Bangladesh Journal of Pharmacology Mini-review Phytochemistry, pharmacology and toxicology of Peganum harmala BJP Introduction Peganum harmala L., belonging to the family Zygophy- llaceae, is a highly branched and perennial herbaceous plant with the special smell. The whole plant is 20 to 70 cm tall with short creeping roots. Its stem is scattered from the base, supine in the lower parts and oblique in the upper parts. The leaves are oval, born singly, and finely divided into long narrow segments 1 to 3.5 cm long and 1.5 to 3 mm width. The flowers, produced during summer, are pale yellow or white. Each bloom has five oblong elliptic petals as well as five narrow sepals of slightly longer length. Developed from the flower, the fruit of P. harmala stands erect on the stalk and is three-valve seed capsule with a diameter of 6 to 10 mm. Over 50 small black-brown triangular seeds, about 1.5 to 2 mm long, are implicit in one capsule matured in July or August (Asgarpanah and Ramezan- loo, 2012; Niroumand et al., 2015). P. harmala spontaneously generally grows in arid and semiarid regions, steppe areas, and sandy soils. The plant originated from central Asia but now is widely cultivated and distributed in large numbers of areas, including the Middle East (known as “Espand” or “Wild Syrian rue”), China (known as “Luo Tuo Peng”), north of Africa (known as “Harmel”), Mediterranean, Australia and America (known as “African rue,” “Mexican rue” or “Turkish rue”) (Asgarpanah and Ramezanloo, 2012). P. harmala is claimed as a holy plant in many beliefs. In areas of West Asia and Xinjiang (China), its dry plants are suspended in homes or cars and used as the amulet to prevent jealous forces or exorcise evil spirits. Shaman priests of Pakistan Hunzas believe that they can communicate with God by inhaling the smoke of P. harmala. In Iran, Afghanistan, Azerbaijan, and some Middle East countries, people pray for relief from “evil eyes” in the smoke produced by burning the dried P. harmala mixed with other ingredients. In addition, burning seeds of P. harmala is a common benediction in Persian weddings. In some countries of West Asia, the extracts of its fruits and seeds can be used as red and yellow dyes to stain Abstract This systematic review focuses on the phytochemical, pharmacological and toxicological aspects of P. harmala, which aims to construct the scientific foundations of P. harmala-based drugs. Until now, over 390 secondary metabolites, including alkaloids, flavonoids, triterpenoids, phenolic acids, anthraquinones, fatty acids, and essential oils, had been identified from different parts of P. harmala. The plant and its important bioactive compounds demonstrated various pharmacological activities, mainly including anti- microbes, anti-cancer, anti-atherogenesis, anti-diabetes, anti-inflammation, neuropsychological, analgesic, hepatoprotective, bronchodilating, gastropro- tective, diuretic, and hypothermic effects. However, excessive use of high doses of P. harmala extract could lead to serious hepatic, nephritic, and neuro- pathic toxicities. Current evidence validates the claimed effectiveness of traditional uses of P. harmala for many symptoms. Article Info Received: 23 August 2022 Accepted: 11 September 2022 Available Online: 19 November 2022 DOI: 10.3329/bjp.v17i4.61326 Cite this article: Liu C, Gao J, Liang Y. Phytochemis- try, pharmacology and toxicology of Peganum harmala. Bangladesh J Pharmacol. 2022; 17: 124-140. Phytochemistry, pharmacology and toxicology of Peganum harmala Chengling Liu1, Jiayu Gao1 and Ying Liang2 1School of Chemical Engineering and Pharmaceutics, Henan University of Science and Technology, Luoyang, China; 2Institute of Mental Health, Peking University, Beijing, China. This work is licensed under a Creative Commons Attribution 4.0 License. You are free to copy, distribute and perform the work. You must attribute the work in the manner specified by the author or licensor. A Journal of the Bangladesh Pharmacological Society (BDPS) Bangladesh J Pharmacol 2022; 17: 124-140 Journal homepage: www.banglajol.info; www.bdpsjournal.org Abstracted/indexed in Academic Search Complete, Agroforestry Abstracts, Asia Journals Online, Bangladesh Journals Online, Biological Abstracts, BIOSIS Previews, CAB Abstracts, Current Abstracts, Directory of Open Access Journals, EMBASE/Excerpta Medica, Global Health, Google Scholar, HINARI (WHO), International Pharmaceutical Abstracts, Open J-gate, Science Citation Index Expanded, SCOPUS and Social Sciences Citation Index ISSN: 1991-0088 carpets and wool as well. More importantly, various parts of P. harmala, including seeds, fruits, roots, and barks, have been used as herbs in many traditional medicine systems around the world for centuries. Accumulated evidence from laboratory research and clinical trials could construct the scientific foundations of its medicinal application stemming from those traditional uses, and even inspire the further development of P. harmala-based drugs. Therefore, this study aims to systematically review the traditional medicinal uses, research outcomes of phytochemistry and pharmacological aspects of P. harmala. Views regar- ding the toxicology and safety of this plant are discuss- ed as well. Materials and Methods The authors searched several electronic databases, including PubMed, Scopus, Web of Science, Google- Scholar, and Science Direct up to the date on 31 July 2022. The following keywords were used as filters and were searched both alone