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Butterfly Pea (Clitoria ternatea), a Cyclotide-Bearing Plant With Applications in Agriculture and Medicine

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Georgianna K. OguisEdward K. GildingMark A. Jackson, and David J. Craik*

Abstract

The perennial leguminous herb Clitoria ternatea (butterfly pea) has attracted significant interest based on its agricultural and medical applications, which range from use as a fodder and nitrogen fixing crop, to applications in food coloring and cosmetics, traditional medicine and as a source of an eco-friendly insecticide. In this article we provide a broad multidisciplinary review that includes descriptions of the physical appearance, distribution, taxonomy, habitat, growth and propagation, phytochemical composition and applications of this plant. Notable amongst its repertoire of chemical components are anthocyanins which give C. ternatea flowers their characteristic blue color, and cyclotides, ultra-stable macrocyclic peptides that are present in all tissues of this plant. The latter are potent insecticidal molecules and are implicated as the bioactive agents in a plant extract used commercially as an insecticide. We include a description of the genetic origin of these peptides, which interestingly involve the co-option of an ancestral albumin gene to produce the cyclotide precursor protein. The biosynthesis step in which the cyclic peptide backbone is formed involves an asparaginyl endopeptidase, of which in C. ternatea is known as butelase-1. This enzyme is highly efficient in peptide ligation and has been the focus of many recent studies on peptide ligation and cyclization for biotechnological applications. The article concludes with some suggestions for future studies on this plant, including the need to explore possible synergies between the various peptidic and non-peptidic phytochemicals.

Keywords: peptides, forage crop, anthocyanins, organic pesticide, butelase, medicinal plant

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Introduction

Clitoria ternatea, commonly known as butterfly pea, is a perennial herbaceous plant from the Fabaceae family. It has recently attracted a lot of interest as it has potential applications both in modern medicine and agriculture, and as a source of natural food colorants and antioxidants. C. ternatea has long been cultivated as a forage and fodder crop, and early studies assessed the plant for these purposes (Reid and Sinclair, 1980Barro and Ribeiro, 1983Hall, 1985). Numerous field trials in Queensland, Australia, eventually led to the registry of C. ternatea cv. ‘Milgarra’ (Oram, 1992), the only cultivar in Australia that was released for grazing purposes (Conway and Doughton, 2005). Additionally, C. ternatea has been widely used in traditional medicine, particularly as a supplement to enhance cognitive functions and alleviate symptoms of numerous ailments including fever, inflammation, pain, and diabetes (Mukherjee et al., 2008).

In as early as the 1950s, studies on C. ternatea sought to elucidate its pharmacological activities, phytochemical composition and active constituents (Grindley et al., 1954Piala et al., 1962Kulshreshtha and Khare, 1967Morita et al., 1976). The novel C. ternatea anthocyanins termed “ternatins” which render C. ternatea flowers with their vivid blue color, were first isolated in 1985 (Saito et al., 1985). Following further isolation and structural characterization of numerous other ternatins, the ternatin biosynthetic pathway was postulated a decade later (Terahara et al., 1998). In 2003, comparison of C. ternatea lines bearing different floral colors provided insights into the role of acylation on C. ternatea floral color determination (Kazuma et al., 2003a). The abundance of these unique anthocyanins alongside other secondary metabolites in C. ternatea makes the plant an ideal source of natural additives that can enhance the appearance and nutritive values of consumer products (Pasukamonset et al., 201620172018Siti Azima et al., 2017). Although a number of recent studies has endeavored to elucidate the pharmacological activities of C. ternatea (Adhikary et al., 2017Kavitha, 2018Singh et al., 2018), the contribution of individual extract components on any bioactivity measured remains unknown.

Figure 1 summarizes some of the key agricultural and biochemical studies conducted on C. ternatea from the 1950s to the present, providing a convenient timeline of discoveries. The corresponding references to the key studies and milestones are listed in Table 1. In recent years, the small circular defense molecules called cyclotides, in C. ternatea (Nguyen et al., 2011Poth et al., 2011a,bNguyen et al., 2014) have fueled scientific innovations that may have impact in modern agriculture, biotechnology and medicine. In 2017, Sero-X®, a cyclotide-containing eco-friendly pesticide made from extracts of C. ternatea, was approved for commercial use in Australia1. In addition, the C. ternatea cyclotide processing enzyme, butelase-1, which is the fastest ligase known to date and is capable of ligating peptides across a vast range of sizes (26 to >200 residues), can potentially be used in the large scale synthesis of macrocycle libraries and peptide-based pharmaceuticals (Nguyen et al., 20142015).

