Next Article in Journal
A Concise Review of Extraction and Characterization of Chondroitin Sulphate from Fish and Fish Wastes for Pharmacological Application
Next Article in Special Issue
Induction of Apoptosis and Effect on the FAK/AKT/mTOR Signal Pathway by Evodiamine in Gastric Cancer Cells
Previous Article in Journal
Higher NADH Dehydrogenase [Ubiquinone] Iron–Sulfur Protein 8 (NDUFS8) Serum Levels Correlate with Better Insulin Sensitivity in Type 1 Diabetes
Previous Article in Special Issue
Indole-3-Carbinol, a Phytochemical Aryl Hydrocarbon Receptor-Ligand, Induces the mRNA Overexpression of UBE2L3 and Cell Proliferation Arrest
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
CIMB
Volume 44
Issue 9
10.3390/cimb44090267
cimb-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Anticancer Secondary Metabolites: From Ethnopharmacology and Identification in Native Complexes to Biotechnological Studies in Species of Genus Astragalus L. and Gloriosa L.

by
Iliana Ionkova
,
Aleksandar Shkondrov
,
Yancho Zarev
*,
Ekaterina Kozuharova
and
Ilina Krasteva
Department of Pharmacognosy, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria
*
Author to whom correspondence should be addressed.
Curr. Issues Mol. Biol. 2022, 44(9), 3884-3904; https://doi.org/10.3390/cimb44090267
Submission received: 27 June 2022 / Revised: 21 July 2022 / Accepted: 21 August 2022 / Published: 26 August 2022
(This article belongs to the Special Issue New Sights: Phytochemicals and Cancer)
Browse Figures
Review Reports Versions Notes

Abstract

:
Some of the most effective anticancer compounds are still derived from plants since the chemical synthesis of chiral molecules is not economically efficient. Rapid discovery of lead compounds with pronounced biological activity is essential for the successful development of novel drug candidates. This work aims to present the chemical diversity of antitumor bioactive compounds and biotechnological approaches as alternative production and sustainable plant biodiversity conservation. Astragalus spp., (Fabaceae) and Gloriosa spp. (Liliaceae) are selected as research objects within this review because they are known for their anticancer activity, because they represent two of the largest families respectively in dicots and monocots, and also because many of the medicinally important plants are rare and endangered. We summarized the ethnobotanical data concerning their anticancer application, highlighted the diversity of their secondary metabolites possessing anticancer properties such as saponins, flavonoids, and alkaloids, and revealed the potential of the in vitro cultures as an alternative way of their production. Since the natural supply is limited, it is important to explore the possibility of employing plant cell or organ in vitro cultures for the biotechnological production of these compounds as an alternative.

Graphical Abstract

1. Introduction

Malignant diseases are the second cause of mortality, and their treatment remains a serious problem [1]. Some of the most powerful products in cancer therapy are still obtained from plants because the chemical synthesis of these chiral molecules is not economical [2,3]. Identification of plants that are efficient in cancer treatment relates to ethnobotanical and ethnopharmacological records; however, finding such information is not easy. The origin of the word “cancer” is credited to the Greek physician Hippocrates (460–370 BC), but the oldest description of this disease dates back to about 3000 BC in Egypt [1]. Cancer is not a modern disease, but research shows that it was only about a third as common in medieval Britain as in modern Britain [4]. Up to 50% prevalence of cancer is recorded at the time of death in modern Britain, which is explained by the effects of modern carcinogens, the spread of viruses that trigger malignancy, industrial pollutants, etc. [5]. Although cancer has been known since ancient times and has long been studied, neither the tumor types nor their causes are clear and well defined [6]. This is a serious challenge to the ethnobotanical research of cancer treatment, but at the same time, the results are rewarding. Plant-specific secondary metabolites have long been seen as a prospective approach in human therapy [7]. The interest in plant secondary metabolites from research to industry increases because synthetic chemicals are perceived as potentially toxic [8]. Many compounds are difficult to be synthesized via chemosynthesis, or the cost of their synthesis outweighs their commercial availability [9,10]. Most of the plant secondary metabolites with pharmaceutical use are still isolated from wild or cultivated plants. Plant resources, however, are not endless. Many of these plant species are endangered either due to their excessive collection or their limited distribution. Sometimes there are conservational restrictions, which can limit the commercial production of some compounds from wild populations. Some valuable substances can only be isolated from extremely rare plants. Conservation of biodiversity is curtailed [11,12,13,14,15]. A good and comparatively inexpensive method to obtain plant biomass for sufficient bioactive compounds’ extraction is cultivation [16,17,18], although, for some plants, it is difficult or takes several years. Additionally, isolating pharmaceutical products from plants is difficult due to their extremely low concentrations. However, modern science and practice have found a solution for these complications. It has become possible to use plant cells to produce specific pharmaceutical products by applying biotechnological approaches. The biotechnological approach offers a quick and efficient method of producing highly valuable compounds [19,20,21]. In this context, alternative methods for producing secondary metabolites appear as plant cell and tissue culture techniques. Starting from callus tissue, cell suspension cultures can be established and can even be grown in large bioreactors. In addition, the biotechnological production of these plant compounds is more environmentally friendly. Some of the advantages of the in vitro techniques are the propagation of the plants in aseptic controlled conditions and their large-scale production in a year-round system without seasonal constraints [22]. The plant cell techniques provide some highly efficient methods for isolating and extracting the secondary metabolites within a short time compared to the wild plant populations. The simplicity of these in vitro-produced tissue methods makes them suitable for commercial application [23]. Additionally, some metabolites can be produced by in vitro cultures, but generally, they are not found in intact plants [24].
In this work, we aim to integrate the chemical diversity of antitumor bioactive compounds and medicinal plant biodiversity conservation with a biotechnological approach. The research objects Astragalus spp. div., (Fabaceae) and Gloriosa spp. div. (Liliaceae) were selected firstly because they are known for their anticancer activity, secondly because they represent two of the largest families respectively in dicots and monocots, and also because many of the medicinally important plants are rare and endangered. The aim of this review study is (1) to summarise the ethnobotanical data about their anticancer application, (2) to highlight the diversity of their secondary metabolites possessing anticancer properties, (3) to reveal the potential of the in vitro cultures as an alternative way of their production.

2. Materials and Methods

We accessed Web of Science (https://www.webofscience.com/wos/woscc/basic-search, accessed on 1 January 2022) and PubMed (https://pubmed.ncbi.nlm.nih.gov/advanced/, accessed on 1 January 2022). A time range of 2018–2022 was set. The following keywords were used: “Astragalus”, “Gloriosa”, “traditional”, “ethnobotany”, “cancer”, “secondary metabolites”, “biotechnology”, and “tissue cultures”, alone or in combination. Some of the revised information is connected with previous research of our work groups and published before. More than 200 articles were analyzed for this review. Publications not included in the review are either: (1) found online only as an abstract (without access to full text); (2) not possible to translate correctly by the authors (articles not in English, German, Russian, Bulgarian, etc.); or combination of both criteria. Based on those, 43 of the results given by both databases were rejected (comprising 22% of the results).

3. Results and Discussion

3.1. Characteristics of Target Astragalus Species

The genus Astragalus L. is the largest in the family Fabaceae (syn. Leguminosae), with more than 3500 species [25]. Astragalus, excluding Astracantha (formerly Astragalus subgenus Tragacantha), has a world total of ca. 2500 species, of which ca. 500 are in the Americas [26]. Many of the species have conservation status “vulnerable” or “critically endangered” [27].

3.2. Ethnobotanical Data of Astragalus Species Used against Cancer

Astragalus mongholicus Bunge is the accepted name of A. membranaceus var. mongholicus (Bunge) P.G. Xiao often referred to as A. membranaceu [28] is a key plant in Chinese Traditional Medicine used mainly as a Qi (Chi) tonic [29,30] but also prescribed against cancer [30]. A study found that A. membranaceus is an ingredient in 172 of the 200 analyzed Chinese herbal formulae [31].
In Table 1 are summarized ethnobotanical data of Astragalus species medicinal application. Various species have been used in folk medicine as an antihypertensive, diuretic, anti-inflammatory, emollient, etc. Aerial parts, seeds, fruits, roots, or gum are utilized [32]. For instance, A. glycyphyllos, the herb decoction is administered in Bulgaria as an infusion in cases of abdominal pain, colic, renal inflammation, menstrual disorders, and sciatica [33]. Both roots and leaves of this plant are used as a diuretic in Italy [34]. In Turkish traditional medicine, several Astragalus species are used to cure throat diseases, diabetes, cardiac disorders, toothache, and abdominal pain [35,36,37,38,39,40], but also against unspecified cancer [41]. The most used herbal drug derived from the genus is Radix Astragali (roots and rhizomes of A. mongholicus (syn. A. membranaceus). The plant substance is listed in the European Pharmacopeia [42].

