Pharmacological and Phytochemical Appraisal of Selected Medicinal Plants from Jordan with Claimed Antidiabetic Activities

Plant species have long been regarded as possessing the principal ingredients used in widely disseminated ethnomedical practices. Different surveys showed that medicinal plant species used by the inhabitants of Jordan for the traditional treatment of diabetes are inadequately screened for their therapeutic/preventive potential and phytochemical findings. In this review, traditional herbal medicine pursued indigenously with its methods of preparation and its active constituents are listed. Studies of random screening for selective antidiabetic bioactivity and plausible mechanisms of action of local species, domesticated greens, or wild plants are briefly discussed. Recommended future directives incurring the design and conduct of comprehensive trials are pointed out to validate the usefulness of these active plants or bioactive secondary metabolites either alone or in combination with existing conventional therapies.


Introduction
Diabetes mellitus (DM) is highly recognised as the most common metabolic and endocrine disorder worldwide. It is linked to disturbances in carbohydrate, fat, and protein metabolism [1]. It is especially important because the global prevalence of diabetes is projected to escalate relentlessly. At least 250 million individuals worldwide suffer from diabetes and this number will double by 2030. Increases in complications will undeniably Apparently, there is a repository of ethnobotanical studies in the Mediterranean basin, providing a new and key tool for a quest after invaluable phytopharmaceuticals or the development of functional foods or nutraceuticals [13][14][15][16][17][18][19][20]. Traditional medicine practices, being part of the Jordanian culture, are considered responsible for an impartial role in primary health care despite modern medicine accessibility [21] where vegetables, culinary herbs, and medicinal plants are among the main choices in the management of diabetes [13,[21][22][23][24][25][26][27][28][29][30]. Essentially important, traditional medicine has not only survived, but thrived in the transcultural environment and intermixture of many ethnic traditions and beliefs despite the 'aging' or 'vanishing' of folk phytotherapy in the sense that the wealth of knowledge of medicinal plants resides mostly in elderly rural people with modest tuition [31]. Also, it is officially neither integrated in the health care system nor recognized in the national policies of the country. Furthermore, as the use of medicinal plant remedies constitutes the common legacy of Jordanians, reliability fractions on herbal medicine vary from rural and desert areas to heavily populated urban ones [21][22][23][24]. In the last decades, more plants have been added to the list of endangered species. This results in the urgent inevitability for local communities to implement nationwide conservation and sustainability programs [32].
The objective of this review is to emphasize the ethnopharmacological practices related to 20 selected ethnobotanicals with claimed antidiabetic properties in light of their comprehensive scientific evaluation and bioactive plant secondary metabolites. Considering the hugely diverse plant species in diabetes traditional medicine, the present manuscript can be complementary to our previous report of 30 indigenous plants [33]. In fact, all our attempts in this direction serve to bring together the Jordanian inventory of diabetes ethnomedicine. Still, further studies might also be integrated into this line of work.