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FIGURE 1

Timeline of the key studies and milestones on Clitoria ternatea research from the 1950s to the present. The biological (blue) and biochemical (purple) studies pursued from the 1950s to early 1970s characterized the properties of roots and seeds. Toward the end of the 1970s, researchers began to isolate and characterize the phytochemical compounds from C. ternatea. Ternatins, the anthocyanins that render C. ternatea its vivid blue color, were first isolated in 1985; and the structure of the largest of the ternatins, ternatin A1, was characterized in 1989. Further isolation and characterization of the ternatins in C. ternatea led to the elucidation of the ternatin biosynthetic pathway in 1998. Parallel to the studies that characterized the phytochemical composition of C. ternatea, were agricultural studies that evaluated C. ternatea as a forage and fodder crop. A series of field studies in Queensland, Australia lead the development and eventual release of the C. ternatea Milgarra cultivar in 1991. From 2001 to the present, studies have been determining the pharmacological activities and biological activities of C. ternatea extracts. In 2011, cyclotides, the circular insecticidal molecules which can also be used as scaffolds for peptide-based therapeutics, were discovered in C. ternatea. While cyclotides had previously been characterized in other angiosperm species, C. ternatea is to date, the only legume that is known to produce them. In 2014, butelase-1, the ligase that facilitates cyclization in C. ternatea cyclotides, was discovered and characterized. Cyclotides and the auxiliary enzymes, have applications both in modern medicine and agriculture. In 2017, Sero-X® an eco-friendly insecticide made from C. ternatea extracts was registered for commercial use in Australia.

fpls-10-00645

References:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546959/

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Ivermectin – Niacin Research

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A review on phytochemistry and medicinal properties of the genus Achillea

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  • Received 30 Apr 2011; Revised 2 July 2011; Accepted 2 July 2011

1Saeidnia S., *1Gohari AR., 1Mokhber-Dezfuli N, 2 Kiuchi F.
1 Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical
Sciences, Tehran, Iran. 2 Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku,
Tokyo 105-8512, Japan.

Abstract

Achillea L. (Compositae or Asteraceae) is a widely distributed medicinal plant throughout the world and has been used since ancient time. Popular indications of the several species of this genus include treatment of wounds, bleedings, headache, inflammation, pains, spasmodic diseases, flatulence and dyspepsia. Phytochemical investigations of Achillea species have revealed that many components from this genus are highly bioactive. There are many reports on the mentioned folk and traditional effects. Although, the medicinal properties of Achillea plants are recognized worldwide, there are only one review article mainly about the structures of the phytochemical constituents of Achillea. The present paper reviews the medicinal properties of various species of Achillea, which have been examined on the basis of the scientific in vitro, in vivo or clinical evaluations. Various effects of these plants may be due to the presence of a broad range of secondary active metabolites such as flavonoids, phenolic acids, coumarins, terpenoids (monoterpenes, sesquiterpenes, diterpenes, triterpenes) and sterols which have been frequently reported from Achillea species.

Keywords: Achillea, Asteraceae, Bioactive compounds.

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INTRODUCTION

The genus Achillea L. belongs to Asteraceae (Compositae), the largest family of vascular plants. Asteraceaeous plants are distributed throughout the world and most common in the arid and semi-arid regions of subtropical and lower temperate latitudes. Achillea contains around 130 flowering and perennial species and occurs in Europe and temperate areas of Asia and a few grow in North America. These plants typically have hairy and aromatic leaves and flat clusters of small flowers on the top of the stem. Since these flowers have various colors, a number of species are popular garden plants (14). The basic chromosome number of this genus is X=9 and most of the species are diploid with great ecological ranges from desert to water-logged habitats (5).

The name of Achillea is referred to the Achilles in the literary Trojan War of the Iliad who used yarrow to treat the soldiers’ wounds (6). The majority of the Achillea species are as the medicinal plants which have therapeutic applications (4). There are few review papers on the different aspects of Achillea as a noteworthy and medicinal genus. Recently, Si and co-authors (7) published a review article mainly about the structures of phytochemical constituents and a brief section of biological properties of Achillea (7). Literature reviews show that there are many reports on pharmacological, immunological, biological and other therapeutic activities of these valuable herbs which are reviewed in this article.

Traditional usages 

Since Achillea genus is widespread all over the world, its species have been used by local people as folk or traditional herbal medicines. Bumadaran is a popular name for several species of Achillea in Persian language. They are reported as tonic, anti-inflammatory, anti-spasmodic, diaphoretic, diuretic and emmenagogic agents and have been used for treatment of hemorrhage, pneumonia, rheumatic pain and wounds healing in Persian traditional literature (89).

In Spanish-speaking New Mexico and southern Colorado, A. millefolium L. is called plumajillo, or “little feather”, because of the shape of the leaves. Native Americans and early settlers used yarrow for its astringent qualities that made it effective in wound healing and anti-bleeding (10).

