Phytochemical and Pharmacological Review of Allium Species from Georgia

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Introduction

The genus Allium belongs to family Alliaceae. The plants of the genus Allium are very important herbaceous plants. This genus involves up to 800 species, growing especially in the northern hemisphere (Gagnidze RI, et al., 2005).

Plants of the genus Allium have a long history of traditional uses worldwide dating back to the early ages as food and medicine. The story of Allium cultivation starts over 4000 years ago in ancient Egypt (Rahman K, 2001). Allium species are widely used in Georgian traditional medicine as an antifungal, antiseptic and antibacterial remedy.

Georgia has very rich and diverse vegetation. This is due to diverse and contrasting physical and geographical conditions of the country, its complex geological past, and its location on the crossroad of different botanical and geographical provinces.

The flora of the Caucasus, and especially that of Georgia, is highly endemic. In the region, about 21% of the flora (900 species) is endemic. Out of them, about 600 are Caucasian endemic species and about 300 species are endemic to Georgia. Also, there is a high level of endemic genera with 17 endemic and sub endemic genera.

The aim of this review is to provide comprehensive information about phytochemistry and pharmacological activity of the plants belonging to the genus of Allium, growing in Georgia.

Literature Review

Allium species in Georgia

According to the book of Gagnidze RJ, et al. “Vascular Plants of Georgia” 36 species of genus Allium are described in Georgia. Among them 5 species are endemic for Georgia and 2 for Caucasus region (Gagnidze RI, et al., 2005) (Table 1).

Table 1: List of plants genus Allium described in Georgia

A.albovianum;A.candolleanum;A.chevsuricum;A.gracilescens and A.otschiauriaeare endemic species of Georgia, A.ledschanenseand A.leucanthumare endemic species of Caucasus region.

Phytochemistry of plants genus Allium, growing in Georgia

From plants genus Allium growing in Georgia, were isolated following compounds: Atroviolaceoside, Eruboside B, isorhamnetin-3-O-β-D-glucopyranoside; diosgenin-3-O-α-rhamnopyranosyl-(1→2)-β-D-glucopyranoside (Prosapogenin A of dioscin), Deltonine, Yayoisaponin C, Aginoside, Leucospiroside A, β-sitosterol 3-O-β-glucopyranoside, quercetin 3-O-β-glucopyranoside, isorhamnetin 3,4'-di-O-β-glucopyranoside, isorhamnetin 3,7-di-O-β-glucopyranoside, Astragalin (Ghavam-Haghi F and Dinani MS, 2017), 2-Methoxy tyrosol, Trillin, Dideglucoeruboside B, Aginoside, Allicin; Malondialdehyde (MDA); Carotenoids; Kaempferol-3,7-di-O-β-D-glucopyranoside; Kaempferol-(acetylhexoside)-hexoside; Acetyl-kaempferol-deoxyhexose propylene sulfide; Dimethyl disulfide; Dimethyl thiophene- (E)-methyl-2-propyl disulfide; (Z)-Methyl- 2-propenyl disulfide; Dimethyl trisulfide; Di-2-propenyl disulfide; 2-Vinyl- 1,3-dithiane; (E)-Propenyl propyl disulfide; (Z)-Propenyl propyl disulfide; Methyl-2-propenyl trisulfide; 3,4-Dihydro-3-vinyl-1,2-dithiine; 2-Vinyl- 4H-1,3-dithiine; Dimethyl tetrasulfide; (E)-Di-2-propenyl trisulfide; (Z)-Di-2-propenyl trisulfide; Di-2-propyl trisulfide; Di-2-propenyl tetrasulfide; Inulin, Nystose; I-Ketose; Allivictoside A–H; Allumine A and B; Cyclopent-1-enecarboxylate; Alliumonoate (Khan S, et al., 2011); β-Amyrin acetate; β-Sitosterol acetate; 22-Cyclohexyl-1-docosanol; β-Amyrin; β-Sitosterol; β-Sitosterol 3-O-b-D-glucopyranoside; Ophiopogonin C; 2-Furaldehyde; (2E)-Hexenal; (3Z)-Hexenol; 2,4-Dimethylthiophene; Allyl methyl disulfide; Methyl (Z)-1-propenyl disulfide; methyl (E)-1-propenyl disulfide; Benzaldehyde; Dimethyl trisulfide; Diallyl disulfide; Allyl (Z)-1-propenyl disulfide; Allyl (E)-1-propenyl disulfide; 1-Propenyl propyl disulfide; Methyl (methylthio)methyl disulfide; Allyl methyl trisulfide; 4-Methyl-1,2,3-trithiolane; Methyl propyl trisulfide; Methyl (Z)-1-propenyl trisulfide; Methyl (E)-1-propenyl trisulfide; Dimethyl tetrasulfide; Allyl (methylthio)methyl disulfide; Diallyl trisulfide; Allyl (Z)-1-propenyl trisulfide; p-Vinylguaiacol; Allyl propyl trisulfide; 5-Methyl-1,2,3,4-tetrathiane; Methyl (methylthio)methyl trisulfide; Allyl methyl tetrasulfide; Allyl (methylthio)methyl trisulfide; 4-Methyl-1,2,3,5,6-pentathiepane;