and as combinations: “Peganum harmala L.”, “Espand”, “Wild rue”, “Syrian rue”, “Harmel”, “African rue”, “Mexican rue” and “Turkish rue”. Searching was limited to articles in English only. Two reviewers extracted papers indepen- dently. The duplication articles were firstly deleted. The papers unrelated to phytochemistry and medicinal properties of P. harmala were then excluded. Patents, abstracts, case reports, and abstracts in symposium and congress were excluded as they didn’t contain sufficient information for evaluation and comparison with other studies. The review articles were excluded as they did not contain the original data. Based on the criteria above, 187 articles were eligible to be evaluated. Uses in Traditional Medicines For centuries, P. harmala is used as a traditional herbal medicine to treat various ailments in different regions around the world. In Persian, it is used as an analgesic to relieve heart or colic pain in folk medicine (Abbas et al., 2021; Diba et al., 2011). The smoke from its seeds is traditionally used as a disinfectant agent in Iran (Darab- pour et al., 2011) and as an antimicrobial appro-ach in India and North Africa (Iranshahy et al., 2019). Seeds and aerial parts of P. harmala are used in Algeria as anti- inflammatory remedies (Bensalem et al., 2014). In tradi- tional Chinese medicine, P. harmala seeds are an impor- tant constituent of the related herbal formulae used in the treatment of cancer, cough, diabetes, asthma, rheu- matism, jaundice, hypertension, colic, and lumbago (Wu et al., 2020). Aerial parts of P. harmala is used to treat amnesia in Uighur medicine (Deng et al., 2019). In Iran and Turkey, seeds, fruits, roots, and bark of P. harmala were traditionally used to treat coughs, rheu- matism, hypertension, diabetes, and asthma as well (Moradi et al., 2017). The P. harmala seed was one of the most frequently used natural products in the traditional treatment of hypertension and diabetes in south-eastern Morocco (Tahraoui et al., 2007). Generally, the seed is the most frequently used part of P. harmala for medicinal purpose. However, it should be applied in different forms for different conditions. The decoction is commonly used to control the symptoms involved in psychosis, kidney stones, laryngitis, rheumatism, jaundice, sciatica, and sexual impotency, while the powder and smoke can treat asthma, boils, pimples, and alimentary system issues. In addition, numbness, paralysis, joint pain, back pain, and coxalgia could be relieved using the seed poultice, but tooth- ache and mosquitos bites need to be treated by the incense (Elansary et al., 2020; Sadaf et al., 2021). Phytochemistry The bioactive secondary metabolites are the basic functional units of herbal medicines. To date, multiple classes of phytochemicals, mainly including alkaloids, flavonoids, triterpenoids, phenolic acids, anthraqui- nones, and fatty acids, have been isolated directly from different parts of P. harmala (Table SI). Generally, alka- loid compounds are the most abundant constituents identified. In addition, a chemometric analysis indica- ted the significant differences in the metabolites within different parts of P. harmala. Compared to the other parts (stems, roots, flowers, and leaves), the seeds con- tained relatively higher amounts of bioactive alkaloids, mainly including harmaline, harmine, and vasicine. Moreover, the dominant amino acid proline and lysine, and sucrose contents were specified in the root parts (Li et al., 2018b). Among the numerous secondary metabolites of P. harmala, harmine, harmaline, and vasicine are the representative compounds responsible for its various pharmacological effects. Harmine (7-methoxy-1-methyl- 9H-pyrido[3,4-b]indole, C13H12ON2) is a tricyclic β- carboline alkaloid widely spread throughout the animal, marine creature, plant, and insect species. It has fully aromatic α-β-carboline structures and can also be isolated from Banisteria caapi (Malpighaceae) (Huang et al., 2022), Tribulus terrestris (Zygophyllaceae) (Nikam et al., 2009), Passiflora spp. (Passifloraceae) (Boeira et al., 2002). A wide range of its pharmacological properties have been reported as anti-cancer (Li et al., 2017), antimicrobial (Nenaah, 2010), anti-inflammatory (Niu et al., 2019), anti-oxidant (Ali et al., 2022), neuroprotective (Deng et al., 2019), antidiabetic (Waki et al., 2007), and vasorelaxant (Berrougui et al., 2006b) and central excitation (Herraiz and Guillén., 2018). Harmine can inhibit the growth of various types of cancer cells, such as gastric cancer (Li et al., 2017), lung cancer (Shen et Bangladesh J Pharmacol 2022; 17: 124-140 125 al., 2018), melanoma (Hamsa and Kuttan, 2011a & b), colon cancer (Liu et al., 2016), leukemia (Wang et al., 2015b) and cervical cancer cells (Ayoob et al., 2017). The anti-cancer mechanisms of harmine may contribute to the induced apoptotic and autophagic death of cancer cells through the reduced expression of both p-Akt/Akt and p-mTOR/mTOR and the enhanced phosphoryla- tion of adenosine monophosphate-activated protein kinase (Li et al., 2017; Liu et al., 2016). Harmine exhibited its anti-inflammatory effects via the inhibition of the TLR4-NF-κB and NLRP3 inflammasome pathway (Niu et al., 2019). In addition, some bioactive molecules involved in the inflammatory process, including myelo- peroxidase (Bensalem et al., 2014), TNF-α, IL-1β and IL- 6 (Liu et al., 2017b), are considered to be targets of harmine. Regarding the neuropsychological