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Lippia javanica (Burm.f.) Spreng.: Traditional and Commercial Uses and Phytochemical and Pharmacological Significance in the African and Indian Subcontinent.

1. Introduction

Lippia javanica (Burm.f.) Spreng. (Verbenaceae) (Figure 1(a)) has a long history of traditional uses in tropical Africa as indigenous herbal tea or tisane (Figure 1(b)), refreshing beverage, or food additive based on its perceived health and medicinal properties. Lippia javanica is rich in volatile oil, particularly caryophyllene, carvone, ipsenone, ipsdienone, limonene, linalool, myrcene, myrcenone, ocimenone, p-cymene, piperitenone, sabinene, and tagetenone [1-5]. Research by Viljoen et al. [3] revealed that the essential oil profiles of L. javanica are characterized by inter- and intraspecies variations because they are produced by different metabolic pathways. Using cluster analysis, Viljoen et al. [3] identified five chemotypes of L. javanica in South Africa and Swaziland, myrcenone-rich type (36-62%), carvone-rich type (61-73%), piperitenone-rich type (32-48%), ipsdienonerich type (42-61%), and linalool-rich type (>65%). The relative proportion of the chemical constituents of L. javanica essential oil is important as this determines the biological properties of the species chemotypes.

Lippia javanica belongs to the Verbena or vervain family (Verbenaceae) comprising approximately 32 genera and 840 species [97]. The genus Lippia L. is named after Augustin Lippi (1678-1701), an Italian botanist and natural historian who was killed in Ethiopia at the age of 23 [98]. Phylogenetic relationships within family Verbenaceae demonstrated that genus Lippia and other closely related genera, namely, Aloysia Palau, Lantana L., and Phyla Lour., are not monophyletic [97]. The boundaries separating these four genera are historically weak, with many taxonomic researchers including species belonging to Aloysia, Lantana, and Phyla in the genus Lippia [99]. Lippia and Lantana genera are the most difficult to separate, as species of these two genera show similarities in their inflorescences that are spicate, often subcapitate during anthesis and elongating in fruit and pedunculated [98]. According to de Campos et al. [100], the genus Lippia comprises about 200 species of herbs, shrubs, and small trees distributed throughout south and central America and tropical Africa. Only 15 Lippia species have been recorded in tropical Africa [101]. The specific name "javanica" was given by the Dutch Botanist Nicolaas Laurens Burman (1734-1793) in 1768, who mistakenly thought that the type specimen was collected in Java, Indonesia [102]. He placed the species in the genus Verbena, and the German botanist Sprengel (1766-1833) transferred Burman's name to the genus Lippia in 1825 [103]. Lippia javanica is morphologically similar to L. scaberrima Sond. but is much taller and its bracts are shorter than the flowers (Figure 1(a)), while L. scaberrima has many stems arising from ground level and is usually less than 0.5 metres high, and its bracts are not longer than the flowers [104].

Lippia javanica is an erect woody perennial herb or shrub of up to 4.5 m tall, with strong aromatic leaves which give off a lemon-like fragrance when crushed [105]. Stems are brownish, usually erect or spreading with short stiff tubercle-based whitish hairs and small glands, and branched with inflorescences in nearly all axils. Leaves are opposite or in whorls of 3, blades lanceolate to oblong and densely pubescent, rounded and then cuneate at the base, and crenate-serrate or closely serrulate on the margins except near the leafbase [106]. Flowers occur in conical or oblong spikes, purple or dull-reddish in fruit, dark brownish on drying [101, 106]. The flowers are sessile or with short peduncles, lower bracts of spikes ovate and upper bracts smaller, pubescent, glandular, and densely spreading [101]. The calyx is 2-lobed, half as long as the corolla, pubescent, and densely spreading. The corolla is white, yellowish-white to greenish (Figure 1(a)), usually with a yellow throat, glandular and pubescent outside in the upper half, tube narrowlyfunnel-shaped from a narrow base [101, 106]. Anthers are sulphur-yellow and nutlets are brown and half ovoid [101,106].

Lippia javanica occurs naturally in central, eastern, and southern Africa (Figure 2) and has also been recorded in the tropical Indian subcontinent [12, 13, 23, 39, 47, 61]. In sub-Saharan Africa, the species is native to Angola, Botswana, Central African Republic, Democratic Republic of Congo, Ethiopia, Kenya, Malawi, Mozambique, South Africa, Swaziland, Tanzania, Uganda, Zambia, Zanzibar, and Zimbabwe. Lippia javanica has been recorded in low to high altitude (0-2350 m above sea level) woodlands and wooded grasslands, scrub bushland, and grassy rocky kopjes, in riverine vegetation, and on margins of dambos and swampy ground, sometimes on termite mounds, in montane grasslands, and on evergreen forest margins, also in disturbed ground beside roads, forest clearings, plantations, and cultivated land and becoming a weed in derived rangelands [101,106]. This shows that the plant is highly adaptable to a wide range of climatic, soil, and vegetation conditions.

2. Traditional Uses of Lippia javanica

Lippia javanica is used for a wide variety of traditional uses (Table 1). Based on literature, the most important traditional applications include its uses as herbal tea and ethnomedicinal applications for (in descending order of importance) colds, cough, fever or malaria, wounds, repelling mosquitos, diarrhoea, chest pains, bronchitis, and asthma (Figure 3). These different uses are discussed in the following seven sections: Food Uses; Respiratory Problems; Gastrointestinal Diseases; Fever, Malaria, and Insect Repellent; Wounds, Injuries, Pain, and Skin Infections; Ethnoveterinary Uses; and Other Uses.

2.1. Food Uses. Leaves and twigs of Lippia javanica are used as food additives in Kenya [6] and leafy vegetable in India [12,13]. Lippia javanica is popular as herbal tea, particularly in Botswana, South Africa, and Zimbabwe [7-11]. Lippia javanica herbal tea is prepared by steeping fresh or dried leaves, stems, or twigs in boiling water and letting them stand for two to five minutes to release flavour, with or without milk and sugar added according to taste. A stronger brew, known as a decoction, is prepared by boiling fresh or dried leaves, stems, or twigs for more than five minutes. The herbal tea prepared from L. javanica leaves, stems, or twigs has a lemon or vanilla aroma and is often used as a common tea (i.e., C. sinensis) substitute or a few leaves, stems, or twigs are added to C. sinensis to provide a lemon or vanilla aroma. According to Soukand and Kalle [87], herbal tea or tisane is an English term used to denote a decoction or infusion made of herbs for medicinal purposes. When L. javanica is used as medicinal herbal tea, it is consumed for a limited number of days to treat a specific condition like asthma in Zimbabwe [14], bronchitis in South Africa [19], chest pains in Zimbabwe and South Africa [14, 24], colds in Kenya, South Africa, and Zimbabwe [19, 20, 28-30], cough in South Africa and Zimbabwe [19, 20, 30, 53], and other diseases (see Table 1). From literature, it seems L. javanica herbal tea evolved over the years from medicinal tea decoctions or infusions to nonmedicinal uses, where the herbal tea is now drunk for recreation and enjoyment. According to Shikanga et al. [7], L. javanica tea is appreciated throughout its distributional range as a general health tonic and also because it is naturally caffeine-free and has a calming and relaxing effect. Research done by other workers, for example, Manenzhe et al. [2], Shikanga et al. [7], Parrant [8], Olivier et al. [81], Motlhanka and Makhabu [9], and Bhebhe et al. [10, 11], revealed that L. javanica is a popular recreational tea in southern Africa, consumed on a daily basis within a food context, while medicinal infusions or tisanes of L. javanica are taken for a specific medical purpose. During the past 20 years, the use of herbal teas has increased globally [107] because of their functional properties and consumer interest in the health promoting properties of such beverages [108]. The other advantage associated with L. javanica usage is that the leaves can be sun-dried and later boiled in water and drunk as herbal tea [9].

Most of L. javanica used as herbal tea in rural and periurban communities in central, eastern, and southern Africa is still collected from the wild, although small-scale cultivation has become necessary as it is marketed as herbal tea in Botswana under the brand name "Mosukudu" or "Mosukujane" [109] and in Zimbabwe as "Zumbani" (Figure 1(b)). Although considerable quantities of L. javanica are sold in local markets in Botswana and Zimbabwe and also traded on the Internet, there is no data on present production levels, traded volumes, values, and export figures in these two countries. Research by Whiteside [110] showed that sales of L. javanica tea bags generated an income of R20300.00 (US$5718) during 1994/1995 in Botswana. There is increased demand for L. javanica herbal tea especially in the light of growing health consciousness worldwide, with the estimated potential demand for the species and its products around 100 tonnes per year on the local market and 1000 tonnes per year on the export market (http://bioinnovation.org/work/fever-tea-tree/). Considering the rapid growth of the herbal tea industry worldwide and the increasing demand for L. javanica products, there is need for the improvement of L. javanica products as well as development of new products. Therefore, L. javanica has potential to make the transition from limited local use to commercial and international product. Lippia javanica has been identified as one of the few plant species that should be integrated in the domestication process in farming systems in subSaharan Africa to support medicinal, nutritional, and income security of local communities [107, 111]. According to Van Wyk [111], L. javanica is of commercial value as herbal tea and health drinks. Therefore, commercialization of L. javanica is unlikely to be viable if the product is sorely harvested from the wild. In the same line commercialization of L. javanica might be more worthy if other products other than tea are derived from the plant.

2.2. Respiratory Problems. The different parts of L. javanica, for example, the leaves and twigs, are used for the treatment of asthma, coughs, colds, influenza, pneumonia, tuberculosis, and bronchial problems in Bangladesh, Botswana, Ethiopia, Kenya, South Africa, and Zimbabwe [14-16, 19,20, 23,25,26, 28-32, 53,112]. In Bangladesh, leaf infusion of L. javanica is taken orally mixed with 3-4 pieces of cloves of A. sativum, 2-3 times daily as remedy for chest pains [23]. In Ethiopia, leaves of L. javanica are chewed with butter as remedy for chest pains and cough [26]. In India, L. javanica leaf decoction is taken orally as remedy for respiratory disorders [39]. In Kenya, leaves are sniffed [31] or half glass ofhot leaf infusion is taken orally three times a day [28, 29] as remedy for colds and cough. Research done by Davids et al. [19] in South Africa revealed that about 50 g of leaves is added to a cup of boiling water to produce an infusion which is taken orally as remedy for coughs, colds, and bronchial problems or the infusion is applied to the skin or mixed with Vaseline to make an ointment. In South Africa, leaf or twig decoction is taken orally for asthma, colds, and cough [16, 53], leaves are used in washes and poultices for chest pains [25], and leaves are boiled for 5 minutes and one cup of extract is taken orally thrice a day for chest pains and tuberculosis [24, 42]. According to York [18], two handfuls of L. javanica leaves are boiled in two litres of water and patient is steamed once or twice a dayto treat coughs, chest pain, headaches, fever, chills, a sore throat, or a blocked nose. This decoction can also be taken orally by drinking half a cup daily [18]. Alternatively, a handful of L. javanica roots or leaves are mixed with a handful leaves of A. glabratum or B. transvaalensis or B. uniflora or B. cathartica or C. anisata or C. brachiata or C. molle or E. grandis or H. kraussii or Hypoxis spp. or K. mosambicina or P. neochilus or P. guajava or S. serratuloides or T. sericea or T. riparia or T. emetica to treat blocked nose, chest pain, cough, earache, fatigue, fever, influenza, headache, runny nose, sleepless nights, sore throat, tiredness, and tonsillitis [18]. Leaf and stem infusion of L. javanica are taken orally together with A. afra by the Zulu people in South Africa as remedy for bronchial ailments, colds, and cough [20]. "Imbiza," a popular herbal decoction prepared from L. javanica and C. obliquus, is used by the Zulu people in South Africa as herbal tonic and an immune booster and also for the treatment of cancer, chest pains, colds, diabetes, HIV or AIDS symptoms, skin infections, and tuberculosis [27]. In some communities in South Africa, L. javanica leaf or root infusion is taken orally as remedy for influenza and malaria [33] and respiratory disorders [40, 41]. In Zimbabwe, leaf or root decoction is taken orally or smoke of burnt leaves and roots is inhaled as remedy for chest pains [14] and leaf and twigs are boiled in water and infusion is taken orally as remedy for colds and cough [30]. According to Gelfand et al. [14], Shona people in Zimbabwe rub leaf ointment of L. javanica on the chest and abdomen as remedy for pneumonia and leaf decoction is taken orally and body washed with leaf decoction as remedy for shortness of breath or dyspnoea. In South Africa, a leaf and stem infusion of L. javanica are taken orally together with leaves of A. afra as remedy for measles [20].