From these species were also isolated different types of sapogenins: Diosgenin, Tigogenin, Ruscogenin, Hecogenine, Atroviolacegenin, β-chlorogenin, Gitogenin, Yucagenin, Agigenin, Nuatigenin and Isonuatigenin (Zolfaghari B, et al., 2006).

Detailed information about the plant species, their composition and biological activities are listed in Table 2.

Table 2: List of compounds, reported in Allium species, growing in Georgia

Biological activity

The results from many pharmacological studies revealed several interesting activities of Allium species, for example cytotoxic, antioxidant, thrombolytic, antibacterial, and other.

Cytotoxic activity

Cytotoxic activity of fractions and compounds isolated from Allium species was discussed in many experimental articles. In research Khazaei S, et al. evaluated the cytotoxic activity of bulb of Allium atroviolaceum in MCF7 (Michigan Cancer Foundation-7) and MDA-MB-231 (Human Mammary Carcinoma), HeLa (Henrietta Lacks) and HepG2 (Liver Hepatocellular Carcinoma) cell lines (Khazaei S, et al., 2013). The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) cytotoxicity assay exhibited different growth responses in MCF7, MDAMB-231, HeLa, and HepG2 cells. The IC50 (Half-maximal inhibitory concentration) values after 24, 48, and 72 h of treatment were 91.5, 88, and 75.7 µg/ml for MCF-7 cells, 149, 114, and 101 µg/ml for MDA-MB-231, 154, 89.7, and 74.7 µg/ml for HeLa cells and 97, 70, and 58.7 µg/ml for HepG2, respectively (Khazaei S, et al., 2017). In the study, the anticancer effect of 4′,5,7-Trihydroxy-3′,5′-dimethoxyflavone (Tricin) was investigated with Docetaxel on PC3 (prostate cancer) cell line. Tricin was initially isolated from the Allium atroviolaceum. IC50 of Tricin and Docetaxel were assessed 117.5 ± 4.4 μM and 0.1 ± 0.02 nM by MTT assay, respectively (Ghasemi S, et al., 2019).

The 80% EtOH extract of the flowers of Allium gramineum has been shown to strongly inhibit the growth of breast adenocarcinoma cell lines, with an IC50 of 4.5 ± 0.7 μg/mL for MDA-MB-231 and 4.8 ± 0.9 μg/mL for MCF-7 cells. The cytotoxic activity was related to the saponins which exhibited a potent cytotoxicity, with an IC50 around 3 μM (Mskhiladze L, et al., 2015).

The cytotoxic activities of 7 glycosides extracted from Allium leucanthumwere evaluated against A549, DLD-1 (Colorectal adenocarcinoma). According to the results, compounds 1-3 and 5 possess a relatively similar cytotoxicity against both tumor cell lines, with IC50 values ranging from 3.7 to 5.8 μM for A549 and 5.6 to 8.2 μM for DLD-1 (Mskhiladze L, et al., 2008; Mskhiladze L, et al., 2016).

Demir T, et al. have also determined that the extract of A. scorodoprasum has cytotoxic activity (Demir T, et al., 2022). The amounts of the A. scorodoprasum L. extract inhibiting the 50% activity of MCF-7 and MG-63 cells were recorded as 82.78 and 76.53 μg/mL, respectively (Demir T, et al., 2022).

Cytotoxicity of the extract of A. ursinum was evaluated in the research by Korga A, et al. on MKN28 (Gastric Cancer) and MKN74 (Gastric adenocarcinoma) cell lines. The extract of A. ursinum was toxic for both cell lines 66.77 ± 3.00% viability and 31.55 ± 2.04% viability respectively (Korga A, etal., 2019).