mecha- nism, harmine can stimulate the central nervous system by inhibiting the metabolism of neurotransmitters, such as acetylcholine, 5-hydroxytryptamine, γ-aminobutyric acid, 5-hydroxy-indole-3-acetic acid, glutamic acid and monoamine oxidase (MAO-A), or by direct interaction with acetyl-cholinesterase (AChE) and butyrylcholines- terase (BChE) receptors (Deng et al., 2019; Herraiz and Guillén., 2018). In addition, harmine reduces cardiac hypertrophy and atherosclerosis through the regulation of NF-κB signaling pathway and endothelial activation (Huang et al., 2021; Yang et al., 2021). Harmaline (7-methoxy-1-methyl-4,9-dihydro-3H-pyrido [3,4-b]indole, C13H14N2O) is a β-carboline alkaloid which can also be isolated from Grewia bicolor (Malva- ceae) (Jaspers et al., 1986), Tribulus terrestis (Zygophylla- ceae) (Nikam et al., 2009) and Passiflora incarna- ta (Passifloraceae) (Lamounier et al., 2015). It can be transformed into harmine after oral administration through the dehydrogenation and oxidation metabo- lism by heme peroxidases (Wang et al., 2022), thus exerting multiple pharmacological effects including antimicrobial (Di Giorgio et al., 2004), anti-cancer (Rashidi et al., 2022), antiplatelet (Im et al., 2009), hypo- thermic (Wu et al., 2009) and vasorelaxant activity (Berrougui et al., 2006b). Due to its low toxicity towards human cells, harmaline is a suitable antileishmanial alkaloid as compared with its analogs harmine (Di Giorgio et al., 2004). It is also reported to exhibit inhibi- tory effects on breast and gastric cancer cells (Rashidi et al., 2022; Wang et al., 2015c). The underlying mecha- nisms may include the induced cell cycle arrest and apoptosis through inhibition of mTOR and regulation of p27 and Fas/ FasL (Wang et al., 2015c; Zhang et al., 2021). Moreover, harmaline behaves as tight-binding inhibitor of MAO-A, thus functioning as an antidepre- ssant agent (Herraiz and Guillén., 2018). Vasorelaxant activities of harmaline are attributed to the enhanced NO release and the voltage-dependent Ca2+ channel blockage (Berrougui et al., 2006b; Shi et al., 2000). Vasicine ((3S)-1,2,3,9-tetra-hydropyrrolo[2,1-b] quinazolin-3-ol, C11H12N2O) is a heterocyclic alkaloid which can also be obtained from Adhatoda vasica (Acanthaceae). It has been used to treat respiratory-tract ailments and Alzheimer’s disease (Bhambhani et al., 2012; Liu et al., 2019). Vasicine possesses diverse pharmacological actions including antimicrobial, anti- oxidant, bronchodilator, and anti-allergic activity (Liu Figure 1: The reported anti-cancer mechanisms of P. harmala and its alkaloids 126 Bangladesh J Pharmacol 2022; 17: 124-140 et al., 2019). Vasicine can ameliorate amnesia by inhibiting AChE, activating choline acetyltransferase, regulating neurotransmitters, and reducing oxidative stress (Deng et al., 2019). In addi-tion, it also presents the bronchodilating effects and gastroprotective effects by inhibiting the H+ K+- ATPase activity in animal models (Liu et al., 2015a; Singh et al., 2013). Besides those, as an aromatic plant, P. harmala contains large amounts of essential oils reported by several stu- dies in the literature. Generally, the main components in essential oil are alcanfor, capillin, eugenol, α-pinene, monoterpene hydrocarbons, and propylic acid (Afzal et al., 2014; Apostolico et al., 2016; Faridi et al., 2013; Dastagir et al., 2014; Tahrouch et al., 1998). However, as shown in Table SII, the contents of essential oils are quite varied from those reported by different studies. It suggested that different factors, such as geographical features, climatic conditions, cultivation means, and extraction, and detection methods, could affect the oil composition. Pharmacology As an ethnomedicinal plant used worldwide in numer- ous clinical conditions, many relative pharmacological effects of P. harmala and its secondary metabolites have been evaluated using models of in vitro, in vivo, or clinical trials and reported in the literature. Herein, these effects, mainly including antimicrobial, anti- cancer, antiatherogenic, anti-diabetes, anti-inflamma- tion, and neuropsychological effects, and their under- lying mechanisms were comprehensively reviewed and elucidated as follows: Antimicrobial activities As shown in Table I, the extracts of P. harmala and its constituents have presented the inhibitory activities against various microbes, including bacteria, parasites, fungi, and virus. Generally, the extract from different parts of P. harmala, particularly seeds and roots, exhibi- ted the broad-spectrum antibacterial effects. Most importantly, it could effectively control the growth of several drug-resistant strains, such as MRSA, MDR P. aeruginosa and ESBL-producing E. coli bacteria (Darab- pour et al., 2011; Khadraoui et al., 2022; Saeidi et al., 2015). The β-carboline alkaloids harmane, harmine, harmaline and harmalol were found to be the main bioactive constituents contributing to its antibacterial effects (Nenaah, 2010). The alcoholic extract of P. harmala presented the highest fungicidal effect with MFC at 0.625 mg/mL against Candida glabrata from clinical isolates of Candida species (Diba et al., 2011). In addition, a protein purified from P. harmala displayed the major antifungal activity to inhibit the mycelia growth of Alternaria alternate, Peni- cillium degitatum, Rhizopus stuolonifer, and Magnaporthe grisea. It also presented a maximum inhibition of 69.1% against HIV-1 reverse transcriptase (Ma et al., 2013). The methanol