Ribeiro et al., 2017) Colombia Maceration, Snake bite (Vásquez et al., 2015) Mexico Infusion/oral Diabetes, cough, epilepsy, vermifuge, sore throat, toothache, flu, rash, body pain cramps (Alonso-Castro et al., 2012) Ac ce pt Flu syndrome SOUTH AMERI CA NORTH AMERI CA (Menale et al., 2016; Menale and Muoio, 2014) Abbreviation: NI- Not indicated Table 2: Isolated compounds from A. cepa and their biological properties Compound (s) identified Yellow Ethanol (50%) Quercetin Observed biological activity (if tested)* Antioxidant Mechanism of action References Increased the antioxidant capacity of the hydrophilic fraction in the rat serum Bacterial enzyme activity-enhancer Increased the activity of αglucosidase, β-glucosidase, and β-galactosidase released from bacterial cells (extracellular activity) to the cecum (GrzelakBłaszczyk et al., 2018) Hypolipidemic Reduce the levels of alanine transaminase, aspartate transaminase, total cholesterol, non-HDL cholesterol, triglycerides, and increase HDL level in rats fed high-fat diets t Extracting solvent Quercetin aglycon Quercetin-3,4'-diglucoside Quercetin-4'-monoglucoside Quercetin-3-monoglucoside Kaempferol Myricetin Yellow 80% ethanol containing 0.1% hydrochloric acid Quercetin 3-glycosides Delphinidin 3,5-diglycosides Cyanidin 3,5-diglycosides Cyanidin 3-glycosides Quercetin Quercetin 3-glycosides Yellow Freshly Cut Onions Green Sequentially extracted with hexane and ethyl acetate. The residual material was then extracted with anhydrous methanol NT NT NT NT NT NT - (Zill-e et al., 2011) NT NT NT NT NT NT - (Zhang et al., 2016) Hydrogen sulfide Methanethiol Propanethiol Dipropyl disulfide NT NT NT NT - (Løkke et al., 2012) 5-(hydroxymethyl) furfural Cancer chemopreventive Reduced murine hepatoma (Hepa 1c1c7) cells survival (IC50= 997 μM), induced maximum quinone reductase (QR) activity at a concentration of 958 μM. Also induced maximum activity of glutathione Stransferase at a concentration of 958 μM (Xiao and Parkin, 2007) Cancer chemopreventive Reduced murine hepatoma (Hepa 1c1c7) cells survival (IC50= 1060 μM), induced maximum quinone an Solvent free microwave extraction Ac ce pt ed M Yellow us cr ip Onion type Acetovanillone reductase (QR) activity at a concentration of 888 μM. Also induced maximum activity of glutathione Stransferase at a concentration of 888 μM Cancer chemopreventive Reduced murine hepatoma (Hepa 1c1c7) cells survival (IC50= 890 μM), induced maximum quinone reductase (QR) activity at a concentration of 665 μM, and doubled QR activity at 83.0 μM. Also induced maximum activity of glutathione S-transferase at a concentration of 665 μM Methyl 4-hydroxyl cinnamate Cancer chemopreventive Reduced murine hepatoma (Hepa 1c1c7) cells survival (IC50= 115 μM), induced maximum quinone reductase (QR) activity at a concentration of 65 μM, and doubled QR activity at 20.4 μM. Also induced maximum activity of glutathione S-transferase at a concentration of 109 μM White Distilled water, 2-octanol, and dichloromethane Ceposide A,B,C Antifungal M Acetone extract was partitioned between EtOAc and H2O ce pt ed White an us cr ip t 5-hydroxy3-methyl-4-propylsulfanyl-5Hfuran-2-one Antifungal activity was in the order ceposide B > ceposide A > ceposide C. The three compounds displayed synergistic activity against Botrytis cinerea and Trichoderma atroviride. On the oher hand, Fusarium oxysporum f. sp. lycopersici, Sclerotium cepivorum, and Rhizoctonia solani were very little affected bythese saponins (Lanzotti et al., 2012) (Liguori et al., 2017a) NT NT NT NT - Sulfur-containing compounds 1-Propanethiol Propylene sulfide Dimethyl sulfide Methyl propyl disulfide cis-Methyl-1-propenyl disulfide 5-Methyl-1,3-thiazole trans-Methyl-1-propenyl NT NT NT NT NT NT NT - Ac Aldehydes Propionaldehyde 2-Methyl-2-pentenal Furfuraldehyde 5-Methyl-2-furfuraldehyde - Phenols Gallic acid Ferulic acid Quercetin Kaempferol Chlorogenic acid NT NT NT NT NT - NT NT NT NT NT NT NT NT NT NT - Red - NT - NT NT - Delphinidin 3,5-diglycosides NT - Cyanidin 3,5-diglycosides Cyanidin 3-glycosides Cyanidin 3-(6´´-malonyl)glucopyranoside Quercetin NT NT NT - NT - Cyanidin 3 glucoside Cyanidin 3-arabinoside Cyanidin 3-malonylghtcoside Cyanidin 3-malonylarabinoside Quercetin 3,4’-diglucoside Quercetin 7,4’-diglucoside Quercetin 3-glucoside Dihydroquercetin 3 glucoside Isorhamnetin 4’-glucoside NT NT NT NT NT NT NT NT NT - ce pt 80% ethanol containing 0.1% hydrochloric acid Methanol-acetic acid-water (25:4:21, v:v:v) (PérezGregorio et al., 2010) us NT NT Ac Red an Quercetin 3,7,4'-triglucoside, Quercetin 7,4'-diglucoside Quercetin 3,4'-diglucoside Isorhamnetin 3,4'-diglucoside Quercetin 3-glucoside Quercetin 4'-glucoside Isorhamnetin 4'-glucoside Cyanidin 3-glucoside Cyanidin 3-laminaribioside Cyanidin 3-(3"malonylglucoside) Pedonidin 3-glucoside Cyanidin 3-(6"malonylglucoside) Cyanidin 3-(6"-malonyllaminaribioside) Peonidin 3-malonylglucoside Cyanidin 3dimalonylaminaribioside t NT NT ip Ketones 1,2-Cyclopentanedione Butyrolactone cr - M Acid and alkaline hydrolysis, and enzymatic autolysis NT NT NT NT NT NT NT NT ed Red disulfide 3,4-Dimethyl thiophene Methyl-2-propenyl disulfide Dipropyl disulfide 1,2,4-Trithiolane trans-Propenyl propyl disulfide cis-Propenyl propyl disulfide Methyl propyl trisulfide Dipropyl trisulfide (Zhang et al., 2016) (Ferreres et al., 1996) NT - Quercetin 4'-O-βglucopyranoside Quercetin 3,4'-O-βdiglucopyranoside Taxifolin 4'-O-βglucopyranoside NT - NT - NT - 5% Methanoic acid Cyanidin 3-glucoside NT - 3-malonylglucoside Cyanidin 3-laminaribioside 3-malonyllaminaribioside NT NT NT - Methanol 5-carboxypyranocyanidin 3O-(6"-O-malonyl-βglucopyranoside 5-carboxypyranocyanidin 3-O-βglucopyranoside NT - NT - Antifungal Exerted an inhibitory activity on mycelial growth in several fungal species including Botrytis cinerea, Fusarium oxysporum, Mycosphaerella arachidicola and Physalospora piricola. (Wang and Ng, 2004) NT NT NT - (Zielińska et al., 2008) Antioxidant Exhibited DPPH (IC50= 87.5 μg/ml), FRAP (IC50= 90.4 μg/ml), and OH• (IC50= 78.6 μg/ml) radical scavenging effect (Nile et al., 2017) Enzyme inhibition Inhibited the enzymes urease (IC50= 8.2 μg/ml) and xanthine oxidase (IC50= 10.5 μg/ml) Antioxidant Exhibited DPPH (IC50= 65.2 μg/ml), FRAP (IC50= 70.5 μg/ml), and OH• (IC50= 60.5 μg/ml) radical scavenging effect Enzyme inhibition Inhibited the enzymes urease (IC50= 15.5 μg/ml) and xanthine oxidase (IC50= 17 μg/ml) Antioxidant Exhibited DPPH (IC50= 80.5 μg/ml), FRAP (IC50= 85.4 μg/ml), and OH• Water Allicepin Sochaczewska 80% methanol Quercetin-3,4'-diO-β-glucoside Quercetin-3-O-β-glucoside Quercetin-4'-O-β-glucoside NI Methanol Quercetin (Terahara et al., 1994) (Fossen and Andersen, 2003) ce pt ed M an us Brown (Fossen et al., 1998) t Red Quercetin 3,7,4'-O-βtriglucopyranoside ip Red MethanolAcetic acid cr Red Ac Quercetin-4'-O-monoglucoside Quercetin-3,4'-O-diglucoside (IC50= 75.6 μg/ml) radical scavenging effect Enzyme inhibition Inhibited the enzymes urease (IC50= 10.5 μg/ml) and xanthine oxidase (IC50= 15.3 μg/ml) Isorhamnetin-3-glucoside Antioxidant Exhibited DPPH (IC50= 72.4 μg/ml), FRAP (IC50= 75.2 μg/ml), and OH• (IC50= 68.7 μg/ml) radical scavenging effect Caco-2 cell line derived from human colon carcinoma (ATCC HTB-37) underwent significant reductions in reactive oxidative species (ROS) content after 48 h of exposure to each compound. Higher reductions were shown when Caco-2 cells were exposed to a mixture of both compounds (LlanaRuizCabello et al., 2015) Promoted the restoration of lymphoid cell count and promoted the immune response by dose dependently elevated the production of proinflammatory molecules (COX-2 and nitric oxide) and expression levels of immune regulatory molecule (TNF-α) (Kumar and Venkatesh, 2016) Immunoprotective Using macrophage cell line, RAW264.7 and rat peritoneal macrophages, the compound showed an increase in the production of nitric oxide at 24 h, and stimulated the production of pro-inflammatory cytokines (TNF-α and IL-12) at 24 h. Also enhanced the proliferation of murine thymocytes at 24 h. Also elevated the expression levels of cytokines (IFN-γ and IL-2) in murine thymocytes. (Prasanna and Venkatesh, 2015) Anti-allergy Displayed βHexosaminidase inhibitory activity (IC50 = 6.5 μM) (Sato et al., 2015) Essential oil Dipropyl disulphide, Dipropyl sulphide Antioxidant NI 25% ethanol Lectin (agglutinin) Immunoprotective NI 25 % ethanol NI 100% methanol ce pt ed M an us cr ip t NI Ac Lectin (agglutinin) Quercetin 4′-glucoside Isorhamnetin 4′-glucoside Anti-allergy Displayed βHexosaminidase inhibitory activity (IC50 = 17.5 μM) Quercetin Anti-allergy Displayed βHexosaminidase inhibitory activity (IC50 = 3.2 μM) 96% ethanol 1,3-dion-5-octyl-cyclopentane, 1,3-dion-5-hexylcyclopentane Phytoalexin Inhibit conidial germination and germ-tube growth of Botrytis cinerea in liquid culture (Dmitriev et al., 1990) NI 50% ethanol Zwiebelane A (cis-2,3-dimethyl5,6-dithiabicyclo[2.1.1]hexane 5-oxide) Antifungal Amplifies the disruptive effect of Polymyxin B on the vacuole of Saccharomyces cerevisiae, which has been found to represent a target for antifungal agents. (Borjihan et al., 2010) NI Essential oil Isoamyl alcohol Dimethyl disulfide Diallyl sulfide Dimethyl thiophene Methyl propyl disulfide Methyl 1-propenyl disulfide Dimethyl trisulfide Allyl propyl disulfide Dipropyl disulfide 1-Propenyl propyl disulfide 3,5-Dimethyl-1,2,4-trithiolane Methyl propyl trisulfide Methyl 1-propenyl trisulfide Methyl-1-(methylthio)ethyldisulfide Dimethyl tetrasulfide 3-Ethyl-5-methyl-1,2,4trithiolane 3-Ethyl-5-methyl-1,2,4trithiolane Methyl 1-(methylthiopropyl) disulfide 2-Undecanone Tridecane Dipropyl trisulfide Allyl propyl trisulfide Di-1-propenyl trisulfide 2-Hexyl-5-methyl 3(2H)furanone 2-Tridecanone 2-Methyl-3,4-dithiaheptane Dipropyl tetrasulfide Methyl palmitate Ethyl palmitate Methyl linoleate Ethyl oleate NT NT NT NT NT NT NT NT NT NT NT NT NT NT 80% ethanol Trans-( +)-S-propenyl-L- - (Mnayer et al., 2014) us an M ed ce pt Ac NI cr ip t cv . Skvirsky NT NT - NT - NT - NT NT NT NT NT NT - NT NT NT NT NT NT NT - NT - (Ueda et and boiled water cysteine sulfoxide (PeCSO) y-glutamyl peptide (y-GluPeCSO) NT - al., 1994) Essential oil Methyl propyl disulphide Dimethyl trisulfide Isopropyl disulphide Dipropyl disulphide Dimethyl tetrasulfide Dipropyl trisulfide NT NT NT NT NT NT - (VazquezArmenta et al., 2014) NI 70% methanol Quercetin 3,4'-diglucoside Quercetin 4'-monoglucoside NT NT - (Fredotović et al., 2017) Myricetin Quercetin aglycone Isorhamnetin Peonidin 3'-glucoside Petunidin 3'-glucoside acetate Delphinidin 3'-glucoside Malvidin 3'-glucoside NT NT NT NT NT NT NT - cr ip t NI Ac ce pt ed M an us NI: Not indicated NT: Not tested * The reported biological activities include only those of the isolated compounds from onion which have been tested, and not from other sources. Table 3: Antimicrobial activity of Allium cepa Antimicrobial activity Mircroorganisms Main findings References 33 bacterial isolates of V. cholerae Activity of extracts of two types (purple and yellow), with purple type having minimal inhibitory concentration (MIC) range of 19.2–21.6 mg/mL and yellow type having an MIC range of 66–68.4 mg/mL (Hannan et al., 2010) Methanol extract of red and white inner and outer layer of onion against four bacterial strains. (In vitro) Pseudomonas aeruginosa (ATCC 27852), Escherichia coli (ATCC 25992), Staphylococcus aureus (ATCC 25923) and Staphylococcus aureus (ATCC 43300) The outer layer of onion is rich in flavonols with contents of 103 ± 7.90 μg/g DW (red variety) and 17.3 ± 0.69 μg/g DW (white variety) and had larger inhibition on the growth of Escherichia coli than those of I. verum and C. oxyacantha ssp monogyna. (Benmalek et al., 2013) Efficacy of supercritical CO2 extraction of onion essential oil against food spoilage and food-borne microorganisms. (In vitro) Escherichia coli (ATCC 25922), Bacillus subtilis (ATCC 21216), Staphylococcus aureus (ATCC 25923), Rhodotorula glutinis (ATCC 16740), Saccharomyces cerevisiae (ATCC 9763), Candida tropicalis (ATCC 13801), Aspergillus niger (ATCC 16404), Monascus purpureus (ATCC 36928), and Aspergillus terreus (ATCC 20542) The essential oil exhibited a potent inhibitory effect against all bacteria and moulds. It showed