The apoptosis-inducing capabilities of the extracts were evaluated by the 3-(4,5-dimethyl-2-thiazolyl)2,5-diphenyl-2H-tetrazolium bromide assay, 4',6-diamidino-2-phenylindole staining, and the DNA fragmentation assay in human colon cancer HT-29 cells (Chung HY and Park YK, 2017).

Antioxidant activity

Antioxidants play important roles in health. They are also used to reduce disease risk and can protect the body against oxidative damages, which cause several diseases (diabetes, cancer, and neurodegenerative disorders, etc.). Antioxidants can control oxidative processes, leading to food quality descent caused by Reactive Oxygen Species (ROS) and free radical reactions in the body (Kurnia D, et al., 2021).

Antioxidants may occur naturally in plants, animals and microorganisms or may be synthesized by chemical means. Higher plants and their constituents provide a rich source of natural antioxidants, such as tocopherols and polyphenols which are found abundantly in spices, herbs, fruits, vegetables, cereals, grains, seeds, teas and oils (Shahidi F and Zhong Y, 2015).

Many researches have been done on Allium species, which are growing in Georgia to evaluate their antioxidant activity.

DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging test was used for evaluation of free radical scavenging activity of A. affine hydroalcoholic extract. RC50 for Vit C as a standard antioxidant was 43 µg/mL. The scavenging effect of the plant extract RC50 was found to be 201 µg/mL (Sadeghi M, et al., 2017).

Anti-oxidant activity of isolated compounds from Allium gramineum were evaluated, a strong scavenging effect was obtained with isorhamnetin-3-O-β-D-glucopyranoside with the lowest IC50 values of 20.1 ± 0.8 μM while both Prosapogenin A of dioscin and Deltonine exhibited very weak radical scavenging activity as the IC50 values were higher (>100 μM) (Mskhiladze L, et al., 2015).

Antioxidant activity of the aerial part and bulbs of Allium paradoxum was investigated by eight in vitro assay systems by Ebrahimzadeh MA, et al. The total phenolic content of aerial parts and bulbs was 62.7 ± 3.5 and 7.4± 0.2 mg gallic acid equivalent/g of extract, respectively and the total flavonoid contents of aerial parts and bulbs was 47.9 ± 2.6 and 23.61 ± 1.1 mg quercetin equivalent/g of extract powder, respectively. The aerial and bulb extracts of A. paradoxum exhibited good but different levels of antioxidant activity in all the models studied, both cell-free and in cell systems. They both contained high iron and manganese content (Ebrahimzadeh MA, et al., 2010).

Assadpour S, et al. have investigated in vitro antioxidant and antihemolytic effects of the essential oil and methanolic extract of Allium rotundum (Maisashvili MR, et al., 2008; Maisashvili MR, et al., 2009; Maisashvili MR, et al., 2007; Maisashvili MR, et al., 2009). IC50 for DPPH radical-scavenging activity were 284 ± 11.64 for methanol extract and 1264 ± 45.60 µg ml-1 for essential oil, respectively. The extract has shown better reducing effects versus essential oil. The extract also demonstrated better activity in nitric oxide-scavenging activity. IC50 were 464 ± 19.68 for extract and 1093 ± 38.25 µg ml-1 for essential oil. The extract shows better activity than essential oil in Fe2+ chelating system. IC50 were 100 ± 3.75 for extract and 1223 ± 36.25 µg ml-1 for essential oil. The A. rotundum extract and essential oil showed significant H2O2 scavenging effects at dose-dependent manners in H2O2 induced hemolysis. IC50 was 786 ± 29.08 mg ml-1 for essential oil (Assadpour S, et al., 2016).

The research of Motamed SM and Naghibi F has showed that all the extracts had moderate inhibitory activity against deoxyribose (DR) damage. Among the 10 plants, A. rubellum showed the highest DR degradation inhibitory activity (56.45% ± 1.56%) (Motamed SM and Naghibi F, 2010).

