Improving health benefits with considering traditional and modern health benefits of Peganum harmala

Medicinal plants are potential source of natural products that play an important role in preventing different human diseases. P. harmala is used traditionally as emmenagogue and an abortifacient agent in the Middle East, North of Africa and West of China. It belongs to the family of Zygophyllaceae and it is a wild growing flowering plant. Its seeds are main medicinal part of the plant. The current searching was done by the keywords in main indexing systems including PubMed/MEDLINE, Scopus, and Institute for Scientific Information Web of Science as well as the search engine of Google Scholar. The keywords were wild rue, traditional medicine, Harman, health benefits, and pharmaceutical science. The most important uses of P. harmala in traditional pharmaceutical sciences are in cardiovascular, gasterointestinal, nervous, endocrine, neoplasm and tumors, pain relieving, organisms, diabetes, respiratory, disinfectant, anti-pyretic, skin and hair, rheumatism, arthritis and inflammation, and ulcers. Pharmacological effects of P. harmala are in cardiovascular system, nervous system, antimicrobial effects, antineoplasm, nervous system, endocrine, gastrointestinal effects, osteocytes, endocrine and respiratory system. Phenolic compounds are the main reason of antioxidant capacity. Due to its pharmacological activities, P. harmala is a high potential medicinal herb and the suggestion is to increases by doing research in efficacy and safety.


Background
Wild rue (P. harmala) occurrence and classification Medicinal plants have been used for many years as remedies for both human and animal ailments [1][2][3][4][5]. Aromatic and medicinal plants as the key source of complementary and alternative medicine have been recently bring many hopes in alleviating of symptomatology and curing associated with so many diseases [6][7][8][9]. P. harmala, commonly called Esfand, Wild rue, Syrian rue, African rue, is a plant of the family Nitrariaceae [10]. This plant is native from the eastern Iranian region west to India [11]. P. harmala is a traditional medicinal plant which is used for many purposes, the aim of this review is to survey on some health benefits of this traditional medicinal plant. Scientific classification of harmal is shown in Table 1.
It is considered as one of the most important medicinal plant in Iranian traditional medicine, which has various benefits such as anti infection, anti inflammation, anti tumor and anti parasite. This important multipurpose medicinal plant has many phytochemical features, and contains a number of active alkaloids, particularly beta-carbolines such as harmalol, harmaline, and harmine. The plant is perennial which can grow to approximate 0.8 m tall, and the root can reach a depth of up to 6 m [12]. This perennial herbaceous plant, branched into 5-13 stems, the leaves are palmatisected into 3-5 linear lobes which are 3-6 cms long and 1.5-3.0 mm wide. Flowers arise by 1-3 on apexes of branches which bear whitish-yellow petals in color, and the fruits are globular capsule with 3 chambers, 0.9-1.3 cm in diameter and containing 35-45 angular blackish seeds. Various parts of P. harmala (a) Leaves and Flowers, (b) Fruit, (c) Seeds are shown in Fig. 1.

