Biological activities of Anastatica hierochuntica L.: A systematic review

Biomedicine & Pharmacotherapy 91 (2017) 611–620

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Biological activities of Anastatica hierochuntica L.: A systematic review Siti Rosmani Md Zina , Normadiah M. Kassima , Mohammed A. Alshawshb,* , Noor Eliza Hashima , Zahurin Mohamedb a b

Department of Anatomy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

A R T I C L E I N F O

A B S T R A C T

Article history: Received 24 November 2016 Received in revised form 2 May 2017 Accepted 2 May 2017

Anastatica hierochuntica L. (A. hierochuntica) is a desert plant consumed by people across the globe to treat various medical conditions. This review is aimed at providing a summary of the scientific findings on biological activities of A. hierochuntica and suggests areas in which further research is needed. This systematic review was synthesized from the literature obtained from the following databases; PubMed, Science Direct, Web of Science, Ovid Medline, Scopus, Google Scholar and WorldCat. Previous studies have indicated that the methanolic and aqueous extracts of this plant have antioxidant, antifungal and antimicrobial activities. It was shown to have the ability to activate phagocytes and to possess microbicidal activity, thereby causing increased resistance to infection. Both methanolic and aqueous extracts of this plant were also demonstrated to have a hypoglycaemic property, whilst the methanolic extract significantly exhibited hypolipidaemic effects in diabetic rats. Moreover, the methanolic extract of A. hierochuntica has been suggested to have hepatoprotective properties. This is supported by its ability to significantly decrease transaminase and alkaline phosphatase activities in alloxan-induced diabetic rats. Besides, this desert plant exhibited anti-inflammatory, anti-melanogenic and gastroprotective activities. Even though A. hierochuntica is widely used, studies on this plant are still scarce, thus its reputed biological activities and medical benefits require critical evaluation. Before A. hierochuntica can be used clinically, further studies need to be conducted to increase our understanding of the effects of this plant, its constituents, and possible mechanisms of action. © 2017 Elsevier Masson SAS. All rights reserved.

Keywords: Anastatica hierochuntica Brassicaceae Kaff Maryam Medicinal plant Sanggul Fatimah Pharmacological activities Systematic review

Contents 1. 2. 3. 4.

5. 6.

Introduction . . . . . . . . . . . . . . . . . . . Search strategy . . . . . . . . . . . . . . . . . Phytochemical contents . . . . . . . . . . Biological activities . . . . . . . . . . . . . . Antioxidant activity . . . . . . . 4.1. 4.2. Antimicrobial activity . . . . . Antifungal activity . . . . . . . . 4.3. Hypolipidaemic activity . . . 4.4. 4.5. Hypoglycaemic activity . . . . Hepatoprotective activity . . 4.6. Anti-inflammatory activity . 4.7. Anti-melanogenic activity . . 4.8. 4.9. Gastroprotective activity . . . Immunostimulatory activity 4.10. Toxicological aspects . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . .

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* Corresponding author. E-mail address: [email protected] (M.A. Alshawsh). http://dx.doi.org/10.1016/j.biopha.2017.05.011 0753-3322/© 2017 Elsevier Masson SAS. All rights reserved.

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Disclosure statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619 Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619

1. Introduction Anastatica hierochuntica L. (A. hierochuntica) is a well-known medicinal plant that grows in Saudi Arabia, Egypt, Jordan, Oman, Libya, Iraq, the United Arab Emirates, Iran, Kuwait and North Africa [1,2]. The plant sprouts from a seed during the short period of rainy season. It bears tiny white flowers and rarely grows above 15 cm in height [1,3]. After the rainy season, the plant dries up, and its stems curl inward into a tight woody ball measuring 4–10 cm in diameter. The seeds are hard and can lay dormant for many years. This popular herb belongs to the family Brassicaceae and is the only member of the genus Anastatica [3]. Other than in its countries of origin, A. hierochuntica is also consumed by the people of Asia and other parts of the world. In Arabic countries, A. hierochuntica is called Kaff Maryam. In Europe, it is known as Hand of Fatima, Hand of Maria or Rose of Jericho [1,2,4,5]. In Malaysia, the plant is called Sanggul Fatimah, Genggam Fatimah, Kembang Fatimah or Akar Kayu Bunga Fatimah [2,3,6]. This herb is consumed orally in the form of an extract or fine powder [1]. The extract is prepared by soaking the dried plant in water, which causes the initially shrivelled branches to expand and straighten. Then, the water decoction of the whole plant is consumed [3]. This herb is believed to have various medical benefits. It is mainly used to ease the process of childbirth and for treating reproductive system–related disorders such as menstrual cramps and uterine haemorrhage [1,7–13]. It is also consumed as an alternative treatment for metabolic disorders, mainly diabetes mellitus [11]. Some people consume this herb as an analgesic and as a remedy for epilepsy, gastric disorder, arthritis, bronchial asthma, mouth ulcers, malaria, and mental depression [1,11,13–16]. The purported benefits of A. hierochuntica are known to people across the globe despite limited scientific information and evidence. Therefore, critical scientific evaluation of its apparent medical properties is required. This systematic review aims to be a useful source of information for researchers who are interested in further exploration of the properties of A. hierochuntica.