As a result of the analyses conducted, in the bulb and leaf parts of the A. scorodoprasum, total phenolic matter values were 254.51-927.81 and 1929.05-19645.24 mg/kg, FRAP (Ferric Reducing Antioxidant Power) was 0.80-5.20 and 14.31-47.83 mM TE/g, DPPH free radical scavenger effect was 0.99-9.02 and 36.61-241.06 µmol TE/g and ascorbic acid content was 29.14-314.01 mg/kg and 200.64-1383.16 mg/kg, respectively (Mollica A, et al., 2018). These data reveal that the leafs of A. scorodoprasum subsp. rotundum plants are rich in antioxidants (Taşcı B, et al., 2019). Antioxidant enzyme activity of A. scorodoprasum has showed following results: An increase in Catalase activity, compared with A. sativum, was observed in A. scorodorpasum (36.8%). The GPx (Glutathione peroxidase) and GSH-Px (Plasma glutathione peroxidase) activities were also detected in bulbs of all Allium species investigated. The highest GPx activity was detected in wild A.scorodoprasum(641.7% increase compared with A.sativum) (Štajner D, et al., 2008).

The antioxidant and anti-tyrosinase activity of different A. ursinum extracts and their metal complexes were evaluated using DPPH radical scavenging assay and mushroom tyrosinase assay, respectively (Nikkhahi M, et al., 2018). The results showed that the polarity of extracting solvents and the solubility of the phenolic compounds in the solvents had a noticeable influence on the yield, phenolic content, antioxidant and anti-tyrosinase activity (Bârlă GF, et al., 2016; Nikkhahi M, et al., 2018).

From water extract of A. vineale 4 flavonoids were isolated (1-4) (Chen S and Snyder JK, 1989; Rissato SR, et al., 2007). Total antioxidant activities of crude extract, isolated compounds 1, 2, 3, Trolox and α-tocopherol were determined by the ferric thiocyanate method in the linoleic acid system. The activities of 80 µg/ml concentration over the incubation period (20 h) of crude extract, flavonoids 1, 2, 3, Trolox and α-tocopherol were found to be 64.8%, 79%, 75.6%, 82.2%, 75.7% and 31.4%, respectively (Rissato SR, etal., 2007).

Other biological activities

Except above-described activities, Allium species possess other biological properties which are equally important.

Some steroidal saponins and sapogenins with thrombolytic activity including diosgenin, tigogenin and ruscogenin have been isolated from A. affine (Sobolewska D, et al., 2016; Sadeghi M, et al., 2017; Pkheidze TA, et al., 1971; Chincharadze DG, et al., 1979; Eristavi LI, 1972; Mskhiladze L, et al., 2007; Mskhiladze L, et al., 2007). Study has found that A. atroviolaceum extract has excellent antiplatelet activity and is able to inhibit platelet aggregation in vitro induced by ARA and ADP with each IC50 value of 0.4881 (0.4826-0.4937) and 0.4945 (0.4137-0.5911) mg/mL (Lorigooini Z, et al., 2015). Antiplatelet activity is also described in the leaf extract of A. ursinum. Testing of antiplatelet activity in vitro was conducted using light transmission aggregometry which has been induced with Adenosine Diphosphate (ADP), collagen, A23187, epinephrine and Arachidonic Acid (ARA) (Hiyasat B, et al., 2009).

Antibacterial effect of aqueous and alcoholic extracts of A. atroviolaceumwas investigated, results has shown that After 48 hours’ incubation, the minimum inhibitory concentration of aqueous and alcoholic extractions against S. aureus was 3.125 mg ml-1 and 6.25 mg ml-1 receptively. Also, the minimum inhibitory concentration result of aqueous and alcoholic extractions against Escherichia coli was 3.125 mg ml-1 and 12.50 mg ml-1 receptively (Hafeznia B, et al., 2018). The antimicrobial activities of the concentrated extract, obtained from A. scorodoprasum under optimal conditions, were tested against different microorganisms that are important in terms of food technology (S. aureus; 20.00 mm, E. faecalis; 17.50 mm, E.coli; 14.00 mm, A.niger; 18.50 mm, A.flavus; 14.5 mm). MIC (Minimum Inhibitory Concentration) results showed that only E. coli presented a high resistance (7.5 mg/mL) against A. scorodoprasum L. extract. Among the selected bacteria and mold, A.scorodoprasumL. extract indicated the highest antibacterial activity against S.aureusand the highest antifungal activity against A.niger(Demir T, etal., 2022; Pacirc M, etal., 2011).

