Phytochemistry and therapeutic effects of Alhagi spp. and Tarangabin in traditional and modern medicine: a review

Introduction Alhagi maurorum Medik. (from Fabaceae family) is a perennial plant with a wide geographical distribution. Animal and human studies have been conducted on its effects, some of which include antioxidant, antiinflammatory, antipyretic, diaphoretic, diuretic, expectorant and analgesic properties (1,2). Its morphology, nature, and clinical uses have been explained in the Materia Medica manuscripts in Islamic era by the sage physicians (3-5). Tarangabin, a kind of manna which is produced on some Alhagi species, is collected mostly in Iran and Afghanistan and exported from these areas to other countries. Special attention has been paid to Tarangabin in some major Materia Medica manuscripts of Islamic era as one of the most commonly used medicinal matters in Islamic traditional medicine (ITM) (3,4,6,7). However, few studies have been performed on its pharmacological effects. The aim of this study is to review its uses in ethnobotanical, traditional medical schools, and ITM, and to present its phytochemical plus pharmacological http://www.herbmedpharmacol.com doi: 10.34172/jhp.2020.13


Implication for health policy/practice/research/medical education:
This review highlights the health benefits of Alhagi spp. and Tarangabin in the treatment of human diseases.
Please cite this paper as: Tavassoli  Alhagi maurorum is one of the species of Alhagi genus producing manna of Tarangabin. Tarangabin is mainly prepared in Iran and Afghanistan. The medicinal properties of Tarangabin and A. maurorum have been mentioned in some major Materia Medica manuscripts in the Islamic era. Tarangabin has various pharmacological properties including antioxidant, anti-inflammatory, antipyretic, diaphoretic, diuretic, expectorant, analgesic and gastrointestinal effects. The purpose of this review is to introduce Alhagi plant and its different species, to present its geographical distribution, and to review its phytochemical and pharmacological properties as well as traditional and folklore applications. Phytochemistry of different parts of Alhagi, such as root, leaf and manna is also explained in details. In addition, temperament and medicinal uses of Tarangabin mentioned in the Islamic traditional medicine (ITM) books are presented. Indeed, sparse clinical research has been done on the medicinal properties of Tarangabin, which calls for future well-designed trials.

Introduction
Alhagi maurorum Medik. (from Fabaceae family) is a perennial plant with a wide geographical distribution. Animal and human studies have been conducted on its effects, some of which include antioxidant, antiinflammatory, antipyretic, diaphoretic, diuretic, expectorant and analgesic properties (1,2). Its morphology, nature, and clinical uses have been explained in the Materia Medica manuscripts in Islamic era by the sage physicians (3)(4)(5).
Tarangabin, a kind of manna which is produced on some Alhagi species, is collected mostly in Iran and Afghanistan and exported from these areas to other countries. Special attention has been paid to Tarangabin in some major Materia Medica manuscripts of Islamic era as one of the most commonly used medicinal matters in Islamic traditional medicine (ITM) (3,4,6,7). However, few studies have been performed on its pharmacological effects.
The aim of this study is to review its uses in ethnobotanical, traditional medical schools, and ITM, and to present its phytochemical plus pharmacological Tarangabin (Manna of Alhagi ( Tarangabin is a kind of manna with various names such as Merniabin manna, Alhagi manna, and Caspian manna ( Table 3).
It is sweet, yellowish-white in color and semi-liquid exudate, created on the aerial parts of some Alhagi genera such as A. maurorum. Tarangabin is produced by an insect called Poophilus nebulosus Leth which lives on the aerial parts of the plant. The insect belongs to the genus Larinus, Cercopidae family, Homoptera phylum. Indeed, Tarangabin is the exudation of this insect produced after nourishment on A. maurorum, which crystallizes and dries on the plant. It is not producible from all genera of Alhagi. In addition, the climate condition can play a significant role in the formation of Tarangabin. As a result, in a particular species of Alhagi, presence of P. nebulosus and appropriate climate are necessary for the formation of Tarangabin (16).
Ibn Sina (Avicenna, 980-1037 C.E) mentioned Tarangabin as a crop of Khorasan and Transoxiana (Māwarāʼ an-Nahr). At time, it can be obtained from other provinces of Iran including Yazd, Qom, Bushehr, eastern Azerbaijan and Hamedan, as well as from Afghanistan (Herat and Kandahar) and Uzbekistan (Bukhara). Tarangabin is usually collected during the night and early in the morning depending on the weather conditions of the area, from the end of spring to fall. This manna appears on the shoots and leaves of the herb and dries in air (15,17).