Based on literature, inhalation of smoke from L. javanica appears to be a popular remedy for asthma, chest pains, colds, and chronic coughs in Botswana, South Africa, and Zimbabwe [14, 15, 20, 32]. In Botswana, L. javanica leaf infusion vapour is inhaled as remedy for colds and cough [32]. In South Africa, for example, leaves and twigs are burned and smoke is inhaled as remedy for asthma and cough [15] or steam from leaf infusions is inhaled or hot leaf infusions are taken orally against colds and cough [20]. In Zimbabwe, smoke of burnt leaves and roots is inhaled as remedy for chest pains [14].

2.3. Gastrointestinal Diseases. The leaf and root decoction or infusions of L. javanica are used as remedies of the digestive system diseases such as cholera, diarrhoea, and dysentery. For example, in Mozambique, root decoction is taken orally as remedy for a type of diarrhoea commonly known as "chinhamucaca" which is characterized by milky diarrhoea accompanied by vomiting in children [44]. Leaf decoction is used as herbal medicine for diarrhoea in Kenya [113]. In South Africa, the leaves of L. javanica are crushed and mixed with cold or hot water and the mixture is then sieved and a quarter of a cup (75 mL) is taken twice a day until diarrhoea subsides [34]. The Venda people in South Africa use leaf infusions as prophylactic against diarrhoea [40]. Research done by Palgrave et al. [37] in South Africa revealed that tea infusions of the L. javanica leaves are used as remedies for HIV/AIDS opportunistic infections such as lung infections and diarrhoea. Previous research in Mozambique [114], South Africa [115], and Zimbabwe [116] showed that gastrointestinal disorders, particularly cholera, diarrhoea, and dysentery are among human diseases often treated with herbal medicines. For those patients diagnosed as having intestinal worms in Venda, South Africa, a leaf infusion of L. javanica leaves is used as an anthelmintic [40]. Therefore, these findings illustrate that herbal medicines including L. javanica can play an important role in basic health care of local communities through treatment and management of cholera, diarrhoea, and dysentery.

2.4. Fever, Malaria, and Insect Repellent. Traditionally, L. javanica is commonly used to treat fever and malaria and repel insects throughout its distributional range [4, 14, 16, 17, 33-35, 40, 48-50, 58-60]. In South Africa, a decoction of fresh or air dried leaves is used to wash or steam body parts infested with lice [50]. In India, the whole plant is used to repel lice in poultry [61]. In South Africa and Zimbabwe, whole plant or leaves are burnt to repel mosquitoes [4, 34, 35, 48, 49, 58]. In South Africa and Zimbabwe, L. javanica is widely used to get rid of ticks and other ectoparasites; for example, ticks are sprayed with crushed leaves mixed with water or twigs are used as bedding in fowl runs [58-60]. Leaf and twig decoction of L. javanica are taken orally as remedy for fever [16]. The Venda people in South Africa use leaf infusions of L. javanica as prophylactic against malaria [40]. In Zimbabwe, leaf decoction is taken orally as remedy for fever [14].

Lippia javanica is also cultivated on a commercial scale by a rural community in Giyani, the Limpopo province, South Africa, for the production of mosquito-repellent candles [117]. Clinical studies using human volunteers showed that L. javanica repels no less than 95% of mosquitos, whereas most mosquito repellents repel only 42% of them [118]. Based on these findings, the Council for Scientific and Industrial Research (CSIR), South Africa, signed a benefit sharing agreement with traditional healers allowing for the commercial cultivation of L. javanica aimed at establishing an indigenous oil industry for rural development and large-scale production of antimosquito candles and other insect repellents. The mosquito repellent is registered as a patent under the Fertilisers, Farm Feeds and Stock Remedies Act (Act 36 of 1947) as a pest repellent [119]. These findings and the establishment of a large-scale production of antimosquito candles and other insect repellents strengthen the view that L. javanica is a potential source of antipesticidal agents and to some extent validate the traditional use of the plant species for insect pest control. Pesticidal plants such as L. javanica are increasingly being used as alternatives where synthetic products are unaffordable or are not available or are ineffective. A number of studies have indicated that the use of L. javanica as a pesticide is a long-standing tradition passed down from generation to generation [120].

2.5. Wounds, Injuries, Pain, and Skin Infections. Lippia javanica is used as remedy for a variety of skin infections and injuries in Kenya, South Africa, Swaziland, and Zimbabwe. In South Africa, leaf infusions are used to treat skin disorders, such as boils, chicken pox, febrile rashes, heat rashes, measles, scabies, scratches, and stings [20, 21, 40, 50, 54]. In Kenya, about 50 g of fresh leaves is wrapped around a fresh wound to enhance healing [57] and, in South Africa, leaf infusions are taken orally as remedy for wounds [54]. In South Africa, powder from burnt roots of L. javanica is applied to scarifications made around sprained joints to facilitate healing [20]. In Kenya and Zimbabwe, leaf infusion is taken orally to treat measles or a patient is washed with leaf infusion [14, 38]. The Zulu people in South Africa take a mixture of chopped handful leaves of L. javanica with the same amount of bark of A. burkei, O. engleri, S. birrea, S. cordatum, and T. elegans boiled in two litres of water as an enema for the treatment of sores [56]. In Swaziland, about 30 g of L. javanica leaves and similar amount of Acanthospermum australe Kuntze are boiled in 5 litres of water and decoction is taken as remedy for sores [55]. In Zimbabwe, root ashes of L. javanica mixed with fat are applied to the skin of a patient with scabies [14]. Wound healing is a process which involves distinct overlapping phases of coagulation, inflammation, proliferation, and tissue remodelling [121]. The same authors argued that a set of complex biochemical events takes place in a closely orchestrated cascade to repair the wound and any errors in the wound healing process can lead to delayed healing or formation of hypertrophic scars. Abubakar [122] argued that colonization of wounds by opportunistic microorganisms usually delays the wound healing process and/or may lead to infectious condition. Therefore, application of L. javanica on wounds and skin infections leads to disinfection, debridement, and provision of a suitable environment for aiding the wound healing process. Lippia javanica has potential for therapeutic use in wound and skin diseases management, but there is need for research on the safety, phytochemistry, and biological properties of the species.

2.6. Ethnoveterinary Uses. The leaves, stems, twigs, and whole plants of L. javanica are used as ethnoveterinary medicine in India, Kenya, South Africa, and Zimbabwe. The Xhosa people in the Eastern Cape province, South Africa, use L. javanica leaves for the disinfection of meat that has been infected with anthrax [20]. In Kenya, the stem of L. javanica is used to preserve milk by applying it to the gourd before milk fermentation [62]. In India, whole plants are used as lice repellants while, in South Africa and Zimbabwe, crushed leaves mixed with water are used to get rid of ticks and twigs are used as bedding in fowl runs to get rid of ectoparasites [58-60].

2.7. Other Uses. Lippia javanica is used as a good luck charm, to treat persons experiencing bad dreams, to ward off evil spirits, to protect one from lightening, and to protect the home (Table 1). In Zimbabwe, L. javanica leaves are prepared as an infusion to treat persons experiencing nightmares [64]. In both South Africa and Zimbabwe, evil spirits are cleansed by washing the body of an affected person by leaf infusion of L. javanica [14, 123]. In Swaziland, 50 g leaves of L. javanica and C. molle are ground into a powder and 5 litres of water is added and face and hands are washed to remove bad luck when exposed to a corpse [71]. In South Africa, the whole plant is placed on a patient's bed after the circumcision ceremony [58], to prevent odours and freshen surrounding air. A mixture of L. javanica leaves and roots is used to clean tools and hands before and after funerals, the stems and leaves are used as brooms to sweep grave sites, and the entire plant is also used when coming from the mortuary to remove bad spirits [58, 124]. The corpse is washed with L. javanica infusion after death to prevent odours forming or if the corpse has an odour, women place pieces of L. javanica in the nostrils of the corpse and sweep the room with twigs where the person was sleeping [58]. In KwaZulu Natal, South Africa, if the meat started to smell it will be boiled with L. javanica leaves to take away the smell [58]. The Xhosa people in the Eastern Cape province, South Africa, use L. javanica leaves for the disinfection of meat that has been infected with anthrax [20]. In KwaZulu Natal, South Africa, leaves are sprinkled in toilets to prevent odours [58]. Leaves of L. javanica are sprinkled in houses for pleasant smell in the Limpopo province, South Africa [35], and Kenya [31]. In KwaZulu Natal, South Africa, it is believed that a person can repel snakes by placing a small stem with leaves on his or her head [58]. In Malawi, Swaziland, and Zimbabwe, people showing sign of mental disorder, madness, or hysterical outbursts are required to wash their bodies with leaf infusions [14, 67, 68, 71].

3. Phytochemical Constituents and Nutritional Composition of Lippia javanica

Multiple classes of phytochemicals including volatile and nonvolatile secondary metabolites, such as alkaloids, amino acids, flavonoids, iridoids, and triterpenes as well as several minerals, have been identified from L. javanica [1-5,7,13,27, 73, 78, 81, 83-86, 88-94, 120, 123, 125-127]. Leaves, flowers, and twigs of L. javanica have a wide variety of the so-called classic nutrients, such as minerals, carbohydrates, proteins, fats, and vitamins (Table 2). Lippia javanica leaves are a good source of minerals such as cadmium, calcium, chromium, cobalt, copper, iron, magnesium, manganese, selenium, and zinc [27]. These authors assessed the levels of the elements in L. javanica leaves and found the elements to be in the decreasing order of Ca > Mg > Fe > Zn > Mn > Cu > Se > Cr > Pb > Co > Cd for total concentrations and Ca > Mg > Fe > Zn > Cu > Cr > Pb for water extractable forms. These results corroborate an observation made by Sedaghathoor et al. [128] that Ca and Mg are among the most abundant elements in tea plants. These mineral elements are important in human nutrition since L. javanica is used as herbal tea and food additive (Table 1). Calcium, magnesium, iron, manganese, and zinc play a major role in activating some enzymes and regulating many responses of cells to stimuli [129]. Some of the mineral elements identified from L. javanica leaves are required by the human body for repair of worn out cell tissues and strong bones and teeth and building of red blood cells and other related tissues. Therefore, since L. javanica has appreciable concentrations of mineral elements such as calcium, magnesium, iron, manganese, and zinc (Table 2) which are essential for enzyme metabolism, these mineral elements could enhance the nutritional and curative properties of the species.

Bhebhe et al. [10] determined the total phenolic and tannin content and radical scavenging activities of L. javanica, comparing it with Aspalathus linearis (Burm.f.) R. Dahlgren (Rooibos[TM]), a commercial South African herbal tea, and other popular herbal teas in Zimbabwe (Table 3). Adansonia digitata L., Fadogia ancylantha Schweinf., Ficus sycomorus L., and Myrothamnus flabellifolius Welw. are indigenous herbal teas consumed in Zimbabwe. The tannin content of L. javanica is very low when compared to A. linearis (Rooibos) (Table 3). Lippia javanica has higher radical scavenging activity than A. linearis (Table 3) which is probably due to higher total phenolic content in comparison to A. linearis which is a popular herbal tea consumed by 10% of the global herbal tea market [10]. In another study, Bhebhe et al. [11] determined and compared the effect of several solvents, namely, hot water, 50% methanol, ethanol, 50% ethanol, acetone, 50% acetone, and ethyl acetate, on phenolic composition and free radical scavenging activity in common black tea, C. sinensis, and five other well-known herbal teas including L. javanica. In all the seven solvents used, L. javanica had higher total phenolic content than C. sinensis implying that L. javanica is competitive to the black tea in terms of phenolic content. Shikanga et al. [7] found leaf extracts of L. javanica to have higher phenolic content of 14.8 mg/g gallic acid equivalent of dry weight than flowers (9.9mg/g) and twigs (8.3mg/g). Phenolic compounds found in plants are known to play an important role as antioxidants in exhibiting the medicinal properties such as antibiotic, anti-inflammatory, anticancer, and antiallergic properties [10, 66,130,131].