extract of P. harmala could inhibit the replication of the herpes simplex virus type 2 (HSV-2) over 5 hours after virus penetration. This action was exerted through the block of the specific recognition and binding between the virus envelope and the target cells (Benzekri et al., 2018). Oral administration of the P. harmala extract could effectively reduce the lung virus titer and thus increase the survival rate of BALB/c mice infected with mouse-adapted Influenza A virus (Mora- di et al., 2017a). This effect was associated with the inhibition of viral RNA transcription (Moradi et al., 2017b). The anti-acanthamoeba activity of P. harmala was found to be correlated with the enhanced trans- criptional expression of autophagy mRNA and cyst formation under the extract stress (Boonhok et al., 2021). Compared with placebo and control animals, a signifi- cant decrease in the lesion size and parasite count was observed in Leishmania major infected mice under treat- ment of the P. harmala extract (Khoshzaban et al., 2014; Rahimi-Moghaddam et al., 2011). Besides those, the seed smoke of P. harmala could effectively reduce a load of fungi (up to 94.7%) and bacterial (up to 71.4%) bioaerosols in a closed space (60 m3), which provided the scientific evidence for its traditional uses as a disinfectant in the Middle East (Filban et al., 2022). Anti-cancer activities Clinically, P. harmala is a critical ingredient of the herbal formula prescribed for the treatment of alimentary tract cancers in northwest China (Wang et al., 2016a). Theo- retically, numerous studies have reported in the litera- ture that the extracts of P. harmala and its compounds, especially β-carboline alkaloids, demonstrated signifi- cant cytotoxic activities against a broad of cancer cell lines in vitro (Table SIII). As shown in Figure 1, the underlying mechanisms of those anti-cancer activities are composed of a complica- ted network that regulates the signaling associated with the progress of the cell cycle, autophagic and apoptotic death of cancer cells. The β-carboline alkaloids, inclu- ding harmine, harmaline, harmalacidine and pegahar- mine D, are the representative compounds reported to study the pharmacological mechanisms of anti-cancer effects of P. harmala. Generally, its total β-carboline alkaloids could reduce the protein and mRNAs expre- ssion of FAK, PI3K, AKT, mTOR in either in vitro or in vivo models of gastric cancer, thus initiating the apoptosis via the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin (PI3K/ Akt/mTOR) pathway (Fan et al., 2021). Concretely, harmine enhanced the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) to stimulate the autophagy through phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapa- mycin pathway. Moreover, it reduced the expression of Bangladesh J Pharmacol 2022; 17: 124-140 127 Table I Antimicrobial activities of Peganum harmala Extracts/constituents Types Microbes Activities (MIC) References Methanol extract Parasite Leishmania tropica 16.4-18.6 μg/mL (IC50) Madah et al., 2020 Acanthamoeba castellanii 100% trophozoites killed at 2 mg/mL Shohaib et al., 2016 Ethanol extract Acanthamoeba triangularis 225.1 μg/mL (IC50) Boonhok et al., 2021 Water/ethyl acetate/ ethanol extract Leishmania major 59.4 μg/mL (IC50) Rahimi-Moghaddam et al., 2011 Water extract 40 μg/mL (IC50) Yousefi et al., 2009 Total alkaloid Leishmania tropica 5.0-9.2 μg/mL (IC50) Madah et al., 2020 Harmine Plasmodium falciparum 8.0 μg/mL (IC50) Astulla et al., 2008 Harmaline 25.1 μg/mL (IC50) Methanol extract Bacteria Bacillus subtilis 50 μg/mL Hadadi et al., 2020 Staphylococcus aureus 1.6 μg/mL Rathayibacter toxicus 12.5 μg/mL Escherichia coli 1.6 μg/mL Pseudomonas aeruginosa 25.0 μg/mL Pseudomonas syringae 100 μg/mL Pseudomonas viridifava 25 μg/mL Xanthomonas campestris 25 μg/mL Methicillin-resistant Staphylo- coccus aureus (MRSA) 0.625 mg/mL Darabpour et al., 2011 Bacillus anthracis 1.25-2.5 mg/mL Escherichia coli 0.625 mg/mL Salmonella typhi 0.625 mg/mL Staphylococcus aureus 0.5 mg/mL Abderrahim et al., 2019 Escherichia coli 1.0 mg/mL Pseudomonas aeruginosa 6.0 mg/mL Escherichia coli 2.5 mg/mL Hayet et al., 2010 Klebsiella pneumoniae 5 mg/mL Enterobacter cloacae 5 mg/mL Serratia marcescens 5 mg/mL Acinetobacter baumannii 5 mg/mL Bacillus subtilus 2.5 mg/mL Staphylococcus aureus 1.25 mg/mL MRSA 0.512 mg/mL Streptococcus pyogenes 0.512 mg/mL Streptococcus agalactiae 0.256 mg/mL Enterococcus faecalis 1.25 mg/mL Enterococcus faecium 2.5 mg/mL Corynebacterium spp 2.5 mg/mL Chloroform extract Bacillus subtilis 50 μg/mL Hadadi et al., 2020 Staphylococcus aureus 50 μg/mL Rathayibacter toxicus 50 μg/mL Escherichia coli 50 μg/mL Pseudomonas aeruginosa 1.56 μg/mL Pseudomonas viridifava 12.5 μg/mL Xanthomonas campestris 12.5 μg/mL n-Butanol extract Multidrug‑resistant (MDR) Pseudomonas aeruginosa 250 μg/mL Khadraoui et al., 2022 Escherichia coli 5 mg/mL Hayet et al., 2010 128 Bangladesh J Pharmacol 2022; 17: 124-140 Table I Antimicrobial activities of Peganum harmala (Cont.) Extracts/ constituents Types Microbes Activities (MIC) References n-Butanol extract Bacteria Klebsiella pneumoniae 5 mg/mL Hayet et al., 2010 Enterobacter cloacae 5 mg/mL Serratia marcescens 5 mg/mL Acinetobacter baumannii 5 mg/mL Bacillus subtilus 1.25 mg/mL Staphylococcus aureus 5 mg/mL MRSA 5 mg/mL Streptococcus pyogenes 0.512 mg/mL Streptococcus agalactiae 1.25 mg/mL Enterococcus faecalis 5 mg/mL Enterococcus faecium 5 mg/mL Corynebacterium spp 5 mg/mL Ethyl acetate