Ethnomedicinal Plants from Iraq as Therapeutic Agents against Mycobacterium tuberculosis: A Review

Mycobacterium tuberculosis is a highly infectious pathogen, which can affect both humans and animals. The metabolic products of this bacterium affect the pulmonary, nervous, lymphatic, and cardiovascular systems. The aim of this review is to provide information on certain local herbs from Iraq, which have been found to be effective against Mycobacterium tuberculosis. In this report, we have reviewed 13 medicinal plants and their anti-mycobacterial activities. The family, traditional medicinal uses, common local names, in vitro activity of the crude extract, and information about bioactive chemical composition of these plant species have been described. The crude extracts of these medicinal plants can be used to develop novel drugs against tuberculosis.


MetHODOlOGY
The information in this article takes the reader through the following keywords: "extract", "medicinal plants" and "anti-mycobacterial". We searched for these keywords using electronic databases including Science Direct, Google scholar, PubMed and Scopus. We included both in vivo and in vitro studies in our review.

Ethno-therapy for treatment of tuberculosis caused by Mycobacterium tuberculosis
We selected 13 plants, which have been known to have potential inhibitory effects on Mycobacterium tuberculosis, in this study. Between the years 2000 and 2018, the reports published in Iraq included the following medicinal plants: Apium graveolens, Arachis hypogaea, Arganiaspinosa L, Camphor, Cinnamomum cassia, Commiphora molmol, Cuminum cyminum, Lepidium sativum, Linum usitatissumun, Nigella sativa, Pimpinella anisum, Piper nigerum, and Trigonella foenumgraecum.

Apium graveolens
In Iraq, this plant is known as Karafs and its common English name is Celery. It is commonly cultivated in the European region as a food crop and it is also grown in Algeria, Egypt and the central region of Kingdom of Saudi Arabia (KSA) 15 . The seeds of Apium graveolens have been largely used in local and traditional medicine to treat hepatic disorders, jaundice, arthritis, high uric acids levels and many inflammatory diseases [16][17][18] . Previous ethnomedicinal studies have shown that celery alleviates digestible disturbances, central nervous system and cardiovascular disorders, and also has antimicrobial, anti-inflammatory, and several other pharmacological effects [19][20][21] . This study reviewed the effects of this plant on Mycobacterium tuberculosis using 200 mg/ml of whole-plant extract made using 70% ethanol and found that it inhibited the growth of MTB (only 20 colonies appeared after an incubation period of 4 weeks) 22 .

Arachis hypogaea
This plant species is a member of the Fabaceae family, which is known as Fustik Abeed and Fustic wdani in Arabic and its common English names are groundnut/peanut. It is mainly grown in tropical countries and also cultivated in some sub-tropical areas in different parts of the world 23 . The parts of this plant have several traditional medicinal uses such as the use of peanut oil to treat crust formation in certain skin diseases, for neonatal care, to relieve itching of dermal areas in cases of eczema and dry skin 24 . Modern research on the peanut plant extract has shown its antioxidant properties and in-vitro studies have shown that it possesses free radical scavenging, antimicrobial, anti-parasitic and anti-inflammatory properties [25][26][27] . Further clinical research has shown that peanut skin has an anti-allergic effect as it contains large amounts of polyphenols 28, 29 . The application of 70% ethanol extract of this plant on Mycobacterium tuberculosis (MTB) at 200 mg/ml concentration showed no growth of MTB 22 .

Arganiaspinosa L.
This plant is a small tree from the Amaranthaceae family. It grows in North African regions, especially in Morocco, and the oilproducing varieties of this plant can also be grown in jungles. In its native country, this plant is traditionally used for nutritive as well as several other purposes 30 . On the other hand, modern uses of argan oil, produced by this plant, have shown anti-bacterial activity on diseases involving Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa infections 31, 32 . In addition, several papers have mentioned the activity of argan oil in different diseases such as cancer, heart disease, diabetes and thyroid hormone disturbances 33 . The current review aims to elucidate the effects of argan oil against Mycobacterium tuberculosis. Its therapeutic effects depend on its rich chemical composition including oleic, linoleic, palmitic, stearic and linolenic acids and mixtures of these chemicals at concentrations of 2.5:7.5 and 3:7 yielded good inhibitory effect on Mycobacterium tuberculosis 30 .

Camphor
This chemical is from a plant belonging to the Lauraceae family and it is derived from the camphor wood laurel tree. It is white in color, crystalline in texture, has a specific odor and intense taste 34 . The tree is natively cultivated in India, Mongolia, Japan, Taiwan, and also in the Southern region of USA 35 . The essential oil from this plant has been traditionally used to soothe muscle pain, joint conditions, dermatological conditions, cold, and bronchial congestion 36 . Latest studies have shown its pharmaceutical applications as an analgesic, antipyretic, antiinflammatory, anti-spasmodic, mild expectorant and for alleviating nasal disorders 35, 37 . The volatile oil, which has major medicinal properties, contains safrole, linalool, eugenol, and terpineol and the leaf of the plant is also a powerful source of linalool (94.9%) 38 . The camphor plant extract showed clear activity at 200 mg/ml concentration against MTB with only 18 colonies appearing after an incubation period of 4 weeks 22 .