a high antimicrobial effect on B. subtilis, C. tropicalis and M. purpureus with the diameter of inhibition zones of 19.3, 15.1 and 13.2 mm, respectively. Essential oil (EO) extracted by steam distillation of three types of onion (yellow, green and, red) against microbial strains. (In vitro) Two species of bacteria: Staphylococcus aureus (ATCC 11522) and Salmonella Enteritidis (ATCC 13076) and three species of fungi: Aspergillus niger (ATCC 10575), Penicillum cyclopium (ATTC 26165), and Fusarium oxysporum (ATCC 11850 The inhibition zone increased with increasing concentration of extracts. S. aureus was less sensitive to the inhibitory activity of the onions and garlic extracts than S. enteritidis which was more inhibited at same concentrations of EO extracts. an M ed ce pt Ac (Ye et al., 2013) us cr ip t Ethanol extract (87%) of purple and yellow onion against bacterial isolates of Vibrio cholerae. (In vitro) (Benkeblia, 2004) Isolates of Mycobacterium tuberculosis An inhibitory action against M. tuberculosis by crude onion extracts was effective. (Adeleye et al., 2008) Crude ethanol extracts fresh allium cepa against gram Positive and gramnegative bacteria and fungi. (In vitro) Clinical isolates of Gram positive bacteria: (Bacillus subtilus, Bacillus cereus, Staphylococcus aureus) Gram negative bacteria: (Erwinia caratovora, Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi and Klebsella pneumonia) Fungus: Candida albicans Susceptibility to Allium cepa extracts was positive for B. cereus B. subtilis, S. aureus and C. albicans (Bakht et al., 2013) Onion (Allium cepa L.) oil at a concentration of 0.5ml/disc against bacteria and dermatophytic fungi. (In vitro) Gram-negative bacteria (Escherichia coli, Klebsiella pneumonia, Pseudomonas fluorescens and Serratia rhadnii) Inhibitory effect of onion oil was highly active against all Gram-positive bacteria tested and only one isolate (Klebsiella pneumoniae) of Gram-negative bacteria (Zohri et al., 1995) Gram-positive bacteria (Bacillus anthracis, Bacillus cereus, Micrococcus luteus and Staphylococcus aureus Onion oil completely inhibited mycelial growth of Microsporum canis, M. gypseum and Trichophyton simii and highly reduced the growth of Chrysosporium queenslandicum and Trichophyton mentagrophytes when added to the solid medium at 200 ppm. The growth of Chrysosporium queenslandicum and Trichophyton mentagrophytes was completely inhibited in the presence of 500 ppm of onion oil. ip cr us an M Dermatophytic Fungi: Chrysosporium carmichaelii, C. indicum, C. keratinophilum, C. queenslandicum, C. tropicum, Microsporum canis, M. gypseum, Trichophyton, and mentagrophytes T. simii) t Crude onion extracts by Soxhlet extraction against Mycobacterium tuberculosis isolated from tuberculosis patients’ sputum. (In vitro) ed Ac Anti-tubercular activity of aqueous extracts of A.cepa against 2 multi-drug resistant strains. (In vitro) Bacteria: Escherichia coli and Staphylococcus aureus Fungi: Trichophyton mentagrophytes, Trichophyton rubrurn,Trichophyton tonsurans, Trichophyton schoenleinii, Microsporum canis, Microsporum audouinii and Aspergillus furnigatus, Candida albicans) Mycobacterium tuberculosis (H37Rv) Mycobacterium fortuitum (TMC-1529) ce pt Yellow, white, white boiling, and red Bermuda onion extracted with 0.5 to 2.0 mL buffer per gram tested against microorganisms. (In vitro) Four different types of onion had similar inhibitory activity (MIC = 125-250 mg/mL) for Candida albicans, while onion powder demonstrated a range in activity from some activity to no activity at 200 mg/mL. (Hughes and Lawson, 1991) A. cepa displayed 35% inhibition against M. tuberculosis. (Gupta et al., 2010) Anti-bacterial action of onion extracts made by steam-processing against oral pathogenic bacteria (In vitro) S. mutans (JC-2) and S. sobrinus (OMZ176), P. gingivalis (ATCC33277) and P. intermedia (ATCC256ll) No colony was observed in S. mutans and S. sobrinus at 24 hours. A few colonies were observed for P. gingivalis or P. intermedia at 48 hours (MIC= 40 μg/mL). Survival rates became <1% in S. mutans and S. sobrinus after 3 hours and in P. gingivalis and P. intermedia after 1 hour. (Kim, 1997) Nanoparticles of onion by centrifugation against Proteus sp., Klebsiella sp., Staphylococcus sp., Bacillus sp., The particles showed higher activity against the pathogenic Klebsiella sp. (12.93 ± 0.15) These onion particles also (Lekshmi et al., 2012) some pathogens. (In vitro) Pseudomonas sp. and Enterobacter sp. showed the activity against gram positive and gram-negative organism. Acetone extracts of white onion against soil-borne pathogens, air-borne pathogens, and antagonistic fungi. (In vitro) Soil-borne pathogens: Fusarium oxysporum f. sp. lycopersici, R. solani and Sclerotium cepivorum Ceposides A and C were effective in reducing the growth of all fungi with the exception of A. niger, S. cepivorum, and Fusarium oxysporum f. sp. Lycopersici. Ceposide B showed a significant growth inhibition of all fungi with the excep tion of Fusarium oxysporum f. sp. lycopersici, Sclerotium cepivorum and Rhizoctonia solani. Growth of B. cinerea (a much larger inhibition at 10 and 50 p.p.m.) and Trichoderma atroviride was strongly inhibited. (Lanzotti et al., 2012) Quercetin inhibited all strains of bacteria tested (from 9.8 ± 0.6 to 15.0 ± 1.0 mm). Kaempferol was only efficient against the gram positive bacteria S. aureus and Micrococcus luteus (9.3 ± 1.2 and 10.3 ± 0.6 mm, respectively). Kaempferol works best than quercetin in inhibiting bacterial growth of B. cereus, L. monocytogenes, and P. aeruginosa and found as effective as quercetin in inhibiting the growth of S. aureus and M. luteus (MIC= 40 μg/mL). (Santas et al., 2010) Air-borne pathogens: Alternaria alternata, Aspergillus niger, B. cinerea, Mucor sp., Phomopsis sp. Antagonistic fungi: T. atroviride and Trichoderma harzianum Strains of B. cereus (CECT 5144), S. aureus (CECT 239), M. luteus (CECT 5863), L. monocytogenes (CECT 911), E. coli (CECT 99), P. aeruginosa (CECT 108) and C. albicans (CECT 1002) Aqueous extracts of fresh onion against some pathogenic yeasts and dermatophytes (In vitro) Isolates