Alhagi maurorum and Tarangabin in ITM
Nature of Alhagi and Tarangabin described in ITM Abū Rayḥān Bērōnī (973-1050 C.E) wrote about Alhagi maurorum: The plant has a very long root reaching water or moisture, has a small red fruit that is also covered with red pods. Its leaves are tube-shaped and among them, there are green insects with a broad head. He considered Tarangabin as a product of Alhagi (5). Its temperament is considered hot and dry in Medica manuscripts (3,4).
Ibn Sina knew Tarangabin as a kind of dew coagulated (produced) on Alhagi of the Khorasan and Transoxiana regions. He declared that the best crop for medicinal use should be fresh and white, and recognized its temperament to be moderate and mildly hot.
The therapeutic doses of Tarangabin can range from 35 to 140 g depending on the patient's condition (7).
Pharmacological actions and therapeutic usages of Alhagi and Tarangabin according to ITM literature Aqili described the pharmacological properties of Alhagi as follows: restrainer (radi), opener (mofatih), detergent (jali), and antidote (Padzahr). He recommended it for the treatment of joint pain and headache, and especially advised its blossom for improving hemorrhoid as a wellexperienced treatment (4). It is recommended as a topical treatment for progressive ulcers (3).
Tarangabin is highly used in ITM, which is recommended in the treatment of various diseases (7,20). Tarangabin properties as listed in the majority of ITM literature include laxative, detergent, purgative for yellow bile, cough reliever, thirst quencher, antipyretic, antiemetic, and warming agent of the body. It has been suggested in compound forms to treat some ailments for example with butter for dysuria, with fresh milk to increase libido, and with cumin to resolve flatulence (6,7,13,21).
A combined form of Tarangabin and milk called Davaal-tarangabin has been described in ITM literature and recommended as one of the most effective medications for renal ailments which can be known as chronic kidney disease today (7).
Contraindications for Alhagi and Tarangabin in ITM Based on the Medica manuscripts of ITM, Alhagi is harmful for kidney and it should be consumed with Tragacanth as modifier. Tarangabin is prohibited in acute fever, smallpox, typhoid, bloody diarrhea and hemorrhage. It is also harmful for spleen and for those with hot temperament, but if consumed with tamarind, jujube or decoction of barley, the side effects will be prevented (3,4).
Folklore claims Due to the geographic distribution of Alhagi, people from different countries use the components of this plant in folk medicine to treat various diseases, which are presented in Table 4.

Phytochemical study
Phytochemical studies have revealed the presence of many compounds in the Alhagi species. The majority of these compounds are sugars, polyphenols, flavonoids, essential oil, alkaloids, and other compounds. Table S1 presents the most important compounds isolated from Alhagi species along with their structures (Table 5). Polyphenols are compounds that are abundant in nature, many of which have been identified. Polyphenols are classified according to the number of phenolic rings and structural elements that connect these rings to each other. Flavonoids, lignans, and phenolic acids are among them.
Flavonoids, a large and important group of natural substances with a polyphenolic structure, are found in fruits, vegetables, and certain drinks. These natural compounds are known and have health-promoting effects (33)(34)(35). Flavonoids can be divided into different subgroups depending on their structures. These subgroups include anthoxanthins, flavanones, flavanonols, flavans, and anthocyanidins. Flavanones are an important class of flavonoids, with rutin being an example that is isolated from the aerial parts of A. sparsifolia (36). Anthocyanins are flavonoids responsible for color production in plants, flowers, and fruits. Among these, cyanidin and delphinidin derivatives are of the most important compounds, which are extracted from the aerial parts of A. pseudalhagi (37).
Essential oils are a large group of volatile compounds, which are found in Alhagi species. Essential oils, like other organic compounds, are composed of hydrocarbon molecules and are divided into terpenes, alcohols, esters, aldehydes, ketones, and phenols.
We found few phytochemical studies on Tarangabin. Paucity of phytochemical studies on Tarangabin may be due to the simplicity of its chemical ingredients. These ingredients in Tarangabin are sugars whose content is as follows: melissitoz sugar (47.7%), sucrose (26.44%), and fructose reductant (11.5%) (15).
Attributing all the pharmacological effects of Tarangabin to the sugars seems doubtful, thus requiting interdisciplinary studies in this regard.