The compounds isolated from L. javanica are documented and listed in Appendix A and their structures are presented in Appendix B. Simple phenolic compounds and caffeic acid and its derivatives are some of the compounds that have been identified in L. javanica and examples include coumarin 1, 3,4-dihydroxy-[beta]-phenylethoxy-O-[4"-[beta]-caffeoyl- [alpha]-rhamnopyranosyl-(1"' ,3")-O-[beta]-glucopyranoside], commonly referred to as verbascoside 2, and 3,4dihydroxy-[beta]-phenylethoxy-O- [6"-[beta]-caffeoyl-[alpha]-rhamnopy- ranosyl-(1"',3")-O-[beta]-glucopyranoside] commonly referred to as isoverbascoside 3 isolated by Olivier et al. [81] from the aerial parts of the species. Nonvolatile diterpenes, known as iridoid-glycosides, have also been isolated from L. javanica by Rimpler and Sauerbier [82] represented by theveside-Na 4 and theveridoside 5. Mujovo et al. [83] isolated a long chain alkane "4-ethylnonacosane" 6 and four flavanones apigenin 7, cirsimaritin 8, 6-methoxyluteolin 4'-methyl ether 9, and 6-methoxyluteolin 3',4' ,7-trimethyl ether 10 from ethanolic extracts of L. javanica leaves. Madzimure et al. [120] identified an array of phenolic glycosides and flavonoids which include crassifolioside 11, luteolin 12, diosmetin 13, chrysoeriol 14, tricin 15, isothymusin 16, eupatorin 17, 5-dimethyl noboletin 18, genkwanin 19, salvigenin 20, and an alkaloid xanthine 22. Ludere et al. [84] isolated lippialactone 21 from the ethyl acetate extract of aerial parts of L. javanica. Neidlein and Staehle [85] and Dlamini [86] isolated 19 amino acids, compounds 23 to 41 in Appendix A, from L. javanica. At least 131 different classes of essential oil compounds (compounds 42-172 in Appendices A and B) have been isolated from L. javanica by several researchers [3-5, 83, 85, 86, 88-94, 123]. Hutchings and van Staden [96] isolated a toxic triterpenoid saponin, icterogenin 173, from L. javanica leaves. These different classes of essential oil compounds have been associated with various therapeutic activities such as anaesthetic, analgesic, anti-inflammatory, antimicrobial, cardiovascular, decongestant, digestive, expectorant, hepatoprotective, and sedative activities as well as stimulant of nervous system and tonifying effects [132]. Meanwhile flavonoids possess several pharmacological properties including antibacterial, anticancer, anti-inflammatory, antioxidant, antiviral, and hepatoprotective effects [133] which play important roles in human health. Flavonoid such as apigenin 7 is reported to possess antibacterial [134] and hepatoprotective [135] properties. Apigenin 7 and luteolin 12 are reported to possess anti-inflammatory and analgesic effects [133], affecting the function of enzyme systems involved in the generation of inflammatory processes, especially tyrosine and serine-threonine protein kinases [136,137]. It has also been reported that apigenin 7 prevents HIV-1 activation via a novel mechanism that involves inhibition of viral transcription [138] and luteolin 12 demonstrated synergistic effects with another flavonoid kaempferol against herpes simplex virus [133]. Kamiya [139] documented the importance of essential amino acids such as lysine, valine, isoleucine, and histidine in terms of the risks to health if they are deficient. The author also documented their biological effects which include muscle protein maintenance, potentiation of immune function, tissue repair acceleration after burn or trauma, protecting liver from toxic agents, lowering blood pressure, modulating cholesterol metabolism, and stimulating insulin or growth hormone secretion. Therefore, L. javanica leaves and other plant parts which have shown to be rich in flavonoid and polyphenolic compounds, amino acids, and essential oil could play an important role in the treatment and management of diseases such as hypertension and inflammation listed in Table 1.

4. Pharmacological Activities

Scientific studies on L. javanica indicate that it has a wide range of pharmacological activities (Table 4), which include anticancer [140], antidiabetic [141], antimalarial [4, 49,142], antimicrobial [2, 3, 7, 17, 73-75, 77, 83, 84, 126, 143], antioxidant [7, 10, 11, 75, 77, 125], antiplasmodial [2, 79, 80, 84, 144, 145], and pesticidal effects [1, 2, 59, 95, 120, 146-150] and cytotoxicity [2, 73, 79, 120] activities. Table 4 summarizes some ofthe pharmacological studies undertaken on L. javanica extracts aimed at evaluating some of the ethnomedicinal uses of the species documented throughout its distributional range (see Table 1). Some of the listed pharmacological activities may not relate directly to the documented ethnomedicinal uses of the species but may provide some insight into the species' potential therapeutic value and bioactive properties and application.

4.1. Anticancer Activity. Fouche et al. [140] reported anticancer activity of dichloromethane root extract of L. javanica against three human cells, exhibiting TGI value of 1.82 [micro]g/mL for breast MDA-MB-435,1.86 [micro]g/mL for breast MDA-N, and 2.09 [micro]g/mL for melanoma MALME-3M. Based on literature, a couple of terpenoid compounds that have been isolated from L. javanica are known to have antitumor properties. For example, linalool 120 is known to have antitumor activity which plays a protective role against hepatotoxicity and the compound has anti-inflammatory activities as well [151]. Research by Yang et al. [152] showed limonene 92 to have inhibitory effect on pancreatic and mammary tumors. Another terpenoid compound, a-pinene 44, is known to inhibit translocation of NF-[kappa]B or p65 protein into nuclei of LPS-stimulated THP-1 cells [153]. These findings serve as a scientific validation for the use of L. javanica as a component of a herbal concoction known in KwaZulu Natal province as "imbiza," prepared by mixing L. javanica with C. obliquus as herbal medicine for cancer [27].

4.2. Antidiabetic Activity. Arika et al. [141] determined the in vivo antidiabetic activity of aqueous leaf extracts of L. javanica in white male alloxan-induced albino mice. The aqueous leaf extracts of L. javanica at all dose levels significantly lowered the blood glucose levels in both oral and intraperitoneal routes. The antidiabetic effect of L. javanica could have been due to the observed presence of flavonoids. The polyhydroxylated flavonol enhances lipogenesis and glucose uptake in the adipocytes and flavanoids have demonstrated insulinmimetic properties as the compound is known to be effective at controlling blood sugar levels. These findings strengthen the view that L. javanica is a potential source of antidiabetic agents and to some extent validate the traditional use of the plant species mixed with C. obliquus to form a herbal concoction known in KwaZulu Natal province, South Africa, as "imbiza" used against diabetes [27].

4.3. Antimalarial Activity. Govere et al. [142] found that topical application of L. javanica alcohol extract leads to 76.7% protection against Anopheles arabiensis for 4 hours. Lippia javanica has been used as a mosquito repellent by the rural communities in Zimbabwe for a long time and previous studies have shown that essential oils from the species have very strong and lasting repellent activity against female A. arabiensis [64]. Research by Lukwa et al. [4] revealed that topical application of 5 mg/[cm.sup.2] of L. javanica leads to 100% protection against Anopheles aegypti for 8 hours. Mavundza et al. [154] screened dichloromethane and ethanol leaf extracts of L. javanica for adulticidal activity against A. arabiensis. The authors observed dichloromethane and ethanol activities of 45% and 55% mosquito mortality, respectively. These findings strengthen the view that L. javanica is a potential source of antimalarial agents and to some extent validate the traditional use of the plant species as mosquito repellent in India [47], South Africa [34, 49, 58], and Zimbabwe [4, 48].

4.4. Antioxidant Activity. Leaf infusions of L. javanica exhibited antioxidant activity with [EC.sub.50] value of 358 [micro]g/mL and contained 14.8 mg/mL of dry weight gallic acid equivalent phenolic compounds [7]. The [EC.sub.50] value of 358 [micro]g/mL obtained for L. javanica by Shikanga et al. [7] compares well to those of many commercial teas, including antioxidant capacity of Rooibos Fresh Pack[TM] herbal teas (A. linearis) with the best antioxidant activity of 333 [micro]g/mL. The high antioxidant activities displayed by L. javanica infusions can be partially attributed to the high levels of verbascoside 2 (1.5mg/g dry weight) reported by Olivier et al. [81] in the leaf extract of the species. Earlier research by Muchuweti et al. [125] reported 74.4% inhibition of the DPPH radical by an ethanolic leaf extract of L. javanica. Lekganyane et al. [75] reported antioxidant activity in L. javanica and the acetone extracts of the species displayed antioxidant activity on BEA chromatogram [77]. Bhebhe et al. [10] reported the antioxidant activities of L. javanica based on the DPPH, reducing power and inhibition of phospholipid peroxidation assays. Free radical scavenging activity of L. javanica is attributed to phenolic compounds since these compounds have an ideal structural chemistry for free radical scavenging activity [155]. Bhebhe et al. [11] determined the effect of several solvents on the free radical scavenging activity of L. javanica using the DPPH assay. Free radical scavenging activity expressed as [IC.sub.50] ranged from 0.022 [+ or -] 0.001 g/mL to 0.066 [+ or -] 0.001 g/mL; see Table 4.

4.5. Antiplasmodial Activity. Prozesky et al. [144] evaluated L. javanica leaf acetone extract for in vitro antiplasmodial activity using PfUP1, a chloroquine resistant strain of the malaria parasite Plasmodium falciparum by means of the flow cytometric test. The [IC.sub.50] value for L. javanica was 4.26 [micro]g/mL. Manenzhe et al. [2] evaluated essential oil, piperitenone 162, isolated from L. javanica for antiplasmodial activity using chloroquine diphosphate as positive control and found it active against a chloroquine sensitive strain of P. falciparum in micromolar concentrations with [IC.sub.50] of 8 [micro]g/mL. Clarkson et al. [80] evaluated L. javanica roots and stems extracts for in vitro activity against P. falciparum using the parasite lactase dehydrogenase (pLDH) assay and chloroquine diphosphate (Sigma) as the positive control. The dichloromethane, methane, and water extracts showed [IC.sub.50] values ranging from 3.8 to >100 [micro]g/mL; see Table 4. Omolo et al. [145] screened the essential oil of L. javanica for fumigant toxicity to Anopheles gambiae which exhibited LD50 of 4.3 x [10.sup.-3] mg [cm.sup.-3]. Ayuko et al. [79] showed that L. javanica root extracts have antiplasmodial activity against P. falciparum with [IC.sub.50] ranging from 1.35 to 18.59 [micro]g/mL; see Table 4. Lippialactone 21, derived from the ethyl acetate extract of aerial parts of L. javanica, exhibited some activity against the chloroquine sensitive D10 strain of P. falciparum with an [IC.sub.50] value of 9.1 [micro]g/mL and is also mildly cytotoxic [84]. Compared to chloroquine, the compound is approximately 2000 times less active against the D10 strain of P. falciparum [84].

4.6. Antimicrobial Activities. Lippia javanica is widely used in the treatment of a wide range of infectious diseases caused by microorganisms. Viljoen et al. [3] determined the antimicrobial properties of L. javanica by evaluating the time kill studies of the species' essential oil using the disc diffusion assay on three respiratory pathogens Klebsiella pneumoniae, Cryptococcus neoformans, and Bacillus cereus. This study showed that the killing rate was greatest for K. pneumoniae followed by C. neoformans and very little reduction of microbial populations was observed for B. cereus. The efficacy of L. javanica oil for K. pneumoniae showed a killing rate within 30 minutes for the concentrations 0.25, 0.5, 0.75, and 1%, C. neoformans showed a killing rate for concentrations 0.5, 0.75, and 1% within 1 hour, and the lowest concentration of 0.25% took 8 hours before a bactericidal effect was noted while B. cereus showed some reduction in colonies [3]. The positive antimicrobial activity of L. javanica as revealed by the time kill study could be attributed to linalool 120 which averages between 65 and 70% in yield [3, 5, 88, 90] and has known antimicrobial properties [93,156-159]. These findings somehow corroborate the traditional use of L. javanica as herbal medicine for a wide range of bacterial and fungal respiratory ailments indicated in Table 1.