Medicinal Uses and Potential Health Benefits in Traditional Medicine and Modern Medicine Industry
The most important therapeutic effects of P. harmala are included candidiasis, anti-inflammatory, anticholinesterase, anti-bacterial, anti-microbial, antitumor, angiogensis, antiparasitic, antioxidant and cytotoxicity activities, prevent of hepatoprotective, abortifacient potential, and pesticide effects [41,42]. The most important traditional uses of P. harmala are cardiovascular, gasterointestinal, nervous, endocrine, neoplasm and tumors, pain relieving, diabetes, respiratory diseases, disinfectant, anti-pyretic, skin and hair, ulcers, rheumatism, arthritis and inflammation [43,44]. Wang et al. [44] reported P. harmala as a traditional Chinese and Uygur medicine to treat cancer. They have found Osteoarthritis (OA) as a promising leading compound for the development of an anti-lung cancer drug. Mamedov et al. [39] found that Syrian rue used for centuries in traditional medicine and shows a potential treatment of anxiety and depression. Abolhassanzadeh et al. [45] demonstrated that topical application of Peganum oil for knee osteoarthritis is an effective pain-reducing treatment. Shatarat et al. [46] indicated that the root extract of P. harmala possesses antispasmodic activity and justifies its use traditionally in alleviating gastrointestinal disorders. In most parts of Iran, dried capsules mixed with other ingredients are burnt to produce scented smoke that is used to purify the air and the mind and it is also used as a charm against the evil eye [47]. The most popular activities of P. harmala in traditional Iranian medicines are analgesic, intoxicating, abortive, disinfectant, anthelmintic, insect repellant, carminative and its beneficial effect in colic disorder [48]. Shahverdi et al. [49] described that P. harmala seeds , smoke is traditionally used in Iran as both a disinfectant agent and for all kinds of rituals against evil eye and bad luck. They have reported the antimicrobial activity of dichloromethane condensate prepared from P. harmala seeds (Esphand). Lamchouri et al. [50] extracted four alkaloids namely, harmalicidine, harmine, peganine (vasicine) and vasicinone and discovered that P. harmala alkaloid inhibited the growth of four tumor cell lines, and proliferation of Jurkat cells with varying potencies, harmine was the most potent in inhibiting cell growth, and vasicinone was the most active as anti-proliferation substance. The analgesic, anti-inflammatory [51], disinfectant [52], growth promoting [53], cholesterol lowering and hepato protective effects [54] have been reported. Eini et al. [55] concluded that methanolic extract of P. harmala could be effectively used in rat to optimize serum lipid profile. Rahimi-Moghaddam et al. [56] showed P. harmala extract showed significant in vitro and in vivo antileishmanial activities. Ataee et al. [25] discovered that drinking a glass of boiled Esfand seeds may reduce blood sugar, and complaining of nausea, general weakness, abdominal pain, dizziness and several vomiting episodes. High dose of Esfand can reduce spermatogenesis in mice [57]. Aboualigalehdari et al. [58] revealed that P. harmala as antibiofilm herbal medicine for C. albicans, they have concluded that it seems to be necessary to investigate traditional herbs against pathogenic microorganisms. It has been reported that the seeds contain a red pigment used for coloring wool and carpets and also use as a spice as important aphrodisiac in traditional medicine [39]. Ismahane et al. [59] indicated that P. harmala essential oils have an ovicidal, adulticidal and larvicidal effects against Ectomyelois ceratoniae and it may be used as an alternative of chemical pesticides. Rezaei et al. [60] concluded that aqueous extract of P. harmala could prevent symptoms and reduced oxidative stress markers in rats with Parkinson induced by 6hydroxydopamine. Singh et al. [61] showed that the ethanolic extract of P. harmala is as effective as metformin in reducing the blood glucose levels of normoglycemic and streptozotocin-induced diabetic rats. Darabpour et al. [62] noted that P. harmala can be assigned as a source of antibacterial compounds for treatment of infections caused by multi-drug resistant (MDR) bacterial pathogens. Chegeni et al. [63] noted that ethanolic extracts of P. harmala could be considered a new natural compound against the Acanthamoeba trophozoites and cysts. Tanweer et al. [64] discovered that methanolic extract of P. harmala could be effectively used in broilers to optimize serum lipid profile to decrease feeding cost and to maximize gross return. Shah and Khan [65] reported that P. harmala seeds are antiseptic, and used is the treatment of asthma, paralysis, gastrointestinal, urinary problems, epilepsy and also menstrual disorders. Khademalhosseini et al. [66] confirmed that ethanol extract of P. harmala has appropriate effect on the microorganisms and the healing of skin wounds in comparison with Betadine. Mohsenipour and Hassanshahian [67] suggested that P. harmala extracts applied as antimicrobial agents testing bacteria particularly in biofilm forms. Shirani-Boroujeni et al. [68] noted that the application of P. harmala seed can be useful in reducing urinary symptoms in patients with benign prostatic hyperplasia (BPH). Berrougui et al. [69] suggested that P. harmala compounds could be a major source of compounds that inhibit low density lipoprotein (LDL) oxidative modification induced by copper. The seeds of P. harmala have been widely used for the treatment of nervous, cardiovascular, gastrointestinal, respiratory and endocrine diseases and some human aliments [70,71]. Harmaline has multiple pharmacological impacts such as antileishmanial, antimicrobial, antiplatelet, antiplasmodial, antitumoral, hypothermic and vasorelaxant activity [72][73][74]. P. harmala alkaloids are capable of disrupting the permeability of the membranes of red blood cells of ruminants [75]. Pharmaceutical benefits of P. harmala are shown in