Results and Discussion
Based on centuries of beliefs and observations, plants are primarily used in preparatory forms of infusions or decoctions in ethnomedicinal practices. Worldwide, more than 1,200 species of plants have been reported to be used empirically for their claimed antidiabetic activity [34] while in the Jordanian traditional medicine, almost 70 plant species are used by diabetic patients. Although indigenously grown plants are consumed in the countryside, in the vast cities, including the capital Amman, however, the herbalists' shops display a wide variety of imported plant species, like Zingiber officinalis, Terminalia chebula, or Emblica officinalis, alongside the likely obtainable native ones [11,23,35,36].
On the other hand, reports on the concomitant use of plants in orthodox therapy are evidently understated. In this aspect, interviews with diabetes patients in specialized health centres in Jordan further signified a more diversified list of selected plants [21,26]. The reported plants were: Camellia sinensis, Pimpinella anisum, Zingiber officinale, Matricaria recutita, Salvia fruticosa, Trigonella foenum-graecum, Nigella sativa, Lupinus albus, Teucrium polium, Allium sativum, Cinnamomum zeylanicum, and Olea europea. It is tempting to speculate that the high frequency of use is related to the high efficacy and safety of the plant material, such as green tea, aniseed, or chamomile, although there are no clinical studies to indicate monitoring of glucose and haemoglobin A1c levels in diabetic patients using these plants [31]. Also, there is no information available on the protection from target organ damage by the long-term use of plant products. Interestingly, white lupin (Lupinus albus), fenugreek (Trigonella foenum-graecum), garlic (Allium sativum), olive leaves (Olea europea), ginger (Zingiber officinale), felty germander (Teucrium polium), or black fennel (Nigella sativa) were not the top/main preference herbs of choice by the Jordanian diabetic patients [21,26], despite being scientifically appraised for their antidiabetic activities and frequent use in communities abroad. This has lent further weight to our major interests and concerns stemming from the unjustified claims and selection pressure of certain herbal ethnomedicines in the treatment of diabetes.
Obviously, the significant efficacy of hypoglycaemic herbs, obtainable, via functioning as pancreatic insulin secretagogues and extrapancreatic insulin mimetics, enhancing glucose uptake by adipose and muscle tissues, or via inhibiting hepatic gluconeogenesis and intestinal carbohydrate digestibility and absorption, is comparable to conventional diabetes pharmacotherapeutics [37][38][39]. Literature surveys of botanicals with traditional uses, critically withstanding pharmacological appraisal, indicated that local target-based and mechanistic reports on diabetes interventional phytotherapies are primarily limited and inadequate. Gharaibeh et al. [40] investigated the hypoglycaemic effects of the aqueous extract of Teucrium polium in normal and streptozocin (STZ)-diabetic rats. Additionally, the hypoglycaemic effects of Ballota nigra [41] and Artemisia sieberi [42] were evidenced in alloxan-diabetic rats. Also, the antioxidative properties of an extensive list of Jordanian plants with diabetes ethnotherapeutic claims were closely discussed [43]. In other studies from Jordan, the pancreatic effects of the antidiabetic plants Eriobotrya japonica [44] and Ferula asafoetida were reported [45]. Further comprehensive in vitro and in vivo examinations of indigenous herbs valued as antidiabetic phytomedicines, including Achillea santolina, Eryngium creticum, Geranium graveolens, Paronychia argentea, Pistacia atlantica, Rheum ribes, Sarcopoterium spinosum, Teucrium polium, and Varthemia iphionoides, have been recognised with elaboration [46][47][48][49]. These research findings could collectively resonate with the prevention/modulation of postprandial hyperglycaemia, budding from the natural therapeutic inhibitors of α-amylase and αglucosidase, with ethnopharmacological claims in the local communities. Table 1, demonstrating the antidiabetic and/or other pharmacological activities of the compiled 20 plants, provides an updated overview of their reported phytoconstituents as well. In the present review, flavonoids are among the major classes of secondary metabolites detected in most of the tabulated plants. The antidiabetic activity is welldocumented for numerous flavonoids [50]. Achillea santolina and A. fragrantissima are widely distributed in Jordan and used for their claimed antidiabetic activities. In STZ diabetic rats, hypoglycaemic activity was only evaluated for the former species though both species are rich in flavonoids among other similar volatile oil constituents. Hence, an antidiabetic activity can be likely assumed and verified for flavonoid-rich A. fragrantissima [51]. Also, the promoted antidiabetic activity of Anthemis pseudocotula might be due largely to its flavonoid content. On equal footing, similar postulations can be deduced for plant species with reported antioxidative capacities. Basically, natural antioxidants are well-linked with antidiabetic therapeutic/preventive pharmacology [34,43,[52][53][54][55]. Consequently, despite the lack of scientific scrutiny, it can be speculated that the antioxidative propensities of Alhagi marourum, Alchemilla vulgaris, Cucurbita maxima, Juniperus phoenicea, Quercus coccifera, and Ambrosia maritima can in principle justify their reported phytotherapeutic claims and ethnomedicinal uses. Sci Pharm. 2013; 81: 889-932

Tab. 1.
Antidiabetic plants indigenous to Jordan used for the treatment of diabetes in folk medicine in Jordan.
In alloxan-induced diabetic mice reduced oxidative stress in addition to antihyperglcemic activity [125].
Suppressive effect on NO production in activated macrophages in vitro [117].
Reducing the oxidative stress in hypercholesterolemic rats by increasing the antioxidant enzymes activity [200]. Antioxidative benefits [201].

Reported antidiabetic efficacy and/or mechanism of action
Other reported pharmacological effects Reported phytoconstituents 13 Poaceae Zea mays L. (Decoction of kernel [26]) In vitro inhibition of glycation [225].
Suppressed the progression of diabetic glomerular sclerosis in STZ-diabetic rat [230]. Decreasing blood glucose and protective action on the kidney and pancreas injury of STZ diabetic rats [231]. Inhibition of hyperglycaemia-relevant αglucosidase but not α-amylase [227,232]. Antidiabetic activity might be due PPAR activation [233]. Possible renoprotective role in diabetic nephropathy [229].