extract Escherichia coli 5 mg/mL Hayet et al., 2010 Klebsiella pneumoniae 5 mg/mL Enterobacter cloacae 5 mg/mL Serratia marcescens 5 mg/mL Acinetobacter baumannii 5 mg/mL Bacillus subtilus 1.25 mg/mL Staphylococcus aureus 5 mg/mL MRSA 5 mg/mL Streptococcus pyogenes 5 mg/mL Streptococcus agalactiae 1.25 mg/mL Enterococcus faecalis 5 mg/mL Enterococcus faecium 1.25 mg/mL Corynebacterium spp 5 mg/mL Chloroform extract Escherichia coli 5 mg/mL Klebsiella pneumoniae 5 mg/mL Enterobacter cloacae 5 mg/mL Serratia marcescens 5 mg/mL Acinetobacter baumannii 5 mg/mL Bacillus subtilus 0.256 mg/mL Staphylococcus aureus 1.25 mg/mL MRSA 0.512 mg/mL Streptococcus pyogenes 0.512 mg/mL Streptococcus agalactiae 0.256 mg/mL Enterococcus faecalis 2 mg/mL Enterococcus faecium 0.512 mg/mL Corynebacterium spp 0.256 mg/mL Alcoholic extract The extended-spectrum beta- lactamase-producing Escherichia coli 2.5 mg/mL Saeidi et al., 2015 Staphylococcus aureus 500 μg/mL Jeppesen et al., 2012 Bacillus subtilis 500 μg/mL Escherichia coli 500 μg/mL Acinetobacter sp. 0.19 mg/mL Arshad et al., 2008 Clostridium sp. 0.75 mg/mL Escherichia coli 0.38-1.55 mg/mL Pasteurella multocida 0.75 mg/mL Staphylococci sp. 0.38 mg/mL Streptococci sp. 0.75 mg/mL Proteus sp. 1.55 mg/mL Salmonella sp. 0.38-0.75 mg/mL Bangladesh J Pharmacol 2022; 17: 124-140 129 Table I Antimicrobial activities of Peganum harmala (Cont.) Extracts/ constituents Types Microbes Activities (MIC) References Total alka- loid Bacteria Staphylococcus aureus 125 μg/mL Iranshahy et al., 2019 Escherichia coli 500 μg/mL Pseudomonas aeruginosa 1.5 mg/mL Micrococcus luteus 31.25 μg/mL Harmane Escherichia coli 0.5 mg/mL Nenaah, 2010 Proteus vulgaris 0.666 mg/mL Staphyllococcus aureus 1.0 mg/mL Bacillus subitilis 0.5 mg/mL Asperagillus niger 0.75 mg/mL Arshad et al., 2008 Acinetobacter sp. 9 μg/mL Clostridium sp. 35 μg/mL Escherichia coli 20-155 μg/mL Pasteurella multocida 75 μg/mL Staphylococci sp. 18 μg/mL Harmane Parasite Streptococci sp. 155 μg/mL Proteus sp. 310 μg/mL Salmonella sp. 35-155 μg/mL Harmine Parasite Escherichia coli 0.75 mg/mL Nenaah, 2010 Proteus vulgaris 0.833 mg/mL Staphyllococcus aureus 1.0 mg/mL Bacillus subitilis 0.75 mg/mL Asperagillus niger 0.666 mg/mL Acinetobacter sp. 155 μg/mL Arshad et al., 2008 Clostridium sp. 625 μg/mL Escherichia coli 310-1250 μg/mL Pasteurella multocida 625 μg/mL Staphylococci sp. 310 μg/mL Streptococci sp. 625 μg/mL Proteus sp. 625 μg/mL Salmonella sp. 155-1250 μg/mL Harmaline Parasite Escherichia coli 1.0 mg/mL Nenaah, 2010 Proteus vulgaris 0.75 mg/mL Staphyllococcus aureus 0.75 mg/mL Bacillus subitilis 0.833 mg/mL Asperagillus niger 1.0 mg/mL Acinetobacter sp. 18 μg/mL Arshad et al., 2008 Escherichia coli 1.0 mg/mL Nenaah, 2010 Proteus vulgaris 0.75 mg/mL Staphyllococcus aureus 0.75 mg/mL Bacillus subitilis 0.833 mg/mL Asperagillus niger 1.0 mg/mL Acinetobacter sp. 18 μg/mL Arshad et al., 2008 Clostridium sp. 310 μg/mL Escherichia coli 155-310 μg/mL Pasteurella multocida 310 μg/mL Staphylococci sp. 75 μg/mL 130 Bangladesh J Pharmacol 2022; 17: 124-140 Table I Antimicrobial activities of Peganum harmala (Cont.) Extracts/constituents Types Microbes Activities (MIC) References Harmaline Parasite Streptococci sp. 310 μg/mL Arshad et al., 2008 Proteus sp. 625 μg/mL Salmonella sp. 155-310 μg/mL Harmalol Escherichia coli 0.833 mg/mL Nenaah, 2010 Proteus vulgaris 1.0 mg/mL Staphyllococcus aureus 1.5 mg/mL Bacillus subitiis 1.0 mg/mL Asperagillus niger 1.5 mg/mL Acinetobacter sp. 75 μg/mL Arshad et al., 2008 Clostridium sp. 625 μg/mL Escherichia coli 310-625 μg/mL Pasteurella multocida 1250 μg/mL Staphylococci sp. 310 μg/mL Streptococci sp. 625 μg/mL Proteus sp. 1250 μg/mL Salmonella sp. 625-1250 μg/mL Methanol extract Fungi Candida albicans 0.6 mg/mL Abderrahim et al., 2019 Candida glabrata 2.5 mg/mL Hayet et al., 2010 Candida albicans 2.5 mg/mL Candida parapsilosis 2.5 mg/mL Candida kreusei 2.5 mg/mL n-Butanol extract Candida glabrata 2.5 mg/mL Candida albicans 2.5 mg/mL Candida parapsilosis 2.5 mg/mL Candida kreusei 2.5 mg/mL Ethyl acetate extract Candida glabrata 2.5 mg/mL Candida albicans 2.5 mg/mL Candida parapsilosis 2.5 mg/mL Candida kreusei 2.5 mg/mL Chloroform extract Candida glabrata 2.5 mg/mL Candida albicans 2.5 mg/mL Candida parapsilosis 2.5 mg/mL Candida kreusei 2.5 mg/mL Alcohol extract Candida albicans 1.25 mg/mL Dabi et al., 2011 Candida parapsilosis 0.625 mg/mL Candida keiffir 0.625 mg/mL Candida glabrata 0.312 mg/mL Candida tropicalis 0.312 mg/mL Candida dubliensis 0.625 mg/mL Total alkaloid Candida albicans 62.5 µg/mL Iranshahy et al., 2019 Harmane Candida albicans 0.583 mg/mL Nenaah, 2010 Harmine Candida albicans 0.5 mg/mL Harmaline Candida albicans 0.666 mg/mL Harmalol Candida albicans 0.75 mg/mL Protein of P. harmala Alternaria alternate 1.5 μM (IC50) Ma et al., 2013 Penicillium degitatum 37.5 μM (IC50) Rhizopus stuolonifer 8.44 μM (IC50) Magnaporthe grisea 12.19 μM (IC50) Bangladesh J Pharmacol 2022; 17: 124-140 131 both p-Akt/Akt and p-mTOR/mTOR to progress the apoptosis and autophagy through PI3K/Akt/ERK/ mTOR pathway in cancer cells (Li et al., 2017; Liu et al., 2016). Additionally, a recent study further linked its anti-cancer mechanisms to the recovery of the malig- nant cell morphology by a series of processes involving the reorganization of the actin cytoskeleton, rescued cell -cell adhesion, inhibition of cell motility, and loss of anchorage-independent growth (Le Moigne et al., 2020). Meanwhile, using in vitro and in vivo