Achillea species are the most important indigenous economic plants of Anatolia. Herbal teas prepared from some Achillea species are traditionally used for abdominal pain and flatulence in Turkey (11). Dioscorides also used Achillea for dysentery, whether associated with cholera or other causes, which killed as many soldiers as did steel and lead. In terms of Chinese medicine, Achillea can be said to have three main actions: clear Exterior Wind (diaphoretic), Tonify Deficiency (tonic) and clear Heart Phlegm (anti-hypertention) (12).

Many of these therapeutic usages have been confirmed by new experimental and clinical studies. The consumption of herbal teas from different species of Achillea, especially for treatment of the gastrointestinal tract, is common in folk medicine (13). However, there are still several unknown aspects of Achillea plants that need more attention.

Phytochemical constituents 

Phytochemical investigations of Achillea species have revealed that many components from this genus are highly bioactive. The first anti-spasmodic flavonoids, cynaroside I and cosmosiin II (Scheme 1) were isolated from A. millefolium L. (14), and the first natural proazulene, achillicin III (Scheme 2) was identified from the genus Achillea (15). Literature search shows that the, flavonoids, terpenoids, lignans, amino acid derivatives, fatty acids and alkamides such as p-hydroxyphenethylamide IV (Scheme 2) have been identified in Achillea species. The main constituents of the most species have been previously reviewed (7). Therefore, in this article some other minor or rare compounds and especially their medicinal or industrial usages which have been less described are reviewed. Among them,alkamides, the lipophilic and nitrogen containing compounds, are responsible for insecticide, anti-inflammation and some immunological activities of Achillea and Echinacea plants (16). The genus Achillea comprises flavored species which produce intense essential oils. The volatile oils of Achillea contain monoterpenes as the most representative metabolites. However, there are reports on high levels of sesquiterpenes compared with monoterpenes (1718). There are several pharmacological actions which have been mostly attributed to the presence of azulenogenous sesquiterpene lactones in the essential oil of Achillea. Results of studies have indicated that tetraploid species are accumulating proazulenes such as achillicin III (Scheme 2) (19).Except for the essential oil constituents, yarrow (A. tenuifolia Lam.) seeds consist of the high oil content which is rich in linoleic acid, an essential polyunsaturated fatty acid. This makes yarrow seed as a potential source of edible oil for human consumption (20). Recently, A. millefolium has been introduced as a new source of natural dye for wool dyeing due to the presence of the flavonoids, luteolin V and apigenin VI (Scheme 1). A. millefolium was found to have good agronomic potential as a natural dye in Iran (21). In the plant kingdom, hydroxycinnamoyl conjugates of quinic acid represent common end metabolites of the shikimate-phenylpropanoid pathway, and feruloylcaffeoylquinic acid derivates VII have been isolated only from two species of genus Achillea so far (22). From the aerial parts of Achillea species, proline VIII, stachydrine IX, betonicine X, betaine XI and choline XII have been isolated as the major nitrogen containing compounds (Scheme 2) (2324). Betaines, containing the permanent positive charge on the quaternary ammonium moiety, belong to an important class of naturally occurring compounds that function as compatible solutes or osmoprotectants (25). These compounds have shown immunosuppressive activity in the experimental animals (2627).

DARU-19-173

Reference:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232110/

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Yerba Mate (Ilex paraguariensis) Beverage: Nutraceutical Ingredient or Conveyor for the Intake of Medicinal Plants? Evidence from Paraguayan Folk Medicine

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Monika Kujawska

Abstract

The use of medicinal plants mixed with yerba mate (Ilex paraguariensis) has been poorly studied in the ethnopharmacological literature so far. The Paraguayan Mestizo people have the longest tradition of using the yerba mate beverage, apart from the indigenous Guarani people. This study analyses the role of yerba mate and medicinal plants in the treatment of illnesses within Paraguayan folk medicine. The research was conducted among 100 Paraguayan migrants living in Misiones, Argentina, in 2014 and 2015. Yerba mate is not considered to be a medicinal plant by its own virtues but is culturally a very important type of medicinal plant intake. Ninety-seven species are employed in hot and cold versions of the yerba mate beverage. The most important species are as follows: Allophylus edulis (highest number of citations), Aristolochia triangularis (highest relative importance value), and Achyrocline flaccida and Achyrocline tomentosa (highest score by Index of Agreement on Species). The plants are used in the treatment of 18 medicinal categories, which include illnesses traditionally treated with plants: digestive system, humoral medicine, and relatively new health conditions such as diabetes, hypertension, and high levels of cholesterol. Newly incorporated medicinal plants, such as Moringa oleifera, are ingested predominantly or exclusively with the mate beverage.