Cinnamomum cassia
This plant is classified under the Lauraceae family. It is commonly known as Chinese cassia, and it is cultured in various regions in the world. It is harvested from the inner cortex of the tree belonging to the genus Cinnamomum 39 . The cinnamomum plant has been used for the oldest traditional herbal medicine used and it is also used in mouth fresheners and chewing gums for its flavor 40, 41 . In addition, the cinnamon plant improves digestive ability and reduces colon disorder 42, 43 . All parts of the cinnamon tree, including the leaves, bark, root, or fruits, possess medicinal properties. The bark and leaves contain the volatile oils in large amounts with chemicals having medicinal and pharmaceutical properties such as antimicrobial, antioxidant and anti-inflammatory activities 41, 44 . Latest studies elucidating the local uses of Cinnamomum plants have shown that they have anti-tuberculosis activity 45 .

Commiphora molmol
This plant is classified under the Burseraceae family and its common name myrrh is derived from the Arabic word Mur. Various species of the Commiphora plant are cultivated in different regions of the world 46 . The traditional medicinal use of this genus Commiphora includes treatment of headache, wound care, joint pain, bone fractures, and diarrhea 47 . Latest research shows that the active compound of commiphora extract has anti-cancer activity and in vitro experiments have shown its anti-microbial activity 48,49 . Latest studies on the application of Commiphora molmol in treating tuberculosis have shown its activity against clinical isolated TB sample at 200 mg/ml concentration, resulting in no growth of MTB 22 .

Cuminum cyminum
This plant species is a member of the Apiaceae family, which is known as Kamoun in Arabic and as Cumin in English 50 . It is cultivated and grown in the MENA regions -Middle East and North Africa. In addition, the plant is also grown in the United States of America, India and China 50, 51 . The traditional medicinal uses of cumin include as a treatment for diarrhea and jaundice, and it also has diuretic and astringent properties. The oil of the cumin plant is used in food manufacturing for making cheese and soups 52 . The extract of the cumin seed has anti-microbial and bactericidal properties, as shown by in vitro experiments 53 . Through phytochemical analysis of the parts of this plant, the phenolic content in the methanol extract was evaluated and found to exhibit anti-oxidant and anti-inflammatory activities 54, 55 . The crude plant extract made using 70% ethanol at 200 mg/ ml concentration completely inhibited the growth of MTB after an incubation period of 4 weeks 22 .

Lepidium sativum
This species of herbs is a common garden plant. It is classified under the Brassicaceae family and is found in countries like Africa and Ethiopia. However, it can also be found in different parts of the world such as Southwest Asia 56 . The plant has several names including garden pepper cress, pepperwort and El Rashad 57 . It is used in the Arabic countries as traditional medicine to treat asthma, cough, bronchitis and as an expectorant 57,58 . The chemicals found in this plant, such as oleic acid, stearic acid, linoleic acid and ascorbic acid, have several pharmaceutical effects. All of the chemicals have significant diuretic, anti-inflammatory, antidiarrheal, anti-microbial, analgesic and laxative activities [59][60][61] . Through whole plant extraction using 70% ethanol solvent, its activity against MTB was shown; at 200 mg/ml concentration, it completely suppressed MTB growth (no colonies seen) 9 .

Linum usitatissumun
This particular plant species has been cultivated for its oil since a long time. Its common name is flax or linseed and it belongs to the Linaceae family 62 . The flax plant is native to Egypt and it is commonly distributed between the Arabic gulf and Red Sea. However, it can also be found in certain other countries like India, Pakistan, and Afghanistan 63 . There are quite a few traditional medicinal uses of Linum usitatissimum and it has several therapeutic benefits such as an anti-tussive, laxative, expectorant, and diuretic 64 . The linseed shell is characterized by its shape, which is hard with different colors. Its chemical composition is as follows: 41% fat, 28% fiber, and 20% protein with high internal polyunsaturated fatty acids content 65 . In modern therapy, there are abundant data available on the properties of flaxseed such as its anti-coagulant, anti-diabetic, anti-microbial, anti-oxidative activities as well as its nephro-, hepato-and cardio-protective effects [66][67][68] . The ethanol extract of flax plant showed antituberculosis activity at 200 mg/ml concentration and only 25 MTB colonies grew after the 4-week incubation period 22 .