dosages and outcomes. All of the selected literature was studied for related significant information and limitations. 3. Phytochemical contents A. hierochuntica contains significant amounts of carbon, oxygen, silica, calcium (Ca), magnesium (Mg), aluminium, potassium, zinc (Zn), and iron (Fe), as revealed by energy-dispersive X-ray microanalysis [1,3]. It is also a source of chromium, manganese (Mn), cobalt, and copper (Cu) [1]. According to Daur (2012) [1], the Mg, Ca and Mn concentrations in A. hierochuntica are greater than those in other medicinal plants such as mint, thyme and rosemary [18]. Furthermore, the concentrations of Fe, Cu, and Zn are either comparable or greater than those in other plants, namely cinnamon, Withania somnifera and Vetiveria zizanioides [18–20]. In 2003, Yoshikawa and team [21] reported the isolation of new skeletal flavonoids namely anastatin A and B, followed by another report on the isolation of another three new (7R, 8S) and (7S, 8R) 85' linked neolignans named hierochins A, B and C from the methanolic extracts of the whole plants of A. hierochuntica [22]. Other isolated compounds include (+)-lariciresinol, kaempferol, luteolin, rutin, b-sitosterol-3-O-b-D-glucopyranoside, (+)-dehydrodiconiferyl alcohol, (+)-balanophonin and evofolin B [22]. Various compounds were also isolated from an aqueous extract of this plant seeds [23]. The isolation was performed by Al-Gamdi et al. (2011) using high-performance liquid chromatography

2. Search strategy Research articles describing the key area of interest were obtained from a range of databases. The strategy for identifying keywords involved the search for the name of the herb of interest, A. hierochuntica and other related names. The following keywords were used to retrieve all the included studies; “Anastatica hierochuntica” (Title/Abstract) OR “Kaff Maryam” (Title/Abstract) OR “Hand of Fatima” (Title/Abstract) OR “Hand of Maria” (Title/ Abstract) OR “Sanggul Fatimah” (Title/Abstract) OR “Genggam Fatimah” (Title/Abstract) OR “Kembang Fatimah” (Title/Abstract) OR “Akar Kayu Bunga Fatimah” (Title/Abstract) OR “Rose of Jericho” (Title/Abstract). Further information was obtained using the combination of its scientific name and other variables such as “medicinal plants”; “alternative medicine” and “chemical properties”. Some references cited by the initially referred articles were further mined for more details and additional information. The literature was searched electronically using PubMed, Science Direct, Web of Science, Ovid Medline, Scopus, Google Scholar and WorldCat databases (Fig. 1). Titles and abstracts were reviewed to identify suitable references. Key data were extracted, including types of extract, methods of study, number of samples,

Fig. 1. Flow chart of the systematic review information adopted with modification from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [17].

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(HPLC) with photodiode array (PDA) and tandem mass spectrometric (MS2) detection [23]. The most abundant compounds, as revealed by the assay, were flavones, which included luteolin-6-Chexosyl-8-C-pentoside, luteolin-6-C-pentosyl-8-C-hexoside, apigenin-6,7-C-diglucoside (isovitexin-7-O-glucoside) (1), apigenin6-C-arabinosyl-8-C-hexoside, luteolin-8-C-glucoside (orientin) (2), luteolin-6-C-glucoside (isoorientin) (3), apigenin-6-C-glucoside (isovitexin) (4), luteolin-O-glucoside, diosmetin-8-C-glucoside (5), luteolin-O-glucuronide, luteolin-6-C-glucosyl-2”-Oglucoside (isoorientin-2”-O-glucoside) (6) and luteolin-O-glucuronide. The level of flavones ranged from 0.5
0.0 mM to 542
35 mM, with the diosmetin-8-C-glucoside as the compound with highest concentration. Phenolic acids and hydroxycinnamates were also present in considerable amounts. This included dihydroxybenzoic acid hexoside, 3, 4-dihydroxybenzoic acid (7), 5O-caffeoylquinic acid (8), 3, 4-O-dicaffeoylquinic acid (9) and 4, 5O-dicaffeoylquinic acid (10). The concentration of each compound ranged from 17
0 mM to 210
1 mM. Moreover, the aqueous extract contained low concentration of flavonols such as taxifolinO-hexose and kaempferol-3-O-glucoside (11) (Fig. 2) [23]. On the other hand, Nakashima et al. (2010) [24] had isolated numerous other compounds from the ethyl acetate (EtOAc)-

613

soluble fraction of the methanolic extract of the whole plant of A. hierochuntica using ordinary- and reversed-phase silica gel column chromatography, and HPLC. The known compounds were anastatin A (12), anastatin B (13), (+)-silychristin (14), ()-silychristin (15), silybin A (16), silybin B (17), isosilybin A (18), isosilybin B (19), naringenin (20), eriodictyol (21), aromadendrin (22), (+)-taxifolin (23), (+)-30 -O-methyl taxifolin (24), (+)-epitaxifolin (25), luteolin (26), kaempferol (27), quercetin (28), rutin (29), hierochin A (30), hierochin C (31), (+)-dehydrodiconiferyl alcohol (32), (+)-balanophonin (33), hierochin B (34), (+)-lariciresinol (35), ()-evofolin B (36), p-hydroxybenzoic acid (37), p-methoxybenzoic acid (38), 3,4dihydroxybenzoic acid (39), 3-methoxy-4-hydroxybenzoic acid (40), p-hydroxybenzaldehyde (41), 3,4-dihydroxybenzaldehyde (42), vanillin (43), acetovanillone (44), 2,40 -dihydroxy-30 -methoxyacetophenone (45), hydroxypropioguaiacone (46), (+)-2,3-dihydroxy-1-(4-hydroxy-3-methoxyphenyl-1-propanone) (47), transcinnamic acid (48), trans-ferulic acid (49) and coniferaldehyde (50) (Figs. 3 and 4) [2,24]. In addition, the methanolic extract of the fruit part of A. hierochuntica was found to contain glucose, galactose, fructose, sucrose, raffinose, and stachyose [2,24]. Another report was published in the same year by Marzouk et al. (2010), which listed all the flavonoids isolated from the methanolic extract of A. hierochuntica whole plant [25]. The compounds were kaempferol 3-O-(6”-a-L-rhamnopyranosyl)-b-Dglucopyranoside, quercetin, quercetin 3-O-6”-a-L-rhamnopyranosyl)-b-D-glucopyranoside, apigenin 6-C-b-D-glucopyranoside [isovitexin], naringenin (5,7,40 -trihydroxydihydroflavone) and 0 0 (+)-taxifolin (3,5,7,3 ,4 -pentahydroxydihydroflavone) [25].< 4. Biological activities Due to its purported varied pharmacological activities, A. hierochuntica has been used for many medicinal purposes for a long time. However, only some of its apparent activities have been supported by scientific studies. The extracts of A. hierochuntica were reported to have antioxidant, antimicrobial, antifungal, hypolipidaemic and hypoglycaemic properties [23,26–31]. The extracts have also been shown to have hepatoprotective, antiinflammatory, and anti-melanogenic activities [16,21,24,30,32,33]. Furthermore, a report by Shah and team showed that A. hierochuntica also has gastroprotective activity [11]. 4.1. Antioxidant activity