models of B16F-10 melanoma and A549 non-small cell lung cancer (NSCLC), harmine was also found to exhibit anti- metastatic and anti-invasive effects by activating the reversion-inducing cysteine-rich protein with kazal motifs (RECK) signaling and down-regulating the pro- metastatic factors, such as AKT, extracellular regulated protein kinases (ERK), matrix metalloproteinase-9 (MMP-9) and vascular endothelial factors (VEGFs) (Hamsa and Kuttan, 2011b; Shen et al., 2018). Acting as a mTOR inhibitor and a regulator of CDK-Cyclin com- plex, harmaline could suppress the tumor growth of esophageal squamous cell carcinoma (50% volume reduction at 100 mg/kg p.o) and stomach adenocarci- noma (30% volume reduction at 15 mg/kg p.o) with minimal toxicity in patient-derived xenograft models (Wang et al., 2015c; Zhang et al., 2021). Harmalacidine targeted and inactivated the mitochon- drial and protein tyrosine kinase signaling pathways (PTKs-Ras/Raf/ERK) to inhibit the proliferation and then introduced apoptosis in leukemia cells (Wang et al., 2015b). Pegaharmine D, another β‑carboline alkaloid of P. harmala, functioned as a G-quadruplex interactive ligand, thus playing an important regulatory role in c- MYC oncogene transcription and genome stability (Wang et al., 2016a). Besides alkaloids, 3α-acetoxy-27-hydroxyolean-12-en-28 -oic acid methyl ester, a triterpenoid isolated from P. harmala, especially presented an anti-non-small cell lung cancer (NSCLC) activity through inactivation of the epidermal growth factor receptor (EGFR) and its downstream signals, thus leading to the mitochondrial apoptosis of cancer cells (Wang et al., 2016b). Moreover, the hydroalcoholic extract of P. harmala presented an anti-angiogenic effect via down-regulation of vascular endothelial growth factor (VEGF), which could be a potential approach to inhibit tumor growth as well (Yavari et al., 2015). Neuropsychological effects The aerial part of P. harmala extracts is claimed to use as a traditional medicine to improve memory function and relieve neurodegenerative illnesses. The plant and its alkaloid ingredients have been reported to possess the effective acetylcholinesterase (AChE) and butyrylcholi- nesterase (BChE) inhibitory activities, which can improve the learning and memory impairment of animal models (Adhami et al., 2015; Ali et al., 2013; Liu et al., 2017a; Yang et al., 2015). In addition, harmine could effectively enhance the spatial cognition of scopo- lamine-induced mice and repair the impaired memory of transgenic Alzheimer's disease mice. The action was linked to the enhanced cholinergic neurotransmission through the AChE inhibitory activity as well (He et al., 2015). Deoxyvasicine, the main quinazoline alkaloid of P. harmala, could ameliorate the amnesia of scopola- mine-induced mice via restoration of cholinergic Table I Antimicrobial activities of Peganum harmala (Cont.) Extracts/constituents Types Microbes Activities (MIC) References Methanol extract Virus Herpes simplex virus type 2 49 μg/mL (IC50 Vir); 43.36 (SIvir) Benzekri et al., 2018 & 2020. Human cytomegalovirus 95% inhibition at 100 μg/mL Hayet et al., 2010 Coxsackie B virus type 3 52% inhibition at 100 μg/mL n-Butanol extract Virus Human cytomegalovirus 75% inhibition at 100 μg/mL Coxsackie B virus type 3 31% inhibition at 100 μg/mL Ethyl acetate extract Virus Human cytomegalovirus 65% inhibition at 100 μg/mL Coxsackie B virus type 3 24% inhibition at 100 μg/mL Influenza A 15.7 μg/mL (IC50); 8.87 (SIvir) Moradi et al., 2017a 9.87 μg/mL (IC50); 12.45 (SIvir) Moradi et al., 2017b Chloroform extract Virus Human cytomegalovirus 51% inhibition at 100 μg/mL Hayet et al., 2010 coxsackie B virus type 3 16% inhibition at 100 μg/mL Total alkaloid Virus Influenza A 5.8 μg/mL (IC50); 23.1 (SIvir) Moradi et al., 2017b Harmine Virus 4.06 μM (IC50 Vir); 21.5 (SIvir) Wu et al., 2020 Pegaharine B Virus 25.22 μM (IC50 Vir); 3.0 (SIvir) Pegaharine C Virus 31.82 μM (IC50 Vir); 3.1 (SIvir) Pegaharine D Virus 2.12 μM (IC50 Vir); 35 (SIvir) Protein of P. harmala Virus HIV-1 1.26 μM (IC50) Ma et al., 2013 132 Bangladesh J Pharmacol 2022; 17: 124-140 function (AChE inhibition and choline acetyltransferase activation), regulation of neurotransmitters (acetylcho- line, 5-hydroxytryptamine, γ-aminobutyric acid, 5- hydroxyindole-3-acetic acid and glutamic acid), and attenuation of neuroinflammation (necrosis factor-α suppression) and oxidative stress (increased gluta- thione peroxidase) (Deng et al., 2019). A novel mecha- nism that P. harmala could enhance the hippocampal contents of glucagon-like peptide (GLP-1) and insulin, which could subsequentially promote the glucose trans- porter type (GLUT4) production to attenuate the insidious progression of Alzheimer's disease in the AlCl3‑induced pathology model (Saleh et al., 2021). Besides Alzheimer's disease, another two neurodegene- rative disorders, including Huntington's and Parkin- son’s diseases, were also reported to be sensitive to the P. harmala treatment. Using Caenorhabditis elegans as the model, the polysaccharides of P. harmala demonstrated an effect to reduce polyglutamine (polyQ) aggregation through the proteasome-mediated protein degradation pathway and then alleviating the associated neurotoxi- city, thus providing a promising candidate against Huntington's disease (Guo et al., 2020). Aqueous extract of P. harmala could improve the symptoms by inhibiting AChE, and decreasing lipid peroxidation and protein oxidation in the brain of the