Benefits Mechanisms and impacts Reference
Anti-cancer effects a. P. harmala alkaloids extract may be helpful in providing of new cytotoxic agents against chemo-resistant cancer cells. b. P. harmala extracts significantly decreased the growth rate and cell survival of cancer cell lines, and the extract may induce cell death regarding natural cell growth rate. c. P. harmala , s seed extract induced cell death and decreased the cell growth in the breast cancer cell line; they have suggested that herb might be useful for preventing the development of tumors. d. B-9-3, a semi-synthetic derivative of β-carboline, has an anti-proliferative effect against tumor cells via induction of apoptosis and inhibition of cell migration.
[ [76][77][78] Anti-viral effects a. P. harmala extract contains an anti-HSV-1 (herpes simplex virus type 1) substance b. P. harmala extract and its total alkaloids showed the inhibitory effect against influenza A virus replication. c. Its aerial parts are an effective traditional folk medicine for the treatment of cough with potent antitussive, expectorant and bronchodilating activities. d. Antiviral activity of the extract against influenza virus is most probably associated with inhibiting viral RNA transcription. e. P. harmala MeOH seed extract showed anti-herpes simplex virus type 2 (HSV-2) activity.
Harmine was identified as antiviral active compound.
[ [79][80][81] Anti-inflammatory effects a. Harmine reduced inflammatory cytokines. b. Harmine averted inflammatory damage in the lung of LPS (lipopolysaccharides)challenged mouse. c. The alkaloids, steroids, flavonoids in ethyl acetate extract of P. harmala seeds could be attributed for the anti-inflammatory activities. d. Methanol extracts of P. harmala has the highest anti-inflammatory activity. [24,82,83] Anti-bacterial effects a. Methanol and ethanol extracts of it seems may have antibacterial activity. b. P. harmala extracts possesses strong antibacterial activity against methicillin and cefixime resistant S. aureus strains. c. Styrene and some other components with potential antimicrobial and immunomodulatory activities were formed in the smoke. d. Flavonoids extract of P. harmala may be useful to treat uropathogenic bacteria. e. Total alkaloidal extract of P. harmala seeds exhibited inhibitory impact in vitro against some phytopathogenic bacteria.
[ [84][85][86][87][88][89][90] Anti-proliferative effects a. Some triterpenoids isolated from P. harmala exhibited potent anti-proliferative activities. [91] Antioxidant effects a. The methanol extract of P. harmala demonstrated the highest antioxidant activity and good antiviral activity against human cytomegalovirus (HCMV). b. The isolated protein from P. harmala seeds possessed strong antioxidant activity. [92,93] Antihyperglycemic effects a. Treatment with 4-HPA (4-hydroxypipecolic acid) stimulated both glucose uptake and glucose transporter-4 (GLUT4) translocation from intracellular to cell surface in skeletal muscle cells in a concentration-dependent manner, which might be leading to antihyperglycemic effect. [94] Antidepressant activity a. The seed extract can correct the depression and the normal state of the treated animals. [95,96] Herbicidal effects a. Harmaline is a potential herbicide by its inhibition of PSII activity, b. Hamraline inhibits multiple sites in electron transfer chain in PSII. [97][98][99] Anti-tuberculosis effects a. The ethanolic extracts of P. harmala has anti-tuberculosis effects comparable to isoniazid and rifampin and can be good candidates for novel and safe natural products against tuberculosis. [100,101] Anti-diabetes effects a. P. harmala seed extract has good antidiabetic activity in streptozotocin-induced diabetic rats. b. It has benefit procedures in controlling blood glucose and harmful results induced in pancreas and liver as a natural antidiabetic drug. C. The harmine in the P. harmala seed extract exerts its anti-apoptotic effects by decreasing caspase-3 and may alleviate damages to the kidney histology in diabetic rats compared to the control group.
[ [102][103][104][105][106][107] Antileishmanial activity a. Leishmaniasis is a major public health problem worldwide. P. haramala has natural components with anti-Leishmania activity. [108,109] Alzheimer a. The alkaloid may be valuable source for lead compounds discovery and drugs development for treatment of memory impairment such as Alzheimer , s disease. [110,111] Insecticidal effects a. The ethanol extract of P. harmala had a good insecticidal activity on P. xylostella. b. The methanol extracts of P. harmala has insecticidal impacts on the larvae and adults of stored grain pest. [112][113][114] antioxidant effect, cerebroprotective effect, cancer effect, hepatoprotective effect, hypoglycemic effect, antibacterial effect, pesticide effect, antitumor effect, antinociceptive effects, haemosporidian infections effect and different unknown beneficial properties. This review article suggests the important potential of P. harmala to be employed in both new western and eastern therapeutic drugs. This review article emphasizes on the need of widespread researches and studies for covering the supplementary information and knowledge on the importance of medicinal crops. This review also suggests more evidences for other researchers to use P. harmala as an ancient efficacious natural drug.

Funding
This work was supported by the National Key R&D Program of China (Research grant 2019YFA0904700).
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The authors consent for the publication of this review.

Competing interests
The authors declare that they have no potential conflicts of interest.