Fig. 2. Chemical structures of the isolated compounds of aqueous extract of A. hierochuntica.

Antioxidants from plants are generally preferred over synthetic compounds because natural sources are believed to be safer. Like other antioxidants, they can terminate free radical–mediated oxidative reactions, which is beneficial for protecting the human body against diseases [34]. Phenols are known to be one of the most highly effective free radical scavengers and antioxidants from plant sources [35]. Therefore, an increase in the content of phenolic compounds in plant extracts is a direct indication of their antioxidant activity [30]. Determination of total phenolics in A. hierochuntica methanolic extract was initially carried out by Mohamed and team in 2010 using the Folin-Ciocalteu reagent assay [31]. They reported presence of phenolic compounds at 51.97 mg gallic acid equivalent (GAE)/g dry weight (d.w) [31]. Besides, the aqueous infusion of dry seeds of A. hierochuntica was also subjected to determination of total phenolic content in GAE using the Folin-Ciocalteu method. The findings showed a high concentration of total phenolics, which was 4.0
0.01 mmol/L GAE [23]. Total flavonoid content is another indication of the antioxidant capacity of a plant extract [36]. Mohamed et al. (2010) recorded 42.53 mg/g d.w of flavonoids in quercetin equivalent in A. hierochuntica methanolic extract [31].

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Fig. 3. Chemical structures of the isolated compounds of methanolic extract of A. hierochuntica.

The determination of antioxidant activity of the A. hierochuntica methanolic extract had been carried out using various methods. One of these is using the 2,2-diphenyl-1-picrylhydrazyl hydrate (DPPH) radical scavenging assay, which is a widely used method for evaluating antioxidant activity. Mohamed et al. (2010) demonstrated a significant decrease in the concentration of DPPH radical due to the scavenging action of methanolic extracts from A. hierochuntica [31]. The scavenging effect was 55.87% at a concentration of 150 mg/ml, which indicated the obvious effect of A. hierochuntica on free radicals [31]. The antioxidant activity of A. hierochuntica was also determined by evaluating its chelating ability against iron ions [31]. The metal chelating effect helps to reduce the redox potential, thus stabilising the oxidised metal ions, which have been associated with obstruction of the peroxidative process and oxidative damage [37]. Mohamed et al. (2010) showed that the iron chelating effect of A. hierochuntica extract was concentration-dependent [31]. The percentage of metal scavenging capacity by 200 mg/ml methanol extract of A. hierochuntica was found to be 16.72% [31].

Another method for A. hierochuntica antioxidant activity assessment was performed by determining its superoxide anion scavenging activity using phenazine methosulfate–nicotinamide adenine dinucleotide (PMS-NADH) system [38]. The scavenging effect of A. hierochuntica methanolic extract on superoxide radicals generated in a PMS-NADH system in vitro was comparable to that of quercetin [31]. The inhibition percentage of superoxide radical generation at 300 mg/ml A. hierochuntica and quercetin were 52.61% and 75.31%, respectively [31]. Moreover, a ferric reducing antioxidant potential (FRAP) assay was used to measure the antioxidant activity of A. hierochuntica aqueous extract which had also revealed high antioxidant activity (1262
0.05 mmol/L Fe+2) [23]. Besides determination of antioxidant activity in crude extract, Al Gamdi et al. (2011) [23] also evaluated the antioxidant potential of individual A. hierochuntica compounds using HPLC with 2,20 azino-bis [3-ethylbenzothiazoline-6-sulphonic acid] diammonium salt (ABTS)-based online antioxidant detection system. In this assay, the antioxidant potential of the aqueous extract was

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615

Fig. 4. Chemical structures of the isolated compounds of methanolic extract of A. hierochuntica.

calculated as the concentration of trolox required to produce an equivalent antioxidant potential. The finding revealed the exhibition of antioxidant activity by 13 of 20 identified compounds in the A. hierochuntica aqueous extract. The highest contribution (56%) was from phenolic acids and hydroxycinnamates, mostly 5-Ocaffeoylquinic acid (chlorogenic acid), with a trolox equivalent value of 60 mM [23]. All antioxidant determination assays performed by Mohammed et al. (2010) and Al-Gamdi et al.