Manenzhe et al. [2] evaluated essential oil, piperitenone 162, isolated from L. javanica for antibacterial activity on cultures of Bacillus subtilis, Staphylococcus aureus, and Escherichia coli using imipenem, cefazolin, and ampicillin as positive controls. The authors found piperitenone 162 to inhibit S. aureus and E. coli at 1% dilution. Acetone, hexane, and methanol leaf extracts and essential oil isolated from L. javanica showed some activity against fifteen Grampositive and Gram-negative bacteria with MIC values ranging from 1.5 to >12 mg/mL [60]; see Table 4. In a similar study, Samie et al. [73] demonstrated that a pure compound piperitenone 162 isolated from L. javanica has antibacterial activities against Acinetobacter calcoaceticus, Micrococcus kristinae, Salmonella typhi, and S. aureus using dimethyl sulphoxide and kanamycin as controls, with MIC values ranging from 12 to 50 [micro]g/mL; see Table 4. Shikanga et al. [7] evaluated the antibacterial activity of L. javanica methanolic leaf extract against S. aureus, Enterococcus faecalis, E. coli, and Pseudomonas aeruginosa using the serial microdilution method with gentamycin (Virbac[R]) and acetone as positive and negative controls, respectively. Lippia javanica displayed antibacterial activities with MIC values ranging from 0.13 to 0.42 mg/mL against all four pathogens; see Table 4. The obtained minimum inhibitory concentrations are promising, since natural products with MIC values below 1 mg/mL are generally considered to be noteworthy findings [160]. Lippialactone 21, derived from the ethyl acetate extract of aerial parts of L. javanica, exhibited some activity against the E. coli and S. aureus at a concentration of 10 mg/mL [84]. Lekganyane et al. [75] reported antibacterial activity of L. javanica acetone leaf extracts against E. coli, E. faecalis, P. aeruginosa, and S. aureus with MIC values ranging from 0.32 to 0.64 mg/mL and total activity of the same species ranging from 127 to 253 mg/mL; see Table 4. Methanol and water leaf extracts of L. javanica exhibited some antiproteus activity against Proteus mirabilis and Proteus vulgaris with MIC values <2000 [micro]g/mL with standard discs of ampicillin (2 [micro]g) and chloramphenicol (10 [micro]g) as positive controls [74]. Some of the antibacterial properties of L. javanica can be attributed to the phytochemical constituents of the species; for example, the phenolic compound apigenin 7 is a well-known antibacterial agent [7, 134]. Apigenin 7 was shown to be highly active against Vibrio cholera and E. faecalis [161], while Basile et al. [162] reported the inhibition of S. typhi, P. mirabilis, and P. aeruginosa by the compound. Therefore, results from these antibacterial evaluations of L. javanica give credence to the use of the species' infusions against bacterial infections and other related diseases.

Shikanga et al. [126] investigated the antifungal activities of leaf extracts and essential oil compounds isolated from L. javanica leafy extracts against a Guazatine[R]-resistant strain of Penicillium digitatum. The methanolic leafy extracts, isoverbascoside 3 and verbascoside 2 compounds, isolated from L. javanica inhibited fungal growth at concentrations above 0.6 mg x [mL.sup.-1], causing significant inhibition of mycelial growth. Verbascoside 2 is well-known for its antimicrobial properties and has been found to inhibit viruses, bacteria, and fungi [163]. Similarly, Samie et al. [143] investigated antifungal effects of acetone and hexane leaf extracts of L. javanica against Candida albicans, Candida krusei, and C. neoformans isolated from AIDS patients using the microdilution method with nystatin, Roche, and DMSO as positive and negative controls, respectively. Noteworthy moderate antifungal activities were recorded from C. krusei with MIC value of 1.88 mg/mL and other recorded MFC and MIC values for other species ranged from 1.88 mg/mL to >7.5 mg/mL; see Table 4. Thembo et al. [76] investigated the antifungal activity of aqueous and organic extracts of L. javanica using a serial microdilution assay. Generally, extracts of L. javanica exhibited weak activity; see Table 4.

4.7. Antimycobacterial Activity. Mujovo et al. [83] evaluated L. javanica compounds against a drug-sensitive strain of Mycobacterium tuberculosis using the radiometric respiratory techniques. Of all the isolated compounds, only one triterpenoid carboxylic acid, euscaphic acid 172, exhibited antimycobacterial activity with MIC value of 50 [micro]gm [L.sup.-1] against this strain. In a similar study, the leaf extract of L. javanica exhibited antimycobacterial activity against M. smegmatis in an evaluation which used microdilution assay and rifampicin as control [77]. Acetone extract was the best extractant with MIC value of 0.47 mg/mL; it extracted antibacterial agents which was indicated by the lowest MIC value [77]. Masoko and Nxumalo [77] also evaluated the total activityof L. javanica which averaged 13 mL/g suggesting that the extract prepared from one gram of L. javanica could be diluted to a volume of 13 mL and will still inhibit M. smegmatis efficiently. According to Semenya and Maroyi [115], tuberculosis caused by M. tuberculosis is a serious disease requiring effective strategies and tools to control and manage it. Therefore, preliminary evaluations done by Mujovo et al. [83] and Masoko and Nxumalo [77] serve as a scientific validation for the use of L. javanica in traditional medicine for treatment of tuberculosis and other respiratory ailments in South Africa [24,27,115] and Uganda [43] as well as their efficiency in tuberculosis drug discovery.

4.8. Antiviral Activity. Mujovo et al. [83] found that (E)-2(3)-tagetenone epoxide 42 and piperitenone 162 inhibited the HIV-1 reverse transcriptase enzyme by 91% and 53%, respectively, at 100 [micro]gm [L.sup.-1] based on a nonradioactive HIV RT colorimetric ELISA kit. Little is known about the HIV RT activity of L. javanica extracts or compounds, but flavonoids are known to be active against viral RT and also as potent inhibitors of the cellular alpha and beta DNA polymerase [83], while luteolin 12 is active against HIV RT [164, 165]. Lippia javanica is traditionally used to treat HIV/AIDS symptoms in South Africa [65, 66] and several viral and HIV/AIDS opportunistic diseases and infections such as bronchitis [15, 19-22], chicken pox [50], diarrhoea [17, 34, 37, 44, 113], measles [14, 20, 38], pneumonia [14], shingles [15], and venereal diseases [44]. Despite significant advances in the utilization of L. javanica in southern Africa over the years for numerous viral diseases (Table 1), very little antiviral evaluations have been done on crude extracts and purified compounds of the species. There is need, therefore, for more pharmacological research as L. javanica could be harbouring potent (RT) inhibitors which could be useful for the development of new pharmaceutical products important for use against viral diseases and infections.

4.9. Pesticidal Effects. Magano et al. [95] evaluated the repellent effects of hexane extracts of L. javanica essential oil using the in vitro tick climbing repellency bioassay on adults of Hyalomma marginatum rufipes Koch ticks. The authors found that 107 mg/mL caused repellency index of 100% at one hour and 30 minutes. In a similar study by Madzimure et al. [120], L. javanica aqueous leaf extracts at 10% and 20% w/v were effective at controlling cattle ticks (Amblyomma species, Boophilus species, Hyalomma species, Rhipicephalus appendiculatus, and Rhipicephalus evertsi evertsi) and were as good as the positive control amitraz-based acaricide Trickbuster[R]. These authors found no parasites on microscopic examination of the Giemsa-stained thin blood smear collected from treated cattle implying that the animals did not suffer from clinical tick-borne diseases. Similarly, Nyahangare et al. [59] tested the pesticidal activity of L. javanica water extracts against cattle ticks. The authors found no significant difference between cattle treated with a commercial synthetic acaricide and those under L. javanica treatment. Martinez-Velazquez et al. [166] evaluated pesticidal effects of two essential oils, namely, [gamma]-terpinene 82 and [rho]-cymene 99, isolated from Lippia graveolens Kunth against 10-day-old Rhipicephalus (Boophilus) microplus (Canestrini) tick larvae using the larval packet test bioassay. The two essential oils produced high mortality ranging from 90 to 100% in all tested concentrations of 20 to 1.25% (v/v). Therefore, L. javanica can provide an effective tick control option where synthetic products are unavailable or unaffordable particularly in remote rural areas in sub-Saharan Africa. Lippia javanica is popular for tick control and management among resource-poor smallholder farmers in South Africa [58, 95] and Zimbabwe [59, 60,120]. While these preliminary evaluations may serve as confirmation that L. javanica has some bioactivities against ticks, a comprehensive method of tick control is required for the resource-constrained smallholder farmers based on ethnopharmacological properties of L. javanica.

McGaw et al. [146] screened L. javanica for the anthelmintic test systems using the free living nematode Caenorhabditis elegans. The crude ethanol and hexane extracts showed some activity at a concentration of 2 mg/mL, with the 7-day incubation assay appearing to be more sensitive than the shorter assay. Earlier research by Mwangi et al. [1] indicated that L. javanica was active against Aedes aegypti larvae and Sitophilus zeamais Motschulsky (maize weevil). Katsvanga and Chigwiza [147] reported that L. javanica is an effective natural pesticide which can be used to control aphid species (Brevicoryne brassicae). In their study, Katsvanga and Chigwiza [147] found that 1 : 1 powdered aqueous leaf extract of L. javanica reduced B. brassicae by 53.2% against 78.3% and 96.7% of two synthetic pesticides, Aphid kill and Bexadust "L," respectively. Chikukura et al. [149] found L. javanica powdered leaf extracts to have insecticidal properties with potential to control grain damage by 21-33%. Mashela et al. [148] reported that the application of ground L. javanica leaves to soil in nematode-infested (Meloidogyne incognita) pots reduced the nematode numbers by 79-92% and significantly increased fresh fruit yield, dry shoot mass, plant height, and stem diameter of the tomato plants, as well as levels of potassium, nitrogen, and manganese in leaf tissue. Muzemu et al. [150] evaluated water extracts of L. javanica leaf powder for pesticidal effects against rape (Brassica napus L.) aphids, B. brassicae, and tomato (Solanum lycopersicum Lam.) red spider mites, and Tetranychus evansi as alternatives to conventional pesticides. Lippia javanica reduced B. brassicae and Tetranychus evansi by 12.5% and 63%, respectively [150]. The study demonstrated that L. javanica has pesticidal effects on B. brassicae and T. evansi. The reduced number of B. brassicae and T. evansi could be due to L. javanica's extracts having repellent, toxic, and antifeedant effects since the species has essential oils with pesticidal properties [2]. Therefore, these findings indicate that L. javanica has both nematicidal and plant growth-promoting properties.

4.10. Toxicity and Cytotoxicity Activity. Lippia javanica is known to cause liver damage and photosensitisation in livestock, resulting in stock losses [167]. Triterpenoids isolated from the genus Lippia are icterogenic and cause jaundice as a result of liver damage [167]. The characteristic swelling, yellowing, and later peeling of unpigmented skin are due to the presence of phylloerythrin, a photodynamic porphyrin that reacts with sunlight and causes severe cell damage [167]. The compound is normally formed when chlorophyll is broken down by microorganisms in the rumen, but it now accumulates in the liver as a result of the damage caused by triterpenoids [167]. In view of the known toxicity of Lippia species, the prolonged use of high doses of L. javanica is potentially harmful [167]. Lippia javanica showed low toxicity after 48 h exposure with the percentage of mortality below 50% [74].

Ayuko et al. [79] evaluated the toxicity of L. javanica using a brine shrimp cytotoxicity assay with LC50 value of 1138 [+ or -] 1.33 [micro]g/mL. Ayuko et al. [79] found the cytotoxicity to antiplasmodial activity ratios for the methanolic extracts of the two tested strains to be 843.0 and 650.3, and since these are greater than 100, it may be concluded that the extracts are of low toxicity. Samie et al. [73] demonstrated that a pure compound piperitenone 162 isolated from L. javanica essential oil has low cytotoxicity activity against intestinal adenocarcinoma cells (i.e., the HCT-8 monolayers with [IC.sub.50] of 265.6 [+ or -] 5.3 [micro]g/mL). Lukwa [64] evaluated the toxicity of L. javanica aqueous leaf extracts using sexually mature BALB/c mice with the placebo as control. Within 48 hours, all mice fed with the L. javanica leaf aqueous extract at 12.5-37.5% v/v were lethargic, and the overall mortality was 37.5%. Previous research by Manenzhe et al. [2] showed that hydrodistillation of L. javanica leaves, flowers, and stems produced oil that was poisonous against P. falciparum when diluted to 1% (v/v). These findings imply that, despite its apparent safety, water extracts of L. javanica leaves may have deleterious health implications on humans and animals if consumed at very high doses.

Many compounds that have been isolated from L. javanica including phenolic glycosides, flavonoids, and essential oils are not known to have acute toxic properties with the exception of icterogenin 173. Icterogenin 173 has been shown to inhibit biliary excretion in rabbits [168]. Reports in literature indicate that the consumption of xanthine 22 has resulted in mammalian toxicity. According to Madzimure et al. [64], xanthine 22 is a demethylated derivative of caffeine with pharmacological actions such as central nervous system (CNS) stimulation, relaxation of smooth muscle (especially bronchial muscle), myocardial stimulation, peripheral vasoconstriction, and diuresis. Considering the widespread use of L. javanica as herbal tea and medicine, it is important to determine if any toxicological effects can occur from its chronic or subchronic usage.