3.3. Secondary Metabolites of Astragalus Species Anticancer Properties

In recent years, progress in phytochemical studies has been made on Astragalus species due to their effects as immunostimulants or anticancer agents [45,47,49,50,51,52,53,54,55,56,57,58].
Many Astragalus species contain cycloartane saponins–astragalosides, which are cycloastragenol derivatives. Some saponins isolated from representatives of the genus are based on an oleanane skeleton [51,53]. The high intake of flavonoids is generally associated with a reduced risk of neoplasms [59,60]. Over 160 different flavonoids of 90 species of Astragalus have been isolated and identified as revised previously [52,53]. Polysaccharides have been shown to play a role in immune modulation. Astraglucanes have been isolated from roots and rhizomes of A. mongholicus (syn. A. membranaceus) [42] and other species. The polysaccharide fraction contains highly branched, predominantly 1,3-β-glucans. These products find their application as an aid in radiation antineoplastic therapy and chemotherapy, as well as in the treatment and prevention of bacterial and viral infections [61].
Different Astragalus extracts have been shown to increase resistance to the immunosuppressive effects of chemotherapy drugs while stimulating macrophages to produce interleukin-6 and tumor necrosis factor (TNF). Human clinical trials demonstrated a substantial increase in survival rates when extracts from Astragalus plants are given to cancer patients receiving chemo- or radiotherapies. They have also increased IgA, IgC, and interferon production in humans [51]. Astragaloside IV inhibited the development of non-small cell lung cancer by inhibiting the Akt/GSK-3p/p-catenin signaling pathway. It also increased the expression of Bax (a cell death marker) while decreasing the expression of Bcl-2 (anti-apoptotic protein). This demonstrates the importance of astragaloside IV as a potential antitumor agent [62].
A. angustifolius is an endemic Bulgarian species that has been reported to contain cyclosiversigenin (cycloastragenol), siversigenin (astragenol), and soyasapogenol B [51]. The antiproliferative activity of compounds isolated from A. angustifolius in cervical (HeLa), human lung (H-446), human colon (HT-29) cancer, and human monocyte lymphoma (U937) cell lines are examined [63], and only 3-O-[α-L-rhamnopyranosyl-(1→2)-β-D-xylopyranosyl-(1→2)-β-D-glucuronopyranosyl]-3β,22β,24-trihydroxyolean-12-en-29-oic acid possessed weak cytotoxicity against HeLa.
Another endemic Bulgarian plant is A. aitosensis which afforded 5,6-dehydro-6-desoxyastragenol [51], as shown in Table 2.
Recently, a novel and unusual for the genus Astragalus group of compounds, flavoalkaloids, is identified in A. monspessulanus subsp. monspessulanus. Before, they were known only as aglycones (Figure 1). One novel quercetin tetraglycoside and eight known flavonoids are isolated as well [53]. Also, from the aerial parts of this species, two saponins are reported [64]. Two rare flavonoids with an unusual hydroxymethylglutaric acid as a moiety: quercetin-3-O-α-L-rhamnopyranosyl-(1→2)-[6-O-(3-hydroxy-3-methylglutaryl)-β-D-galactopyranoside and kaempferol-3-O-α-L-rhamnopyranosyl-(1→2)-[6-O-(3-hydroxy-3-methylglutaryl)-β-D-galactopyranoside are isolated from the aerial parts of A. monspessulanus subsp. illyricus (Figure 1) [65].
Phytochemical investigation of A. glycyphyllos led to the isolation of six saponins, and their structures are partially elucidated [66,67]. After acid hydrolysis of a saponin mixture obtained from the aerial parts of the plant, soyasapogenol B and 3β,22β,24-trihidroxyolean-12-en-19-one are identified [68]. Cycloartane saponins askenoside C and F [68] and 17(R), 20(R)-3β,6α,16β-trihydroxycycloartanyl-23-carboxylic acid 16-lactone 3-O-β-D-glucopyranoside are later isolated from the species [69]. Several known flavonoids, including the rare camelliaside A, are also identified [53,69]. The antineoplastic activity in vitro of the saponin-containing fractions obtained from wild-grown and cultivated A. glycyphyllos, respectively, were tested in a panel of human tumor cell lines of different origin and characteristics. A standard MTT-based protocol for assessing cell viability was used. Both fractions inhibited tumor cell growth in a dose-dependent manner. However, according to the calculated IC50 value, the fraction obtained from the in vitro shoot cultures showed relatively superior cytotoxic activity compared to that of the wild-type species in all of the screened tumor cell lines (our unpublished data). In vitro cultures of A. glycyphyllos could be an alternative way to produce saponins, with promising antineoplastic activity.
Table
Table 2. Notable metabolites from wild and in vitro cultures of targeted species and cytotoxicity of some on a panel of malignant cells.
Table 2. Notable metabolites from wild and in vitro cultures of targeted species and cytotoxicity of some on a panel of malignant cells.
Plant SpeciesType Compounds IsolatedCytotoxicity on Cell Lines (IC50)References
A. aitosensiscallus, suspensioncycloartane saponins, sterols, flavonoidsn.d.[51]
aerial pars, wild grown *5,6-dehydro-6-desoxyastragenoln.d.[51]
A. angustifoliuscallus, suspensioncycloartane saponins, flavonoidsn.d.[53]
aerial parts, wild grown *β-sitosterol, cycloastragenol, astragenol, soyasapogenol B,
3-O-[α-L-rha-(1→2)-β-D-xyl-(1→2)-β-D-glc]-3β,22β,24-trihydroxyolean-12-en-29-oic acid		n. d.
HeLa (36 µM); HT-29 (50 µM)		[63]
[53]
A. asperaerial parts, wild grown *saponins, flavonoidsn.d.[53]
A. boeticuscallus, suspension,
hairy roots		saponins, soyasapogenol B, β-sitosterol, flavonoids n.d.[70]
A. brachycerahairy roots **
shoots **		cycloartane saponins, sterolsn.d.[51]
A. canadensishairy rootscycloartane saponins, cycloastragenol, astragenol, n.d.[51]
A. centralpinusaerial parts, wild grown *flavonoidsn.d.[53]
A. corniculatusaerial parts, wild grown ***two oleanane type saponins and a corresponding lactoneGraffi tumour–in vivo, i.p., hamsters (50 mg/kg) ***; in vitro (20 µg/mL) ***[71]
A. eduliscallusquercetin, kaempferol, isorhamnetin, saponins n.d.[70]
A. englerianushairy rootscycloartane saponins n.d.[51]
A. falcatushairy rootscycloartane saponins n.d.[51]
A. glycypylloshairy roots **, callus
shoots ***		cycloastragenol, astragenol, soyasapogenol B
epoxycycloartanes		n.d.
T-24 (125 µg/mL); CAL-29 (90 µg/mL); MJ (75 µg/mL); HUT-78 (78 µg/mL)		[51]
[53]
[72]
aerial parts, wild grown ***epoxycycloartanesK-562 (50 µg/mL) ***; HL-60 (40 µg/mL) ***; BV-173 (70 µg/mL) ***[73]
aerial parts, wild grown ***epoxycycloartanesT-24 (168 µg/mL); CAL-29 (105 µg/mL); MJ (126 µg/mL); HUT-78 (87 µg/mL)[72]
aerial parts, wild grown17(R),20(R)-3β,6α,16β-trihydroxycycloartanyl-23-carboxylic acid 16-lactone 3-O-β-D-glucopyranosideT-24 (66 µg/mL); CAL-29 (52 µg/mL); MJ (52 µg/mL); HUT-78 (18 µg/mL)[74]
A. hamosuscallus, suspension, hairy rootssaponins, soyasapogenol B, β-sitosterol, astragalin, rutin, isorhamnetin-3-O-glycoside n.d. [53,70]
aerial parts, wild grown ***saponinsHL-60 (63 µg/mL); HL-60/Dox (25 µg/mL); SKW-3 (84 µg/mL)[75]
A. missouriensisCallus **, suspension, hairy rootsisoquercitrin, quercitrin, rutin, hyperoside, saponinsn.d.[70,71]
A. mongholicus (syn. A. membranaceus)hairy roots **, shoots **astragalosides, β-sitosterol, stigmasterol, campesteroln.d.[51,72]
A. monspessulanusaerial parts, wild grown *flavoalkaloids, acylated flavonoids, flavonoidsn.d.[65]
A. onobrychisaerial parts, wild grown *flavonoids, saponinsn.d.[76]
A. oxyglotishairy rootscycloartane saponinsn.d.[51]
A. sesameusShoots **-HL-60/Dox (87 µg/mL); SKW-3 (68 µg/mL)
A. spruneriaerial parts, wild grown *flavonoidsn.d.[77]
A. sulcatushairy rootscycloartane saponins, sterols, swensoninen.d.[51]
A. thracicuscallus, suspensionsaponins, flavonoidsn.d.[53]
aerial parts, wild grown *saponins, flavonoidsHT-29 (52 µg/mL); HL-60 (67 µg/mL); HL-60/Dox (53 µg/mL); SKW-3 (83 µg/mL)[53]
A. vesicarius ssp. carniolicuscallusflavonoidsHL-60 (8.8 µg/mL) *; HL-60/Dox (11.8 µg/mL) *[78]
callus5-hydroxy-7-methoxy-2′, 5′-dihydroxyisoflavoneHL-60 (38.9 µg/mL); HL-60/Dox (35.2 µg/mL)[78]
5, 7-dihydroxy-4′-methoxyisoflavoneHL-60 (41.4 µg/mL); HL-60/Dox (42.4 µg/mL)[78]
7-methoxy-5-hydroxy-4′-methoxy-2′-hydroxyisoflavoneHL-60 (64.1 µg/mL); HL-60/Dox (41.8 µg/mL)[78]
8-pregnyl genisteinHL-60 (36.1 µg/mL); HL-60/Dox (36.1 µg/mL)[78]
5,7-dihydroxy-8-pregnyl-4′-methoxy-2′-hydroxyisoflavone HL-60 (56.3 µg/mL); HL-60/Dox (56.8 µg/mL)[78]
sophorophenoloneHL-60 (78.0 µg/mL); HL-60/Dox (63.0 µg/mL)[78]
G. superbaseedscolchicoside, colchicine, 3-O-demethylcolchicinePANC-1, PANC02 (GS ++ 0.45–0.59 µg/mL)
PANC02 (GS2B + 9.49 µg/mL)		[79]
[80]
glorioside, colchicodiside A, gloriodiside, colchicodiside B, colchicodiside C, dongduengoside A-C, colchicine, 2-demethilcolchicine, colchicoside and luteolin 7-O-β-D-glucopyranosideDLA (29 µg #; 21 µg ##)[81]
[82]
[83]
rhizomespeptidesSW620 (n.d.)[84]
rootscolchicineHT-29 (0.12 μg/mL *)[85]
G. rothschildianaaerial partsgloriosamine A-D, colchicine, colchiciline, colchifoline and N-deacetyl-N-formylcolchicine-[86]
* Extract was tested; ** Extract from this culture was tested; *** Purified saponins’ mixture was tested; + GS2B, colchicine poor extract; ++ GS, G. superba total extract; # Methanolic extract of G. superba seeds; ## AgNPs; n.d., not defined.
Three saponins are isolated from A. corniculatus: two of them with an aglycone 3β,21α-dihydoxyolaean-12-ene-28-oic acid, and the third–with its corresponding lactone [22,87]. A series of studies demonstrated that a purified saponin fraction containing these compounds had a protective effect against the invasiveness of bone marrow carcinoma (Graffi myeloid tumor) in hamsters. Administration of the saponin mixture increased the number, migration, and phagocytic index of peritoneal macrophages and blood polymorphonuclear leukocytes in animals with implanted tumors. Also, due to the hamster treatment with the mixture, an increased mitogenic response to phytohemagglutinin and lipopolysaccharides is observed, i.e., the saponins have an immunostimulatory effect [88,89,90].
Rhamnocitrin 4′-β-D-galactopyranoside and a mixture of two saponins are isolated from aerial parts of A. hamosus and investigated for antiproliferative activity on SKW-3 cells. Significant apoptosis-induction activity is proved for the saponin mixture compared to the flavonoid glycoside at equal concentrations. After co-administration of rhamnocitrin 4′-β-D-galactopyranoside, with Cisplatin and Gentamicin, there is significant protection of human kidney cells HEK-293T against the cytotoxic effects of nephrotoxic drugs [75]. The same mixture of two saponins is examined on cell lines HL-60, HL-60/Dox, SKW-3, RPMI-8226, U-266, and OPM-2 [75]. The saponins caused concentration-dependent suppression of the proliferative activity of malignantly transformed cells. These data are confirmed by an ELISA test evaluating apoptosis-specific DNA fragmentation. The significance of the transcription factor NFκB, as well as the mitochondrial protein Bcl-xL for the antitumor activity of the saponin mixture, is established. Selective cytotoxic activity of saponins in cell lines originating from breast cancer is demonstrated. The saponin mixture showed cytotoxicity concerning both cell lines and clearly demonstrated inhibitory properties against the mitochondrial anti-apoptotic protein Bcl-xL. This gives a reason to believe that unlocking the internal pathway of apoptosis by suppressing the expression of BclxL is a part of the mechanism of action of the saponins. Furthermore, the mixture of two saponins showed no cytotoxic effect on the non-malignant cell line MCF-10A, which originated from the mammary gland, suggesting that it exhibited selective malignant cell toxicity and may be the subject of further studies [91].
Data on the phytochemical content as well as the cytotoxic activity of extracts and purified fractions from wild-grown and in vitro cultivated selected Astragalus species on notable malignant lines is presented in Table 2. Some structures of the compounds of interest are shown in Figure 1.
All the data from the phytochemical analysis and the activity suggest that these plants are valuable as anticancer agents.

3.4. Biotechnology of Astragalus Species

Many in vitro cultures are established not only to increase the production of important secondary metabolites in selected Astragalus plants but also to preserve the endemic and/or endangered species. In general, the most investigated species both in phytochemical and biotechnological means is A. mongholicus (syn A. membranaceus) [92].

3.4.1. Cell Culture

The active substances from wild and field-grown plants usually have different quality and quantity and vary depending on the environmental conditions. The diseases and the application of pesticides further reduce the quality of the plant material. In vitro plant cultures surmount these problems as environmental conditions affecting the metabolism of plants can be precisely controlled. Working with tissue cells dramatically decreases preparation time, processing, and storage costs associated with traditional plant approaches [93]. There are several advantages to producing secondary metabolites in plant cell culture compared to in vivo cultivation. Production can be more predictable, reliable, and independent from unpredictably changing climatic conditions. Isolation of the phytochemical metabolites can be more rapid and efficient than extraction from the whole plant. Interfering compounds in the wild plant can be avoided in tissue cultures. Cell cultures can produce phytochemicals in large volumes.
Astragalus genus possesses characteristics that make it significant for in vitro cultivation. Reducing natural supplies due to excessive collection is already present and, therefore, industrial or consumer interest. Due to their complex structures, saponins, flavonoids, and polysaccharides are still most efficiently produced by the plants. There are a lot of problems involved with this production method. Variable qualities and quantities of the plant material, plants that need to grow several years before being ready for harvesting (Astragalus roots), and the over-collecting of some species (A. mongholicus, syn. A. membranaceus), A. angustifolius, A. missouriensis, A. thracicus, A. aitosensis, etc.) are just a few of the problems connected with the production of these natural products. Therefore, tissue cultures might be explored as an alternative production method [7].

3.4.2. Effects of Medium Composition and Growth Regulators

The flavonoid biosynthesis in cell cultures of A. missouriensis and A. angustifolius is strongly suppressed by 2,4-dichlorophenoxyacetic acid (2,4-D). The higher concentrations of 2,4-D decreased the content of flavonoids. In this respect, 1-naphthaleneacetic acid (NAA) is weaker than 2,4-D. Therefore, flavonoid production is inhibited by adding 2,4-D to the medium. In all tested concentrations of cytokinins, such as 6-benzylaminopurine (BAP) or kinetin (Kn), under the light cultivation regimen, induction of flavonoid production in cell suspension cultures is achieved. Kinetin was found to be the most effective. The sucrose levels of the medium have a tremendous impact on saponins production. The growth and the saponins production are favored by the higher concentrations of sucrose. The investigation was carried out on A. membranaceus hairy roots cultures (HR) with different concentrations of sucrose in the MS medium. A basic MS medium supplemented with 2% sucrose increases overall saponins yield but inhibits the growth of HR. The growth of Astragalus-HR is promoted by high concentration (6%), but the yield of saponins remains very low. The optimal medium for both yield and growth is supplemented with 4% sucrose [94].