of M. furfur, C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, T. mentagrophytes, T. rubrum, M. canis, M. gypseum, E. fluccosum High inhibitory effect against M. fufur (MIC = 8.062 mg/ml) and C. albicans (MIC = 4.522 mg/ml) was reported for the first time. (ShamsGhahfarokhi et al., 2006) Effects of onion powder on the selected gut microflora and intestinal histomorphology in broiler (320 days old). (In vivo) Lactobacillus species, Streptococcus species, E. coli Birds fed with onion at the rate of 2.5 g/ kg of feed showed a decrease in the population of E. coli in the ileum whereas an increased number of Lactobacillus was observed. (ur Rahman et al., 2017) The ethanolic extract of onion gave the widest zone of inhibition (11mm with 0.8mgl-1) against P. aeruginosa. (Azu et al., 2007) M ed ce pt Isolates of Staphylococcus aureus and Pseudomonas aeruginosa Ac Different onion extracts against microorganisms isolated from high vaginal swab from patients with urinary tract infection. (In vitro) an us cr ip t 75% methanol extracts of three Spanish onion (two white and one yellow) against food spoilage microorganisms in microwell dilution assay (In vitro) Effect of dietary supplementation with fresh onion on performance, carcass traits and intestinal microflora composition in broiler chickens (1 day old) (In vivo) Isolates of Lactobacilli spp. and Escherichia coli The Lactobacilli spp. population in birds supplemented with onion at the level of 30 g/kg significantly was higher than other groups at 42 d of age (P<0.05). The lowest Escherichia coli loads were detected in broilers fed diets containing 15 mg virginiamycin/kg. The Escherichia coli loads significantly decreased in broilers fed diets containing 10 or 30 g onion/kg (P<0.05). (Goodarzi et al., 2014) Influence of Serbian Three yeasts: Rhodotorula sp. (isolated Concentrations of 1 and 4% inhibited the (Kocić- from air), Candida tropicalis (clinical isolate), Saccharomyces cerevisiae 112 Hefebank Weinhenstephan, Three moulds: Aspergillus tamarii, Penicillium griseofulvum and Eurotium amstelodami (isolated from spices) growth of two yeasts, C. tropicalis and S. cerevisiae, with inhibition zones of 13 14 mm, and 14-16 mm, respectively, and complete inhibition at concentration of 7%. Strong influence of 1% of onion essential oil on the growth of S. cerevisiae (21 mm inhibitory zone) High concentrations (7 and 10%) lowered the growth of these moulds by 18.5 and 57% (A. tamarii) and 21.7% (P. griseofulvum). E. amstelodami was completely inhibited with concentration of 10% Tanackov et al., 2009) Efficacy of Egyptian red onion concentration (100, 50,20 and 10%) on some sensitive and multiresistant microbes. (In vitro) Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Streptococcus pyogenes ATCC 19615, Staphylococcus aureus; (MethicillinSensitive Staphylococcus aureus MSSA) ATCC 25923, (MethicillinResistant Staphylococcus aureus-MRSA) ATCC 10442, Enterococcus faecalis; (VancomycinSensitive Enterococci VSE) ATCC 29212, (Vancomycin Resistant Enterococci - VRE) ATCC 51299 and Candida albicans ATCC 10291 Onion showed inhibition properties against all microbes but Staphylococcus aureus was more sensitive. (Al Masaudi and Al Bureikan, 2012) Dehydrated onion bulb by Soxhlet extraction (ethyl alcohol and acetone solvent) against some filamentous fungi. (In vitro Isolates of Aspergillus niger and Fusarium oxysporum from food. Candida albicans ATCC 10231 and Metschnikowia fructicola A. cepa extract biosynthesized silver nanoparticles (AgNPs) against some pathogenic microorganisms. (In vitro) ip cr us an (Irkin and Korukluoglu, 2009) Bacillus subtilis (ATCC 6633,) Bacillus subtilis (NCTC 10400), Bacillus cereus (ATCC14579), Bacillus licheniformis (ABRII6), Bacillus sp. (BSG-PDA-16), Bacillus sp. (DV2-37), Staphylococcus aureus (NCTC 7447), Streptococcus mutans (ATCC 3654), Escherichia coli (NCTC 10418), Klebsiella pneumonia (ATCC 10031), Salmonella typhimurium (NCIMB 9331), Pseudomonas aeruginosa (ATCC 10145), Proteus vulgaris (ATCC 27973), Serratia marcescens (ATCC 25179), Cida albicans (ATCC 70014) All the microorganisms had inhibitory properties except for Klebsiella pneumonia, Proteus vulgaris and Serratia marcescens. These three microorganisms (Bacillus subtilis (MIC=5mg/ml), Bacillus licheniformis (MIC=5 mg/ml), Cida albicans (MIC = 10 mg/ml) had the highest MIC amongst the others. (Gomaa, 2017) 1) Gram-negative bacteria: Chromobacterium Tiolaceum, Escherichia coli, Enterobacter faecalis, Klebsiella pneumonia, Proteus mirabilis, Pseudomonas aeruginosa, Salmonella paratyphi S. typhi 2) Gram-positive bacteria: Bacillus subtilis, Staphylococcus aureus 3)Fungi: A.cepa had inhibitory effect against all microorganisms except for Klebsiella pneumonia and the largest inhibition zone formed was for Candida albicans (22mm). (Srinivasan et al., 2001) ce pt ed M A. niger and F. oxysporum were inhibited strongly (75 and 100 mg/mL MFC) by ethyl alcohol extract of dehydrated onion. Ac Aqueous extract of onion bulb against bacterial and fungi strains. (In vitro) t essential oil extracts from onion on three yeasts isolated from air and clinically, and three moulds isolated from spices (In vitro) Aspergillus flatus, A. fumigatus, A. niger, Candida albicans Essential oil extract of A. cepa against bacterial strains of Escherichia coli (In vitro) Escherichia coli O157:H7 The strain tested had MIC= 93.8 ± 44.2 μl/ml and MBC= 312.5 ± 265 μl/ml showing that A cepa had antibacterial effect to a certain extent. (Golestani et al., 2015) Efficacy of essential oil of onion extracted by hydrodistillation against food-borne bacterial strains. (In vitro) Bacillus cereus, Listeria monocytogenes Micrococcus luteus, Staphylococcus aureus, Escherichia coli and Salmonella typhimurium All bacteria projected inhibition zone but a greater inhibitory effect was seen for Staphylococcus aureus (IZD=6.90±1.26) (Bag and Chattopadhyay, 2015) Inhibitory properties of fresh onion juice (onion) towards 11 bacteria and 10 yeasts. (In vitro) Bacteria: B. cereus, B. subtilis, E. aerogenes, E. coli, K.pneumoni, P. vulgaris, P. aeruginosa, S. aureus, S.typhimurium, S.marcescens, V. parahaemolyticus