4.11. Other Activities. Mpofu et al. [169] determined the effect of inclusion of L. javanica leaf meal in broiler diets on growth performance, carcass characteristics, and fatty acid profiles. The authors found that the L. javanica fed broilers had higher total polyunsaturated fatty acids and n-3 fatty acids. The findings from the study showed that inclusion of L. javanica in broiler diets at 5 g/kg feed has positive influences on growth performance, carcass characteristics, and fatty acid profiles of broiler meat and, therefore, L. javanica has potential as growth-promoting feed additive in broilers. Samie et al. [73] evaluated antiamoebic activity of a pure compound piperitenone 162 isolated from L. javanica essential oil against Entamoeba histolytica using microdilution method with metronidazole as the positive control, diluents (i.e., culture medium with an appropriate concentration of dimethyl sulphoxide as the negative control), and a blank (i.e., culture medium without dimethyl sulphoxide). Samie et al. [73] demonstrated that piperitenone 162 had marked antiamoebic activity with [IC.sub.50] value of 25 [micro]g/mL. More research is required as L. javanica could be harbouring potent antiamoebic properties which could be useful for managing amoebiasis, an infection that remains a significant cause of morbidity and mortality worldwide.

5. Conclusion

Lippia javanica has been used in African and Asian countries as herbal tea and medicine for many centuries. Utilization of L. javanica because of its flavour and medicinal properties forms the basis of the current demand for the plant species in central, eastern, and southern Africa. Research on L. javanica over the past decade on health promoting properties has greatly contributed to the increased consumption of the species as herbal or recreational tea. The focus of this research has been on phytochemical compounds, particularly phenolic content and antioxidant and free radical scavenging activities. Phenolic compounds present in L. javanica are largely responsible for the antioxidant properties possessed by the species. More research in this regard is required and future research should focus on more comprehensive chemical characterization of both crude and pure extracts and evaluate potential for commercialization and development of nutraceutical products based on traditional uses of L. javanica. Most of the pharmacological researches conducted on L. javanica so far have focused on the phytochemistry and biological properties of leaves, and little or no research has been done on roots and other plant parts. Therefore, future research on the species should focus on other plant parts, for example, flowers, roots, and stems, as well as organ-to-organ, age, and seasonal variation evaluations in the phytochemical content and pharmacological activities of the species.

The recent increase in the demand for L. javanica products may partly be ascribed to growing body of scientific evidence indicating important health benefits. Lippia javanica is widely sold as herbal tea in Botswana, South Africa, and Zimbabwe. Leaves and stems of L. javanica are also sold as herbal medicines in the medicinal plant "muthi" markets in South Africa [35, 170]. For local people who rely on herbal medicines as part of their primary healthcare as well as cultural beliefs, they prefer L. javanica harvested from the wild and unprocessed plant parts sold in informal medicinal "muthi" markets [170]. In the past, there were no records of overexploitation of L. javanica wild populations in southern Africa, resulting in Raimondo et al. [171] listing the species as Least Concern (LC) under the IUCN Red List Categories and Criteria version 3.1 of threatened species (http://www.iucnredlist.org). Recently, signs of over-harvesting have been noted, where local people or plant traders have uprooted whole plants to supply medicinal plant "muthi" markets or use the plants as herbal medicines, brooms, or herbal tea. Therefore, large-scale commercial utilization of L. javanica is not sustainable if the species is harvested from the wild. Currently, L. javanica is cultivated on a commercial scale in Kenya [28] and South Africa [117] for essential oil production for the mosquito-repellent candles and perfume industry. Cultivation of L. javanica is therefore, a solution to the sustainability problems associated with harvesting of the species from the wild, and this option is also necessary for establishing commercial scale medicinal production and processing and trade enterprises. The success of commercial cultivation of L. javanica will depend on how the species is marketed as herbal tea and medicine and source of essential oil and health care products and as a source of functional foods.

Significant research has been made in the past 50 years into the chemistry and pharmacology of L. javanica. These studies have shown L. javanica to display various chemical and different biological activities some of which justify its ethnopharmacological utilization in variety of cultures. In the light of the evidence that L. javanica is combined with other plant species in traditional medicine, it will be valuable to investigate the possibility of synergistic effects of the different extracts. Deep phytochemical studies of L. javanica and its phytochemical properties, especially the mechanisms of action of its bioactive constituents to illustrate the correlation between ethnomedicinal uses and pharmacological activities, should be the focus of further research on the species. There is need for extensive in vivo experiments to validate the existing pharmacological activities. However, because L. javanica contains potentially toxic compounds, its toxicological properties need to be properly established via proper quality control of product development to ensure that potentially toxic components are kept below tolerance levels.

Appendix

A. Chemical Compounds Isolated and Characterized from Lippia javanica

See Table 5.

B. Chemical Structures of

Phenolic Compounds, Alkaloids, Amino Acids, and Essential Oils Isolated from Lippia javanica

See Figure 4.

http://dx.doi.org/10.1155/2017/6746071

Competing Interests

The author declares that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

The author would like to express his gratitude to the National Research Foundation (NRF) and Govan Mbeki Research and Development Centre (GMRDC), University of Fort Hare, for financial support to conduct this research.

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Alfred Maroyi

Department of Botany, University of Fort Hare, Private BagX1314, Alice 5700, South Africa Correspondence should be addressed to Alfred Maroyi; amaroyi@ufh.ac.za

Received 5 September 2016; Revised 25 October 2016; Accepted 20 November 2016; Published 1 January 2017

Academic Editor: Rainer W. Bussmann

Caption: Figure 1: (a) Lippia javanica (Burm.f.) Spreng. flowers and leaves (photo: BT Wursten) and (b) L. javanica herbal tea traded as Zumbani in Zimbabwe (http://specialityfoods.co.zw/product/zumbani/).

Caption: Figure 2: Lippia javanica naturally occurs in central, eastern, and southern Africa.

Caption: Figure 3: Main ethnobotanical applications of Lippia javanica in central, eastern, and southern Africa. An ethnobotanical use is counted only once per publication.

Caption: Figure 4
Table 1: Traditional uses of Lippia javanica in central, eastern, and
southern Africa.

Use                 Plant part(s)     Mode of use
                    used

Food uses Food      Leaves, twigs     Leaves and twigs boiled
additive                              together with maize, cassava,
                                      groundnuts, and common tea
                                      (Camellia sinensis (L.)
                                      Kuntze)

Herbal tea          Leaves            Leaves can be sun dried for
                                      later use

Leafy vegetable     Leaves            Eaten as vegetable with meat
                                      or fish

Respiratory problems

Asthma              Leaves, twigs     Decoction taken orally or
                                      smoke inhaled

Blocked nose        Leaves            Leaf decoction of L. javanica
                                      alone taken orally or mixed
                                      with any of these species:
                                      Brachylaena uniflora Harv.,
                                      Clausena anisata (Willd).
                                      Hook.f. ex Benth., Clematis
                                      brachiata Thunb., Combretum
                                      molle R. Br. ex G. Don,
                                      Eucalyptus grandis W. Hill,
                                      Helichrysum kraussii Sch.
                                      Bip., Krauseola mosambicina
                                      Pax & Hoffm., Plectranthus
                                      neochilus Schltr., Senecio
                                      serratuloides DC.,or Trichilia
                                      emetica Vahl taken orally

Bronchitis          Leaves, roots,    Leaf infusion of L. javanica
                    and stems         alone taken orally or applied
                                      to skin as ointment or leaf
                                      and stem infusion of L.
                                      javanica mixed with leaves of
                                      Artemisia afra Jacq. ex Willd.
                                      taken orally

Chest pains         Leaves, roots     Leaves and roots of L.
                                      javanica alone chewed or
                                      decoction taken orally or used
                                      in washes and poultices or
                                      smoke inhaled or "imbiza,"
                                      decoction prepared from L.
                                      javanica and Cyrtanthus
                                      obliquus (L. f.) Aiton, taken
                                      orally or leaf decoction of L.
                                      javanica mixed with leaves of
                                      any of these species:
                                      Brachylaena transvaalensis
                                      Hutch, ex E. Phillips &
                                      Schweick., C. brachiata, E.
                                      grandis,H. kraussii, or T.
                                      emetica taken orally or leaf
                                      juice taken orally with cloves
                                      oi Allium sativum L.

Colds               Leaves, twigs     Leaf infusion of L. javanica
                                      alone taken orally or inhaled
                                      or applied as an ointment or
                                      "imbiza," decoction prepared
                                      from L. javanica and C
                                      obliquus, taken orally

Cough               Leaves, stems,    Leaves of L. javanica alone
                    and twigs         chewed or infusion inhaled or
                                      taken orally or applied as an
                                      ointment or leaf and stem
                                      infusion of L. javanica mixed
                                      with leaves of any of these
                                      species: Acanthospermum
                                      glabratum (DC.) Wild., A.
                                      afra, B. uniflora, B.
                                      transvaalensis, Bridelia
                                      cathartica Bertol., C.
                                      anisata, C. brachiata, C.
                                      molle, E. grandis, H.
                                      kraussii, K. mosambicina, P.
                                      neochilus, Psidium guajava L.,
                                      S. serratuloides, Terminalia
                                      sericea Burch. ex DC.,
                                      Tetradenia riparia (Hochst.)
                                      Codd, or T. emetica taken
                                      orally

Influenza           Leaves, roots     Decoction taken orally

Lung infections     Leaves            Infusions taken orally

Measles             Leaves, stems     Leaf decoction of L. javanica
                                      alone taken orally or body
                                      washed with infusion or leaf
                                      and stem infusion of L.
                                      javanica mixed with leaves of
                                      A. afra taken orally

Pneumonia           Leaves            Ointment rubbed on chest and
                                      abdomen

Respiratory         Leaves            Decoction taken orally
disorders

Runny nose          Leaves, roots     Leaf and root decoction of L.
                                      javanica alone taken orally or
                                      leaf decoction of L. javanica
                                      mixed with leaves of any of
                                      these species: B.
                                      transvaalensis, B.
                                      cathartica, C. anisata, C.
                                      brachiata, E. grandis, Hypoxis
                                      spp., K. mosambicina; P.
                                      guajava, S. serratuloides, P.
                                      neochilus, or T. emetica taken
                                      orally

Shortness of        Leaves            Decoction taken orally or body
breath                                washed with decoction
(dyspnoea)

Sore throat         Leaves            Leaf decoction of L. javanica
                                      alone taken orally or leaf
                                      decoction of L. javanica mixed
                                      with leaves of E. grandis or
                                      T. riparia taken orally

Tonsillitis         Leaves            Leaf decoction of L. javanica
                                      alone taken orally or leaf
                                      decoction of L. javanica mixed
                                      with leaves of E. grandis
                                      taken orally

Tuberculosis        Leaves            Leaf decoction of L. javanica
                                      alone taken orally or
                                      "imbiza," decoction prepared
                                      from L. javanica and C.
                                      obliquus, taken orally

Gastrointestinal diseases

Amoebiasis          Leaves, twigs     Decoction taken orally

Anthelmintics       Leaf              Infusions taken orally

Diarrhoea           Leaves, roots     Decoction taken orally

Gangrenous          Leaves            Infusions taken orally
rectitis

Prophylactic        Leaves            Infusion taken orally
against
diarrhoea

Vomiting            Leaves            Decoction taken orally

Fever, malaria, and as insect repellent

Fever               Leaves,           Leaf and twig decoction of L.
                    stems, and        javanica alone taken orally or
                    twigs             leaf and stem infusion of L.
                                      javanica mixed with leaves of
                                      any of these species: A. afra,
                                      B. transvaalensis, C. anisata,
                                      C molle, E. grandis,P.
                                      guajava, S. serratuloides, T.
                                      riparia, or T. emetica taken
                                      orally

Getting rid of      Leaves, twigs,    Used in washes and poultices
lice, insects,      and whole         or as steam or sprayed or
and lice and as     plant             burnt to chase away mosquitoes
mosquito
repellent

Malaria             Leaves, roots     Decoction taken orally

Prophylactic        Leaves            Infusion taken orally
against malaria

Wounds, injuries, pain, and skin infections

Abdominal pains     Leaves            Leaves chewed and juice
                                      swallowed

Acne                Leaves            Not specified

Antidotes           Roots             Used as antidote for food
                                      poisoning

Backache            Roots             Infusion taken orally

Bleeding from       Leaves            Fresh leaves inserted into
the nose                              nose or powdered leaves
(epistaxis)                           sniffed