Species
Reported antidiabetic efficacy and/or mechanism of action Other reported pharmacological effects Reported phytoconstituents 16 Rosaceae Alchemilla vulgaris L.(Decoction of leaves, roots [28]) Weight reduction in obese subjects [279] despite lack of antihyperglycemic activity in STZ diabetes mice [280].
Hypoglycemic and protective activities of β-cells of Langerhans in hyperglycemic rats [329]. Proliferation of the beta cells of the diabetic rats [330]. Chronic exposure (24 h) to U. dioica significantly enhanced glucose uptake in L6-GLUT4myc myoblast cells [331]. Anti-hyperglycemic effect in STZ-rats via potentiating insulin activity, thus enhancing glucose utilization [332] and plausible activation of the human peroxisome proliferator-activated receptor in glucose homeostasis [333]. Protective effect on hepatocytes of STZ rats [334], neuro-protective effect in diabetes-induced loss of pyramidal cells [335].
Antioxidant, antiradical, antimicrobial and antiulcerogenic effects [314][315][316]336]. Antimicrobial activity [337]. Promotes learning performance in the brain of rats [338]. Immunostimulatory activity of the flavonoid fraction and intracellular killing activity of the isolated flavonoid glycosides suggesting that they could possibly be useful for treating patients suffering from neutrophil function deficiency and chronic granulomatous diseases [317]. Immunostimulatory activity [317,318,339]. Cardiovascular effects like hypotensive responses, through a vasorelaxing effect mediated by the release of endothelial NO and the opening of potassium channels, and through a negative inotropic action [340].
Six of the enlisted plants, namely Ajuga iva, Cleoma droserifolia, Urtica dioica, Sarcopoterium spinosum, Rheum ribes, Zea mays, and Geranium graveolens exhibited hypoglycemic activity in STZ and/ or alloxan diabetic animal models via inhibition of α-amylase and/or α-glucosidase or glucose absorption as plausible in vitro action mechanisms among many others (Table 1). On the other hand, neither in vivo nor in vitro bioactivity could be detected in antidiabetes pharmacology appraisals with Peganum harmala or Ferula persica. These findings strongly negate the claimed ethnotherapeutic uses promoted for these plant species. As for Varthemia iphionoides and Zizyphus spinachristi, the lack of complementary in vivo or in vitro testing necessitates further experimental design and verification on future accounts [56].
The hypoglycaemic properties of several classes of phytochemicals, including alkaloids, flavonoids, glycosides, glycolipids, polysaccharides, peptidoglycans, carbohydrates, amino acids, saponins, and terpenoids, have been exhaustively reported in the literature [37,38,[57][58][59][60]. Additionally, it is well-accepted that certain herbs may alleviate considerably evident hyperglycaemia in clinical trials with well-characterised mechanisms of action [61,62]; their test results, however, are subject to multiple factors. Among which, different parts of an herb may have different ingredient profiles or different extraction methodologies may yield diverse active ingredients. In addition, each plant species contains multiple compounds, only a few of which may be therapeutically effective either alone or acting in synergism [63,64]. Hence, an urgent need exists for research proceedings in identifying the phytoconstituent(s) directly associated with hypoglycaemic/ antihyperglycemic bioactivity with equivalent assessments of the intra-and inter-species variations in secondary metabolites. Future research directives may also incur extensive clinical population-based studies for selected species. Moreover, investigating the combination formulations of natural products with synthetic drugs of complementary pharmacologies may determine the optimal and cost-effective therapies. Additionally, as herb-drug interactions in diabetic treatments/supplements have not been well-evidenced or documented [65], it is warranted that follow-up studies on their long-term side-effects be conducted. Subsequently, this may invite the potential development of food products fortified with clinically safe and effective plant extracts and possible downstream planning and incorporation into diabetic diets [66].
In conclusion, the reported findings, uniquely indicating the potential use of medicinal plants as antidiabetic agents, are among the very few that explored Jordanian flora from semi-arid and arid bioclimatic areas for pharmaceutical leads. Comprehensive research aiming at fully exploiting any of the promising species from the Jordanian flora, either alone or in combination with existing therapies, might lead to discovery of new avenues for medicinal plants/natural compounds in reducing the major public health impact of diabetes. Characterization of molecular targets and elucidation of relevant mechanisms of action also stand for another set of plausible requirements. Then, despite modern medicine accessibility, traditional medicine can be propagated as a viable health alternative.