Chloroform, ethanol and aqueous extracts of A. Cepa against growth of microbes by Kirby-Bauer Method (In vitro) Fermented aqueous, aqueous and methanol extract of A.cepa against five gram-negative bacteria and five grampositive bacteria. (In vitro) t ip cr us Highest inhibition zone was formed by Hexane extracts of onion against S. aureus (IZD=16mm). Acetone extract showed inhibition zone for all bacteria. Hexane and ethanol extracts were not effective towards E. coli. (Penecilla and Magno, 2011) Culture of Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis, Proteus mirabilis and Salmonella spp Chloroform extract of A. cepa was more effective compared to ethanol and aqueous extracts. (Yousufi, 2012) Streptococcus mutans Crude onion extracts had inhibitory effects against Streptococcus mutans (IZD = 6.0mm) (Ohara et al., 2008) Fermented aqueous extract induced a growth inhibition on all Gram-negative bacterial strains compared to methanolic and aqueous extracts and slightly reduced the growth of the Gram-positive strains. (Millet et al., 2012) ed ce pt Ac Hexane, ethyl acetate and methanol extract of onion against Streptococcus mutans. (In vitro) (Kivanc and Kunduhoglu, 1997) M S. aureus, B. subtilis, E.coli, P.aeruginosa an Yeast: C. crucei, C. utilis, C. tropicalis, P. membrafaciens, R. rubra, S. bailii, S. cerevisiae, S. octoporus, S. pombe, S. rouxii Different extracts (Ethanol, Ethanol/methanol, Acetone, Hexane and Aqueous) of onion from the Philippines against some microorganisms. (In vitro) Three cultivars of onion were tested (1, 2 and 3). Onion 1 had inhibitory properties towards B. cereus (IZD=14mm), B. subtilis (IZD=28mm) and E. aerogenes (IZD=12mm). Onion 2 was effective towards, E. aerogenes (IZD=12mm) and S.marcescens (IZD=20mm). Onion 3 had inhibited B. cereus (18mm) and E. aerogenes (IZD=13mm). The three onion cultivars had inhibitory effect towards all yeast except onion 3 was not effective towards S. bailii. Gram- negative strains: Klebsiella pneumoniae (ATCC 700603), Stenotrophomonas maltophilia (ATCC 13637), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), and Acinetobacter baumannii (ATCC 19606), Gram- positive strains: Staphylococcus aureus (ATCC 29213 and ATCC 43300), Staphylococcus epidermidis (ATCC 12228), Enterococcus faecalis (ATCC 29212), The growth of K. pneumoniae was slightly induced by aqueous extracts and methanolic extracts. The growth of P. aeruginosa was strongly induced by methanolic extracts. Aqueous extracts of onion against Bacillus licheniformis strain 018 and Bacillus tequilensis strain ARMATI by KirbyBauer method. (In vitro) Isolates of Bacillus licheniformis strain 018 and Bacillus tequilensis strain ARMATI An inhibition zone of 18 mm with A. cepa extracts was seen for Bacillus licheniformis strain 018 only. (Khusro et al., 2013) Four concentrations (1000, 100, 10, and 1 μg/ml) of A. cepa crude extract on Staphylococcus aureus. (in vitro) Cultures of Staphylococcus aureus Methanolic suspension at 1000 μg/ml was found to be more effective than the other concentrations with an inhibition zone reached to 29 mm. For aqueous extract an inhibitory zone of 23 mm was the highest which obtained by the effect of the concentration of 1000 μg/ml. The lowest effect (13 mm) was gained with the concentration of 1 μg/ml. (Eltaweel, 2013) Essential oil extract of onion by hydrodistillation against two gram-negative bacteria and two grampositive bacteria. (In vitro) Gram-positive bacteria: Staphylococcus aureus (ATCC 25923), Listeria monocytogenes (ATCC 19115) Gram-negative bacteria Salmonella Typhimurium (ATCC 14028), Escherichia coli (ATCC 8739), Campylobacter jejuni (ATCC 33291) The essential oil of onion with the antibacterial effects produced the largest inhibition zone 15.5 ± 2.1 mm diameter for S. aureus and lowest inhibition zone 6 mm for E. coli. (Mnayer et al., 2014) 95% ethanol extracts of onion bulb on Salmonella typhi isolates in Nigeria. (In vitro) Isolates of Salmonella typhi Alcohol extracts of onion by maceration against multi-resistant gram positive and gram negative bacteria by agar well diffusion method (In vitro) Bacterial strains of Staphylococcus aureus (ATCCBAA1026), Klebsiella pneumoniae (ATCC33495), and Escherichia coli (ATCC10536) cr us an ce pt ed M Onion extracts inhibited the growth of S. typhi at MIC=0.4 g/ml and inhibition diameter=13mm. Bacterial Test strains: Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, and Staphylococcus aureus. Fungal test Strains: Fusarium oxysporum, Colletotrichum spp, and Phythium Ac 95% ethanol extract of A. cepa against bacterial strains by agar well diffusion method. (In vitro) ip t and Enterococcus faecium (ATCC 6057) (Odikamnoro et al., 2015) Onion extracts (100μg/ml) had inhibitory effects towards S. aureus (IZD= 12 ± 0.707 mm), K. pneumoniae (IZD= 18±0.707) and E. coli (IZD = 10.8±0.490) (Palaksha et al., 2013) Klebsiella pneumonia is the most sensitive bacteria while Pseudomonas aeruginosa is susceptible but least. Fusarium Oxysporum is susceptible as compared to the Colletotrichum spp. and Phythium spp. shows no activity against any extract. (Begum and Yassen, 2015) 80% methanol extract of onion by maceration against standard strain of Listeria Monocytogenes. (In vitro) L. monocytogenes ATCC 19114 Positive inhibitory effect was seen with MIC=125 μg /ml and MBC= 500 μg /ml. (Anzabi, 2015) Aqueous and ethanol extracts of 50 onion bulbs against pathogenic microorganisms. (In vitro) E. coli, Salmonella spp., Streptococcus pneumonia, Shigella spp., Staphylococcus aureus Both extracts were effective towards inhibiting the bacteria. (Oyebode and Fajilade, 2014) Fresh juices of red and Isolates of Pseudomonas aeruginosa, Fresh juice of white onion was more (Adeshina et Staphylococcus aureus, Escherichia coli and Salmonella typhi effective towards inhibition of Pseudomonas aeruginosa (MIC=3.125 % v/v), Escherichia coli (MIC=25 % v/v) and Salmonella typhi (MIC=3.125 % v/v). al., 2011) Effect of boiling water and organic solvents (mixture of chloroform, cyclohexane, and methanol) extracts of white onion bulb on Listeria