Boils               Leaves            Infusion taken orally

Chicken pox         Leaves            Used in washes and poultices
                                      or as steam

Earache             Leaves            Decoction taken orally mixed
                                      with leaves of E. grandis

Febrile rashes      Leaves            Infusions taken orally

Headache,           Leaves, roots     Leaf and root decoction of L.
migraine                              javanica alone taken orally or
                                      leaf decoction of L. javanica
                                      mixed with leaves of any of
                                      these species: B.
                                      cathartica,C. brachiata, E.
                                      grandis, T. riparia, and T.
                                      emetica taken orally

Inflammation        Leaves            Not specified

Pubic sores         Leaves            Decoction taken orally mixed
                                      with leaves of Acanthospermum
                                      australe (Loefl.) Kuntze

Scabies             Leaves, roots     Infusion taken orally or used
                                      in washes and poultices or as
                                      steam

Shingles            Leaves, twigs,    Applied as an ointment
                    and roots

Skin disorders,     Leaves, twigs     Applied as an ointment or
such as heat rash                     "imbiza," decoction prepared
scratches,                            from L. javanica and C.
stings, and bites                     obliquus, taken orally

Sores               Leaves            Decoction of L. javanica mixed
                                      with bark of Acacia burkei
                                      Benth., Ozoroa engleri R.
                                      Fern. & A. Fern., Sclerocarya
                                      birrea (A. Rich.) Hochst.,
                                      Syzygium cordatum Hochst. ex
                                      Krauss, and Tabernaemontana
                                      elegans Stapf taken orally

Sore eyes,          Leaves, roots     Juice squeezed into eyes
cataracts

Sprained joints     Roots             Root powder applied to
                                      scarifications around sprained
                                      joints

Ulcers              Leaves            Juice taken orally with cloves
                                      of A. sativum

Wounds              Leaves            Fresh leaves wrapped around
                                      wound to enhance healing or
                                      infusion taken orally

Ethnoveterinary uses

Disinfecting        Whole plant       Whole plants used to disinfect
suspected                             suspected anthrax-infested
anthrax-                              meat
infested meat

Getting rid of      Leaves, twigs,    Crushed leaves mixed with
ticks and other     and whole plant   water and sprayed, twigs used
ectoparasites                         as bedding in fowl runs

Lice repellant      Whole plant       Whole plant used to repel lice
                                      in poultry

Milk                Stem              Stem applied to milk gourd
preservative                          before milk fermentation

Other uses          Leaves            Decoction taken orally
Anaemia in
pregnancy

Broom               Whole plant       Whole plants cut and tied
                                      together to make rough brooms

Cancer              Leaves            "Imbiza," decoction prepared
                                      from L. javanica and C
                                      obliquus, taken orally

Ceremonial          Leaves, whole     Used before and after funerals
                    plant             or placed on patients' bed
                                      after circumcision

Convulsions         Leaves            Leaves rubbed on face

Diabetes            Leaves            "Imbiza," decoction prepared
                                      from L. javanica and C
                                      obliquus, taken orally

Fatigue or          Leaves            Leaf decoction of L. javanica
tiredness                             mixed with leaves of A.
                                      glabratum or E. grandis or T.
                                      riparia taken orally

Fence               Whole plant       Planted around homesteads

Fodder              Leaves            Leaves eaten by goats

Fuelwood            Whole plant       Whole plant used as fuelwood

Human               Leaves            "Imbiza," decoction prepared
immunodeficiency                      from L. javanica and C
virus (HIV) or                        obliquus which is taken orally
acquired
immunodeficiency
syndrome (AIDS)
symptoms

Kidney problems     Root              50 g root powder boiled in 2
                                      litres of water; patient takes
                                      a cup of this mixture once per
                                      day for 3 days

Madness             Leaves, whole     Body washed with leaf infusion
                    plant

Marasmic infants    Roots             Infusions used to bath infants

Night blindness     Leaves            Face washed with infusion

Nightmares          Not specified     Not specified

Pre-, intra-, and   Stem, roots       Smear powder of root or stem
postpartum
complications

Preventing odours   Leaves, whole     Leaves sprinkled in toilets to
or being used       plant             prevent odours or whole plant
indoors to                            placed in vase or room
freshen air

Protection          Leaves            Leaves smeared on body
against dogs and
crocodiles

Psychotropic        Leaves            Infusion taken orally
behaviour

Removing bad luck   Leaves            Face and hands washed with
                                      infusion of L. javanica leaves
                                      mixed with C. molle leaves

Sleepless nights    Leaves            Leaf decoction of L. javanica
                                      mixed with leaves of E.
                                      grandis and T. riparia taken
                                      orally

To drive away bad   Leaves            Body washed with infusion
spirits

To prevent          Leaves            Leaves rubbed on forehead,
infants from                          elbows, and knees after
contracting                           committing adultery
illness caused by
father or mother
committing
adultery

Venereal diseases   Roots             Decoction taken orally

Weak joints         Leaves            Decoction taken orally

Use                 Country practised         Reference(s)

Food uses Food      Kenya                          [6]
additive            Botswana, South

Herbal tea          Africa, and                  [7-11]
                    Zimbabwe

Leafy vegetable     India                        [12,13]

Respiratory problems

Asthma              South Africa,                [14-17]
                    Zimbabwe

Blocked nose        South Africa                  [18]

Bronchitis          Botswana, South            [15,19-22]
                    Africa

Chest pains         Bangladesh,              [14,18, 23-27]
                    Ethiopia, and South
                    Africa

Colds               Botswana, Kenya,       [15,16,19, 21, 27-
                    South Africa, and              32]
                    Zimbabwe

Cough               Botswana,                  [15,16,18-
                    Ethiopia, South          21, 26, 30, 32]
                    Africa, and
                    Zimbabwe

Influenza           Mozambique, South          [7, 33-36]
                    Africa

Lung infections     South Africa                  [37]

Measles             Kenya, South Africa,      [14, 20, 38]
                    and Zimbabwe

Pneumonia           Zimbabwe                      [14]

Respiratory         India, South Africa          [39-41]
disorders

Runny nose          South Africa                  [18]

Shortness of        Zimbabwe                      [14]
breath
(dyspnoea)

Sore throat         South Africa                  [18]

Tonsillitis         South Africa                  [18]

Tuberculosis        South Africa, Uganda      [24, 42, 43]

Gastrointestinal diseases

Amoebiasis          Kenya                          [6]

Anthelmintics       South Africa                  [40]
                    Kenya,

Diarrhoea           Mozambique,            [17, 29, 34, 37, 44]
                    South Africa

Gangrenous          South Africa                  [45]
rectitis

Prophylactic        South Africa                  [40]
against
diarrhoea

Vomiting            Zanzibar, Tanzania            [46]

Fever, malaria, and as insect repellent

Fever               South Africa,            [14,16,18, 20]
                    Zimbabwe

Getting rid of      Ethiopia, South        [4, 26, 34, 47-51]
lice, insects,      Africa, and
and lice and as     Zimbabwe
mosquito
repellent

Malaria             Mozambique, South         [17, 33, 52]
                    Africa

Prophylactic        South Africa                  [40]
against malaria

Wounds, injuries, pain, and skin infections

Abdominal pains     Zimbabwe                      [14]

Acne                Botswana                      [22]

Antidotes           Botswana                      [22]

Backache            South Africa,               [14, 20]
                    Zimbabwe

Bleeding from       South Africa,               [14, 53]
the nose            Zimbabwe
(epistaxis)

Boils               South Africa                  [54]

Chicken pox         South Africa                  [50]

Earache             South Africa                  [18]

Febrile rashes      South Africa                  [40]

Headache,           Kenya, South           [14,18, 33, 34, 38]
migraine            Africa, and
                    Zimbabwe

Inflammation        South Africa                  [41]

Pubic sores         Swaziland                     [55]

Scabies             South Africa,             [14, 50, 54]
                    Zimbabwe

Shingles            South Africa                  [15]

Skin disorders,     South Africa                [21, 27]
such as heat rash
scratches,
stings, and bites

Sores               South Africa                  [56]

Sore eyes,          Botswana, Zimbabwe          [14, 22]
cataracts

Sprained joints     South Africa                  [20]

Ulcers              Bangladesh                    [23]

Wounds              Kenya, South Africa         [54, 57]

Ethnoveterinary uses

Disinfecting        South Africa                  [20]
suspected
anthrax-
infested meat

Getting rid of      South Africa,                [58-60]
ticks and other     Zimbabwe
ectoparasites

Lice repellant      India                         [61]

Milk                Kenya                         [62]
preservative

Other uses          Zanzibar, Tanzania            [46]
Anaemia in
pregnancy

Broom               South Africa                  [53]

Cancer              South Africa                  [27]

Ceremonial          Kenya, South Africa       [31, 58, 63]

Convulsions         Zimbabwe                    [14, 64]

Diabetes            South Africa                  [27]

Fatigue or          South Africa                  [18]
tiredness

Fence               Ethiopia                      [26]

Fodder              Kenya                         [31]

Fuelwood            Zanzibar, Tanzania            [46]

Human               South Africa                [65, 66]
immunodeficiency
virus (HIV) or
acquired
immunodeficiency
syndrome (AIDS)
symptoms

Kidney problems     Swaziland                     [67]

Madness             Malawi, Zimbabwe            [14, 68]

Marasmic infants    South Africa,               [14, 20]
                    Zimbabwe

Night blindness     Zimbabwe                      [14]

Nightmares          Zimbabwe                      [64]

Pre-, intra-, and   Kenya                         [69]
postpartum
complications

Preventing odours   Kenya, South Africa       [31, 35, 58]
or being used
indoors to
freshen air

Protection          South Africa                  [70]
against dogs and
crocodiles

Psychotropic        Swaziland                     [71]
behaviour

Removing bad luck   Swaziland                     [72]

Sleepless nights    South Africa                  [18]

To drive away bad   Zimbabwe                      [14]
spirits

To prevent          Zimbabwe                      [14]
infants from
contracting
illness caused by
father or mother
committing
adultery

Venereal diseases   Mozambique                    [44]

Weak joints         Zimbabwe                      [14]

Table 2: Nutritional composition of Lippia javanica leaves.

Caloric and nutritional               Values                Reference
composition

Ash                            1.60 [+ or -] 0.001 g           [13]
Calorific value              50.64 [+ or -] 5.63 kcal          [13]
Crude fat                      0.16 [+ or -] 0.001 g           [13]
Crude fibre                    2.63 [+ or -] 0.002 g           [13]
Crude protein                 1.22 [+ or -] 0.0004 g           [13]
Dry matter                     15.46 [+ or -] 1.40 g           [13]
Moisture                       90.44 [+ or -] 0.26 g           [13]
Total carbohydrate             6.55 [+ or -] 0.26 g            [13]
Vitamin C                     22.42 [+ or -] 0.001 mg          [13]
Ca                         2856-9225 [micro]g [g.sup.-1]       [27]
Mg                         1598-5619 [micro]g [g.sup.-1]       [27]
Fe                          75-750 [micro]g [g.sup.-1]         [27]
Mn                          40.1 [+ or -] 1.16 [micro]g        [27]
                                    [g.sup.-1]
Zn                         15.6-27.3 [micro]g [g.sup.-1]       [27]
Cu                          3.0-8.5 [micro]g [g.sup.-1]        [27]
Cr                           0-2.7 [micro]g [g.sup.-1]         [27]
Se                          2.57 [+ or -] 0.19 [micro]g        [27]
                                    [g.sup.-1]
Pb                         0.38-1.19 [micro]g [g.sup.-1]       [27]
Cd                          0.53 [+ or -] 0.05 [micro]g        [27]
                                    [g.sup.-1]
Co                          0.19 [+ or -] 0.01 [micro]g        [27]
                                    [g.sup.-1]

Table 3: Total phenolic content (TPC) as gallic acid equivalents (GAE)
and tannin content as leucocyanidin equivalents (LE) and free radical
scavenging activity (FRSA) of herbal tea extracts (after Bhebhe et al.
[10]).