Nigella sativa
This plant is commonly known as black seed in Arabic and its common English name is black cumin 69 . It is a herb belonging to the Ranunculaceae family 70 . Nigella seeds have been used to improve human health, particularly in the Middle Eastern countries. This plant species is cultivated in many areas in the world, especially in Arabic countries. It has been, in fact, mentioned by Prophet Mohammed as having the property to enhance physical power and health 71,72 . Nigella sativa is commonly used in traditional medicine as a diuretic, and as a cure for liver disorders, digestive system problems, fever, and jaundice 72,73 . Different studies describing the modern applications of the black nigella seeds have shown that it has therapeutic activity against several conditions such as bacterial, fungal, parasitic, and viral infections as well as in metabolic disorders, hypertension, diabetes, gastrointestinal disease and hepatic disorders 69,72 . The published articles on the black seed plant show chemical composition consisting of high oil content of approximately 28 to 36% as well as different bio-active chemicals such as flavonoids and saponins. The pharmaceutical benefits exerted by these phytochemicals include anti-cancer, anti-microbial, anti-inflammatory, anti-oxidant and detoxifying activities 73,74 . This plant is also effective against Mycobacterium tuberculosis and it showed significant inhibitory effect at a concentration ratio of 2.5:7.5 and 3:7 after completion of the incubation period 75 .

Pimpinella anisum
Pimpinella anisum is one of the oldest herbal medicinal plants that belongs to the Umbelliferae family. It is grass-like in shape and is about 50 cm in length. Its common English name is anise 76 . Pimpinella anisum is grown and cultivated in various areas such as Asia, Middle Eastern regions like Iran and Egypt. It has also been reported to grow in Europe and Mexico 77 . Every year, the anise fruit is harvested between August and September. Its traditional medicinal uses include alleviation of various conditions such as digestive disorders, GIT spasms, and constipation and also to increase the breast milk production in women 76,77 . The secondary metabolism products of this plant consist of various chemicals with anti-microbial and anti-oxidant activities [78][79][80]. Several studies in the medical field have shown that the essential oils of this plant have many positive health benefits such as anti-inflammatory, analgesic, anti-convulsant and hepatoprotective activities [81][82][83] . The 70% ethanol whole-plant extract along with distilled water showed significant inhibitory activity at 200 mg/ml concentration against MTB growth in the 4-week incubation period as only 3 colonies were seen 22 .

Piper nigerum
Piper nigerum is commonly known as black pepper and it is considered to be the oldest medicinal herb in the world. It is grown in different regions like Asia, Europe and Africa 84 . In Arabic, it is known as Filfil Aswad and it belongs to the Piperaceae family 85 . It has several important uses in traditional medicine and has been used to treat preclinical cases such as asthma, skin disorder, sore throat, snake bite and as an antipyretic medication 86 . The black pepper seed contains several potent chemicals. Many studies have shown that it has anti-bacterial, anti-diarrheal, anti-colic, anti-fungal and anti-inflammatory activity against various infectious diseases 87,88 . In this review, we have shown the anti-mycobacterial activity of Piper nigerum, which has potent inhibitory activity at 200 mg/ml concentration and suppresses the growth of MTB with only 4 colonies seen after the 4-week incubation period 22 .

Trigonella foenum-graecum
This medicinal plant, commonly known as fenugreek, is considered to be one of the oldest plants used in traditional medicine. It belongs to the Papilionaceae family 89 . It is cultivated throughout the world due to its adaptive behavior 90 . Although it is grown worldwide under various climatic conditions, it is especially found in Asia and Africa. Due to its widespread distribution, its medicinal role has been well documented. For instance, in Iran, the extract of this plant is used to lower blood sugar level 91 . In China, its seeds are used to treat digestive disorders, gastritis, and gastric ulcers and also, in food manufacturing 90 . Several studies have reported the bioactive chemicals found in this plant and have shown their applications in the medical field. Furthermore, it has many pharmacological activities such as hypoglycemic, anti-diabetic, anti-lipidemic, anticancer, antimicrobial and anti-inflammatory activities 92,93 . The plant has clear anti-mycobacterial effect as after completion of the entire incubation of 4 weeks, no MTB growth was seen when it was used at 200 mg/ml concentration 22 .

CONClUSION
It is evident that the aforementioned herbal medicinal plants from Iraq exhibit antimycobacterial activity and hence, can be used against Mycobacterium tuberculosis. There is a significant positive correlation between the traditional used of medicinal plants and their anti-mycobacterial activity. Further research in the field of modern pharmaceutical science should be conducted to isolate and identify the bioactive chemical compounds from these plants. We expect that these findings will encourage the researchers to engage in drug discovery and develop novel natural products that may eventually facilitate the development of a novel anti-TB drug.

ACKNOWleDGeMeNtS
We are thankful to Al Maarif University College (AUC) Alanbar, Iraq and the Dean of the college for providing and supporting the study.

CONFlICt OF INteReSt
The authors declare that there is no conflict of interest.

FUNDING
None.

DAtA AVAIlABIlItY
All datasets generated or analysed during this study are included in the manuscript.

AUtHORS' CONtRIBUtION
All authors have made substantial, direct and intellectual contribution to the work and approved it for publication.

etHICS StAteMeNt
This research article does not contain any studies involved with human participants or animals.