monocytogenes (In vitro) Listeria monocytogenes Inhibition was more effective with organic solvents extract compared to boiling water extracts and cold water extracts. (Shakurfow et al., 2016) Aqueous onion extracts (50% concentration) against 8 Gram negative, 5 Gram positive and 1 yeast isolated from patients. (In vitro) Isolates of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus pneumoniae and Streptococcus viridans (G+ve), and Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter aerugenes, Acinetobacter baumanni, Escherichia coli, Serratia marcescans and Salmonella typhi (G-ve), and Candida albicans (fungus). Aqueous onion extract inhibited all of the microorganism and Salmonella typhi had the largest inhibition zone (30mm) (Hamza, 2015) Aqueous, ethanolic, chloroform and petroleum ether extracts of fresh onion bulb against some fungi by disc diffusion method. (In vitro) A. niger, A. fumigatus, C. albicans and A. flavus The chloroform extract of onion showed highest zone of inhibition with A. niger (IZD=28±1.4 mm), A. fumigatus (IZD=31±1.3mm) and C. albicans (IZD=32±1.5mm) but less in case of A. flavus (IZD=24±1.1) (Singh, 2017) Time-Kill and Antiradical Assays on Green Onion ethanolic extract (75%) against gastrointestinal tract pathogens. (In vitro) Pure cultures of E. arerogenes and E. coli 100% aqueous extracts of green onion bulbs displayed maximum bacterial kill and its kill rate is slightly higher than the kill rate by positive control for E.arerogenes (Thampi and Jeyadoss, 2015) Cold water extract and fresh onion extracts (70% ethanol) on some pathogenic bacteria associated with ocular infections. (In vitro) Isolates of E. coli, S. aureus, S. pneumonia and S. pyogenes (Shinkafi and Dauda, 2013) S. pyogenes and S. aureus were sensitive to the fresh onion extracts with the zone of inhibition ranging from 17mm in S. aureus to 20mm in S. pyogenes. E. coli was sensitive to fresh onion extracts with the zone of inhibition of 15mm in diameter and S. pneumonia had a zone of inhibition of 8mm on fresh onion extract. Aqueous extraction and methanolic extract (95%) of onion against Streptococcus mutans isolated from dental caries of humans (In vitro) Isolates of Streptococcus mutans from the patients having dental caries. Aqueous extract of onion at 50% concentration displayed an inhibition zone of 10.37±0 .65 mm against Streptococcus mutans. (Shukla et al., 2013) Active compounds from methanolic extract of onion against gramnegative and gram-positive Gram- negative E. coli and Grampositive S. aureus The highest zone of inhibition for S.areus was observed to be 13.5 ± 0.9 mm for the red onion extract, whereas for the yellow onion extract was 11.3 ± (Sharma et al., 2017) Ac ce pt ed M an us cr ip t white onion bulb against multidrug resistant bacteria. (In vitro) 0.7 mm Brochothrix thermosphacta (CECT 847), Escherichia coli (ATCC 25922), Listeria innocua (CECT 910), Listeria monocytogenes (CECT 5873), Pseudomonas putida (CECT 7005), Salmonella typhimurium (ATCC 14028) and Shewanella putrefaciens (CECT 5346) The highest inhibition zone detected was 32 mm for Shewanella putrefaciens. (Teixeira et al., 2013) Aqueous and oil extract of onion at 50% concentrations on 8 gramnegative, 5 gram-positive, and 1yeast isolates by disk diffusion method. (In vitro) S.aureus, S.epidermidis, S.pyogenes, S.pneumoniae& S.viridans, and Pseudomonas aeruginosa, Klebsiella pneumonia, Proteus mirabilis, E. aerugenes, Acinetobacterbaumanni,Escherichia coli,Serratiamarcescans& Salmonella ,and Candida albicans(fungi). The maximum inhibition zone of Gram positive bacteria to Onionextract were observed against S. pyogenes (25 mm), S. pneumonia (25 mm) and the minimum was against S.epidermidi (18mm). The maximum inhibition zone of Gram negative bacteria to same extract were observed against Salmonella typhi (30mm), the minimum was against Proteus mirabilis (18mm). (Hamza, 2015) Effects of onion extract on haematological parameters, histopathology and survival of catfish Clarias gariepinus (burchell, 1822) sub-adult infected with Pseudomonas aeruginosa (In vitro) P. aeruginosa ATCC 27853 Onion extract achieved the same inhibition level (19.50 ± 0.5) chloramphenicol achieved at 50% at 100% concentration. A. cepa was found to be active against P. aeruginosa. It exhibited a high antibacterial activity against the test organism (19.04 ± 4.0mm) and an MIC and MBC of 190mg/ml and 50 mg/ml respectively. (Oyewusi AJ et al., 2015) Crude extract of onion (98.8 methanol) by Soxhlet extraction tested on bacterial and fungal cultures. (In vitro) E.coli, Staphylococcus aureus, Bacillus subtilis, Klebsiella pneumoniae (Aspergillus niger (ATCC 9763), Candida albicans (ATCC 7596) The methanol extract of bulbs of Allium cepa exhibited high activity against Bacillus subtilis (2.3 cm), and A. niger (0.9 cm) and was moderately active against others. (Sharma et al., 2009) Essential oil extract, aqeous, and ethanolic extract of fresh red onion against three pathogenic and three fungal strains. (In vitro) S. typhimurium was more sensitive to ethanolic aqueous extracts and essential oils of onion than E. coli O157:H7, S. aureus, A. niger, H.U.B., 1, A. ochrecies, H.U.B., 2 and F. oxysporum, H.U.B., No.3 . F. oxysporum exhibited inhibition zones 7, 9 and 10 mm for aqueous at concentrations (20, 40 and 60 mg/ml) respectively. (Abdel-Salam et al., 2014) ed M an us cr ip t Essential oil of onion by steam distillation against food-borne spoilage and pathogenic bacteria. (In vitro) ce pt bacteria. (In vitro) Ac Bacterial strains: E. coli O157:H7, S. aureusand S. typhimurium Fungal strains: A. niger, H.U.B., 1, Aspergillus ochrecies, H.U.B., 2 and Fusarium oxysporum, H.U.B., 3) Abbreviation: IZD-Inhibition Zone Diameter, MIC- Minimum Inhibition Concentration Table 4. Summary of pharmacological studies on Allium cepa Model Used/ Assay Onion variety used NI Extract type Positive Control Results References Antioxidant In vitro, DPPH assay, Methanol extract Dimethyl sulfoxide Quercetin extracts from A.cepa had the strongest antioxidant activity with IC50 = 125 μl/ml compared to other quercetin extracts (Lesjak et al., 