3.4.3. Effects of End-Product Inhibition

Because phytosterols (campesterol, stigmasterol, and β-sitosterol) are present in the hairy roots of Astragalus species, the effect on the total saponin production of these substances is examined. Since the biosynthetic route of saponins and that of phytosterols are branched at 2,3-epoxyscvalen, it may be possible to increase the production of saponins by end-product inhibition. In the experiments, contents of saponins after adding 0.2 mg/mL of β-sitosterol in MS liquid medium without ammonium nitrate are examined at different stages of growth. The saponin content (total saponins) in the hairy roots induced by Agrobacterium rhizogenes LBA 9402 reached 5.25% of dry wt on day 28 of cultivation. When β-sitosterol is added to the culture media of these hairy roots, astragaloside production is remarkably increased to 7.13% of dry wt and led to an increase of 36% of the total saponin content in comparison with the control. From these data, β-sitosterol seems to behave as an inhibitor in the biosynthetic route when the amount added is relatively large. These results prove that the hairy root cultures of Astragalus mongholicus can be a valuable alternative for overproducing cycloartane saponins compared with the whole plant. Using a selected high productive clone, inducing by Agrobacterium rhizogenes LBA 9402, optimized culture medium (MS without ammonium nitrate), and end-product inhibition, a relatively high saponin production can be achieved [94,95].

3.4.4. Genetic Transformation of Astragalus Species by Agrobacterium Rhizogenes

In a specific soil, A. rhizogenes can induce a certain type of “hairy roots” culture, which can be maintained without phytohormones in the medium [96]. Usually, four different bacterial strains are used—TR 105, R 1601, ATCC 15834, and LBA 9402. With the same Agrobacterium strain, the susceptibility of Astragalus species to infection is highly variable. Some species of the genus (A. membranaceus, A. mongholicus, A. monspessulanus) have more difficulties establishing transformed roots. In some plants (A. englerianus, A. mongholicus, A. missouriensis, A. sulcatus), a callus is formed initially, and transformed roots subsequently emerge from it. Still, in others (A. glycyphyllos, A. hamosus, A. boeticus), a profusion of roots appear directly at the site of inoculation [70].

3.4.5. In Vitro Production of Secondary Metabolite

Optimization of cultures and production conditions has been achieved to produce flavonoids from cell cultures of different Astragalus species: A. monspessulanus, A. aitosensis, A. missouriensis, A. edulis, A. hamosus, and A. angustifolius [53,65]. Flavonoids within complex plant tissues can be more difficult to separate in an intact polymeric form than cell culture-derived flavonoids. A novel vehicle for depth investigation of flavonoids individually represents the production of these compounds in uniform plant-cell culture systems.
All in vitro cultures of A. missouriensis and A. angustifolius produced flavonoids. Quercetin is the main aglycone identified in the in vitro cell suspension in both free and bound forms (as glycosides). The main flavonoid glycosides are isoquercitrine and quercitrine. Rutin and hyperoside have also been detected. The maximum total amount of flavonoids, 1.78% for A. angustifolius (unpublished results) and 1.34% for A. missouriensis, is achieved after optimization of the production medium [97].
Different types of in vitro culture lines of A. monspessulanus subsp. monspessulanus, native to Bulgaria are established, i.e., shoots, callus, and suspension. Significant differences in the flavonoid content are observed. In suspension cultures, callus, and shoot cultures, small amounts of flavonoids are quantified in comparison to wild overground parts, in which, among other flavonoids, the rare flavonoid alcesefoliside is found [98]. In vitro cultivated A. hamosus afforded astragalin and isoquercitrin [53]. Five isoflavonoids such as 5-hydroxy-7-methoxy-2′, 5′-dihydroxyisoflavone, 5, 7-dihydroxy-4′-methoxyisoflavone, 7-methoxy-5-hydroxy-4′-methoxy-2′-hydroxyisoflavone, 8-pregnyl genistein, 5,7-dihydroxy-8-pregnyl-4′-methoxy-2′-hydroxyisoflavone and one coumarochromone–sophorophenolone are isolated from ethylacetate fraction of in vitro callus cultures of Astragalus vesicarius ssp. carniolicus, after enzymatic hydrolysis with β-glucosidase and investigated for antiproliferative activity against chemosensitive human promyelocyte cell line HL-60 and its multidrug-resistant variant HL-60/Dox (Table 2). Despite the strong activity of the ethylacetate fraction, prenylated compound 8-pregnyl genistein also showed antiproliferative activity [78].
The fast growth of the biomass, as well as relatively high saponin production, can be achieved through the HR cultures of A. mongholicus. These produced cycloastragenol-saponins: astragalosides I-III [80,99]. Part of the saponin products (about 16–20% of the total saponin) produced by HR cultures of Astragalus spp. is released into the medium, essential to establish continuous saponin production. Heterogenous acid hydrolysis of the total mixture of saponins isolated from selected HR of A. membranaceus yielded three aglycones: astragenol, cycloastragenol, and soyasapogenol B. In vitro cultivation of A. hamosus and the latter phytochemical analysis of the cultures established (Table 2) revealed the presence of soyasapogenol A [51]. In vitro callus, shoot, and suspension cultures of A. glycyphyllos are developed when cultivated on MS, as well as using modified media (supplemented with various concentrations and combinations of plant hormones). Compared to the wild-grown species, in vitro shoot cultures accumulated double the amount of the main saponin (our unpublished data). Among them, Astragaloside (AG) IV has a tremendous interest due to its health benefits as antitumor, cardioprotective, antiviral, hepatoprotective, immunoregulatory anti-inflammatory, antidiabetic, and neuroprotective activities [51,52,81]. Due to the complicated stereochemical ring, the chemical synthesis of AG IV is difficult and commercially infeasible A. membranaceus hairy root cultures (AMHRCs) are developed as a biotechnology system that can supersede field-grown plants for the production of AGs [100]. However, the quantity of AG IV in AMHRCs is still low-0.02% dry weight (DW). The microbial biotransformation has been recognized to be superior to conventional chemical procedures for producing AG IV, owing to its high catalytic efficiency, inherent selectivity, low cost, and simple downstream processing [83,84]. There are many materials concerning fungus-mediated biocatalysis [83,85,86,87]. An elicitation effect of immobilized Prunus canescens (IPC) has been reported for in vitro cultures of plants [101]. The microorganisms have taken on greater significance in producing pharmaceuticals, chemicals, and food ingredients [89,90,102]. The fungi, especially the fungal endophytes, are a source of novel biocatalysts with numerous applications [103]. Currently, an ideal method in biotransformation procedures for producing biologically active substances represents the immobilization of microorganisms by Ca-alginate gel (CAG) [83,93,94,95]. Except through microorganisms’ biotransformation of exogenous substrates such as quercetin, kaempferol, and apigenin is achieved via suspension cultures of Astragalus vesicarius ssp. carniolicus. Respective mono-O-glycosylated derivatives are detected by ultra-high performance liquid chromatography-high resolution electrospray ionization mass spectrometry (UHPLC-HR-ESI-MS) analysis [104]. Suspension cultures of A. glycyphyllos was evaluated for possible increase in flavonoid production when treated with exogenous quercetin. Suspensions cultures, cultivated on modified G48 medium [105] supplemented with 10, 20 and 30 mg/mL quercetin achieved higher total flavonoid content (0.09, 0.10 and 0.13 mg/mg DW). In addition, biotransformation of quercetin to isoquercitrin is achieved. The highest concentration of isoquercitrin (56.73 ng/mg DW) was observed on suspensions cultures cultivated on a modified G48 medium supplemented with 20 mg/mL quercetin [106].
Many research groups have investigated the hairy root cultures of A. mongholicus [96,98,107] since the first report on HR Astragalus cultures [70]. Through the genetic transformation of A. rhizogenes, LBA9402 successfully induced eight A. membranaceus hairy root lines (I–VIII). The various AMHRCs lines showed variations in the contents of the astragalosides and isoflavonoids accumulation [100].
A. membranaceus field-grown roots (3-year-old) can produce 2.4 mg/g DW of total AG, while the hairy roots cultures of A. membranaceus can produce a higher amount (2.7 mg/g DW). The genes RolB and RolC from the plasmidic Ri-DNA of A. rhizogenes are responsible for the induction of AG accumulation in AMHRCs. However, for further promoting AG production in AMHRCs, there is a possibility to exploit external elicitations. There are several advantages of elicitation to induce/enhance the biosynthesis of secondary plant metabolites. Methyl jasmonate (MJ), salicylic acid (SA), and acetylsalicylic acid (ASA) are individually applied to AMHRCs to find the best elicitor for AG production. The quantity of AG increased in the range of 3.0–4.9 mg/g DW when MJ, SA, and ASA were individually fed to 34-day-old AMHRCs at 100 µM. The quantity of AG in non-treated control is 2.6 mg/g DW and 2.7 mg/g DW in ethanol-treated control. In terms of applying the three elicitors, the AG yield decreased in the following order MJ (4.9 ± 0.11 mg/g DW) > ASA (3.8 ± 0.08 mg/g DW) > SA (3.0 ± 0.15 mg/g DW). Therefore, the highest AG yield is achieved by elicitation with MJ [107].
The effect of elicitors depends on the elicitation doses [108]. Different types of UV elicitation treatments have been investigated [100,101,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126].

3.5. Characteristics of Target Gloriosa Species

Genus Gloriosa (Liliaceae) includes 12 species and, despite its taxonomic complication, was found to be monophyletic [127]. Few of them are of commercial, pharmaceutical, or ethnobotanical interest.

3.5.1. Ethnobotaical Data of Gloriosa Species Used against Cancer

Gloriosa superba is one of the plants used as an antidote against snakebite in the Southern part of Tamilnadu, India [128], and several drops of extract of this plant are rubbed onto the cuts and wounds in Rajouri and Poonch districts of Jammu and Kashmir, India [129]. It has wide application in folk medicine in tropical Africa and Asia, such as abdominal and general pain, anthelminthic and antiparasitic, leprosy, leucorrhea, mental illness, skin diseases, ulcers, etc. [130]. But also, in traditional applications in Asia and Africa, in addition to diseases such as gout, scrofula, antipyretic, anthelmintic, purgative, and antiabortive activity, anticancer use is indicated [131]. This activity is well confirmed in recent pharmacological tests against pancreatic cancer [79], colon cancer [84], and other cancer cells [132]. Due to the boom in harvesting and export trade, some populations of G. superba are on the edge of extinction [127].

3.5.2. Secondary Metabolites of Gloriosa Species with Anticancer Properties

The main secondary metabolite is colchicine, which has anticancer activity but its toxicity profile is not acceptable. Several studies suggested the cytotoxic activity of semisynthetic derivatives of colchicine and thiocolchicoside; thus, the reported IC50 values have no relevance to naturally occurring tropolones [133,134,135,136]. Gene expression, as well as cytotoxic effects of colchicine in human gastric cancer ASG and NCI-N87 cell lines, are evaluated. It was found that only 6 ng/mL of colchicine had the desired antiproliferative effect on both lines. Interestingly, the gene regulation of those cells is affected in the same manner as the stated concentration leading to apoptosis [137]. Despite this compound, the interesting colchicinoids such as gloriosamine A-D are isolated from the aerial part of G. rothschildiana [86].
Nowadays, the focus on G. superba is also due to the presence of glycosylated colchicine derivatives, especially colchicoside, which is considered ten times less toxic than colchicine, as shown in Table 2 [79]. Recently, four novel colchicinoids named N-deacetyl-N-formyl-3-de-O-methylcolchicine-3-O-β-D-glucopyranoside (glorioside), 3-de-O-methylcolchicine-3-O-β-D-glucopyranosyl-(1→6)-3-O-β-D-glucopyranoside (colchicodiside A), N-deacetyl-N-formyl-3-de-O-methylcolchicine-3-O-β-D-glucopyranosyl-(1→6)-3-O-β-D-glucopyranoside (gloriodiside) and 3-de-O-methylcolchicine-3-O-β-D-glucopyranosyl-(1→3)-3-O-β-D-glucopyranoside (colchicodiside B) are isolated from the seeds of the species [81]. Also, from a seedless pot of Thai origin, G. superba was identified in novel glycosylated colchicinoids–dongduengoside A-C, and colchicine, 2-demethilcolchicine, colchicoside, and luteolin 7-O-β-D-glucopyranoside [82]. Some colchicinoids are obtained using biotechnological approaches. Riva et al. (1997) describe that β-1,4-galactosyltransferase catalyzes galactosylation of colchicoside, and Pišvejcová et al. (2006) describe the influence of various parameters on the activity of β-1,4-galactosyltransferase derived from beef milk and the optimization of the conditions leading to the preparation of galactosylate and glycosylated colchicoside derivatives [138,139].
Within a survival experiment carried out in a murine model of pancreatic adenocarcinoma induced by PANC02 cells and the semi-long-term toxicity, slightly longer survival is observed for the group treated with colchicoside rich extract (GS2B) containing 0.07% colchicine, 2.26% colchicoside and 0.46% 3-O-demethylcolchicine. In contrast, combinatory treatment of total seed extract of G. superba (GS) with gemcitabine demonstrates a significant effect on tumor growth [80]. Among 23 selected plants from the Thai/Lanna medicinal database “MANOSROI III” frequently used in the anticancer recipes, methanolic extracts of G. superba roots demonstrated the highest antiproliferative activity against colon cancer cell line (HT-29) (Table 2). Significantly higher, dose-dependent apoptotic morphological changes on HT-29 cancer cells at a concentration of 50 μg/mL are observed for methanol extract and the hexane, methanol-water, and n-butanol fractions obtained therefrom when compared to cisplatin and doxorubicin [85]. Methanolic extract of G. superba seeds is employed in forming silver nanoparticles (AgNPs) with reduced toxicity [140]. Thus, the anticancer properties of G. superba seeds methanolic extract and AgNPs are studied against dalton lymphoma ascites (DLA) cells (Table 2). Using the rhizome extract of G. superba, biomolecule-coated nanotitania catalysts were synthesized, which showed an IC50 value of 46.64 µg/mL MCF-7 cancer cell line compared with L929 normal cells (IC50 61.81  µg/mL) [141]. In addition, in vivo study with DLA tumor-bearing mice demonstrated an increased survival rate from 20 days without treatment up to 72 days when seed extract was administered and 75 days for AgNPs treated group, respectively. Despite the undisputed activity of the phenethylisoquinoline alkaloids, major secondary metabolites, and also peptides obtained from the rhizome of G. superba are investigated against colon cancer [84]. In vivo study suggests that ethanol leaf extract of G. superba contains phytochemicals that can induce apoptosis via mitochondrial permeability transition pore opening and protect against monosodium glutamate-induced hepato-cellular injury and proliferative disorder in prostate and uterus [142]. Partially purified protein hydrolysate (30 ng/mL) significantly inhibited viability (by 40%) of SW620 human colon cancer cells and induced apoptosis by the up-regulation of p53 and down-regulation of NF-kB, considered potential targets for anticancer therapy.