Parkinson’s rat model induced by 6-hydroxydopamine (Rezaei et al., 2016). Moreover, the seed and root extracts of P. harmala also showed a potent and selective inhibition of human monoamine oxidase (MAO-A), which could contribute to the antidepressant treatment (Herraiz et al., 2010; Herraiz and Guillén., 2018). Anti-atherogenesis activities According to the evidence-based studies reported previously, the extracts and beta-carboline alkaloids of P. harmala have been implicated as effective agents for the treatment of atherothrombotic diseases. The seed extracts, harmine, and harmaline all presented protec- tive effects against human low-density lipoprotein oxi- dation which was the key event in the pathogenesis of atherosclerosis (Berrougui et al., 2006a). Harmane and harmine could prevent collagen-induced platelet aggre- gation by inhibiting PLCγ2 and protein tyrosine phosphorylation with sequential suppression of cyto- solic calcium mobilization and arachidonic acid libera- tion (Im et al., 2009). Moreover, harmane also function- ed as a lipid accumulation inhibitor by decreasing the expression of adipogenic and lipogenic factors, increa- sing adipocyte browning markers, and activating the liver kinase B1 (LKB1)- AMPK– sirtuin 1 pathway (Li et al., 2020c). Harmine could block the binding between protein tyrosine phosphatase non-receptor type 14 (PTPN14) and yes-associated protein (YAP) to reduce the oscillatory shear stress-induced endothelial activa- tion, thus alleviating the atherosclerosis of mice models (Yang et al., 2021). In both spontaneously hypertensive rats and norepinephrine-induced hypertrophy of human embryonic stem cell-derived cardiomyocytes, harmine could reduce cardiac hypertrophy by modula- ting the activity of NF-κB signaling pathway (Huang et al., 2021). In addition, harmane, harmine, and harma- line all demonstrated vasorelaxant effects which were related to the enhanced NO release on the endothelial cells and the blockage of the voltage-dependent Ca2+ channel on vascular smooth muscle (Berrougui et al., 2006b; Shi et al., 2000). Anti-diabetes effects Ethanol extracts of P. harmala seeds have been reported to present hypoglycemic and antihyperlipidemic effects on streptozotocin-induced diabetic rats (Komeili et al., 2016; Singh et al., 2008). Moreover, one of its com- pounds, 4-hydroxypipecolic acid, could control hyper- glycemia, hyperlipidemia and oxidative stress-media- ted damage, thus relieving the characteristic symptoms of type 2 diabetes in the C57BL/KsJ-db/db mice (Singh et al., 2012). The anti-diabetes effects of P. harmala and its compound might be partially related to an enhanced glucose uptake caused by translocating insulin-sensi- tive glucose transporter-4 from the intracellular to the plasma membrane (Naresh et al., 2012). Anti-inflammation effects In both in vitro (heat-induced hemolysis) and in vivo (carrageenan-induced paw edema in rats) models, the P. harmala extract exhibited anti-inflammatory activities and inhibitory effects on egg albumin denaturation (Abbas et al., 2021; Edziri et al., 2018). Moreover, it could notably restore the level of C-reactive protein, rheumatoid factor, alkaline phosphatase, alanine trans- aminase, aspartate transaminase, prostaglandin-E2, and tumor necrosis factor-α in the serum of complete Freund’s adjuvant-induced arthritis rat or cecal ligation and perforation-induced septic rat models (Akhtar et al., 2022; Özkanlar et al., 2015). The anti-inflammatory activities might be attributed to alkaloids, flavonoids, phenols, and polyunsaturated fatty acids (Akhtar et al., 2022; Khadhr et al., 2016). Among them, total alkaloids, especially harmine, harmaline, and harmane demons- trated significant inhibition of myeloperoxidase, a key enzyme in the inflammatory process (Bensalem et al., 2014). In acute lung injury mouse models, harmine could prevent the inflammatory damages accompanied by decreased levels of TNF-α, IL-1β and IL-6, which indicated its anti-inflammatory responses were via the inhibition of NF-κB signaling pathway (Liu et al., 2017b). In lipopolysaccharide-induced acute kidney injury mice, harmine reduced oxidative stress and inflammation responses by inhibiting the TLR4-NF-κB and NLRP3 inflammasome pathway (Niu et al., 2019). Others Besides the activities described above, P. harmala has also been reported many other pharmacological effects Bangladesh J Pharmacol 2022; 17: 124-140 133 including analgesic, hepatoprotective, bronchodilating, gastroprotective, diuretic, and hypothermic effects. The total alkaloids of P. harmala presented both central and peripheral antinociceptive activities to release the nociception of writhing, formalin, or hot plate-induced pain response in mice models, which was mediated by opioid receptors (Farouk et al., 2008; Shoaib et al., 2016). Meanwhile, the extracts of P. harmala possessed a pro- tective role against ethanol hepatoxicity via inhibition of lipid peroxidation by decreasing aminotransferase contents and increasing 17β-estradiol, superoxide dis- mutase, catalase and glutathione peroxidase activities (Bourogaa et al., 2015; Hamden et al., 2008; Hamden et al., 2009). The P. harmala extract, alkaloid fraction, and its quinazoline alkaloids vasicine and deoxyvasicine all presented the antitussive, expectorant, and bronchodi- lating activities in mice and guinea pig models (Liu et al., 2015a; Liu et al., 2015b). Furthermore, vasicine also could significant-ly reduce free acidity, total acidity and enhance