2018) Antioxidant In vitro Red A.cepa polysaccharide extracted as HBSS, CHSS, DASS and CASS Ascorbic acid At a concentration of 0.52.0 mg/mL, CHSS provide the highest antioxidant action towards ABTS radical cations (97.52%), Fe2+ chelating (98.94%) and superoxide anion radical scavenging (76.27%). (Ma et al., 2018) Antioxidant In vitro, DPPH assay Stanley, Safrane, Fortress, Lasalle and Ruby Ring Ethanolic extract Quercetin Ascorbic acid Antioxidant In vivo, hypercholesterol emic male Wistar rats weighing 250g Recas Onion powder (Manohar et al., 2017) NI There was a significant improvement in HCO-fed rats by ameliorating hepatotoxicity, decreasing oxidative stress and modulating inflammation. It was confirmed by the decrease in circulating levels of ALT and AST enzymes, the enhancement of defence systems against oxidative damage, and the modification of cytokine levels amongst other parameters (ColinaCoca et al., 2017) NI Essential oils extracts have more stronger antioxidant properties than ethanol and aqueous extracts of red onion. (AbdelSalam et al., 2014) ed M an us Ruby Ring, the red onion variety, showed the highest percentage of inhibition of 21.52 ± 1.30% using 0.5 mg/ml of extract, followed by Lasalle (15.46 ± 3.88%), Fortress (13.44 ± 4.19%), Stanley (11.38 ± 1.96%) and Safrane (11.1 ± 2.89%). ce pt Ac Antioxidant In vitro, DPPH assay Red cr ip t Activity Tested Essential oil, aqueous and ethanol extract In vitro, DPPH assay, Red: Sel-383, Pusa Madhvi, Pusa red, Sel-402, N53, H-44, Yellow: Sel-126 White: Pusa white flat, Pusa white round Early grano Ethanol extract Gallic acid Sel-383 had the highest antioxidant activity by FRAP assay (3.4 mmol Trolox/g) and CUPRAC method (7.6 mmol Trolox/g). In the DPPH test, Pusa red had the highest percentage of inhibition (85%). (Kaur et al., 2009) Antioxidant In vitro, DPPH assay Red Ethanol extract Butylated hydroxyanisole IC50 >1.0 mg/mL for red onion. Red onion had a higher TPC (i.e. 53.43 ±1.72 mg GAE/100 g) compared to garlic (i.e. 37.60 ±2.31 mg GAE/100 g) (Che Othman et al., 2011) Antioxidant In vitro, F-C assay DPPH assay Red Yellow White Fresh juice extract Methanolic extract Gallic acid M an us cr ip t Antioxidant Antioxidant ce pt (Lee et al., 2015) In DPPH assay, antioxidant activity were between 20 and 80 μg GAE/mL and were less than those of the F-C assay (400-800 μg GAE/mL). ed Antioxidant In vitro, DPPH assay Giza 6 and Photon Fresh onion extract Frozen onion extract NI Antioxidant activity was greater in fresh onion (25.61%) compared to processed onions by freezing. (El-Hadidy et al., 2014) In vitro, TEAC Assay Red White Yellow Methanol extraction Trolox Red onion obtained the highest values 28.18 ± 4.59 (μmol Trolox/g FW) for total antioxidant activity. (Lu et al., 2011) In vitro, FRAP assay Red Raw onion extract Cooked onion extract NI After incubation, the FRAP value of ascorbic acid in the presence of onion cell walls (1.22 mM) retained 92% of antioxidant activity which was considerably higher than that of ascorbic (SunWaterhouse et al., 2008) Ac Antioxidant White onion had the lowest levels of ~440 μg GAE/mL. Yellow onions showed medium AOA between 500 and 750 μg GAE/mL. The red onion showed the highest levels between 700 and 780 μg GAE/mL. acid alone (0.34 mM) In vitro, DPPH assay Red, yellow, white and grelot onion Methanol extraction NI The IC50 values ranging from 17.09 mg/ml to 85.18 mg/ml. The red onion extracts had the lowest IC50 values followed by the yellow, white and grelot onions. The yellow onion extract obtained by microwave hydrodiffusion and gravity has IC50 of 36.35mg/ml versus 58.61 mg/ml by conventional solid–liquid extraction. (Zill-e et al., 2011) Antioxidant In vitro, DPPH assay ‘Grano de Oro’ Methanol extract of pressurized onion NI There was an increase in onion antioxidant activity when applying pressures from 100 to 400 MPa and the mass of onion used was 1g. (RoldánMarín et al., 2009) Antioxidant In vitro, DPPH assay, FRAP assay and ABTS assay White Yellow Red Ethanolic extract Gallic acid The red onion presented the maximum antioxidant activity ((82.04±1.98) mg 100 g–1 (Zhang et al., 2016) us an M Antithrombotic, antiplatelet and anticoagualant In vivo, Male Wistar ST rats, 10-11 weeks old and male C57BL/6 mice, 10 weeks old using laserinduced thrombosis test In vitro (haemostatometr y) In vivo Swiss albino Ac Neuroprotective NI ed In vitro, cell viability analysis FW for DPPH ̇; (175.2±4.35) mg 100 g–1 FW for ABTS ̇+; (143.37±2.82) mg 100 g–1 FW for FRAP, respectively). Methanol extracts of fermented onion NI All extracts increased PBMCs proliferation in a dose-dependent manner up to 350μg/mL. (Ravanbakh shian and Behbahani, 2017) Yellow: Kitamiko27, Toyohira, Kitawase3, Tsukisappu, Superkitamomiji, CS3-12, Tsukiko22, Rantaro, 2935A, K83211 Red: Gekko22 Methanol extract of onion juice NI Toyohira showed a significant inhibition of thrombus growth was observed after a single oral treatment of 3.85ml/kg onion juice. (Yamada et al., 2004) Agrifound Hydroethanolic extract, soxlet ce pt Anti-cancer cr ip t Antioxidant Toyohira inhibited both platelet reactivity and dynamic coagulation. Tsukisappu and Rantaro had inhibitory effects on platelet reactivity and coagulation at a ratio of blood:filtrate = 9:1. NI Attenuation of oxidative damage, indicated by (Singh and Goel, 2015) male mice weighing 22–28 g dark red extraction reduction in lipid peroxidation, nitrate/nitrite levels with elevated GSH and catalase activities. AChE activity and abnormal aluminium deposition were reduced. The dosage taken ranges from 50-200 mg/kg/day of A. cepa orally with aluminium chloride 50 mg/kg/day. Androgenic In vivo, 30 adult Wistar albino male rats were 8 weeks old and weighed 250 ± 10 g Yellowishwhite bulb Onion juice Quercetin Antiallergic In vitro, βHexosaminidase inhibitory activity assay and HPLC Advance, Answer, Momiji No. 3, Momiji no kagayaki, Satsuki, Shippokan 70, Shippososei No. 7, and Tarzan Methanol extract NI Antispasmodic In vitro, ileum of Male guinea pigs (250-350 g,) Tropea (red) Methanol extract (Khaki et al., 2011) Satsuki cultivar exhibited the highest anti-allergic activity (44.3 ± 4.0%) at 100 μg/mL. Quercetin 4′glucoside (IC50 = 6.5 ± 0.5 μM) was the most effective substance for the suppression of type I allergy. (Sato et al., 2015) NI Tropeosides A1/A2 and B1/B2 reduced, in a concentration-dependent manner, the contractions evoked by both acetylcholine and histamine at a significant concentration of 10-5 M (∼50% inhibition). (Corea et al., 2005) Azathioprine, cyclophosphamide ACA administration improves the immune parameters in immunesuppressed animals. SRBC (group C) and 10μg ACA (group E) treatment significantly increased (~1.5 fold) the weight of spleen. 