Pharmacological properties of Alhagi
Gastrointestinal effects An animal study on rats evaluated the anti-ulcerogenic effects of A. maurorum extract (AME) in two types of gastric ulcers induced by alcohol and water immersion restraint-stress. The AME reduced gastric acid content and elevated gastric pH in water immersion restraintstress ulcer (38). In an experimental study on rats, administration of A. maurorum ethanol extract protected against inflammation caused by aspirin. The acid output diminished for Alhagi extract more than for ranitidine (39). Another study on rabbit showed the antidiarrheal activity of AME. This study investigated the effect of A. maurorum on the castor oil-induced diarrhea. The antidiarrheal effect of Alhagi might be due to its calcium channel-blocking properties (40).

Hepatoprotective effects
In a study, the crude extracts of aerial parts of A. maurorum at the doses of 250 and 500 mg/kg were devoid of any hepatoprotective effects in Wistar albino rats with liver injury induced by carbon tetrachloride (41). However, in another study administration of 660 mg/kg of the ethanol extract of A. maurorum to mice yielded a significant hepatoprotective effect against carbon tetrachloride and acetaminophen; it revealed a significant decrease in the

Country or Area
Medicinal properties Ref.

Egypt
Used to treat various types of gastrointestinal discomfort, liver and urinary tract disorders.    A. sparsifolia Aerial parts (36) No.

Name of compounds Structures Species Plant parts Ref
Urinary tract effects In a study oral administration of the methanol extracts of A. maurorum in a single or repeated (1 × 5 days) oral dose of 500 or 1000 mg/kg orally compared to furosemide 20 mg/kg, increased urine volume, sodium and potassium excretion rate, and had significant diuretic, kaluretic, and saluretic effects (44). The diuretic effect of A. maurorum was also evaluated in an in vivo study. The results indicated that oral administration of 8-16 ml/kg of the distilled product of A. maurorum had diuretic effects (1).
A new aliphatic ester isolated from the root of A. maurorum, glyceryl-n tetracosan-17-ol-1-oate demonstrated a relaxant effect in guinea-pig ureter due to suppression of histamine-induced spasms. It can help relieve the pain of kidney stones resulting from contraction of the ureter (45). Addition of the ethanol extract of A. maurorum powdered roots completely suppressed contractions at doses of 5 mg/mL bathing to the isolated guinea-pig ureter with continuous contractions induced by histamine at doses of 3 μg/mL bathing fluid (46).
Anti-inflammatory, anti-nociceptive, and antipyretic effects In a study, the aerial parts of A. graecorum were extracted and aqueous ethanol extract was evaluated in vivo, using two animal models: the carrageenan induced rat paw edema and the granuloma formation in albino Wistar rats induced by cotton pellets. The isolation of bioactive components including one hydrolysable tannin and four flavonol glycosides kaempferol compared with diclofenac sodium as a positive control, demonstrated anti-inflammatory effect of extract of A. graecorum (47). The effects of the ethanolic extract of A. maurorum on intraperitoneal administration into mice reduced the rectal temperature by 0.2-3.3ºC in a dose-dependent manner (46). An aqueous extract of A. maurorum had anti-inflammatory activities among mice in the model of formalin-induced paw edema assay. The aqueous extract of Alhagi expressed protective effects against free radicals mediated inflammatory diseases (48). The antinociceptive effect of methanol extracts (200 and 400 mg/kg) of A. maurorum in oral administration has been shown in a study using acetic acid-induced writhing and tail-flick tests in mice (49). Intraperitoneal administration of a new phytocompound, glyceryl-n-tetracosan-17-ol-1-oate, isolated from the root of the A. maurorum, also lowered the body temperature in mice (45).

Musculoskeletal effects
The ethanol extract of A. maurorum at a concentration of 4 μg/mL bathing fluid for 5 minutes antagonized acetylcholine-induced contraction in the exposure of the frog's rectus abdominis muscle and blocked the action of the neurotransmitter non-competitively and acted as a skeletal muscle relaxant.
Intraperitoneal administration of the ethanolic extract of A. maurorum at a dose of 1.6 g/kg in conscious mice also generated mild sedation, decreased the locomotion activity, and induced skeletal muscle relaxation indicating a skeletal muscle neuromuscular junction effect (46).