mucin secretion by inhibiting the H+K+- ATPase activity, thus providing the gastroprotective effects against cold restraint, aspirin, alcohol, and pyloric ligation-induced gastric ulcer in rat models (Singh et al., 2013). Additionally, P. harmala was an effective diuretic that could significantly increase the urine output and urinary electrolyte excretion in experimental animals (Al-Saikhan and Ansari, 2016). Toxicology In addition to the therapeutic effects, cases of human intoxication caused by the application of P. harmala extracts or its products have been widely reported as well. Generally, intentional ingestion of P. harmala seed infusion could lead to toxic symptoms mainly in neuro- logical, gastrointestinal, and cardiovascular systems, such as visual and auditory hallucinations, locomotor ataxia, nausea, tinnitus ringing, vomiting, agitation, disturbances of consciousness, hypertension, tachycar- dia, tachypnea, uterine contraction, and oliguria (Achour et al., 2012; Berdai et al., 2014; Frison et al., 2008; Sadr Mohammadi et al., 2016). Moreover, these intoxications might further cause anemia, thrombo- cytopenia, acute kidney disease, multiple areas of cere- bral ischemia with subarachnoid hemorrhage, and interior hemorrhage of the uterus (Ghizlane et al., 2021; Yuruktumen et al., 2008). In addition, the aqueous extracts of P. harmala have also been found to exert adverse effects on somniferous tubules and the pitui- tary testicular axis, thus inhibiting the processes of spermatogenesis and fertility in the animal models (El- Dwairi and Banihani, 2007). However, there was no acute and subacute toxicity detected in rats when P. harmala extract was given at dose under 3 g/kg and 0.8 g/kg, respectively (Abbas et al., 2021). Subchronic toxi- city was also not detected in rats under the treatment of total alkaloid extracts of P. harmala at dose as high as 45 mg/kg/day (Wang et al., 2019). Moreover, clinically no toxicity of either chloroform or aqueous extract of P. harmala was found in experimental rabbits (Ahmad et al., 2013). The toxicology of P. harmala was mainly attributed to the β-carboline alkaloids through the regulation of amine neurotransmitters, inhibition of human mono- amine oxidase, or direct interaction with related recep- tors for serotonin, dopamine and benzodiazepines in the central nervous system. The main toxicological compounds reported are harmaline, harmane, harma- lol, harmol, and tetrahydroharmine (Frison et al., 2008; Herraiz et al., 2010; Nasehi et al., 2010). Moreover, the repeated dosing of the total alkaloids of P. harmala at a dose of 150 mg/kg/day could lead to the following tolerance after the initial tremor responses in rats. The tolerance was caused by the degeneration of cerebellar Purkinje cells resulting from the overexpression of c-fos and increased oxidative stress via multiple stimulations of P. harmala (Wang et al., 2020). Taken together, the current data indicated that excessive use of high doses of P. Harmala could lead to serious damage to alimentary, urinary, neurological, and even reproductive systems, thus requiring great vigilance during their therapeutic uses. Conclusion and Future Perspectives Traditional records worldwide claim enormous health benefits and therapeutic effects of P. Harmala. In this review, we summarized the scientific research-based evidence of its phytochemical constituents, multiplex pharmacological and toxicological effects and associa- ted mechanisms. Specifically, P. Harmala contains over 390 secondary metabolites, mainly including alkaloids, flavonoids, triterpenoids, phenolic acids, anthraqui- nones, fatty acids, and abundance essential oils. P. Harmala and its secondary metabolites, mainly β- carboline alkaloids, present many pharmacological activities, including antimicrobials (bacteria, parasites, fungi and virus), anti-cancer, anti-atherogenesis, anti- diabetes, antiinflammation, antioxidant, neuropsycho- logical, analgesic, hepatoprotective, bronchodilating, gastroprotective, diuretic, and hypothermic effects. Concerning to the mechanistic aspects, P. Harmala exerts its antimicrobial effects by interfering the recognition of microorganisms and host cells, and regulating the genetic transcription. The anti-cancer actions of P. harmala and its β-carboline alkaloids are attributed to a complicated network which regulates the signals associated with the cell cycle arrest, and the autophagic and apoptotic death. In addition, numbers of molecules related to the neurotransmission, infla- mmation and oxidative stress, such as MAO-A, (GLUT) 4, PLCγ2, NF-κB, NLRP3, AChE and BChE receptors, 134 Bangladesh J Pharmacol 2022; 17: 124-140 have been identified as targets of P. harmala and its alkaloids to exert neuroprotective, antiatherogenic, anti- diabetes, anti-inflammation and antioxidant effects. However, the higher doses and long periods of P. harmala exposure can cause serious hepatic, nephritic and neuropathic toxicities, thus need extra attentions. Financial Support Self-funded Conflict of Interest Authors declare no conflict of interest References Abbas MW, Hussain M, Qamar M, Ali S, Shafiq Z, Wilairatana P, Mubarak MS. Antioxidant and anti-inflammatory effects of Peganum harmala extracts: An in vitro and in vivo study. Molecules 2021; 26: 6084. Abderrahim AL, Taïbi K, Ait Abderrahim C. Assessment of the antimicrobial and antioxidant activities of Ziziphus lotus and Peganum harmala. 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