3.5.3. Biotechnology of Gloriosa Species

The medicinal interest in G. superba and its nonstop over-exploitation are the main reasons to apply in vitro techniques for the conservation, production, and enhancement of secondary metabolites. The species has a very low rate of seed germination as well as seed production is quite low and uneconomical. One of the problems with commercial cultivation is the poor viability of the seeds [143]. Four or five vegetative cycles are necessary for the complete reproductive phase [144]. Commercially these plants are propagated using daughter corms with a week multiplication ratio (1:1), slow and insufficient for conservation of this species [145]. Thus, in vitro cultivation is needed to conserve this taxon, otherwise we will lose it by 2020 [146]. Plant biotechnological approaches, such as in vitro mass multiplication, have been taken for the conservation, and various methods and techniques have been studied for the production and enhancement of secondary metabolites. An efficient protocol is established for in vitro micro-propagation using corm bud explant [147]. Extracts from buds inoculated at MS medium supplemented with different concentrations of 2,4-D (1.0–10.0 mg/L) and IAA (0.5–5.0 mg/L) indicated that higher concentrations of 2,4-D and IAA reduce the callus induction. The shoot initiation depends on the combination of cytokinins. Most shoots are obtained in the presence of 9.84 μM 2iP combined with 4.64 μM Kin after 21-day culturing. Sivakumar et al. (2019) developed an efficient protocol for in vitro mass propagation of G. superba using callus derived from non-dormant corm buds [148]. Medium supplemented with a combination of plant growth regulators such as BAP (1.5 mg/L), NAA (0.6 mg/L), and polyamine putrescine (15 mg/L) as secondary messengers in signaling pathways, induced maximum shoot buds (87.5). Within this study, optimal seed germination of 86% is also achieved when seeds are treated with 70% sulphuric acid for 2 min. Mahendran et al. (2018) initiated cell suspension cultures of G. superba with a callus derived from rhizomes cultivated on MS medium supplemented with 2.0 mg/L, 2,4-D, and 0.5 mg/L NAA [149].
Despite the general advantages which make the plant cell suspension cultures suitable for the production of secondary metabolites, using classical fermentation technology the opportunity to scale up for bigger manufacturing and regulatory requirements following established once for microbial and mammalian cells, plant cell suspension can serve as tools for biotransformation of foreign substrates. Biotransformation is in vitro tissue culture technique used for commercial exploitation of secondary metabolites in which chemical conversions of an exogenously supplied substance are catalyzed by microorganisms, cells, or their enzymes, including oxidation, reduction, hydroxylation, esterification, hydrolysis, methylation, glycosylation, etc. Biotransformation of colchicinoids into their 3-O-glucosyl derivatives using Bacillus megaterium is reported [150]. In vitro glycosylation of colchicine to its 3-O-demethylglucoside has been investigated with different modern biotechnology tools, especially using selected microbial strains such as Bacillus aryabhattai [151]. Only non-selective demethylation of colchicine has been obtained using a Colchicum variegatum culture yielding a mixture of 3-demethylcolchicine and 2-demethylcolchicine [152]. Regio-specific demethylation at the C-3 position of colchicine has been achieved when using selected bacterial microorganisms [152]. Glycosylation of exogenous thiocolchicine by plant cell suspension cultures of Centella asiatica resulted in monoglycosydated derivatives at C-2 and at C-3 of the aromatic ring, which is not highly selective biotransformation [153]. Zarev et al. (2018) achieved region-specifically demethylation of the C-3 methoxy group bound to the aromatic ring A of the colchicine, and subsequent glycosylation of the demethylated derivative at the same site, using plant suspension cultures of A. vesicarius, which normally do not produce tropolone type of alkaloids. Thus, quantitative HPLC-UV analysis showed two times fold increase in colchicoside yield of 9.35 µmol/g DW when compared to its natural source, G. superba seeds, 4.26 µmol/g [154].
Using modern biotechnology, Sivakumar et al. (2019) reached concentrations of colchicine (2.65 µg/mL, 3.56 µg/mL, and 5.69 µg/mL) within the methanolic extract of in vitro treated leaf samples with spermidine, spermine, and putrescine, resp. [148]. The obtained amount of colchicine is much higher when compared to the leaf samples from field-grown plants (2.41 µg/mL). Among four elicitors tested to cell suspension cultures of G. superba, casein hydrolysate (CH) exhibited the maximum level of colchicine production [8.290 mg/g dry weight (DW)] at 300 mg/L concentration for 15 days’ exposure, while after 30 days’ exposure salicylic acid (SA) at 27.62 mg/L concentration showed an enhanced colchicine production rate (8.149 mg/g DW), when compared to non-elicited control cultures. Treatment for 15- and 30-days with 200 and 300 mg/L AgNO3 resulted in thiocolchicoside content in a cell suspension culture of 4.55 mg/g DW and 1.53 mg/g DW, respectively [149]. The highest colchicine content (0.29%) in the tubers of micropropagated plantlets raised from non-dormant tuber explants is achieved when combinatory treatment of Glomus mosseae and Acaulospora laevis arbuscular mycorrhizal fungi strains is applied [155]. Also, random amplified polymorphic DNA (RAPD) and inter simple sequence repeat (ISSR) profiles of micropropagated plants of G. superba is compared to evaluate the possible somaclonal variations [156]. The homogeneity of the micropropagated plants is proved as amplification products showed similar banding patterns to that of non-dormant tuber explants.

4. Conclusions

In this review, we summarize the research efforts made in recent years concerning the secondary cytotoxic metabolites obtained from plant species belonging to the genera Astragalus L. and Gloriosa L., many of them with conservational status. Our integrative approach bonds phytochemistry with cancer therapy, offering a possible supply of valuable metabolites without contributing to the global biodiversity loss. The biotechnological production of some of the molecules in plant cell and tissue cultures obtained of the studied species preserves the wild populations of the rare ones. This way of production of the target compounds, such as isoflavonoids, saponins, etc., detected with UHPLC-HR-ESI-MS is promising and prospective as often the quantity of the desired metabolites exceeds many times that in native plants. We believe that cell cultures of species from Astragalus L. and Gloriosa L. as a source of biologically active anticancer compounds could one day play a role in large-scale processes. However, this review has only the aim of combining information to date. It could be the basis for future research on these valuable compounds and their in vitro production. Of course, a single report on the possibility of biotechnological production of a molecule is not enough for its practical production. Our findings are only a preliminary step in biotechnological production. Implications for further research are the aspects of automation, large-scale production, the stability of the reported culture itself, as well as cost-effectiveness, which are in the major part missing in most of the sources.