[23,31] showed high antioxidant potential of A. hierochuntica extracts. 4.2. Antimicrobial activity The antimicrobial properties of the A. hierochuntica aqueous and ethanolic extracts against food borne bacterial strains were initially assessed by Tayel and El-Tras using paper disc diffusion

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assay [26]. In the assay, sterile paper discs were placed on the surface of inoculated nutrient agar plates, followed by the addition of 10 ml extract on each plate. Inhibition zones were measured after 24 h incubation of the plates at 37  C. The results revealed antimicrobial properties of the aqueous extract against Bacillus subtilis (B. subtilis), Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Pseudomonas fluorescens (P. fluorescens) and Staphylococcus aureus (S. aureus). The ethanol extract meanwhile, exhibited antimicrobial activities on the same microorganisms except E. coli and P. fluorescens [26]. Later, in 2010, another study by Mohamed and team also reported antimicrobial activities of A. hierochuntica against some microorganisms [31]. In the study, dried and sterilised paper discs that were impregnated with 40 mg/ml extracts were plated on assay plates (containing soft agar inoculated with the tested microorganisms layered over 10 ml hard agar) [31]. The methanolic and aqueous extracts of A. hierochuntica whole plant were demonstrated to have antimicrobial properties against grampositive bacteria (B. subtilis), but not against gram-negative bacteria (E. coli, P. aeruginosa, and Salmonella typhi (S. typhi)) [31]. The latest study conducted by Al Sobeai demonstrated antibacterial activities by A. hierochuntica methanolic extract at 100 mg/ml, against Klebsiella pneumonia (K. pneumonia) and Proteus mirabilis (P. mirabilis) with inhibition zone of 22.7
1.3 mm and 22.3
1.3 mm respectively [39]. In addition, the methanolic extract showed inhibitory effects against B. subtilis, Enterococcus faecalis, S. typhi, Streptococcus faecalis (S. faecalis), Streptococcus pyogenes (S. pyogenes), Shigella sonnei (S. sonnei) and Listeria monocytogenes (L. monocytogenes) [39]. Al Sobeai also showed antibacterial activities of A. hierochuntica aqueous extracts against P. mirabilis (20.3
1.3 mm), S. typhi (18.7
0.9 mm), Salmonella paratyphi (18
0.6 mm) and K. pneumonia (18
1.3 mm). Furthermore, the aqueous extract displayed inhibitory effects against S. faecalis, S. pyogenes, S. sonnei and E. faecalis, with no effect against L. monocytogenes [39]. The antimicrobial activity of the A. hierochuntica against both gram positive and gram negative bacteria suggests presence of broad spectrum antibacterial compounds in the plant extract [39]. In fact, A. hierochuntica extract was shown to contain flavonoids [31] which were shown to possess potential immune modulatory effects [39]. The antibacterial activity of the plant extract may involve complex mechanisms, such as the inhibition of the synthesis of cell membrane, nucleic acid and protein [40]. However, the specific active compounds that contributed to the antimicrobial effects in all mentioned studies [26,31,39] and their full spectrum of efficacy have yet to be revealed. 4.3. Antifungal activity An earlier disc assay conducted by Mohamed et al. using 40 mg/ ml A. hierochuntica methanolic and aqueous extracts revealed no antifungal activities against Aspergillus niger (A. niger), and Candida albicans (C. albicans) [31] while another assay performed by Daoowd (2013) demonstrated positive antifungal activities of aqueous, acetone and methanol extracts of A. hierochuntica leaves [27]. The prepared extracts were evaluated against C. albicans, A. niger, Penicillum digitatum (P. digitatum), Fusarium oxysporum and Cryptococcus neoformans using paper disc diffusion method. All methanol extract concentrations showed positive antifungal effects against all tested fungi, with the highest activity demonstrated against C. albicans (28 mm inhibition zone) at 250 mg/ml. The best antifungal activity (16 mm inhibition zone) of the acetone extract was observed against P. digitatum at 250 mg/ ml, while A. hierochuntica aqueous extract exhibited the lowest activity (6 mm inhibition zone) against A. niger at 250 mg/ml [27].