Plant species             TPC g GAE/100g         Tannin content
                                                  of LE/100 g

Lippia javanica        12.46 [+ or -] 4.31     0.12 [+ or -] 0.01
Aspalathus linearis     6.69 [+ or -] 0.83     0.94 [+ or -] 0.04
Adansonia digitata      0.79 [+ or -] 0.28     1.69 [+ or -] 0.01
Fadogia ancylantha      2.88 [+ or -] 0.48     0.20 [+ or -] 0.12
Ficus sycamores        14.02 [+ or -] 0.01     1.98 [+ or -] 0.12
Myrothamnus             4.75 [+ or -] 0.33     1.04 [+ or -] 0.01
 flabellifolius

Plant species            Percentage FRSA      [IC.sub.50]
                                                  g/mL

Lippia javanica         83.77 [+ or -] 0.8        0.016
Aspalathus linearis     67.27 [+ or -] 0.25       0.053
Adansonia digitata      43.07 [+ or -] 1.0        0.132
Fadogia ancylantha       70.0 [+ or -] 0.40       0.051
Ficus sycamores         86.13 [+ or -] 0.85       0.009
Myrothamnus             80.93 [+ or -] 0.75       0.019
 flabellifolius

Table 4: Summary of pharmacological activities of the extracts
isolated from different parts of Lippia javanica.

Activity tested       Extract        Plant part          Model

Antiamoebic       Piperitenone 162     Leaves        Microdilution
                                                         assay

Antibacterial     Piperitenone 162     Leaves        Microdilution
                                                         assay

Antibacterial         Methanol         Leaves       Disc diffusion
                                                         assay

(Antiproteus)          Water           Leaves       Disc diffusion
                                                         assay

Antibacterial         Acetone          Leaves        Microdilution
                                                         assay

                      Acetone          Leaves        Microdilution
                                                         assay

                       Hexane          Leaves        Microdilution
                                                         assay

                      Methanol         Leaves        Microdilution
                                                         assay

                   Essential oil       Leaves        Microdilution
                                                         assay

                      Methanol         Leaves        Microdilution
                                                         assay

                      Methanol         Leaves        Microdilution
                                                         assay

                      Methanol         Leaves        Microdilution
                                                         assay

                      Methanol         Leaves        Microdilution
                                                         assay

                      Acetone          Leaves        Microdilution
                                                         assay

                       Hexane          Leaves        Microdilution
                                                         assay

                      Acetone          Leaves        Microdilution
                                                         assay

Antifungal        Dichloromethane   Aerial parts     Microdilution
                                                         assay

                       Hexane       Aerial parts     Microdilution
                                                         assay

                      Methanol      Aerial parts     Microdilution
                                                         assay

                      Methanol      Aerial parts     Microdilution
                                                         assay

                      Acetone          Leaves        Microdilution
                                                         assay

Antimycob-        Dichloromethane      Leaves        Microdilution
acterial                                                 assay
                       Hexane          Leaves      Microdilution assay

                      Methanol         Leaves        Microdilution
                                                         assay

Antioxidant            Water           Leaves         DPPH assay

                       Water           Leaves             --

                       Water           Leaves         ABTS assay

                       Water           Leaves         DPPH assay

                       Water           Leaves         FRAP assay

Antiplasmodial        Hexane,           Roots        Microdilution
                     chloroform                          assay

                   Ethyl acetate        Roots        Microdilution
                                                         assay

                      Methanol          Roots        Microdilution
                                                         assay

                      Hexane,           Roots        Microdilution
                     chloroform                          assay

                   Ethyl acetate        Roots        Microdilution
                                                         assay

                      Methanol          Roots        Microdilution
                                                         assay

                  Dichloromethane       Roots         pLDH assay

                  Dichloromethane/      Roots         pLDH assay
                      methanol

                      Methanol          Roots         pLDH assay

                       Water            Roots         pLDH assay

                  Dichloromethane       Stems         pLDH assay

                  Dichloromethane/      Stems         pLDH assay
                      methanol

                      Methanol          Stems         pLDH assay

                       Water            Stems         pLDH assay

Free radical           Water             --           DPPH assay
scavenging
activity            50% methanol         --           DPPH assay

                      Ethanol            --           DPPH assay

                    50% ethanol          --           DPPH assay

                      Acetone            --           DPPH assay

                    50% acetone          --           DPPH assay

                   Ethyl acetate         --           DPPH assay

Toxicity              Methanol          Leaf         Brine shrimp
                                                    lethality assay

                      Methanol          Roots        Brine shrimp
                                                    lethality assay

                      Methanol          Roots        Brine shrimp
                                                    lethality assay

Activity tested       Extract       Effect

Antiamoebic       Piperitenone 162  Active with [IC.sub.50] value of
                                    25 [micro]g/mL against E.
                                    histolytica

Antibacterial     Piperitenone 162  Active with MIC value of 50
                                    [micro]g/mL against A.
                                    calcoaceticus, M. kristinae (50
                                    [micro]g/mL), S. typhi (25
                                    [micro]g/mL), and S. aureus (12
                                    [micro]g/mL)

Antibacterial         Methanol      Active with MIC value of 313
(Antiproteus)                       [micro]g/mL against P. mirabilis
                                    and 926 [micro]g/mL against P.
                                    vulgaris

                       Water        Exhibited weak activity against P.
                                    mirabilis with MIC value of 1873
                                    [micro]g/mL and 1768 [micro]g/mL
                                    against P. vulgaris

Antibacterial         Acetone       Active against E. coli with MIC
                                    value of 0.64 mg/mL, E. faecalis
                                    (0.64), P. aeruginosa (0.32), and
                                    S. aureus (0.64). Total activity
                                    MIC values were as follows: E.
                                    coli (127 mg/mL), E. faecalis (127
                                    mg/mL), P. aeruginosa (253 mg/
                                    mL), and S. aureus (127 mg/mL)

                      Acetone       Active against B. cereus with MIC
                                    value of 3 mg/mL, Bacillus pumilus
                                    (6 mg/mL), B. subtilis (>12 mg/
                                    mL), S. aureus (12 mg/mL), E.
                                    faecalis (6 mg/mL), E. cloacae (6
                                    mg/mL), E. coli (6 mg/mL), Pantoea
                                    agglomerans (12 mg/mL), P.
                                    aeruginosa (12 mg/mL), Shigella
                                    flexneri (1.5 mg/mL), Aeromonas
                                    hydrophila (12 mg/mL), P.
                                    mirabilis (>12 mg/mL), K.
                                    pneumoniae (12 mg/mL), Salmonella
                                    choleraesuis (6 mg/mL), and
                                    Serratia marcescens (>12 mg/mL)

                       Hexane       Active against B. cereus with MIC
                                    value of 12 mg/mL, B. pumilus (12
                                    mg/mL), B. subtilis (12 mg/mL), S.
                                    aureus (6 mg/mL), E. faecalis (12
                                    mg/mL), E. cloacae (12 mg/mL), E.
                                    coli (6 mg/mL), P. agglomerans (12
                                    mg/mL), P. aeruginosa (12 mg/mL),
                                    S. flexneri (6 mg/mL), A.
                                    hydrophila (12 mg/mL), P.
                                    mirabilis (12 mg/mL), K.
                                    pneumoniae (12 mg/mL), S.
                                    choleraesuis (6 mg/mL), and
                                    antiamoebic effect (12 mg/mL)

                      Methanol      Active against B. cereus with MIC
                                    values of 1.5 mg/mL, B. pumilus (6
                                    mg/mL), B. subtilis (>12 mg/mL),
                                    S. aureus (12 mg/mL), E. faecalis
                                    (3 mg/mL), E. cloacae (6 mg/mL),
                                    E. coli (6 mg/mL), P. agglomerans
                                    (12 mg/mL), P. aeruginosa (12 mg/
                                    mL), S. flexneri (1.5 mg/mL), A.
                                    hydrophila (6mg/mL), P. mirabilis
                                    (>12mg/mL), K. pneumoniae (12 mg/
                                    mL), S. choleraesuis (6 mg/mL),
                                    and S. marcescens (12 mg/mL)

                   Essential oil    Active against B. cereus with MIC
                                    values of 6 mg/mL, B. pumilus (6
                                    mg/mL), B. subtilis (3 mg/mL), S.
                                    aureus (1.5 mg/mL), E. faecalis (3
                                    mg/mL), E. cloacae (12 mg/mL), E.
                                    coli (6 mg/mL), P. agglomerans (6
                                    mg/mL), P. aeruginosa (12 mg/mL),
                                    S. flexneri (3 mg/mL), A.
                                    hydrophila (3 mg/mL), P. mirabilis
                                    (>12 mg/mL), K. pneumoniae (3 mg/
                                    mL), S. choleraesuis (1.5 mg/mL),
                                    and S. marcescens (>12mg/mL)

                      Methanol      Active against E. faecalis with
                                    MIC value of 0.14 mg/mL

                      Methanol      Active against E. coli with MIC
                                    value of 0.31 mg/mL

                      Methanol      Active against P. aeruginosa with
                                    MIC value of 0.42 mg/mL

                      Methanol      Active against S. aureus with MIC
                                    value of 0.13 mg/mL

                      Acetone       Active against C. albicans with
                                    MIC value of >7.5 mg/mL, C. krusei
                                    (1.88 mg/mL), and C. neoformans
                                    (>7.5 mg/mL)

                       Hexane       Active against C. albicans with
                                    MIC value of >3.75 mg/mL, C.
                                    krusei (3.75 mg/mL), and C.
                                    neoformans (>7.5 mg/mL)

                      Acetone       Active against C. krusei with MFC
                                    value of 7.5 mg/mL

Antifungal        Dichloromethane   Active against Fusarium
                                    proliferatum with MIC value of
                                    0.14 mg/mL and Fusarium
                                    verticillioides (0.19 mg/mL)

                       Hexane       Active against F. proliferatum
                                    with MIC value of 0.23 mg/mL and
                                    F. verticillioides (0.45 mg/mL)

                      Methanol      Active against F. proliferatum
                                    with MIC value of 1.77 mg/mL and
                                    F. verticillioides (0.43 mg/mL)

                      Methanol      Active against F. proliferatum
                                    with MIC value of >2.50 mg/mL and
                                    F. verticillioides (>2.50mg/mL)

                      Acetone       Active with MIC value of 0.47 mg/
                                    mL and total activity of 10 mL/g
                                    against M. smegmatis

Antimycob-        Dichloromethane   Active with MIC value of 1.25 mg/
acterial                            mL and total activity of 23 mL/g
                                    against M. smegmatis

                       Hexane       Active with MIC value of 0.62 mg/
                                    mL and total activity of 13 mL/g
                                    against M. smegmatis

                      Methanol      Active with MIC value of 1.25 mg/
                                    mL and total activity of 7 mL/g
                                    against M. smegmatis

Antioxidant            Water        Exhibited activity with EC50 value
                                    of 358 [micro]g/mL

                       Water        Exhibited activity with 209
                                    ascorbic acid equivalent (mg/g dry
                                    weight)

                       Water        Active with TEAC value of 1.5
                                    mmol/100 g

                       Water        Active with TEAC value of 1462.54
                                    mmol/100 g

                       Water        Active with TEAC value of 2.38
                                    mmol/100 g

Antiplasmodial        Hexane,       Active against P. falciparum
                     chloroform     chloroquine sensitive with
                                    [IC.sub.50] value of 12.25
                                    [+ or -] 0.72 [micro]g/mL

                   Ethyl acetate    Active against P. falciparum
                                    chloroquine sensitive with
                                    [IC.sub.50] value of 12.12
                                    [+ or -] 0.79[micro]g/mL

                      Methanol      Active against P. falciparum
                                    chloroquine sensitive with
                                    [IC.sub.50] value of 1.35
                                    [+ or -] 0.06[micro]g/mL

                      Hexane,       Active against P. falciparum
                     chloroform     chloroquine resistant with
                                    [IC.sub.50] value of 18.59
                                    [+ or -] 0.26 [micro]g/mL

                   Ethyl acetate    Active against P. falciparum
                                    chloroquine resistant with
                                    [IC.sub.50] value of 15.80
                                    [+ or -] 0.26 [micro]g/mL

                      Methanol      Active against P. falciparum
                                    chloroquine resistant with
                                    [IC.sub.50] value of 1.75
                                    [+ or -] 0.17 [micro]g/mL

                  Dichloromethane   Active against P. falciparum
                                    with[IC.sub.50] value of 3.8
                                    [micro]g/mL

                  Dichloromethane/  Active against P. falciparum
                      methanol      with[IC.sub.50] value of
                                    27[micro]g/mL

                      Methanol      Active against P. falciparum
                                    with[IC.sub.50] value of
                                    24[micro]g/mL

                       Water        Active against P. falciparum with
                                    [IC.sub.50] value of >100[micro]g/
                                    mL

                  Dichloromethane   Active against P. falciparum
                                    with[IC.sub.50] value of 4.5
                                    [micro]g/mL

                  Dichloromethane/  Active against P. falciparum
                      methanol      with[IC.sub.50] value of 21.8
                                    [micro]g/mL