Author Contributions

Conceptualization, I.K., I.I. and E.K.; Data curation, A.S., I.K., I.I., Y.Z. and E.K.; Writing—original draft, A.S. and Y.Z.; Writing—review & editing, I.K., I.I. and E.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Ministry of Education and Science of the Republic of Bulgaria through the contract number DO1-217/30.11.2018 (BioActiveMed), agreement number DO1-278/03.12.2021. The APC was funded by the same funder.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. American Cancer Society. Understanding Cancer Causes: Ancient Times to Present; American Cancer Society: Atlanta, GA, USA, 2022. [Google Scholar]
  2. Clark, A.M. Natural Products as a Resource for New Drugs. Pharm. Res. 1996, 13, 1133–1141. [Google Scholar] [CrossRef] [PubMed]
  3. Wink, M.; Alfermann, A.W.; Franke, R.; Wetterauer, B.; Distl, M.; Windhövel, J.; Krohn, O.; Fuss, E.; Garden, H.; Mohagheghzadeh, A.; et al. Sustainable Bioproduction of Phytochemicals by Plant in Vitro Cultures: Anticancer Agents. Plant Genet. Resour. 2005, 3, 90–100. [Google Scholar] [CrossRef]
  4. DiGiulio, S. 3 QUESTIONS ON… Cancer Rates in Medieval Populations: With Piers Mitchell, MD, Director of the Ancient Parasites Laboratory at University of Cambridge. Oncol. Times 2021, 43, 42. [Google Scholar] [CrossRef]
  5. Mitchell, P.D.; Dittmar, J.M.; Mulder, B.; Inskip, S.; Littlewood, A.; Cessford, C.; Robb, J.E. The Prevalence of Cancer in Britain before Industrialization. Cancer 2021, 127, 3054–3059. [Google Scholar] [CrossRef] [PubMed]
  6. Senga, S.S.; Grose, R.P. Hallmarks of Cancer—the New Testament. Open Biol. 2021, 11, 200358. [Google Scholar] [CrossRef]
  7. Atanasov, A.G.; Waltenberger, B.; Pferschy-Wenzig, E.-M.; Linder, T.; Wawrosch, C.; Uhrin, P.; Temml, V.; Wang, L.; Schwaiger, S.; Heiss, E.H.; et al. Discovery and Resupply of Pharmacologically Active Plant-Derived Natural Products: A Review. Biotechnol. Adv. 2015, 33, 1582–1614. [Google Scholar] [CrossRef]
  8. Lucera, A.; Costa, C.; Conte, A.; Del Nobile, M.A. Food Applications of Natural Antimicrobial Compounds. Front. Microbiol. 2012, 3, 287. [Google Scholar] [CrossRef]
  9. Greger, H. Phytocarbazoles: Alkaloids with Great Structural Diversity and Pronounced Biological Activities. Phytochem. Rev. 2017, 16, 1095–1153. [Google Scholar] [CrossRef]
  10. Koehn, F.E.; Carter, G.T. The Evolving Role of Natural Products in Drug Discovery. Nat. Rev. Drug Discov. 2005, 4, 206–220. [Google Scholar] [CrossRef]
  11. Akerele, O.; Heywood, V.; Synge, H. (Eds.) Conservation of Medicinal Plants, 1st ed.; Cambridge University Press: Cambridge, UK, 1991. [Google Scholar] [CrossRef]
  12. Hamilton, A.C. Medicinal Plants, Conservation and Livelihoods. Biodivers. Conserv. 2004, 13, 1477–1517. [Google Scholar] [CrossRef]
  13. Evstatieva, L.; Hardalova, R.; Stoyanova, K. Medicinal Plants in Bulgaria: Diversity, Legislation, Conservation and Trade. Phytol. Balc. 2007, 13, 415–427. [Google Scholar]
  14. Soetan, K.O.; Aiyelaagbe, O.O. The Need for Bioactivity-Safety Evaluation and Conservation of Medicinal Plants—A Review. J. Med. Plants Res. 2009, 3, 324–328. [Google Scholar]
  15. Chen, S.-L.; Yu, H.; Luo, H.-M.; Wu, Q.; Li, C.-F.; Steinmetz, A. Conservation and Sustainable Use of Medicinal Plants: Problems, Progress, and Prospects. Chin. Med. 2016, 11, 37. [Google Scholar] [CrossRef] [PubMed]
  16. Schippmann, U.; Leaman, D.; Cunningham, A. Impact of Cultivation and Gathering of Medicinal Plants on Biodiversity: Global Trends and Issues. In Biodiversity and the Ecosystem Approach in Agriculture, Forestry and Fisheries; United Nations: San Francisco, CA, USA, 2002; pp. 142–167. [Google Scholar]
  17. Ramawat, K.G.; Arora, J. Medicinal Plants Domestication, Cultivation, Improvement, and Alternative Technologies for the Production of High Value Therapeutics: An Overview. In Medicinal Plants; Ekiert, H.M., Ramawat, K.G., Arora, J., Eds.; Sustainable Development and Biodiversity; Springer International Publishing: Cham, Switzerland, 2021; Volume 28, pp. 1–29. [Google Scholar] [CrossRef]
  18. Cao, P.; Wang, G.; Wei, X.; Chen, S.; Han, J. How to Improve CHMs Quality: Enlighten from CHMs Ecological Cultivation. Chin. Herb. Med. 2021, 13, 301–312. [Google Scholar] [CrossRef]
  19. Canter, P.H.; Thomas, H.; Ernst, E. Bringing Medicinal Plants into Cultivation: Opportunities and Challenges for Biotechnology. Trends Biotechnol. 2005, 23, 180–185. [Google Scholar] [CrossRef]
  20. Yue, W.; Ming, Q.; Lin, B.; Rahman, K.; Zheng, C.-J.; Han, T.; Qin, L. Medicinal Plant Cell Suspension Cultures: Pharmaceutical Applications and High-Yielding Strategies for the Desired Secondary Metabolites. Crit. Rev. Biotechnol. 2016, 36, 215–232. [Google Scholar] [CrossRef]
  21. Mora-Vásquez, S.; Wells-Abascal, G.G.; Espinosa-Leal, C.; Cardineau, G.A.; García-Lara, S. Application of Metabolic Engineering to Enhance the Content of Alkaloids in Medicinal Plants. Metab. Eng. Commun. 2022, 14, e00194. [Google Scholar] [CrossRef]
  22. Isah, T.; Umar, S.; Mujib, A.; Sharma, M.P.; Rajasekharan, P.E.; Zafar, N.; Frukh, A. Secondary Metabolism of Pharmaceuticals in the Plant in Vitro Cultures: Strategies, Approaches, and Limitations to Achieving Higher Yield. Plant Cell Tissue Organ Cult. 2018, 132, 239–265. [Google Scholar] [CrossRef]
  23. Kolewe, M.E.; Gaurav, V.; Roberts, S.C. Pharmaceutically Active Natural Product Synthesis and Supply via Plant Cell Culture Technology. Mol. Pharm. 2008, 5, 243–256. [Google Scholar] [CrossRef]
  24. Pavlov, A.; Popov, S.; Kovacheva, E.; Georgiev, M.; Ilieva, M. Volatile and Polar Compounds in Rosa Damascena Mill 1803 Cell Suspension. J. Biotechnol. 2005, 118, 89–97. [Google Scholar] [CrossRef]
  25. Frodin, D.G. History and Concepts of Big Plant Genera. Taxon 2004, 53, 753–776. [Google Scholar] [CrossRef]
  26. Podlech, D. Taxonomic and Phytogeographical Problems in Astragalus of the Old World and South-West Asia. Proc. Sect. B Biol. Sci. 1986, 89, 37–43. [Google Scholar] [CrossRef]
  27. IUCN. Available online: https://www.iucnredlist.org/search?query=astragalus&searchType=species (accessed on 1 January 2022).
  28. Xu, L.; Podlech, D. Astragalus Mongholicus Bunge. Flora China 2010, 10, 338–339, 343. [Google Scholar]
  29. Tierra, M.; Tierra, L. Chinese Traditional Herbal Medicine; Lotus Light Pub: Twin Lakes, WI, USA, 1998. [Google Scholar]
  30. Shahrajabian, M.H. A Review of Astragalus Species as Foodstuffs, Dietary Supplements, a Traditional Chinese Medicine and A Part of Modern Pharmaceutical Science. Appl. Ecol. Env. Res. 2019, 17, 13371–13382. [Google Scholar] [CrossRef]
  31. Wang, S.F.; Wang, Q.; Jiao, L.J.; Huang, Y.L.; Garfield, D.; Zhang, J.; Xu, L. Astragalus-Containing Traditional Chinese Medicine, with and without Prescription Based on Syndrome Differentiation, Combined with Chemotherapy for Advanced Non-Small-Cell Lung Cancer: A Systemic Review and Meta-Analysis. Curr. Oncol. 2016, 23, 188–195. [Google Scholar] [CrossRef] [PubMed]
  32. Amiri, M.S.; Joharchi, M.R.; Nadaf, M.; Nasseh, Y. Ethnobotanical Knowledge of Astragalus spp.: The World’s Largest Genus of Vascular Plants. Avicenna J. Phytomed. 2020, 10, 128–142. [Google Scholar]
  33. Ahtarov, B.; Davidov, B.; Yavashev, A. Materials for the Bulgarian Botanical Glossary; Balgarska Akademia na Naukite Pridvorna Pechatnitsa: Sofia, Bulgaria, 1939. [Google Scholar]
  34. Guarino, C. Ethnobotanical Study of the Sannio Area, Campania, Southern Italy. Ethnobot. Res. App. 2008, 6, 255. [Google Scholar] [CrossRef]
  35. Sezik, E.; Yeşilada, E.; Honda, G.; Takaishi, Y.; Takeda, Y.; Tanaka, T. Traditional Medicine in Turkey X. Folk Medicine in Central Anatolia. J. Ethnopharmacol. 2001, 75, 95–115. [Google Scholar] [CrossRef]
  36. Cakilcioglu, U.; Turkoglu, I. An Ethnobotanical Survey of Medicinal Plants in Sivrice (Elazığ-Turkey). J. Ethnopharmacol. 2010, 132, 165–175. [Google Scholar] [CrossRef]
  37. Tetik, F.; Civelek, S.; Cakilcioglu, U. Traditional Uses of Some Medicinal Plants in Malatya (Turkey). J. Ethnopharmacol. 2013, 146, 331–346. [Google Scholar] [CrossRef]
  38. Mükemre, M.; Behçet, L.; Çakılcıoğlu, U. Ethnobotanical Study on Medicinal Plants in Villages of Çatak (Van-Turkey). J. Ethnopharmacol. 2015, 166, 361–374. [Google Scholar] [CrossRef] [PubMed]
  39. Nadiroğlu, M.; Behçet, L.; Çakılcıoğlu, U. An Ethnobotanical Survey of Medicinal Plants in Karlıova (Bingöl-Turkey). Indian J. Tradit. Knowl. 2019, 18, 76–87. [Google Scholar]
  40. Ergül Bozkurt, A.E. Folk Medicinal Plants Used for Treatment of Gynecological Disorders by Rural Population of Zorlu Village (in Turkey). Ethnobot. Res. App. 2021, 22, 1–17. [Google Scholar] [CrossRef]
  41. Bozyel, M.E.; Merdamert Bozyel, E.; Canli, K.; Altuner, E.M. Türk Geleneksel Tıbbında Tıbbi Bitkilerin Antikanser Kullanımları. Kahramanmaraş Sütçü İmam Üniversitesi Tarım Doğa Derg. 2019, 22. [Google Scholar] [CrossRef]
  42. Council of Europe; European Pharmacopoeia Commission; European Directorate for the Quality of Medicines & Healthcare. European Pharmacopoeia; Council of Europe: Strasbourg, France, 2019. [Google Scholar]
  43. Bussmann, R.W.; Zambrana, P.; Narel, Y.; Sikharulidze, S.; Kikvidze, Z.; Kikodze, D.; Tchelidze, D.; Batsatsashvili, K.; Hart; Robbie, E. Ethnobotany of Samtskhe-Javakheti, Sakartvelo (Republic of Georgia), Caucasus. Indian J. Tradit. Knowl. 2017, 16, 7–24. [Google Scholar]
  44. Lysiuk, R.; Darmohray, R. Pharmacology and Ethnomedicine of the Genus Astragalus. Int. J. Pharmacol. Phytochem. Ethnomed. 2016, 3, 46–53. [Google Scholar] [CrossRef]
  45. Auyeung, K.K.; Han, Q.-B.; Ko, J.K. Astragalus Membranaceus: A Review of Its Protection Against Inflammation and Gastrointestinal Cancers. Am. J. Chin. Med. 2016, 44, 1–22. [Google Scholar] [CrossRef]
  46. McCulloch, M.; See, C.; Shu, X.; Broffman, M.; Kramer, A.; Fan, W.; Gao, J.; Lieb, W.; Shieh, K.; Colford, J.M. Astragalus-Based Chinese Herbs and Platinum-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer: Meta-Analysis of Randomized Trials. JCO 2006, 24, 419–430. [Google Scholar] [CrossRef]
  47. Lin, S.; An, X.; Guo, Y.; Gu, J.; Xie, T.; Wu, Q.; Sui, X. Meta-Analysis of Astragalus-Containing Traditional Chinese Medicine Combined With Chemotherapy for Colorectal Cancer: Efficacy and Safety to Tumor Response. Front. Oncol. 2019, 9, 749. [Google Scholar] [CrossRef]
  48. Ali, M.; Aldosari, A.; Tng, D.Y.P.; Ullah, M.; Hussain, W.; Ahmad, M.; Hussain, J.; Khan, A.; Hussain, H.; Sher, H.; et al. Traditional Uses of Plants by Indigenous Communities for Veterinary Practices at Kurram District, Pakistan. Ethnobot. Res. Appl. 2019, 18, 1–19. [Google Scholar] [CrossRef]