The findings from Daoowd study [27], confirmed the antifungal effects of A. hierochuntica [27]. Although different levels of activities were observed in various types of extracts, this could just be due to their varying degrees of solubility in different solvents. The concentration of extract used by Daoowd [27] was far higher than that of the assay performed by Mohamed et al. [31]. Therefore, the absence of antifungal effect observed in the latter was most probably attributed to inadequate dosage required to achieve the expected activities. The antifungal activities exhibited by A. hierochuntica extracts might be attributed to the presence of either single or synergistic effect of more than one compound. Tannins and flavonoids were revealed by the preliminary phytochemical analysis of the A. hierochuntica extract [27]. These compounds were also identified in other plants and have been demonstrated to possess antifungal properties. For example, tannins have been reported to act as an antifungal agent at higher concentration by coagulating the protoplasm of the micro-organism [41]. In addition, tannins and flavonoids have also been reported to inhibit cell wall formation in fungi leading to the death of the organism [41]. In fact, a number of antifungal compounds were reported to exhibit their effects via disruption of the synthesis of the essential fungal cell wall components namely chitin and b-glucans [42]. The crude A. hierochuntica extracts should be further purified through antifungal activity guided fractionation to identify the compounds responsible for the antifungal activity and further analyse their specific mechanisms of action. 4.4. Hypolipidaemic activity As far as our literature survey could ascertain, we found only 2 studies relating to hypolipidaemic activity, and these were conducted by Shaban et al. (2011) and Salah et al. (2011) [29,32]. The former showed that daily oral administration of 100 mg/kg methanolic extract of A. hierochuntica whole plant significantly reduced the levels of triglyceride (TG), low-density lipoprotein (LDL), very low–density lipoprotein (VLDL), and total cholesterol (TC) in alloxan-induced diabetic male Swiss albino rats after 4 weeks of treatment [32]. It also caused significant improvement in the level of high-density lipoprotein (HDL) cholesterol, which is associated with reduced risk of coronary heart disease [43]. Similar findings were demonstrated by Salah et al. (2011) who reported significant improvement of lipid profiles (TG, TC, LDL, and HDL) in alloxan-induced diabetic rats treated with 150 mg/kg methanolic extract of A. hierochuntica for 15 days [29]. Both studies demonstrated improvement in lipid profiles of alloxan-induced diabetic rats [29,32]. The abnormal lipoprotein levels in those animals might be due to the alteration in lipoprotein metabolism [32] or inhibition of adiponectin secretion from adipose tissue, secondary to decreased serum insulin level [29]. Adiponectin is an important protein that is involved in the regulation of lipid metabolism [29]. Flavonoids of A. hierochuntica may stimulate adiponectin secretion which can, in turn, stimulate the action of insulin in lipid metabolism. Increased insulin level following administration of flavonoids is expected to reduce hepatic triglyceride synthesis and lipolysis. Perhaps, in vivo studies on the action of this herb on animals fed a high-fat diet may lead to further discussion on the mechanism of its hypolipidaemic activity [29]. 4.5. Hypoglycaemic activity Considering the pathophysiology of diabetes mellitus, triggering the regeneration of pancreatic islets will be a fundamental approach for the treatment of insulin-dependent diabetes mellitus.

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Interestingly, A. hierochuntica has been found to be a medicinal plant that exhibits regenerative properties on pancreatic b-cells [32]. Shaban et al. (2011) reported that alloxan-induced diabetic rats treated with 100 mg/kg methanolic extract of A. hierochuntica for 28 days exhibited evidence of restoration of b-cells of the pancreas [32]. The outcome from the restoration was evidenced in a 74% reduction of glucose levels as compared with the basal levels in the control group, which was given only distilled water (vehicle). This finding indicates the presence of hypoglycaemic agents in the crude whole plant methanolic extract of A. hierochuntica, which was found to becomparable with the effect of metformin given to diabetic rats at the same dosage [32]. This is consistent with a study conducted by Rahmy and El-Ridi, who reported an improvement in the pancreatic tissue injury of streptozotocin (STZ)-induced diabetic rats [28]. In the study, 12.5 mg/rat aqueous extract of A. hierochuntica was administered daily via the oral route to male albino Wistar rats for 2 weeks. The hypoglycaemic effects were then observed in both non-diabetic and STZ-induced diabetic rats. The effects observed in the STZ-induced diabetic rats could have been due to the presence of flavone glycosidic components which increased serum insulin levels secondary to the regeneration of pancreatic cells [28]. This was supported by the stimulation of the appearance of immunoreactive insulin-secreting cells in many parts of the pancreatic islets, as observed via immunohistochemical study [28]. In addition, A. hierochuntica was shown by Salah et al. to significantly reduce the elevated glucose levels in alloxan-induced diabetic rats treated with 150 mg/kg A. hierochuntica methanolic extract for 15 days [29]. Alloxan was used to produce insulindependent diabetes mellitus in the experimental animals. Development of diabetes leads to oxidative stresses which include stimulation of lipid peroxidation, protein glycation and inhibition of antioxidative enzymes. Further investigation performed by Salah et al. (2011) revealed the role of A. hierochuntica in reducing the oxidative stress thus resulting in the hypoglycaemic effect [29]. The plant methanolic extract has inhibited the frequency of chromosomal aberration and improved serum immunoglobulins (IgG, IgA and IgM) and lipid profiles (TC, TG, LDL and HDL) levels of the experimental animals. These findings could be due to the stimulation of protein biosynthesis process to produce the specific factors required to improve the affected parameters as a result of oxidative stress in experimental diabetes. Therefore, Salah et al. concluded that the flavonoids of A. hierochuntica methanolic extract reduced the harmful effects of diabetes and exhibited their hypoglycaemic effect on the oxidative stress of alloxan-induced diabetes mellitus via nucleic acids and protein metabolism [29]. Significant hypoglycaemic activities of both A. hierochuntica aqueous and alcohol extracts have been observed in diabetic rats [28,29,32]. However, before A. hierochuntica can be used clinically in patients with diabetes, further research must be conducted to expand our understanding of this plant and its constituents, the possible mechanisms of action and their toxicological effects. Future studies with longer periods of higher doses using crude and active compounds are also required to determine the actual phytoconstituents that contribute towards the antidiabetic properties of A. hierochuntica. 4.6. Hepatoprotective activity The EtOAc-soluble fraction of the methanolic extract from whole plants of A. hierochuntica was found to have potent hepatoprotective effects [21]. In that study, the EtOAc-soluble fraction was subjected to ordinary-phase silica gel and reversedphase silica gel column chromatography and HPLC to reveal the presence of flavanones, namely anastatin A (12) and B (13),