Results of the research of Mskhiladze L, et al. has demonstrated that the sum of steroid saponins from A. leucanthum have medium activity towards bacteria, spirostanol fraction has strong activity (Ismailov AI, et al., 1976). Bacterial strains were resistant towards furostanol fraction (Kravets SD, et al., 1990). Glycosids of β-chlorogenine are characterized by stronger activity, than agigenin glycosids (Mskhiladze L, et al., 2008).

Phytochemical study of A. paradoxum, specially the saponin constituents of the plant, resulted in isolation and identification of a Dioscin related steroidal saponin from bulbs of the plant by Rezaee F, et al. The leishmanicidal effects of the isolated compound was evaluated, which interestingly exhibited its significant activity on promastigotes of L. major with both 10 and 50 µg/mL concentrations (Rezaee F, et al., 2018).

Antileishmanial activity was also studied in A. leucanthum by Mskhiladze L, et al. obtained results suggested that the spirostanol fraction, extracted from the plant, was ten-fold more active on Leishmania amastigotes than on human cells (Mskhiladze L, et al., 2008).

Aerial parts and bulbs extracts of A. paradoxum at the doses 500 and 750 mg/kg, i.p. offered significant hepatoprotective effect by reducing the serum marker enzymes, serum Aspartate aminotransferase (AST) and alkaline Phosphatase (ALP) (Nabavi SM, et al., 2012).

The results of in vitro anti-plasmodial activity demonstrated that the highest significant efficacy of A. paradoxum extract was related to 80 µg/mL dosage which led to a 60.43%-growth inhibition of parasites in cultures compared to the control groups. The growth inhibition was also statistically significant with 52.48% when 40 µg/mL was administrated in comparison with the control groups (Elmi T, et al., 2021).

Analgesic activity of methanolic extract of A. paradoxum was evaluated by Hot plate and acetic acid induced Writhing test on male Balb/C mice. Extracts showed significant Analgesic activity in both models. In writhing test extract showed significant analgesic activity in all doses tested compered to control group and reduced writhing behaviors (p<0.001). In Hot plate test Extract caused increase in pain threshold compared to control specifically in 30th minute of the test (p<0.001) (Maghsoodi R, et al., 2018).

The curative effect of extracts from the aerial parts and bulbs of A. paradoxum against gentamicin-induced renotoxicity in mice was determined. Both extracts at the dose 200 mg kg (-1) day (-1) offered nephroprotective effect by change in the blood urea nitrogen and creatinine (Nabavi SF, et al., 2012).

During the research Woo et al. have investigated the inhibitory activities of isolated compounds (allivictoside A-H (1-8)) from A. victorialis on neuroinflammation by measurement of produced NO levels in LPS (Lipopolysaccharide)-activated BV-2 cells, Compounds 2 and 6, from the leaves of A. victorialis significantly inhibited NO production in LPS-activated BV-2 cells. These results indicate that flavonoid derivatives from A. victorialis have anti-neuroinflammatory effects (Woo KW, et al., 2012; Khan S, et al., 2013; Kim YS, et al., 2013).

Anti-inflammatory activity of A. scorodoprasum extract was evaluated. The extract concentration inhibiting the 50% activity LOX (Lipoxygenase) and XO (Xanthine oxidase) were found as 9.75 and 9.71 mg extract/mL, respectively while the quercetin and allopurinol IC50 values for LOX and XO were 1.22 and 2.69 mg/mL, respectively (Demir T, et al., 2022).

Conclusion

In this review, we have complied available literature on plants genus Allium growing in Georgia, considering the compounds, isolated from these species and their biological activity.

From the available literature, it is evident that the major constituent of plants genus Allium are saponins, phenolic and Sulphur compounds which probably play main role in pharmacological activities.

In the literature, no phytochemical studies were provided on these following species of genus Allium, growing in Georgia: A. albovianum, A. aucheri, A. candolleanum, A. cardiostemon, A. chevsuricum, A. globosum, A.gracilescens,A. karsianum, A. kunthianum, A. ledchanense, A. moschatum, A. oreophilum, A. otchiauriae, A. paczoskianum, A. ponticum, A. pseudoflavum, A. pseudostrictum, A. rupestre, A. rupetchii, A. saxatile, A. szovistii, A. tauricola. Therefore, in future, detailed and extensive studies are certainly required to improve the knowledge about the pharmacological activities, chemical constituents and efficacy of these plants.

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