  49. Cho, W.C. Immunomodulatory and Anti-Tumor Activities of Astragalus Ancient Herb—Modern Miracle; LAP LAMBERT Academic Publishing: Saarbrücken, Germany, 2009. [Google Scholar]
  50. Li, R.; Chen, W.; Wang, W.; Tian, W.; Zhang, X. Extraction, Characterization of Astragalus Polysaccharides and Its Immune Modulating Activities in Rats with Gastric Cancer. Carbohydr. Polym. 2009, 78, 738–742. [Google Scholar] [CrossRef]
  51. Ionkova, I.; Shkondrov, A.; Krasteva, I.; Ionkov, T. Recent Progress in Phytochemistry, Pharmacology and Biotechnology of Astragalus Saponins. Phytochem. Rev. 2014, 13, 343–374. [Google Scholar] [CrossRef]
  52. Li, X.; Qu, L.; Dong, Y.; Han, L.; Liu, E.; Fang, S.; Zhang, Y.; Wang, T. A Review of Recent Research Progress on the Astragalus Genus. Molecules 2014, 19, 18850–18880. [Google Scholar] [CrossRef] [PubMed]
  53. Krasteva, I.; Shkondrov, A.; Ionkova, I.; Zdraveva, P. Advances in Phytochemistry, Pharmacology and Biotechnology of Bulgarian Astragalus Species. Phytochem. Rev. 2016, 15, 567–590. [Google Scholar] [CrossRef]
  54. Zhou, R.; Chen, H.; Chen, J.; Chen, X.; Wen, Y.; Xu, L. Extract from Astragalus Membranaceus Inhibit Breast Cancer Cells Proliferation via PI3K/AKT/MTOR Signaling Pathway. BMC Complement. Altern. Med. 2018, 18, 83. [Google Scholar] [CrossRef]
  55. Zhang, J.; Liu, L.; Wang, J.; Ren, B.; Zhang, L.; Li, W. Formononetin, an Isoflavone from Astragalus Membranaceus Inhibits Proliferation and Metastasis of Ovarian Cancer Cells. J. Ethnopharmacol. 2018, 221, 91–99. [Google Scholar] [CrossRef]
  56. Li, W.; Song, K.; Wang, S.; Zhang, C.; Zhuang, M.; Wang, Y.; Liu, T. Anti-Tumor Potential of Astragalus Polysaccharides on Breast Cancer Cell Line Mediated by Macrophage Activation. Mater. Sci. Eng. C 2019, 98, 685–695. [Google Scholar] [CrossRef]
  57. Li, S.; Sun, Y.; Huang, J.; Wang, B.; Gong, Y.; Fang, Y.; Liu, Y.; Wang, S.; Guo, Y.; Wang, H.; et al. Anti-Tumor Effects and Mechanisms of Astragalus Membranaceus (AM) and Its Specific Immunopotentiation: Status and Prospect. J. Ethnopharmacol. 2020, 258, 112797. [Google Scholar] [CrossRef]
  58. Shen, L.; Gwak, S.R.; Cui, Z.Y.; Joo, J.C.; Park, S.J. Astragalus-Containing Chinese Herbal Medicine Combined With Chemotherapy for Cervical Cancer: A Systematic Review and Meta-Analysis. Front. Pharmacol. 2021, 12, 587021. [Google Scholar] [CrossRef]
  59. Le Marchand, L. Cancer Preventive Effects of Flavonoids—A Review. Biomed. Pharmacother. 2002, 56, 296–301. [Google Scholar] [CrossRef]
  60. Thomasset, S.C.; Berry, D.P.; Garcea, G.; Marczylo, T.; Steward, W.P.; Gescher, A.J. Dietary Polyphenolic Phytochemicals—Promising Cancer Chemopreventive Agents in Humans? A Review of Their Clinical Properties. Int. J. Cancer 2007, 120, 451–458. [Google Scholar] [CrossRef] [PubMed]
  61. Zong, A.; Cao, H.; Wang, F. Anticancer Polysaccharides from Natural Resources: A Review of Recent Research. Carbohydr. Polym. 2012, 90, 1395–1410. [Google Scholar] [CrossRef] [PubMed]
  62. Jia, L.; Lv, D.; Zhang, S.; Wang, Z.; Zhou, B. Astragaloside IV Inhibits the Progression of Non-Small Cell Lung Cancer Through the Akt/GSK-3β/β-Catenin Pathway. Ooncol. Res. 2019, 27, 503–508. [Google Scholar] [CrossRef] [PubMed]
  63. Gülcemal, D.; Masullo, M.; Bedir, E.; Festa, M.; Karayıldırım, T.; Alankus-Caliskan, O.; Piacente, S. Triterpene Glycosides from Astragalus Angustifolius. Planta Med. 2012, 78, 720–729. [Google Scholar] [CrossRef]
  64. Bourezzane, S.; Haba, H.; Long, C.; Benkhaled, M. Chemical Composition and Antioxidant Activity of Astragalus Monspessulanus L. Growing in Semiarid Areas of Algeria. J. Serb. Chem. Soc. 2018, 83, 31–38. [Google Scholar] [CrossRef]
  65. Krasteva, I.; Bratkov, V.; Bucar, F.; Kunert, O.; Kollroser, M.; Kondeva-Burdina, M.; Ionkova, I. Flavoalkaloids and Flavonoids from Astragalus Monspessulanus. J. Nat. Prod. 2015, 78, 2565–2571. [Google Scholar] [CrossRef]
  66. Elenga, P.; Nikolov, S.; Panova, D. Triterpene Glycosides and Sterols from Astragalus Glycyphyllos L. Pharmazie 1986, 41, 300. [Google Scholar]
  67. Elenga, P.; Nikolov, S.; Panova, D. Triterpene Glycosides from Astragalus Glycyphyllos L.—A New Natural Compound of the Overground Parts. Pharmazie 1987, 42, 422–423. [Google Scholar]
  68. Linnek, J.; Mitaine-Offer, A.; Miyamoto, T.; Lacaille-Dubois, M. Two Cycloartane-Type Glycosides from the Roots of Astragalus Glycyphyllos. Planta Med. 2008, 74, PB141. [Google Scholar] [CrossRef]
  69. Shkondrov, A.; Krasteva, I.; Bucar, F.; Kunert, O.; Kondeva-Burdina, M.; Ionkova, I. A New Tetracyclic Saponin from Astragalus Glycyphyllos L. and Its Neuroprotective and HMAO-B Inhibiting Activity. Nat. Prod. Res. 2020, 34, 511–517. [Google Scholar] [CrossRef]
  70. Ionkova, I.; Alfermann, A. Transformation of Astragalus Species by Agrobacterium Rhizogenes and Their Saponin Production. Planta Med. 1990, 56, 634–635. [Google Scholar] [CrossRef]
  71. Georgieva, A.; Popov, G.; Shkondrov, A.; Toshkova, R.; Krasteva, I.; Kondeva-Burdina, M.; Manov, V. Antiproliferative and Antitumour Activity of Saponins from Astragalus Glycyphyllos on Myeloid Graffi Tumour. J. Ethnopharmacol. 2021, 267, 113519. [Google Scholar] [CrossRef] [PubMed]
  72. Shkondrov, A.; Krasteva, I.; Ionkova, I.; Popova, P.; Zarev, Y.; Mihaylova, R.; Konstantinov, S. Production of Saponins from in Vitro Cultures of Astragalus Glycyphyllos and Their Antineoplastic Activity. Biotechnol. Biotechnol. Equip. 2019, 33, 1413–1418. [Google Scholar] [CrossRef]
  73. Shkondrov, A. Phytochemical Investigation of Species from Genus Astragalus L. (Fabaceae); Medical University of Sofia: Sofia, Bulgaria, 2017. [Google Scholar]
  74. Mihaylova, R.; Shkondrov, A.; Aluani, D.; Ionkova, I.; Tzankova, V.; Krasteva, I. In Vitro Antitumour and Immunomodulating Activity of Saponins from Astragalus Glycyphyllos. Biotechnol. Biotechnol. Equip. 2021, 35, 1948–1955. [Google Scholar] [CrossRef]
  75. Krasteva, I.; Momekov, G.; Zdraveva, P.; Konstantinov, S.; Nikolov, S. Antiproliferative Effects of a Flavonoid and Saponins from Astragalus Hamosus against Human Tumor Cell Lines. Pharmacogn. Mag. 2008, 4, 269–272. [Google Scholar]
  76. Benbassat, N.; Nikolov, S. Flavonoids from Astragalus Onobrychis. Planta Med. 1995, 61, 100. [Google Scholar] [CrossRef]
  77. Kondeva-Burdina, M.; Shkondrov, A.; Simeonova, R.; Vitcheva, V.; Krasteva, I.; Ionkova, I. In Vitro/in Vivo Antioxidant and Hepatoprotective Potential of Defatted Extract and Flavonoids Isolated from Astragalus Spruneri Boiss. (Fabaceae). Food Chem. Toxicol. 2018, 111, 631–640. [Google Scholar] [CrossRef]
  78. Popova, P.; Zarev, Y.; Mihaylova, R.; Momekov, G.; Ionkova, I. Antiproliferative Activity of Extract from in Vitro Callus Cultures of Astragalus Vesicarius Ssp. Carniolicus (A. Kern.) Chater. Pharmacia 2021, 68, 217–221. [Google Scholar] [CrossRef]
  79. Capistrano, R.; Vangestel, C.; Wouters, A.; Dockx, Y.; Pauwels, P.; Stroobants, S.; Apers, S.; Lardon, F.; Pieters, L.; Staelens, S. Efficacy Screening of Gloriosa Superba Extracts in a Murine Pancreatic Cancer Model Using 18F-FDG PET/CT for Monitoring Treatment Response. Cancer Biother. Radiopharm. 2016, 31, 99–109. [Google Scholar] [CrossRef]
  80. Capistrano, I.R.; Vangestel, C.; Vanpachtenbeke, H.; Fransen, E.; Staelens, S.; Apers, S.; Pieters, L. Coadministration of a Gloriosa Superba Extract Improves the in Vivo Antitumoural Activity of Gemcitabine in a Murine Pancreatic Tumour Model. Phytomedicine 2016, 23, 1434–1440. [Google Scholar] [CrossRef]
  81. Zarev, Y.; Foubert, K.; Ionkova, I.; Apers, S.; Pieters, L. Isolation and Structure Elucidation of Glucosylated Colchicinoids from the Seeds of Gloriosa Superba by LC-DAD-SPE-NMR. J. Nat. Prod. 2017, 80, 1187–1191. [Google Scholar] [CrossRef] [PubMed]
  82. Sahakitpichan, P.; Chimnoi, N.; Namsa-aid, A.; Panyadee, A.; Ruchirawat, S.; Kanchanapoom, T. Colchicinoid Glucosides from Seedless Pods of Thai Origin Gloriosa Superba. Phytochem. Lett. 2016, 16, 299–302. [Google Scholar] [CrossRef]
  83. Saradhadevi, M.; Gnanadesigan, M.; Kapildev, G.; Vasanth, D. Dataset on Antitumor Properties of Silver Nanoparticles from Gloriosa Superba (L.) Seed on Dalton Lymphoma Ascites (DLA) Tumor: Facile and Biocompatible Approach. Data Brief 2017, 14, 524–530. [Google Scholar] [CrossRef] [PubMed]
  84. Budchart, P.; Khamwut, A.; Sinthuvanich, C.; Ratanapo, S.; Poovorawan, Y.; T-Thienprasert, N.P. Partially Purified Gloriosa Superba Peptides Inhibit Colon Cancer Cell Viability by Inducing Apoptosis Through P53 Upregulation. Am. J. Med. Sci. 2017, 354, 423–429. [Google Scholar] [CrossRef] [PubMed]
  85. Manosroi, A.; Akazawa, H.; Akihisa, T.; Jantrawut, P.; Kitdamrongtham, W.; Manosroi, W.; Manosroi, J. In Vitro Anti-Proliferative Activity on Colon Cancer Cell Line (HT-29) of Thai Medicinal Plants Selected from Thai/Lanna Medicinal Plant Recipe Database “MANOSROI III. ” J. Ethnopharmacol. 2015, 161, 11–17. [Google Scholar] [CrossRef]
  86. Kitajima, M.; Tanaka, A.; Kogure, N.; Takayama, H. Four New Colchicinoids, Gloriosamines A–D, from Gloriosa Rothschildiana. Tetrahedron Lett. 2008, 49, 257–260. [Google Scholar] [CrossRef]
  87. Krasteva, I.; Nikolov, S.; Kaloga, M.; Mayer, G. Triterpenoid Saponins from Astragalus Corniculatus. Z. Für. Nat. B 2006, 61, 1166–1169. [Google Scholar] [CrossRef]
  88. Krasteva, I.; Nikolov, S.; Kaloga, M.; Mayer, G. A New Saponin Lactone from Astragalus Corniculatus. Nat. Prod. Res. 2007, 21, 941–945. [Google Scholar] [CrossRef]
  89. Krasteva, I.N.; Toshkova, R.A.; Nikolov, S.D. Protective Effect of Astragalus Corniculatus Saponins against Myeloid Graffi Tumour in Hamsters. Phytother. Res. 2004, 18, 255–257. [Google Scholar] [CrossRef]
  90. Toshkova, R.A.; Krasteva, I.N.; Wesselinova, D.W.; Nikolov, S.D. Influence of Purified Saponin Mixture from Astragalus Corniculatus Bieb. on Phagocytic Cells in Graffi-Tumor Bearing Hamsters. J. Ethnopharmacol. 2007, 109, 394–399. [Google Scholar] [CrossRef]
  91. Dineva, I.; Krasteva, I.; Berger, M.; Konstantinov, S. In Vitro Antineoplastic Activity of Some Cytoreductive Drugs versus New Compounds of Plant Origin. Intern. J. Curr. Chem. 2010, 1, 281–290. [Google Scholar]
  92. Du, M.; Wu, X.J.; Ding, J.; Hu, Z.B.; White, K.N.; Branford-White, C.J. Astragaloside IV and Polysaccharide Production by Hairy Roots of Astragalus Membranaceus in Bioreactors. Biotechnol. Lett. 2003, 25, 1853–1856. [Google Scholar] [CrossRef] [PubMed]