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flavonoids [naringenin (20), eriodictyol (21), aromadendrin (22), (+)-taxofilin (23), 30 -O-methyl taxifolin (24) (Fig. 3), (+)-epitaxifolin (25), and quercetin (28) (Fig. 4), aromatic compounds, phenylpropanoids, lignans, and flavonolignans. Anastatin A, anastatin B and the isolated flavonoids were found to have inhibitory activities on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes [21,44]. Another demonstration of hepatoprotective activity of the isolated compounds of A. hierochuntica ethanolic extract was carried out by Eman et al. [16]. In the study, the compounds namely anastatin A, anastatin B, naringenin, eriodictyol, aromadendrin, (+)-taxifolin, 30 -O-methyl taxifolin and (+)-epitaxifolin showed inhibitory effect on D-galactosamine induced cytotoxicity in primary cultured mouse hepatocytes [16]. In fact, the results of both studies [16,21] showed stronger hepatoprotective activities by anastatin A and B than those of other flavonoids, including silybin, a well-known standard potent hepatoprotective drug that is commercially available [16,21,44]. D-Galactosamine is a well-established hepatotoxicant. It induces a decrease in liver uracil nucleotides which rapidly inhibits both RNA and protein synthesis which resulted in depletion of uridine diphosphate glucose followed by defects in glycoprotein synthesis. This leads to damage of cellular membrane and liver cell necrosis that ultimately provokes development of inflammation resembling viral hepatitis [45]. Hepatocyte damage in D-galactosamine hepatoxicity is also contributed by the release of reactive oxygen species (ROS) and cytokines such as tumour necrosis factor (TNF-a) and Interleukin-1 (IL-1) by Kupffer cells in the liver [45]. The antioxidant and anti-inflammatory activities of the A. hierochuntica constituents [31] may contribute to the attenuation of the D-galactosamine-induced hepatotoxicity. Further study should be conducted in explaining the detail mechanism of hepatoprotective effects of A. hierochuntica-derived flavonoids. Moreover, a 4-week oral treatment of alloxan-induced diabetic rats with 100 mg/kg A. hierochuntica methanolic extract also revealed the hepatoprotective properties of the extract [32]. In the study conducted by Shaban et al., the hepatocellular necrosis following alloxan exposure was indicated by the increased serum glutamic oxaloacetic transaminase (GOT), serum glutamic pyruvic transaminase (GPT), and alkaline phosphatase (ALP) activities. Administration of methanolic extract of A. hierochuntica has significantly restored these enzymes to normal levels and improved the histomorphological changes in the livers of diabetic rats [32]. There is no discussion on the hepatoprotective mechanism of A. hierochuntica by Shaban et al. [32]. However, several studies have shown that oxidative free radicals generated by alloxan administration is the most common cause for the destruction of vital organs including liver [46]. Therefore, the underlying mechanism of the hepatoprotective effect of A. hierochuntica might be due to the presence of antioxidant polyphenolic components in the plant [46]. Improvements in the biomarkers (GOT, GPT and ALP) levels and histopathological changes in the carbon tetrachloride (CCl4)induced liver damage of male albino rats were also reported by El-Sayed et al. (2012) [4]. The results were obtained after feeding the rats with standard diet containing 5% and 10% A. hierochuntica powder for 4 weeks [4]. CCl4-induced liver damage can result from covalent binding of the CCl4 metabolites to cell components or from lipid peroxidation resulting in damage to intracellular and plasma membranes [47,48]. Several studies have shown that some plant products exerted their hepatoprotective effect against CCl4induced hepatotoxicity, via their anti-oxidant effect that reduces lipid peroxidation [49–51]. Therefore, the compounds of A. hierochuntica might have also exhibited their hepatoprotective activity against CCl4-induced liver damage via antioxidant

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property. Further study in its mechanism of action is required in order to describe the biochemical pathway of the actions of A. hierochuntica constituents. The hepatoprotective effects of A. hierochuntica methanol and ethanol extracts have been consistently demonstrated [16,21,32]. However, as the amount of related research is limited, we found no other similar study using A. hierochuntica aqueous extract. Therefore, it is difficult to predict the potential of hepatoprotective effects of A. hierochuntica decoctions in those who consume it. Before we draw any definitive conclusions, it would be prudent to study the effects of A. hierochuntica on the liver-metabolising enzymes which could predict possible involvement in drug-drug interactions. 4.7. Anti-inflammatory activity Rizk et al. demonstrated anti-inflammatory activity of the chloroform extracts of A. hierochuntica [33]. In that study, 10 ml of A. hierochuntica extract was added to platelet-rich plasma a minute prior to the addition of three challenging agents; arachidonic acid (ARC), adenosine diphosphate (ADP) and 12-deoxyphorbol phenylacetate (12-DOP). The result showed 100% inhibition of the aggregation of rabbit blood platelets induced by ADP and 50% inhibition of platelet aggregation induced by 12-DOP tested in vitro. However, the extract did not affect the platelet aggregation induced by ARC [33]. It is believed that 12-DOP induces platelet aggregation by interacting with the platelet membranes and stimulating phospholipid metabolism. Therefore, the researchers postulated the presence of membrane-stabilising anti-inflammatory compounds in A. hierochuntica extracts. The anti-inflammatory effect of the herb was further examined in vivo, in which 12-DOP was applied to the ear of female Swiss albino mice, followed by 100 mg per 5 ml solution of extract 15 min later. The result revealed a 60% inhibition of 12-DOP–induced mouse ear erythema by A. hierochuntica [33]. A recent study by Abou-Elella et al. (2016) [30] supported the suggestion made by Rizk et al. (1985) [33] regarding the possibility of the membrane stabilizing activity of A. hierochuntica. It demonstrated the in vitro human red blood cell (HRBC) membrane stabilization effect of whole ethanolic extract of A. hierochuntica and its various extraction fractions (water, petroleum ether, EtOAc and butanol) [30]. The results revealed the highest anti-inflammatory activity in the 100 mg/ml whole ethanolic extract (57
14.73%), which was close to that of the standard antiinflammatory drug, diclofenac sodium (71.33
2.31%). Lower activity was observed in all ethanolic A. hierochuntica extraction fractions namely water (48
10%), butanol (28
0%), petroleum ether (16.67
0.58%) and EtOAc (7
3.46%) [30]. The findings from the membrane stabilization test showed that ethanolic extracts of A. hierochuntica inhibited heat-induced haemolysis of erythrocytes. This indicates biological membrane stabilization properties of the extracts which prevent stressinduced destruction of the plasma membrane [30]. 4.8. Anti-melanogenic activity Researchers have studied various natural medicines, including A. hierochuntica, to discover the constituents that can inhibit melanogenesis. Nakashima et al. (2010) reported that whole plant A. hierochuntica methanolic extract significantly inhibited melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells with a median inhibitory concentration (IC50) value of 100 mg/ ml [24]. Furthermore, the EtOAc-soluble fraction of the methanolic extract showed significant inhibition of melanogenesis, with an IC50 value of 60 mg/ml [24]. The EtOAc-soluble fraction was then subjected to ordinary- and reversed-phase silica gel column