1. Introduction

Yerba mate (Ilex paraguariensis A.St.-Hil., Aquifoliaceae) is a native tree growing in the subtropics of South America, present in Southern Brazil, Northeastern Argentina, Eastern Paraguay, and Uruguay [1]. The yerba mate beverage has been consumed traditionally by Guarani indigenous people since before the conquest of South America by the Spaniards [2]. The commercial potential of this plant was discovered by the Jesuits, who brought wild growing yerba mate into cultivation. Pedro de Montenegro, a Jesuit monk, in his Materia Medica Misionera described the use of the most important species for the Guarani people, in which yerba mate appeared on the top of the list [3]. The Guarani name for yerba mate is ka’a which means “a plant” or “a herb”; hence yerba mate has been considered by this group as the plant par excellence [3]. Yerba mate was also known as Jesuit tea or Paraguayan tea and shipped as such to Europe [2]. With the expulsion of the Jesuits in 1768, the plantations went wild. By this time, the yerba mate beverage was already popular among Mestizo people (of Spanish and Guarani origin). Since the end of the 19th century, it also became a daily beverage for the European migrants who partly colonized Southern Brazil, Northeastern Argentina, and, to a lesser extent, Eastern Paraguay [4]. Nowadays yerba mate is consumed at the rate of more than one litre per day by millions of people in the above-mentioned countries [45]. It plays a very special social role and constitutes a very important form of caffeine intake [245]. Its popularity is also increasing outside South America due to its pharmacological properties, proven to be beneficial to health [467]. It is also a very important drink in Syria and Lebanon due to Syro-Lebanese migration to Argentina in the second half of the 19th century. Many migrants who returned to the Levant in the 1920s took the habit of drinking mate with them [89].

Over the last 20 years there has been an increase in studies of the pharmacologic properties of Ilex paraguariensis, which have been reviewed [46710]. Numerous active compounds have been identified in yerba mate. Phenolic compounds predominate caffeoyl derivatives (caffeic acid, chlorogenic acid) [1112], xanthines (caffeine and theobromine), which are a class of purine alkaloids found in many other plants such as tea and coffee, flavonoids (quercetin, kaempferol, and rutin), and tannins [7]. Numerous triterpenoid saponins have also been identified, including those derived from ursolic acids known as metasaponins [47]. Saponins are responsible for the distinct flavour of yerba mate extracts [7]. Yerba mate also contains minerals (P, Fe, and Ca) and vitamins (C, B1, and B2) [13].

Research on extracts and isolated compounds from yerba mate has provided a number of pharmacological applications. Studies have demonstrated that yerba mate leaves have antioxidant [11], antiobesity [1415], antidiabetic, digestive improvement and cardiovascular properties [1617], and chemopreventative ones (preventing cellular damage that may cause chronic diseases) [18]. The consumption of yerba mate infusion reduces LDL-cholesterol in parallel with an increase in HDL-cholesterol, as observed in studies on humans [19]. Yerba mate extract also reduces acute lung inflammation, as observed in the animal model [4]. Antimicrobial activity of Ilex paraguariensis has been recently studied as well [20].

Some ethnobotanical studies from the south cone of South America report medicinal uses of yerba mate beverage [2122]. Few ethnobotanical and ethnopharmacological studies mention that various medicinal plants are consumed together with the yerba mate beverage by Mestizo and European migrants living in Argentina and Paraguay [2326]. However, very little is known about how medicinal plants are combined with yerba mate beverage by local people. Additionally, medicinal plant use by Paraguayan Mestizo people is poorly documented in the English-language scientific literature, with very few exceptions [232630]. The documentation of medicinal plants and analysis of traditional knowledge related to the yerba mate beverage by Paraguayan Mestizo people is of paramount importance for two reasons: (1) apart from indigenous Guarani peoples, they have the longest tradition of using yerba mate and mixing it with medicinal plants; (2) The Paraguayan people are described in the literature as knowledgeable about medicinal plants [3031]. Nearly 80% of the population of Paraguay consume medicinal plants on a daily basis [30]. However, the relationship between traditional uses and pharmaceutical properties is poorly studied.

The objectives of this contribution were to (1) document and analyse the role of yerba mate in prophylaxis and treatment by Paraguayan Mestizo people; (2) evaluate the role of medicinal plants in yerba mate beverages, and (3) describe the scope of illnesses treated with yerba mate beverage and medicinal plants. Additionally, two questions guided my research and analysis: (1) Does any pattern exist showing that particular illnesses are treated with a hot version of yerba mate beverage and others with a cold one? (2) How receptive is this traditional mode of plant administration to new health challenges and new medicinal plants, previously unknown to the Paraguayan people?

ECAM2018-6849317

Reference:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872613/

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