  93. Wilson, S.A.; Roberts, S.C. Recent Advances towards Development and Commercialization of Plant Cell Culture Processes for the Synthesis of Biomolecules: Development and Commercialization of Plant Cell Culture. Plant Biotechnol. J. 2012, 10, 249–268. [Google Scholar] [CrossRef] [PubMed]
  94. Ionkova, I. Genetic Transformation in Astragalus spp. In Transgenic Medicinal Plants; Biotechnology in Agriculture and Forestry; Springer: Berlin/Heidelberg, Germany; New York, NY, USA, 1999; pp. 55–72. [Google Scholar]
  95. Ionkova, I.; Kartnig, T.; Alfermann, W. Cycloartane Saponin Production in Hairy Root Cultures of Astragalus Mongholicus. Phytochemistry 1997, 45, 1597–1600. [Google Scholar] [CrossRef]
  96. Giri, A.; Narasu, M.L. Transgenic Hairy Roots. Biotechnol. Adv. 2000, 18, 1–22. [Google Scholar] [CrossRef]
  97. Ionkova, I. Optimization of Flavonoid Production in Cell Cultures of Astragalus Missouriensis Nutt. (Fabaceae). Pharmacogn. Mag. 2009, 5, 92–97. [Google Scholar]
  98. Zdraveva, P.; Popova, P.; Shkondrov, A.; Krasteva, I.; Ionkova, I. Investigation of in vitro cultures of Astragalus monspessulanus L. Comptes Rendus De L’académie Bulg. Des Sci. 2017, 70, 1131–1137. [Google Scholar]
  99. Bratkov, V.; Kondeva-Burdina, M.; Simeonova, R.; Tzankova, V.; Krasteva, I.; others. Phytochemical Evaluation and Effect of Saponins’ Mixture Isolated from Astragalus Monspessulanus on HepG2 Cell Line. Eur. J. Med. Plants 2014, 4, 522–527. [Google Scholar] [CrossRef]
  100. Jiao, J.; Gai, Q.-Y.; Fu, Y.-J.; Ma, W.; Yao, L.-P.; Feng, C.; Xia, X.-X. Optimization of Astragalus Membranaceus Hairy Roots Induction and Culture Conditions for Augmentation Production of Astragalosides. Plant Cell Tissue Organ Cult. 2015, 120, 1117–1130. [Google Scholar] [CrossRef]
  101. Groussin, A.-L.; Antoniotti, S. Valuable Chemicals by the Enzymatic Modification of Molecules of Natural Origin: Terpenoids, Steroids, Phenolics and Related Compounds. Bioresour. Technol. 2012, 115, 237–243. [Google Scholar] [CrossRef]
  102. Toshkova, R.A.; Krasteva, I.N.; Nikolov, S.D. Immunorestoration and Augmentation of Mitogen Lymphocyte Response in Graffi Tumor Bearing Hamsters by Purified Saponin Mixture from Astragalus Corniculatus. Phytomedicine 2008, 15, 876–881. [Google Scholar] [CrossRef] [PubMed]
  103. Chen, C.-Y.; Fu, Y.-J.; Zu, Y.-G.; Wang, W.; Mu, F.-S.; Luo, M.; Li, C.-Y.; Gu, C.-B.; Zhao, C.-J. Biotransformation of Saponins to Astragaloside IV from Radix Astragali by Immobilized Aspergillus Niger. Biocatal. Agric. Biotechnol. 2013, 2, 196–203. [Google Scholar] [CrossRef]
  104. Popova, P.; Zarev, Y.; Ionkova, I. Biotransformation of Quercetin, Kaempferol and Apigenin to Monoglycosylated Derivatives by in Vitro Suspension Cultures of Astragalus Vesicarius Ssp. Carniolicus. Pharmacia 2021, 68, 307–311. [Google Scholar] [CrossRef]
  105. Ionkova, I.; Antonova, I.; Momekov, G.; Fuss, E. Production of Podophyllotoxin in Linum Linearifolium in Vitro Cultures. Pharmacogn. Mag. 2010, 6, 180. [Google Scholar] [CrossRef] [PubMed]
  106. Popova, P.; Zarev, Y.; Shkondrov, A.; Krasteva, I.; Ionkova, I. Induction of Flavonoid Biosynthesis by in Vitro Cultivation of Astragalus Glycyphyllos L. Pharmacia 2020, 67, 95–99. [Google Scholar] [CrossRef]
  107. Jiao, J.; Gai, Q.-Y.; Wang, W.; Luo, M.; Zu, Y.-G.; Fu, Y.-J.; Ma, W. Enhanced Astragaloside Production and Transcriptional Responses of Biosynthetic Genes in Astragalus Membranaceus Hairy Root Cultures by Elicitation with Methyl Jasmonate. Biochem. Eng. J. 2016, 105, 339–346. [Google Scholar] [CrossRef]
  108. Gai, Q.-Y.; Jiao, J.; Luo, M.; Wang, W.; Zhao, C.-J.; Fu, Y.-J.; Ma, W. UV Elicitation for Promoting Astragaloside Production in Astragalus Membranaceus Hairy Root Cultures with Transcriptional Expression of Biosynthetic Genes. Ind. Crops Prod. 2016, 84, 350–357. [Google Scholar] [CrossRef]
  109. Ionkova, I.; Momekov, G.; Proksch, P. Effects of Cycloartane Saponins from Hairy Roots of Astragalus Membranaceus Bge., on Human Tumor Cell Targets. Fitoterapia 2010, 81, 447–451. [Google Scholar] [CrossRef]
  110. Ren, J.; Wang, J.; Li, M.; Wang, L. Identifying Protein Complexes Based on Density and Modularity in Protein-Protein Interaction Network. BMC Syst. Biol. 2013, 7, S12. [Google Scholar] [CrossRef]
  111. Yao, M.; Liu, J.-Z.; Jin, S.; Jiao, J.; Gai, Q.; Wei, Z.; Fu, Y.; Zhao, J. A Novel Biotransformation of Astragalosides to Astragaloside IV with the Deacetylation of Fungal Endophyte Penicillium Canescens. Process Biochem. 2014, 49, 807–812. [Google Scholar] [CrossRef]
  112. Ye, L.; Liu, X.-H.; Zhou, W.; Feng, M.-Q.; Shi, X.-L.; Li, J.-Y.; Chen, D.-F.; Zhou, P. Microbial Transformation of Astragalosides to Astragaloside IV by Absidia Corymbifera AS2. Process Biochem. 2011, 46, 1724–1730. [Google Scholar] [CrossRef]
  113. Augustin, J.M.; Kuzina, V.; Andersen, S.B.; Bak, S. Molecular Activities, Biosynthesis and Evolution of Triterpenoid Saponins. Phytochemistry 2011, 72, 435–457. [Google Scholar] [CrossRef]
  114. Khakimov, B.; Kuzina, V.; Erthmann, P.Ø.; Fukushima, E.O.; Augustin, J.M.; Olsen, C.E.; Scholtalbers, J.; Volpin, H.; Andersen, S.B.; Hauser, T.P.; et al. Identification and Genome Organization of Saponin Pathway Genes from a Wild Crucifer, and Their Use for Transient Production of Saponins in Nicotiana Benthamiana. Plant J. 2015, 84, 478–490. [Google Scholar] [CrossRef] [PubMed]
  115. Moses, T.; Pollier, J.; Faizal, A.; Apers, S.; Pieters, L.; Thevelein, J.M.; Geelen, D.; Goossens, A. Unraveling the Triterpenoid Saponin Biosynthesis of the African Shrub Maesa Lanceolata. Mol. Plant 2015, 8, 122–135. [Google Scholar] [CrossRef] [PubMed]
  116. Borges, K.B.; de S. Borges, W.; Durán-Patrón, R.; Pupo, M.T.; Bonato, P.S.; Collado, I.G. Stereoselective Biotransformations Using Fungi as Biocatalysts. Tetrahedron Asymmetry 2009, 20, 385–397. [Google Scholar] [CrossRef]
  117. Cao, H.; Chen, X.; Jassbi, A.R.; Xiao, J. Microbial Biotransformation of Bioactive Flavonoids. Biotechnol. Adv. 2015, 33, 214–223. [Google Scholar] [CrossRef]
  118. Hegazy, M.-E.F.; Mohamed, T.A.; ElShamy, A.I.; Mohamed, A.-E.-H.H.; Mahalel, U.A.; Reda, E.H.; Shaheen, A.M.; Tawfik, W.A.; Shahat, A.A.; Shams, K.A.; et al. Microbial Biotransformation as a Tool for Drug Development Based on Natural Products from Mevalonic Acid Pathway: A Review. J. Adv. Res. 2015, 6, 17–33. [Google Scholar] [CrossRef]
  119. Zeng, W.-L.; Li, W.-K.; Han, H.; Tao, Y.-Y.; Yang, L.; Wang, Z.-T.; Chen, K.-X. Microbial Biotransformation of Gentiopicroside by the Endophytic Fungus Penicillium Crustosum 2T01Y01. Appl. Env. Microbiol. 2014, 80, 184–192. [Google Scholar] [CrossRef]
  120. Feng, C.; Jin, S.; Xia, X.-X.; Guan, Y.; Luo, M.; Zu, Y.-G.; Fu, Y.-J. Effective Bioconversion of Sophoricoside to Genistein from Fructus Sophorae Using Immobilized Aspergillus Niger and Yeast. World J. Microbiol. Biotechnol. 2015, 31, 187–197. [Google Scholar] [CrossRef]
  121. Jin, S.; Luo, M.; Wang, W.; Zhao, C.; Gu, C.; Li, C.; Zu, Y.; Fu, Y.; Guan, Y. Biotransformation of Polydatin to Resveratrol in Polygonum Cuspidatum Roots by Highly Immobilized Edible Aspergillus Niger and Yeast. Bioresour. Technol. 2013, 136, 766–770. [Google Scholar] [CrossRef]
  122. Karami, O.; Esna-Ashari, M.; Kurdistani, G.; Aghavaisi, B. Agrobacterium-Mediated Genetic Transformation of Plants: The Role of Host. Biol. Plant 2009, 53, 201–212. [Google Scholar] [CrossRef]
  123. Kanazawa, K.; Hashimoto, T.; Yoshida, S.; Sungwon, P.; Fukuda, S. Short Photoirradiation Induces Flavonoid Synthesis and Increases Its Production in Postharvest Vegetables. J. Agric. Food Chem. 2012, 60, 4359–4368. [Google Scholar] [CrossRef] [PubMed]
  124. Martínez-Romero, D.; Guillén, F.; Pérez-Aguilar, H.; Castillo, S.; Serrano, M.; Zapata, P.J.; Valero, D. Is It Possible To Increase the Aloin Content of Aloe Vera by the Use of Ultraviolet Light? J. Agric. Food Chem. 2013, 61, 2165–2170. [Google Scholar] [CrossRef] [PubMed]
  125. Zhang, Z.-Z.; Li, X.-X.; Chu, Y.-N.; Zhang, M.-X.; Wen, Y.-Q.; Duan, C.-Q.; Pan, Q.-H. Three Types of Ultraviolet Irradiation Differentially Promote Expression of Shikimate Pathway Genes and Production of Anthocyanins in Grape Berries. Plant Physiol. Biochem. 2012, 57, 74–83. [Google Scholar] [CrossRef] [PubMed]
  126. Zhang, Z.-Z.; Che, X.-N.; Pan, Q.-H.; Li, X.-X.; Duan, C.-Q. Transcriptional Activation of Flavan-3-Ols Biosynthesis in Grape Berries by UV Irradiation Depending on Developmental Stage. Plant Sci. 2013, 208, 64–74. [Google Scholar] [CrossRef] [PubMed]
  127. Maroyi, A. The Genus Gloriosa (Colchicaceae): Ethnobotany, Phylogeny and Taxonomy; Wageningen University: Wageningen, The Netherlands, 2012. [Google Scholar]
  128. Samy, R.P.; Thwin, M.M.; Gopalakrishnakone, P.; Ignacimuthu, S. Ethnobotanical Survey of Folk Plants for the Treatment of Snakebites in Southern Part of Tamilnadu, India. J. Ethnopharmacol. 2008, 115, 302–312. [Google Scholar] [CrossRef]
  129. Shah, A.; Bharati, K.A.; Ahmad, J.; Sharma, M.P. New Ethnomedicinal Claims from Gujjar and Bakerwals Tribes of Rajouri and Poonch Districts of Jammu and Kashmir, India. J. Ethnopharmacol. 2015, 166, 119–128. [Google Scholar] [CrossRef]
  130. Maroyi, A. Gloriosa Superba L. (Family Colchicaceae): Remedy or Poison? J. Med. Plants Res. 2011, 5, 6112–6121. [Google Scholar] [CrossRef]
  131. Ade, R.; Rai, M.K. Review: Current Advances in Gloriosa Superba L. Biodiversitas 2009, 10, 210–214. [Google Scholar] [CrossRef]
  132. Murugesan, A.K.; Pannerselvam, B.; Javee, A.; Rajenderan, M.; Thiyagarajan, D. Facile Green Synthesis and Characterization of Gloriosa Superba L. Tuber Extract-Capped Silver Nanoparticles (GST-AgNPs) and Its Potential Antibacterial and Anticancer Activities against A549 Human Cancer Cells. Environ. Nanotechnol. Monit. Manag. 2021, 15, 100460. [Google Scholar] [CrossRef]
  133. Gelmi, M.L.; Mottadelli, S.; Pocar, D.; Riva, A.; Bombardelli, E.; De Vincenzo, R.; Scambia, G. N-Deacetyl-N-Aminoacylthiocolchicine Derivatives: Synthesis and Biological Evaluation on MDR-Positive and MDR-Negative Human Cancer Cell Lines. J. Med. Chem. 1999, 42, 5272–5276. [Google Scholar] [CrossRef] [PubMed]
  134. Reuter, S.; Prasad, S.; Phromnoi, K.; Ravindran, J.; Sung, B.; Yadav, V.R.; Kannappan, R.; Chaturvedi, M.M.; Aggarwal, B.B. Thiocolchicoside Exhibits Anticancer Effects through Downregulation of NF-ΚB Pathway and Its Regulated Gene Products Linked to Inflammation and Cancer. Cancer Prev. Res. 2010, 3, 1462–1472. [Google Scholar] [CrossRef] [PubMed]