chromatography and finally HPLC to yield the isolated compounds as shown in Figs. 3 and 4 [24]. Amongst the compounds isolated, anastatin A (12), silybin A (16), isosilybin A (18) and B (19), eriodictyol (21) (Fig. 3), luteolin (26), kaempferol (27), quercetin (28), hierochin A (30) and B (34), (+)-dehydrodiconiferyl alcohol (32), (+)-balanophonin (33), and 3,4-dihydroxybenzaldehyde (42) (Fig. 4) significantly inhibited melanogenesis at an IC50 value of 6.1–32 mM [24]. Isosylibin A and B act by inhibiting tyrosinase activity and messenger ribonucleic acid (mRNA) expression of tyrosine related protein-2 (TRP-2), while luteolin was reported to inhibit tyrosinase activity and melanin production by inhibiting adenyl cyclase in a-melanocyte stimulating hormone (a-MSH) stimulated B16 melanoma cells. Another isolated compound; quercetin was also reported to inhibit tyrosinase and tyrosinase protein levels resulting in the inhibition of melanogenesis in B16 melanoma cells [24]. However, the mechanism of action of the other active constituents including their target molecules in the melanogenesis inhibitory effect of A. hierochuntica has yet to be confirmed, given the very limited number of studies. Hopefully, this review may encourage greater researcher interest in conducting further investigations and experiments, as effective discussion on this matter requires more evidence. 4.9. Gastroprotective activity A. hierochuntica decoctions are also consumed to treat gastric disorders [11]. The gastroprotective potential touted in the folklore was proven by Shah et al. [11]. In their study, a group of Wistar albino rats were treated with 80% ethanol, 0.2 M sodium hydroxide (NaOH), 0.6 M hydrochloric acid (HCl), 25% sodium chloride (NaCl), indomethacin, and a combination of ethanol and indomethacin as necrotising agents to cause damage to the stomach wall [11]. Pretreatment with ethanol extract of the whole plant of A. hierochuntica using oral gavage tube at dose levels between 125 and 500 mg/kg resulted in statistically significant protection against the damage induced by the necrotising agents [11]. The administration of A. hierochuntica ethanolic extract significantly inhibited the depletion of stomach wall mucus caused by the ethanol. Furthermore, A. hierochuntica was reported to show significant gastroprotective activity against the deleterious effects of ethanol on protein and nucleic acid concentrations of the stomach, and gastric mucosal non-protein sulfhydryls (NP-SH) [11]. Pretreatment with this herbal extract was also found to reduce the high concentration of malondialdehyde caused by ethanol. All of the effects were exhibited in a dose-dependent manner [11]. The findings were supported by histopathological studies that showed the inhibition of ethanol-induced necrosis, congestion, haemorrhage, and oedema in the stomach walls of rats pretreated with A. hierochuntica [11]. Ethanol treatment used by Shah et al. has resulted in accumulation of toxic free radicals in the mucosal cells, leading to significant reduction of the stomach protein and nucleic acid contents in rats [11]. Several chemicals isolated from A. hierochuntica extract were confirmed to be free radical scavengers which could contribute to the plant’s gastroprotective activity observed by Shah et al. [11]. The identified compounds were found to belong to different groups include volatile oils, glucosinolates, sterols, triterpenes, tannins, flavonoids and other polyphenols. In addition, the isolated compounds such as quercetin, luteolin and kaempferol derivatives, and anastatin A and B were shown to have anti-ulcerogenic property with significant protective activities [11,21]. Shah et al. also used indomethacin to induce gastric ulcer in the experimental animals which resulted in reduction of prostaglandin level [11]. Prostaglandin was shown to play important role in