                      Methanol      Active against P. falciparum with
                                    [IC.sub.50] value of 29.8
                                    [micro]g/mL

                       Water        Active against P. falciparum
                                    with[IC.sub.50] value of >100
                                    [micro]g/mL

Free radical           Water        Active with [IC.sub.50] value of
scavenging                          0.059 [+ or -] 0.02 g/mL
activity
                    50% methanol    Active with [IC.sub.50] value of
                                    0.04 [+ or -] 0.001 g/mL

                      Ethanol       Active with [IC.sub.50] value of
                                    0.025 [+ or -] 0.001 g/mL

                    50% ethanol     Active with [IC.sub.50] value of
                                    0.027 [+ or -] 0.005 g/mL

                      Acetone       Active with [IC.sub.50] value of
                                    0.057 [+ or -] 0.004 g/mL

                    50% acetone     Active with [IC.sub.50] value of
                                    0.022 [+ or -] 0.001 g/mL

                   Ethyl acetate    Active with [IC.sub.50] value of
                                    0.066 [+ or -] 0.001 g/mL

Toxicity              Methanol      40% mortality recorded after 48 h
                                    exposure towards Artemia nauplii

                      Methanol      Active against P. falciparum
                                    chloroquine sensitive with
                                    [IC.sub.50] value of 843.0
                                    [micro]g/mL

                      Methanol      Active against P. falciparum
                                    chloroquine resistant with
                                    [IC.sub.50] value of 650.3
                                    [micro]g/mL

Activity tested       Extract       Reference

Antiamoebic       Piperitenone 162     [73]

Antibacterial     Piperitenone 162     [73]

Antibacterial         Methanol         [74]
(Antiproteus)
                       Water           [74]

Antibacterial         Acetone          [75]

                      Acetone          [17]

                       Hexane          [17]

                      Methanol         [17]

                   Essential oil       [17]

                      Methanol         [7]

                      Methanol         [7]

                      Methanol         [7]

                      Methanol         [7]

                      Acetone          [7]

                       Hexane          [7]

                      Acetone          [7]

Antifungal        Dichloromethane      [76]

                       Hexane          [76]

                      Methanol         [76]

                      Methanol         [76]

                      Acetone          [77]

Antimycob-        Dichloromethane      [77]
acterial
                       Hexane          [77]

                      Methanol         [77]

Antioxidant            Water           [7]

                       Water           [7]

                       Water           [78]

                       Water           [78]

                       Water           [78]

Antiplasmodial        Hexane,          [79]
                     chloroform

                   Ethyl acetate       [79]

                      Methanol         [79]

                      Hexane,          [79]
                     chloroform

                   Ethyl acetate       [79]

                      Methanol         [79]

                  Dichloromethane      [80]

                  Dichloromethane/     [80]
                      methanol

                      Methanol         [80]

                       Water           [80]

                  Dichloromethane      [80]

                  Dichloromethane/     [80]
                      methanol

                      Methanol         [80]

                       Water           [80]

Free radical           Water           [11]
scavenging
activity            50% methanol       [11]

                      Ethanol          [11]

                    50% ethanol        [11]

                      Acetone          [11]

                    50% acetone        [11]

                   Ethyl acetate       [11]

Toxicity              Methanol         [74]

                      Methanol         [79]

                      Methanol         [79]

Table 5

Chemical compound                                   Reference(s)

Phenolic compounds
Coumarin 1                                              [4]
Verbascoside 2                                          [81]
Isoverbascoside 3                                       [81]
Theveside-Na 4                                          [82]
Theveridoside 5                                         [82]
4-ethylnonacosane 6                                     [83]
Apigenin 7                                            [64, 83]
Cirsimaritin 8                                        [64, 83]
6-Methoxy luteolin                                   [83] [83]
4'-methyl ether 9
6-Methoxy luteolin                                   [83] [83]
3',4',7-trimethyl ether 10
Crassifolioside 11                                      [64]
Luteolin 12                                             [64]
Diosmetin 13                                            [64]
Chrysoeriol 14                                          [64]
Tricin 15                                               [64]
Isothymusin 16                                          [64]
Eupatorin 17                                            [64]
5-Dimethyl noboletin 18                                 [64]
Genkwanin 19                                            [64]
Salvigenin 20                                           [64]
Lippialactone 21                                        [84]
Alkaloid
Xanthine 22                                             [64]
Amino acids
[alpha]-Aminobutyric acid 23                          [85, 86]
Valine 24                                               [86]
Isoleucine 25                                           [86]
Asparagine 26                                           [86]
Phenylalanine 27                                        [86]
[alpha]-Aminoadipic acid 28                             [86]
Lysine 29                                               [86]
Histidine 30                                            [86]
Tyrosine 31                                             [86]
Tryptophan 32                                           [86]
Alanine 33                                              [85]
Glycine 34                                              [85]
Proline 35                                              [85]
Serine 36                                               [85]
Glutamine acid 37                                       [85]
[beta]-Alanine 38                                       [85]
Glutamine 39                                            [85]
[beta]-Aminoisobutyric acid 40                          [85]
4-hydroxyproline 41                                     [85]
Essential oil
(E)-2(3)-tagetenone                                  [83] [83]
epoxide 42
4-Methyl-2-pentanone 43                                 [3]
[alpha]-Pinene 44                                   [3-5, 87-91]
1,3-5-Cycloheptatriene 45                               [4]
(+)-2-Carene 46                                         [4]
3-Carene 47                                             [4]
Eucalyptol 48                                           [4]
1.8 myrcene 49                                          [87]
Ipsdienone 50                                           [87]
Caryophyllene 51                                        [85]
Geranial 52                                         [5, 92, 93]
2,6-Dimethylstyrene 53                                  [92]
Geraniol 54                                             [92]
Octen-3-one 55                                          [5]
6-Methyl-5-hepten-2-one 56                              [5]
[rho]-Mentha-1(7), 8-diene 57                           [5]
Artemisia ketone 58                                     [5]
Linalool oxide 59                                       [5]
Terpinen-4-ol 60                                        [5]
(Z)-[beta]-Ocimenone 61                                 [5]
(E)-[beta]-Ocimenone 62                                 [5]
Carvyl acetate 63                                       [5]
a-Cubebene 64                                           [5]
Sesquithujene 65                                        [5]
Acora-3,5-diene 66                                      [5]
[beta]-Bergamotene 67                                   [5]
Trans-calamenene 68                                     [5]
[beta]-Alaskene 69                                      [5]
[gamma]-Cadinene 70                                     [5]
[delta]-Cadinene 71                               [3, 88, 89, 91]
Cis-calamenene 72                                       [5]
Nerolidol 73                                            [5]
(E)-Nerolidol 74                                    [3, 88, 89]
Spathulenol 75                                          [5]
Epi-a-muurolol 76                                       [5]
[alpha]-Longipinene 77                                  [90]

Chrysanthenone 78                                       [90]
[alpha]-Terpineol 79                               [3, 5, 90, 91]
[alpha]-Amorphene 80                                    [90]
[alpha]-Thujene 81                                      [91]
[gamma]-Terpinene 82                                    [91]
[alpha]-Cubebene 83                                     [91]
Linalool acetate 84                                     [91]
Bicyclosesquiphellandrene 85                            [91]
Camphene 86                                        [3, 5, 88-91]
[beta]-Pinene 87                                     [3, 5, 91]
Sabinene 88                                      [3, 5, 87, 90, 91]
Myrcene 89                                      [3, 5, 87-89, 91-95]
[alpha]-Phellandrene 90                            [3,5, 88, 89]
2-Methylbutyl isobutyrate 91                            [3]
Limonene 92                                        [3, 5, 88-94]
1,8-Cineole 93                                   [3, 5, 90, 91, 95]
[beta]-Phellandrene 94                           [3, 4, 88, 89, 91]
(Z)-3-Hexenal 95                                        [3]
(Z)-[beta]-Ocimene 96                            [3, 5, 88, 89, 91]
(E)-[beta]-Ocimene 97                            [3, 5, 88, 89, 91]
Isomyrcenol 98                                          [3]
p-Cymene 99                                      [3, 5, 85, 88-91]
2-Methylbutyl-2-methyl butyrate 100                     [3]
Terpinolene 101                                         [3]
Dihydrotagetone 102                             [3, 88, 89, 91, 95]
Cis-alloocimene 103                                 [3, 88, 89]
(Z)-3-Hexen-1-ol 104                                    [3]
6,7-Epoxymyrcene 105                                    [3]
Nonanal 106                                             [3]
Perillene 107                                         [3, 91]
Ipsenone 108                                       [3, 87-89, 95]
Trans-Linalool oxide (furanoid) 109                  [3, 88-90]
1-Octen-3-ol 110                                    [3, 88, 89]
Cis-1,2-limonene epoxide 111                            [3]
Ttrans-1,2-limonene epoxide 112                         [3]
cis-Linalool oxide (furanoid) 113                    [3, 88-90]
[alpha]-Copaene 114                                [3, 5, 88-90]
Cis-tagetone 115                                    [3, 88, 89]
Trans-tagetone 116                                  [3, 88, 89]
Camphor 117                                    [3, 5, 88-90, 93, 94]
[beta]-Bourbonene 118                                [3, 5, 91]
Benzaldehyde 119                                       [3,5]
Linalool 120                                       [3, 5, 85, 88-
                                                    90, 92, 93]
Trans-a-bergamotene 121                                 [3]
[alpha]-Cedrene 122                                    [3,5]
Myrcenone 123                                      [3, 5, 83, 91]
[beta]-Caryophyllene 124                       [3, 5, 87-91, 93, 94]
2-Methyl-6-methylene-3,7-octadien-2-ol 125              [3]
Trans -p-mentha-2,8-dien-1-ol 126                       [3]
Cis-p-mentha-2,8-dien-1-ol 127                          [3]
Alloaromadendrene 128                              [3,5, 88, 89]
(Z)-[beta]-Farnesene 129                                [3]
(E)-[beta]-Farnesene 130                               [3,5]
(E,E)-[alpha]-Farnesene 131                         [3, 88, 89]
Ipsdienol 132                                           [3]
(Z)-3-Hexenyl tiglate 133                               [3]
Isovaleric acid 134                                     [3]
[alpha]-Humulene 135                             [3, 5, 88, 89, 91]
[alpha]-Acoradiene 136                                  [3]
[beta]-Acoradiene 137                                   [3]
[gamma]-Muurolene 138                              [3,5, 88, 89]
[alpha]-Muurolene 139                              [3, 5, 88-90]
Cis-tagetenone 140                                      [3]
Trans-tagetenone 141                                    [3]
Borneol 142                                         [3,5, 88-90]
Verbenone 143                                         [3, 91]
Germacrene-D 144                                   [3, 87-89, 93]
[beta]-Bisabolene 145                                  [3,5]
[gamma]-Bisabolene 146                                  [3]
Trans-carvyl acetate 147                                [3]
Carvone 148                                          [3,5, 91]
Bicyclogermacrene 149                            [3, 5, 88, 89, 91]
[beta]-Curcumene 150                                    [3]
Ar-curcumene 151                                        [3]
Cis-piperitol 152                                       [3]
2-Methyl-2-butenoic acid 153                            [3]
Trans-p-mentha-1(7),8-dien-2-ol 154                     [3]
Cis-p-mentha-1(7),8-dien-2-ol 155                       [3]
2,6-Dimethyl-3(E),5(E),7-octatriene-2-ol 156        [3, 88, 89]
Trans-carveol 157                                       [3]
Calamenene 158                                          [3]
Carvone oxide 159                                       [3]
Isopiperitenone 160                                     [3]
Cis-carveol 161                                         [3]
Piperitenone 162                                   [2, 3, 73, 83]
Isocaryophyllene oxide 163                          [3, 88, 89]
Caryophyllene oxide 164                             [3-5, 88-90]
Humulene epoxide II 165                            [3,5, 88, 89]
Hexahydrofarnesyl acetone 166                           [3]
Spathulenol 167                                         [3]
Eugenol 168                                            [3,5]
Germacrene-D-4-ol 169                                   [3]
Caryophylla-2(12),6(13)-dien-5-ol                    [3] [3]
(=Caryophylladienol I) 170
Caryophylla-2(12),6(13)-dien-5a-ol                    [3] [3]
(=Caryophylladienol II) 171
Euscaphic acid 172                                      [83]
Icterogenin 173                                         [96]
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Author:Maroyi, Alfred
Publication:Evidence - Based Complementary and Alternative Medicine
Date:Jan 1, 2017
Words:20099
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