  135. Shi, Q.; Chen, K.; Chen, X.; Brossi, A.; Verdier-Pinard, P.; Hamel, E.; McPhail, A.T.; Tropsha, A.; Lee, K.-H. Antitumor Agents. 183. Syntheses, Conformational Analyses, and Antitubulin Activity of Allothiocolchicinoids. J. Org. Chem. 1998, 63, 4018–4025. [Google Scholar] [CrossRef]
  136. Balkrishna, A.; Das, S.K.; Pokhrel, S.; Joshi, A.; Verma, S.; Sharma, V.K.; Sharma, V.; Sharma, N.; Joshi, C.S. Colchicine: Isolation, LC–MS QTof Screening, and Anticancer Activity Study of Gloriosa Superba Seeds. Molecules 2019, 24, 2772. [Google Scholar] [CrossRef]
  137. Lin, Z.-Y.; Kuo, C.-H.; Wu, D.-C.; Chuang, W.-L. Anticancer Effects of Clinically Acceptable Colchicine Concentrations on Human Gastric Cancer Cell Lines. Kaohsiung J. Med. Sci. 2016, 32, 68–73. [Google Scholar] [CrossRef]
  138. Riva, S.; Sennino, B.; Zambianchi, F.; Danieli, B.; Panza, L. Effect of Organic Cosolvents on the Stability and Activity of the β-1,4-Galactosyltransferase from Bovine Colostrum. Carbohydr. Res. 1997, 305, 525–531. [Google Scholar] [CrossRef]
  139. Pišvejcová, A.; Rossi, C.; Hušáková, L.; Křen, V.; Riva, S.; Monti, D. β-1,4-Galactosyltransferase-Catalyzed Glycosylation of Sugar Derivatives: Modulation of the Enzyme Activity by α-Lactalbumin, Immobilization and Solvent Tolerance. J. Mol. Catal. B: Enzym. 2006, 39, 98–104. [Google Scholar] [CrossRef]
  140. Saradha Devi, M.; Ashokkumar, K.; Annapoorani, S. Phytofabrication and Encapsulated of Silver Nanoparticles from Gloriosa Superba. Mater. Lett. 2017, 188, 197–200. [Google Scholar] [CrossRef]
  141. Mahendran, D.; Kavi Kishor, P.B.; Geetha, N.; Manish, T.; Sahi, S.V.; Venkatachalam, P. Efficient Antibacterial/Biofilm, Anti-Cancer and Photocatalytic Potential of Titanium Dioxide Nanocatalysts Green Synthesised Using Gloriosa Superba Rhizome Extract. J. Exp. Nanosci. 2021, 16, 11–30. [Google Scholar] [CrossRef]
  142. Olowofolahan, A.O.; Olorunsogo, O.O. Effect of Gloriosa Superba Linn (EEGS) on MPT and Monosodium Glutamate-Induced Proliferative Disorder Using Rat Model. J. Ethnopharmacol. 2021, 267, 113498. [Google Scholar] [CrossRef]
  143. Mamatha, H.; Farooqi, A.A.; Joshi, S.S.; Prasad, T.G. Pollen studies in gloriosa superba linn. Acta Hortic. 1993, 331, 371–376. [Google Scholar] [CrossRef]
  144. Samarajeewa, P.K. Clonal Propagation of Gloriosa Superba L. Indian J. Exp. Biol. 1993, 31, 719–720. [Google Scholar]
  145. Sivakumar, G.; Krishnamurthy, K.; Rajendran, T.D. Embryoidogenesis and Plant Regeneration from Leaf Tissue of Gloriosa Superba. Planta Med 2003, 69, 479–481. [Google Scholar] [CrossRef] [PubMed]
  146. Jana, S.; Shekhawat, G.S. Critical Review on Medicinally Potent Plant Species: Gloriosa Superba. Fitoterapia 2011, 82, 293–301. [Google Scholar] [CrossRef] [PubMed]
  147. Arumugam, A.; Gopinath, K. In Vitro Micropropagation Using Corm Bud Explants: An Endangered Medicinal Plant of Gloriosa Superba L. Asian J. Biotechnol. 2012, 4, 120–128. [Google Scholar] [CrossRef]
  148. Sivakumar, S.; Siva, G.; Sathish, S.; Prem Kumar, G.; Vigneswaran, M.; Vinoth, S.; Kumar, T.S.; Sathishkumar, R.; Jayabalan, N. Influence of Exogenous Polyamines and Plant Growth Regulators on High Frequency in Vitro Mass Propagation of Gloriosa Superba L. and Its Colchicine Content. Biocatal. Agric. Biotechnol. 2019, 18, 101030. [Google Scholar] [CrossRef]
  149. Mahendran, D.; Kavi Kishor, P.B.; Sreeramanan, S.; Venkatachalam, P. Enhanced Biosynthesis of Colchicine and Thiocolchicoside Contents in Cell Suspension Cultures of Gloriosa Superba L. Exposed to Ethylene Inhibitor and Elicitors. Ind. Crops Prod. 2018, 120, 123–130. [Google Scholar] [CrossRef]
  150. Ponzone, C.; Berlanda, D.; Donzelli, F.; Acquati, V.; Ciulla, R.; Negrini, A.; Rovati, M.; Evangelista, D.; Fata, E.; Ciceri, D.; et al. Biotransformation of Colchicinoids into Their Corresponding 3-O-Glucosyl Derivatives by Selected Strains of Bacillus Megaterium. Mol. Biotechnol. 2014, 56, 653–659. [Google Scholar] [CrossRef]
  151. Alkaloids Corporation. Process for the Conversion of Colchicinoids to Their 3-Glycosylated Derivatives via Their Respective 3-Demethyl Analogues. European Patent EP3086794B1, 8 January 2010.
  152. Poulev, A.; Bombardelli, E.; Ponzone, C.; Zenk, M.H. Regioselective Bioconversion of Colchicine and Thiocolchicine into Their Corresponding 3-Demethyl Derivatives. J. Ferment. Bioeng. 1995, 79, 33–38. [Google Scholar] [CrossRef]
  153. Solet, J.-M.; Bister-Miel, F.; Galons, H.; Spagnoli, R.; Guignard, J.-L.; Cosson, L. Glucosylation of Thiocolchicine by a Cell Suspension Culture of Centella Asiatica. Phytochemistry 1993, 33, 817–820. [Google Scholar] [CrossRef]
  154. Zarev, Y.; Popova, P.; Foubert, K.; Apers, S.; Vlietinck, A.; Pieters, L.; Ionkova, I. Biotransformation to Produce the Anticancer Compound Colchicoside Using Cell Suspension Cultures of Astragalus Vesicarius Plant Species. Nat. Prod. Commun. 2019, 14, 27–29. [Google Scholar] [CrossRef] [Green Version]
  155. Yadav, K.; Aggarwal, A.; Singh, N. Evaluation of Genetic Fidelity among Micropropagated Plants of Gloriosa Superba L. Using DNA-Based Markers—A Potential Medicinal Plant. Fitoterapia 2013, 89, 265–270. [Google Scholar] [CrossRef] [PubMed]
  156. Yadav, K.; Aggarwal, A.; Singh, N. Arbuscular Mycorrhizal Fungi (AMF) Induced Acclimatization, Growth Enhancement and Colchicine Content of Micropropagated Gloriosa Superba L. Plantlets. Ind. Crops Prod. 2013, 45, 88–93. [Google Scholar] [CrossRef]
Cimb 44 00267 g001a 550Cimb 44 00267 g001b 550
Figure 1. Notable compounds, isolated from Astragalus and Gloriosa species.
Figure 1. Notable compounds, isolated from Astragalus and Gloriosa species.
Cimb 44 00267 g001aCimb 44 00267 g001b
Table
Table 1. Ethnobotanical use of Astragalus species.
Table 1. Ethnobotanical use of Astragalus species.
Astragalus (Incl. Astracantha) SpeciesLocationHealth DisordersReference
Astragalus sp.TurkeyRoots cooked with milk for poultice applied to abdomen[35]
A. amblolepis FischTurkeyUnspecified cancer[41]
A. abolinii PopovUzbekistanKidney disease, hypertension, burns, demulcent[32]
A. americanus (Hook.) M.E.JonesAmerican countriesStomach pain and flu[32]
A. amherstianus Benth.PakistanGalactagogue in animals[32]
A. amphioxys A.GrayAmerica countriesRattlesnake bite[32]
A. angustifolius LamLebanonAstringent[32]
A. armatus Willd. AlgeriaLeishmaniasis, helminthiasis[32]
A. brachycalyx Fisch. ex Boiss. IranLaxative, febrifuge, and digestive[32]
A. brachycalyx Fisch. ex BoissTurkeyUnspecified cancer[41]
A. caucasicus Pall.TurkeyDiabetes[40]
A. caucasicus Pall.Caucasus, GeorgiaFood (tea)[43]
A. canadensisAmerica countriesAnalgesic[32]
A. camptoceras BungeIranCold[32]
A. cephalotes Banks. & Sol. var. brevicalyx Eig.TurkeyDiabetes, wound healing[37]
A. coluteoides Willd.LebanonDiabetes and jaundice[32]
A. chamaephaca FreynTurkeyMouth wounds[39]
A. crassicarpus Nutt.American countriestonic, anticonvulsive and anti-headache[32]
A. creticus Lam.PakistanSedative and tonic[32]
A. crenatus Schult.IranKidney stone, sedative, arthrodynia, carminative[32]
A. cruentiflorus Boiss.LebanonDiabetes and jaundice[32]
A. dasyanthus Pall.UkraineCardiovascular insufficiency and chronic nephritis[44]
A. effusus BungeIranCough[32]
A. fasciculifolius Boiss.IranCough, kidney, stomach ache, chest infection, toothache[32]
A. fischeri Buhse ex Fisch.IranToothache, backache, bone ache, kidney ache, bone fracture, and diabetes, and to induce abortion[32]
A. glaucacanthos Fisch.IranTonic, gastric pain, headache[32]
A. globiflorus Boiss.IranHealing deep infectious wounds[32]
A. glycyphyllos L.Bulgaria Abdominal pain, colic, renal inflammation, menstrual disorders, and sciatica[33]
A. glycyphyllos L.MontenegroIncreasing men’s sexual potency[32]
A. glycyphyllos L.ItalyDiuretic, kidney ailments, gout, and rheumatism.[32]
A. gossypinus Fisch.IranCough[32]
A. grahamianus Benth.PakistanTreatment of abscesses and as an analgesic[32]
A. gummifer Lab.TurkeyThroat diseases[36]
A. gummifer Lab.TurkeyDiabetes[38]
A. hamosus L.IndiaNervous system disorders; liver, kidney, and spleen infection.[32]
A. jolderensis B.Fedtsch.IranTyphoid and dermal problems[32]
A. lamarckii Boiss.TurkeyUlcer[32]
A. longifolius Lam.TurkeyCardiac disorder, diabetes[38]
A. microcephalus Willd.TurkeyUnspecified cancer[41]
A. microcephalus Willd.IranAsthma, strengthen hair[32]
A. mongholicus BungeChinaQi (Chi) tonic[29,30]
A. mongholicus BungeChinaCancer[45,46,47]
A. monspessulanus L.ItalyDiuretic[32]
A. mucronifolius Boiss.IranBackache[32]
A. noaeanus Boiss.TurkeyVaricosis[32]
A. ovinus Boiss.IranStomachache[32]
A. tragalus podolobus Boiss. & Hohen.IranAbdominal pain[32]
A. psilocentros Fisch.PakistanCataract and stomach problems[32]
A. rhizanthus Benth.IndiaDigestive disorders, leucorrhea, and urinary troubles[32]
A. rubrivenosus Gontsch.UzbekistanKidney disease, hypertonic disease, burns, demulcent[32]
A. sarcocolla DymockJordanIncense, pains[32]
A. sieversianus Pall.IranMenstrual disorders[32]
A. spinosus Muschl. PakistanTo treat wounds[48]
A. thomsonianus Benth. ex BungeIndiaGastric troubles, swelling, and joint pains[32]
A. tmoleus Boiss.TurkeyToothache[32]
A. tribulifolius BungeIndiaDiuretic agent and to lower kidney disorders. [32]
A. tribuloides DelileIranUrinary infection[32]
A. verus OlivierIranAntiparasitic, antimycotic, and immunomodulatory activities[32]
A. zanskarensis BungeIndiaAgainst worms[32]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Ionkova, I.; Shkondrov, A.; Zarev, Y.; Kozuharova, E.; Krasteva, I. Anticancer Secondary Metabolites: From Ethnopharmacology and Identification in Native Complexes to Biotechnological Studies in Species of Genus Astragalus L. and Gloriosa L. Curr. Issues Mol. Biol. 2022, 44, 3884-3904. https://doi.org/10.3390/cimb44090267

AMA Style

Ionkova I, Shkondrov A, Zarev Y, Kozuharova E, Krasteva I. Anticancer Secondary Metabolites: From Ethnopharmacology and Identification in Native Complexes to Biotechnological Studies in Species of Genus Astragalus L. and Gloriosa L. Current Issues in Molecular Biology. 2022; 44(9):3884-3904. https://doi.org/10.3390/cimb44090267

Chicago/Turabian Style

Ionkova, Iliana, Aleksandar Shkondrov, Yancho Zarev, Ekaterina Kozuharova, and Ilina Krasteva. 2022. "Anticancer Secondary Metabolites: From Ethnopharmacology and Identification in Native Complexes to Biotechnological Studies in Species of Genus Astragalus L. and Gloriosa L." Current Issues in Molecular Biology 44, no. 9: 3884-3904. https://doi.org/10.3390/cimb44090267

Article Metrics

Back to TopTop