Arum: a plant genus with great medicinal potential

Plants belonging to the genus Arum are being used for nutritional and medicinal purposes since many centuries, despite their toxicity. Few subspecies of this genus were widely investigated by modern research, mainly for potential medicinal goals and drug dicovery. Other subspecies were never studied by modern research despite the fact that some of them have known and well documented traditional medicinal and other uses. In this review article we will present the traditional uses of this plant genus and summarize the published results of modern medicinal and other studies of these plants. Special attention will be drawn to active, natural products that were isolated from these plants. The toxicity of the plants will be discussed extensively.


Introduction
The genus Arum (Araceae) is native to Asia, Europe, and northern Africa. The number subspecies of this genus is not definite: while some researchers consider 29 subspecies, 1 the "U.S. National Plant Germplasm System" counts 44. 2 However, the number of subspecies that have known (reported) traditional uses and were reported in current studies for biological/medicinal activities hardly exceeds two dozens. Archeological evidence indicate uses of Arum by humans since ancient times. 3 Arum subspecies are well known for their thermogenesis. 4 This is to say that alteration of light and dark in the environment of the plant stimulates the primordia of the male plant to produce salicylic acid that triggers thermogenic reactions. For some subspecies like A. italicum and A. maculatum, the temperature of the flower can be higher by 15-25 C than the surrounding air. This phenomenon is one of two major pollination strategies that aim to attract potential pollinators like insects. The other strategy is releasing a very strong odor that attracts insects. In most subspecies of Arum, this odor is foul (dung, A. palaestinum, A. dioscoridis, A. elongated and others) but in some subspecies, it can be from not perceptible (A. jacquemontii) to even pleasant (A. gratum). 4 In addition to many volatile amines that will be presented in next sections, many compound families are represented in these pollination odors. 4,5 Some important compounds are shown in Figure 1.
Detailed study of the floral odor of A. italicum was published earlier in 2004, where several methods of isolation and trapping volatile compounds were used. 6 In this study, very similar results were obtained comparing with the previously cited publications (4,5), and only stereochemical and structural isomerization can be noticed, comparing with the compounds shown in Figure 1. Most texts this property is mentioned and potential users are explicitly warned. Modern research approved this as shown in below (discussion).
b) It is notable that the most important traditional uses of Arum are for nutritional purposes then by medicinal use as an anticancer agent. This using field is also in agreement with current research results.    Table 1, we summarize the traditional uses of Arum, arranged by regions/countries. Roots and fruits of the plants are very toxic, so it's highly recommended to pay attention to the plant parts used.

Modern research reports of Arum subspecies
Many Arum subspecies were studied so far, where the most investigated are A. dioscorides, A. maculatum, and A. palaestinum. It is interesting to see that unlike other plant families that are used by humans for millenia, modern research of Arum started just little more than three decades ago, while other plant families are being studied for much longer periods of time. Many medicinal and other biological activities of Arum plants were reported. In Table 2 a summary of these reports is presented.

Discussion
Arum subspecies are known and used by humans since ancient times. But new subspecies are still identified once in a while. Arum megobrebi was identified and classified as wild subspecies of Arum that grows in Turkey and Georgia. 107 Reading data in Tables 1 and 2 reveals a wide variety of activities of the genus Arum. But it is crucial to notice that many Arum subspecies were never mentioned for traditional uses or reported by recent research publications. These It is evident as well that modern research has studied (so far) more Arum subspecies than those that were documented as having traditional uses. Most investigated subspecies is A. palaestinum.
It is interesting to pay attention to A. cyrenaicum, an endemic subspecies that grows wild only in Libya. In reference 8, authors report two traditional uses of this plant (food and ornaments), and it is interesting to notice that the used parts are corms, not leaves, contrary to most Arum subspecies, where corms are highly toxic. But these authors have mistakenly classified this plant into the Poaceae family, while the correct classification is in the Araceae family. 55 One of the most important properties of Arum that was consistently mentioned by traditional users and approved by modern research is the toxicity of these plants. Despite being recommended for use as food and medicine, the toxicity of Arum is indicated in most texts. 108 Modern reports rank Arum subspecies as one of the most important causes of children poisoning in Brazil. 109 Among these, A. italicum is responsible for the largest number of poisoning cases, and all parts of the plant are toxic.
Toxicity of Arum subspecies results from several single compounds or compound families. Calcium oxalate is one of the primary toxic compounds in Arum plants, 55 but it decomposes with cooking. The same occurs to cyano glycosides such as triglochinin, 76 a toxic compound present in Arum, that its structure is shown in  Among reported Arum subspecies in the toxic context, A. maculatum is the most published by current research publications so far. One of the earliest reports was published in 1861, and it presents some poisoning cases. 110 Part of this toxicity is due to the presence of toxic odorants, especially volatile amines. 111 In addition to oxalates and cyano compounds, the toxicity of A. maculatum is intensified by alkaloids and saponins. 112 The orange-colored fruits of A. maculatum are very attractive yet very poisonous, and they are responsible for most poisoning events caused by this plant. 113 The toxicity of A. palaestinum is also known and published: ethanolic extract of the plant was found toxic to the liver of female rats. 114 Despite that, unlike other natural, plant-derived anticancer therapies, A. palaestinum has no herb-drug contradictions with synthetic drugs. 115 An interesting modern research report presented in Table  2 is about A. Conophalloides. 54 All 18 compounds identified in the essential oil of this plant do not contain nitrogen. No amines or alkaloids. This situation can be understood from two reasons: nitrogen containing compounds, especially amines are volatile and alkaloids are not volatile and mostly water soluble, so they are not present in the essential oil that contains mainly hydrophobic compounds.   Antioxidant capacity of leaves were tested in three forms: fresh, 81 powder and stored. All forms showed similar capacities Analgesic Aqueous extract analgesic activity was compared with that of declofenac-Na and morphine. It was more active than the first and 82 had similar activity of the second Antibacterial 83 Ethanolic extract tested against 7 typyes of bacteria: weak Antibacterial Four extracts (petroleum ether, chloroform, ethyl acetate and 70% methanol) of aerial parts were tested against two bacteria. 84 Hydromethanolic extract showed highets activity Antioxidant Methanolic extract of whole plant was by DPPH assay and found 85 re than ascorbic acid very active, even mo Essential oil, antibacterial, antioxidant Essential oil was tested for antibacterial (