Cardiac effects
The ethanolic extract of A. maurorum powdered roots at a dose of 1 g/kg in anaesthetized rats induced bradycardia without myocardial depression (46).

Antimicrobial effects
The antimicrobial and antifungal activities of the extracts of leaves and flowers have been shown against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella typhimurium, and Candida albicans using disc diffusion method (50). Nevertheless, in another study different concentrations of aqueous extract of A. maurorum had no antibacterial activity against both Gramnegative (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive (S. aureus and Streptococcus pyogenes) bacteria (48). A study revealed the antibacterial activity of methanol extract of A. maurorum at a concentration of 20 mg/mL against two strains of E. coli (51). However, in Neamah's study conducted using cup-plate agar diffusion method, no doses of aqueous extract had any antibacterial activity against P. aeruginosa, E. coli, S. aureus, and S. pyogenes (48). The methanol extract of the leaves of A. maurorum demonstrated growth inhibitory effects against Gram-negative bacteria except of Acinetobacter baumannii (52). Also, the methanol extract of A. maurorum indicated antifungal activities against Aspergillus flavus, Fusarium oxysporum, Alternaria alternate, Fusarium solani, Chaetomium, Bipolaris oryzae, and Mucor (53). The anti-Helicobacter activity of A. maurorum extracts was assessed using agar diffusion method and represented an effective activity (54).

Antioxidant effects
To assay the antioxidant effect of the aqueous extract of A. maurorum, the levels of malondialdehyde and total antioxidant capacity were measured compared to acetylsalicylic acid antioxidant activity. The results showed significantly reduced malondialdehyde levels and potent antioxidant activity (48). In another study, the antioxidant activity of the methanolic extract of A. maurorum was evaluated using free radical scavenging activity method and ferric reducing activity power method. A. maurorum revealed a significant antioxidant activity and was introduced as a natural antioxidant source (55). A. maurorum is a rich source of lupeol and has chemical constituents like flavonoids, coumarins, fatty acids, alkaloids, and sterols with antioxidant activities (56).

Cytotoxic effects
The effects of diethyl ether and petroleum ether extracts of A. maurorum have been investigated on human cancer cell lines by sulforhodamine B assay for their potential cytotoxicity. A. maurorum inhibited the viability of tumor cell lines in a concentration-dependent manner (56). The in vitro cytotoxicity assessment of A. maurorum was performed using methyl thiazolyl tetrazolium on the human acute myeloid leukemia cell line (HL-60). The cytotoxic effects of leaves and flowers extracts were dose and time-dependent where the inhibitory effect against the proliferation of HL-60 cells and the IC50 was 16.0 and 22.0 μg/mL, respectively (50).

Pharmacological properties of Tarangabin
Immunomodulatory Immunostimulatory effects of the total aqueous fraction of Tarangabin manna were proven in a laboratory study. The cell line applied in this study was Jurkat cells. Several carbohydrate macromolecules with different biological activities and structures were isolated from the watersoluble fraction of Tarangabin manna. While three of these macromolecules exhibited some degrees of cytotoxicity in a dose-dependent manner, the crude water-soluble fraction of Tarangabin manna had proliferative effects. This effect was due to smaller molecules in the manna antagonizing the cytotoxic effects of the macromolecules (14).

Hyperbilirubinemia in neonate
The effect of Tarangabin extract on hyperbilirubinemia in neonate was evaluated in a clinical study. Administration of the extract significantly reduced bilirubin levels after 48 hours (57).

Conclusion
The pharmacological properties of Alhagi have been confirmed by in vivo and in vitro studies. These include anti-inflammatory, anti-nociceptive, antipyretic, diuretic, muscle relaxant, hepatroprotective, gastrointestinal, antiulcerogenic, antidiarrheal, antimicrobial, antioxidant and cytotoxic effects. However, some properties of this plant have only been described in traditional medicine and thus need confirmation in modern experimental and clinical studies.
Tarangabin is a kind of manna obtained from A. maurorum. Some of its properties, as listed in the ITM literature, include laxative, detergent, purgative for yellow bile, cough reliever, thirst quencher, antipyretic, antiemetic and warming agent of the body. Due to their vast geographical distribution and therapeutic effects described in the ITM, well-designed pharmacological and clinical studies are warranted to harness the medicinal properties of Alhagi spp.