10 μg and 100 μg of ACA treatment (groups E and F) significantly improved (~2.5 fold) the thymic index. Leucopenia (Kumar and Venkatesh, 2016) Immunoprotective Ac ce pt ed M an us cr ip t An increased in serum total testosterone and sperm motility and viability in both experimental groups as compared to the control group were observed. The dosage taken was 0.5 g/rat and 1 g/rat of freshly prepared onion juice for 20 consecutive days. In vivo, cyclophosphami de induced immunosuppres sion in male Wistar rats (4– 5-weeks-old NI A. cepa agglutinin (ACA) was significantly induced (~5 fold) In vivo, mice (male, 4 weeks old) NI Ethanol extract NI The inhibitory effect against cellular acetylcholinesterase (AChE) showed that the EtOAc fraction of peel (EOP, IC50 value = 37.11 μg/mL) was higher than the EtOAc fraction of flesh (EOF, IC50 value = 433.34 μg/mL). Increased in spontaneous alternation behavior in the TMTinjected mice when tested for impair the spatial cognitive function. (Park et al., 2015) Antiinflammatory In vivo, 24 fertile, inbred, healthy, male Sprague– Dawley rats, weighing 200– 250 g and aged 16 weeks NI A.cepa juice extract (ACE) 20-40% polyphenols In the ACE pretreated group serum aspartate transaminase, alanine transaminase, and tissue MDA and glutathione levels were significantly lower, while superoxide dismutase and glutathione peroxidase were higher compared with the doxorubicin group. A dosage of 1 mL of fresh ACE juice orally for 14 consecutive days was given. (Mete et al., 2016) Attenuation of brain edema In vivo, 150 mice weighing 30-35 g (8weeks old) induced by middle cerebral artery occlusion (MCAO) NI Methanol extract NI Increase of brain ischemia was significantly attenuated by onion extract at 0.3 and 1 g/kg. Onion extract significantly prevented brain ischemiainduced reduction in catalase and glutathione peroxidase activities and elevation of MDA level in the brain tissue. (Hyun et al., 2013) cr us an M ed ce pt Anti-diabetic Ac Wound-healing ip t Anti-amnesic In vivo, 54 adult male and female Clarias gariepinus weighing 1 kg NI Ethanol extract Water Treatment with 1.5% onion bulb residues displayed healing properties in the first 7 days. (Bello et al., 2013) In vivo, 15 Alloxan-induced diabetic rabbits NI Aqueous extract Insulin A. cepa at 100 mg kg1 reduced fasting blood glucose levels by 53.3% (300.2±11.2 to 140.1±3.4) and 300 mg kg-1 it reduced fasting blood glucose levels by 73.3% (Ogunmode de et al., 2012) Anti-diabetic and Antioxidant In vivo, Alloxan-induced diabetic male albino rat weighing 120180g NI Isolates of Smethyl sulphoxide (SMCS) from onion NI Hypoglycemic In vivo, Diabetic Wistar male rats weighing 150180 g NI Raw and boiled juice Insulin Hypoglycemic In vivo, 28 adult male alloxaninduced diabetic rats (240– 300g) NI Onion juice Antihyperlipidemic In vivo, Sprague– Dawley rats fed on 1% cholesterol diet NI SMCS from fresh onion Antihypertensive In vivo, hypertensive rats, male 6 weeks old rats weighing approximately 200 g NI In vivo, Paw edema inducedmale albino White (300.2±11.2 to 80.4±1.2) Diabetic rat showed significant loss in weight after 2 months. Urine sugar showed a gradual decrease. MDA, HP and CD were lowered by 11.6% in diabetic mouse treated with SMCS. (Kumari and Augusti, 2002) A. cepa juice of raw and boiled (400mg/kg and 600mg/kg) respectively reduced the blood glucose in diabetic rats with the group treated with 400 mg/kg of the raw extract of A. cepa showing most reduction in the blood glucose. (Ojieh et al., 2015) Treatment of alloxandiabetic rats with the 1ml onion juice/100 g BW/day reduced their plasma glucose levels by 70% and 68%, respectively compared with the diabetic group. Brain LDH activity was significantly increased by 58% in alloxan-diabetic rats (ElDemerdash et al., 2005) NI The total lipoprotein lipase activity in the adipose tissue was decreased with also a decrease in the free fatty acid levels in serum and tissues at a dosage of 200 mg/kg body weight for 45 days. (Kumari and Augusti, 2007) Freezed-dried onion powder NI The blood pressure in rats of the onion diet group increased more slowly and grew to about 160 mmHg at the end of 4 weeks. The significant antihypertensive effect of onion was observed from 1 to 4 weeks. Dietary onion decreased the thiobarbituric acid reactive substances (TBARS) in plasma in these hypertensive rats. (Sakai et al., 2003) Fresh onion juice Diclofenac 7.5ml/kg dosage had the best analgesic effect for the (Nasri et al., 2012) ip t Metformin Ac ce pt ed M an us cr NI Analgesics and anti-inflammatory mice (25 to 30 g) and male Sprague-Dawley rats (220 to 250 g) first 30 minutes. Ac ce pt ed M an us cr ip t Abbreviation: HCO- hypercholesterolemic onion die, SMCS- S-methyl cysteine sulfoxide, PBMCs- Peripheral blood mononuclear cells, DPPH- 1,1-Diphenyl-2-picryl-hydrazyl, TEAC- Trolox equivalent antioxidant capacity, FRAP- ferric reducing ability of plasm, GAE-Gallic acid Equivalet, FC-Folic-Ciocalteu, HBSS, CHSS, DASS and CASS-fractions of A.cepa polysaccharide, MDH- malondialdehyde, HP- hydroperoxide, CDconjugated dienes, BW-body weight, TMT- trimethyltin ed ce pt Ac t ip cr us an M Figure 1 ed ce pt Ac t ip cr us an M Figure 2 ed ce pt Ac t ip cr us an M ed ce pt Ac t ip cr us an M ed ce pt Ac t ip cr us an M ed ce pt Ac t ip cr us an M ed ce pt Ac t ip cr us an M

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Traditional and modern uses of onion bulb (Allium cepa L.): A systematic review

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