A. palaestinum
New Alkaloid (S)-3,4,5-trihydroxy-1H-pyrrol-2(5H)-one (2 in Figure 6) was isolated from the aqueous extract and characterized. The ethyl acetate extract showed strond antioxidant and sufficient anticancer 90 activities Antioxidant, antidiabetic Aqueous and methanolic extracts were prepared and tested for antioxidant activity (DPPH): moferate. This result is in agreement 91 with total phenolics content and antidiabetic traditional use Anticancer modern herbal medicine Aerial parts, especially leaces are used as anticancer agents in modern herbal Palestinian medicine. It is used raw, cooked (food) or 92 as a decoction Anticancer, antioxidant Aqueous and ethanolic extracts were tested for anticancer and antioxidant activities. Anticancer was very strong (aqueous >> 93 ethanolic), antioxidant was weak (aqueous > ethanolic) Diketopiperazines Two new alkaloids were isolated from the aqueous extract and 94 characterized. Only 3 in Figure 6 showed cytotoxic activity Antimicrobial 70% Aqueous ethanol extract was tested for antibacterial activity against six types of bacteria (weak), and for antidermatophyte 95 activity (2 fungi Two of the major (>5%) compounds are both chemically and biologically interesting. These are the structurally isomeric alcohols T-cadinol (8.9% in the essential oil of A. Conophalloides) and T-muurolol (24.4%). Their structures are shown in Figure 3.

Figure 3. Structures of T-cadinol and T-muurolol
These compounds have many biological activities such as antibacterial of T-cadinol. 116 They are present in relatively high concentrations, and it might be useful to try to isolate them from other subspecies of Arum. A. italicum produces a wide variety of amines during the flowering season. 56 Some of these amines are very interesting regarding the number of nitrogen atoms that they contain. In Figure 4, the structures of three of these amines are shown (with metformin).
The structures of agmatine and metformin are relatively close. Metformin is very well known synthetic antidiabetic drug, and the great medicinal potential and activities of agmatine are being studied, including antidiabetic activity, 117 , but this research must be expanded.
Antibacterial and antimicrobial activities are tested for almost every studied medicinal plant. In the case of Arum subspecies, some were reported, and these reports are not consistent. Even after taking into account the different subspecies, various parts of the plants that were extracted and the various solvents that were used, the overall reporting is confusing and even contradicting. 60,61,68,69,83,84,95 For example, M. Obeidat et al. 60 reported that they tested four extracts (water, ethanol, methanol and acetone) and found the aqueous extract most active. On the contrary, A. Ucar Turker and her colleagues, 68 used aqueous, ethanolic and methanolic extracts, and the aqueous extract was inactive.
In 1994, M. Della Greca et al. isolated and characterized phytosterols and hydroperoxy sterols from A. italicum, where some were new. 70 Despite the fact that similar compounds were isolated from other plants and marine animals, 118 and proved to have significant biological activities, a follow-up study was never reported. It is worth trying to find this compound family in other Arum subspecies, characterize them and test them for biological activities, especially antimicrobial and antifungal activities. The presence of the peroxy group ensures oxidant activity, while the entire compound is hydrophobic and can penetrate the lipophilic membranes of microbes and fungi. The structures of the new hydroperoxy sterols that were reported by M. Della Greca et al. are presented in Figure 5. Alkaloids are the major compound family in Arum subspecies. Their toxic and psychoactive influence affected users of this genus since very ancient times. But the isolation and characterization of these compounds from Arum started relatively late. 89 The polyhydroxy alkaloid that was isolated in the same year, 90 provides an interesting starting material for synthetic purposes. Two other new alkaloids were reported later, and they have even simpler structures. Arum subspecies can be the natural source for such heterocyclic alkaloids. See Figure 6.  99 reveals some confusion regarding the presence of caffeic acid in A. palaestinum. The first reports that it is present, while the second clearly indicated (ND) that it is not. But studying other reports show that this compound is present in A. palaestinum, and many of its derivatives. 90,100 In the same sense, it is not clear why M. M. Farid et al. 102 claim that isovitexin was "isolated (by them) for the first time from the studied taxa," while they reported the isolation of the same compound in one of their earlier works. 96 Conclusions 1) Many subspecies of the genus Arum were never studied, which is a very vast field of future potential research.
2) It is important to invest more research in nitrogen containing compounds of Arum subspecies. The structures of the known compounds so far (very few ssp.) indicate a high potential for antidiabetic activity, which might result from a single compound or synergy of several compounds.
3) Antibacterial activities of Arum subspecies need further studies and organization. 4) Some activities like the antidiabetic potential of Arum were hardly investigated. There is an urgent need to expand the research of these activities.
5) Very few attempts were made so far to prepare synthetic modifications of active natural products isolated from Arum which could be intensified.