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cytoprotective process of gastric ulcer [52]. A. hierochuntica treatment administered to the animals provided a significant protection against indomethacin-induced damage probably due to stimulation of prostaglandin production by its phytochemical constituents [11]. The observed cytoprotective effects of this plant extract were attributed to its antioxidant and possible prostaglandin stimulating properties, and the consequence of its effects on gastric mucus production and NP-SH concentrations [11]. However, the exact mechanism of the gastroprotective or anti-ulcer activity of A. hierochuntica treatment was not yet investigated [11]. 4.10. Immunostimulatory activity Treatment of male Swiss albino mice with the methanolic extract of A. hierochuntica (50 mg/kg) for 2 weeks led to a significant increase in immunoglobulin G (IgG) levels [2]. This finding supported a previous research by Salah et al. which demonstrated a significant increase in the serum levels of IgG, IgA, and IgM in alloxan-induced diabetic rats treated with A. hierochuntica methanolic extract [29]. Abdulfattah suggested that the increased levels of circulating IgG were due to the presence of flavone glycosidic components in the extract [2]. Furthermore, A. hierochuntica extract at a higher dose (100 mg/kg) significantly decreased the level of another immunological parameter, adenosine deaminase activity (ADA) [2]. In addition, Abdulfattah reported that the methanolic extract of A. hierochuntica had potent immunostimulatory effects on the functional activity of phagocytic cells [2]. In that study, a significant increase in the percentage of phagocytosis was observed after 30 min in mice treated with 50 mg/kg and 100 mg/kg A. hierochuntica methanolic extract, and after 60 min in the group treated with 50 mg/kg of the methanolic extract [2]. This stimulation was believed to be associated with the presence of its active compounds, such as phenols and flavonoids, which regulate the innate immunity, stimulate the initiation of the cellular immune response, and accelerate the ability of the immune system to produce T cell aggregation [31]. The ability of the plant extract to activate phagocytosis will lead to improvement of their microbicidal activity. 5. Toxicological aspects Despite the purported medicinal benefits of A. hierochuntica, it is important to study its possible toxicological effects. An acute toxicity study was conducted by Shah et al. according to the recommendations of World Health Organization for herbal drugs [11]. After 24-h observation, no mortality was reported among A. hierochuntica–treated Swiss albino mice [11]. However, they reported a decrease in locomotor activity and behavioural changes such as writhing and piloerection in mice treated with 3 g/kg body weight A. hierochuntica ethanol extract [11]. In the study, 20 mice were randomly assigned to 1 control and 3 treatment groups. The control group received only water, and the remaining groups were orally given 0.5 g/kg, 1 g/kg, or 3 g/kg body weight ethanol extract of A. hierochuntica [11]. Shah et al. also conducted a chronic toxicity study on 40 Swiss albino mice exposed to 100 mg/kg/day A. hierochuntica ethanol extract in drinking water [11]. During the 3-month study, all of the treated mice remained healthy and active. Histopathological analysis of the tissues from the heart, lungs, liver, kidney, and testis revealed no signs of toxicity effects in the treatment groups as compared to the control [11]. Besides, no increase in sperm abnormalities was observed in the treated group. Haematological indices, including white cells, red blood cells, haemoglobin, and platelets, showed no significant deviations. In addition,

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biochemical indices including aspartate transferase (AST), alanine transferase (ALT), creatine kinase–MB fraction (CK-MB), creatinine, urea, and glucose were found to be normal and comparable to that of the control group [11]. In addition, there was one study on fetal toxicity effects of A. hierochuntica, conducted by Rasheed et al. [53]. This study demonstrated an increased incidence of fetal resorption rate (11/105 resorption of the total foetuses examined) with the most detrimental result observed in the high dose group (4 g/kg). Higher incidence of axencephaly were also reported in the foetuses of mice treated with 0.25, 1 and 4 g/kg lyophilized extract of A. hierochuntica at gestational day (GD) 12–14 compared to GD 10–12 and GD 8–10 [53]. These findings suggested a teratogenic potential of lyophilized A. hierochuntica extract at the doses used. There is a lack of toxicity data in the literature to support the safety of A. hierochuntica extracts. The findings from Shah et al. [11] and Rasheed et al. [53] provide basic toxicity information as guidance for future experiments using this natural product. However, more toxicological studies need to be carried out to confirm its safety [11]. 6. Conclusion A. hierochuntica has been used therapeutically for centuries due to the inherent belief in its medicinal benefits. Amongst the purported benefits, the antioxidant, hypoglycaemic and hepatoprotective activities are the ones that have been most studied, using various types of A. hierochuntica extracts, thus supporting the folklore claims. Furthermore, both in vitro and in vivo studies have consistently demonstrated the hepatoprotective activities of this plant. Based on the in vitro study, anastatin A and B were found to be the most potent bioactive compounds with hepatoprotective effects. This review shows that even though there are some information in the literature on the in vivo and in vitro studies that relate to various biological activities of A. hierochuntica, there appears to be some gaps in knowledge such that the biological activities of the plant still remain inconclusive. We hope that this review will encourage more studies on this plant in order to aid further scientific evaluation of its claimed medicinal benefits. It is also necessary to explore the mechanisms of action of the bioactive compounds of this herb that result in its particular biological activities or effects. Knowing that A. hierochuntica is widely consumed across the globe, it seems worthwhile to explore the plant further. Disclosure statement The authors declare no conflict of interest. Acknowledgement We would like to thank Bantuan Kecil Peruntukan (BKP) grant (BK040-2013) of University of Malaya for financial support. References [1] I. Daur, Chemical properties of the medicinal herb Kaff Maryam (Anastatica hierochuntica L.) and its relation to folk medicine use, Afr. J. Microbiol. Res. 6 (23) (2012) 5048–5051. [2] S.Y. Abdulfattah, Study of immunological effect of Anastatica hierochuntica (Kaff Maryam) plant methanolic extract on albino male mice, J. Biotechnol. Res. Center 7 (2) (2013) 3–10. [3] K.S. Law, L.K. Soon, S.S.S. Mohsin, C.G. Farid, Ultrastructural findings of Anastatica hierochuntica L., (Sanggul Fatimah) towards explaining its medicinal properties, Ann. Microsc. 9 (2009) 50–56.

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