Advances in Pharmacological Sciences
Volume 2018 (2018), Article ID 9794625, 15 pages
https://doi.org/10.1155/2018/9794625

Review Article

Astragalin: A Bioactive Phytochemical with Potential Therapeutic Activities

Ammara Riaz,¹ Azhar Rasul,¹ Ghulam Hussain,² Muhammad Kashif Zahoor,¹ Farhat Jabeen,¹ Zinayyera Subhani,³ Tahira Younis,¹ Muhammad Ali,¹ Iqra Sarfraz,¹ and Zeliha Selamoglu⁴

¹Department of Zoology, Faculty of Life Sciences, Government College University, Faisalabad 38000, Pakistan
²Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad 38000, Pakistan
³Department of Biochemistry, University of Agriculture, Faisalabad 38000, Pakistan
⁴Department of Medical Biology, Faculty of Medicine, Nigde Ömer Halisdemir University, Nigde 51240, Turkey

Correspondence should be addressed to Azhar Rasul; drazharrasul@gmail.com

Received 8 January 2018; Revised 5 April 2018; Accepted 12 April 2018; Published 2 May 2018

Academic Editor: Paola Patrignani

Copyright © 2018 Ammara Riaz et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Natural products, an infinite treasure of bioactive chemical entities, persist as an inexhaustible resource for discovery of drugs. This review article intends to emphasize on one of the naturally occurring flavonoids, astragalin (kaempferol 3-glucoside), which is a bioactive constituent of various traditional medicinal plants such as Cuscuta chinensis. This multifaceted compound is well known for its diversified pharmacological applications such as anti-inflammatory, antioxidant, neuroprotective, cardioprotective, antiobesity, antiosteoporotic, anticancer, antiulcer, and antidiabetic properties. It carries out the aforementioned activities by the regulation and modulation of various molecular targets such as transcription factors (NF-κB, TNF-α, and TGF-β1), enzymes (iNOS, COX-2, PGE2, MMP-1, MMP-3, MIP-1α, COX-2, PGE-2, HK2, AChe, SOD, DRP-1, DDH, PLCγ1, and GPX), kinases (JNK, MAPK, Akt, ERK, SAPK, IκBα, PI3K, and PKCβ2), cell adhesion proteins (E-cadherin, vimentin PAR-2, and NCam), apoptotic and antiapoptotic proteins (Beclin-1, Bcl-2, Bax, Bcl-xL, cytochrome c, LC3A/B, caspase-3, caspase-9, procaspase-3, procaspase-8, and IgE), and inflammatory cytokines (SOCS-3, SOCS-5, IL-1β, IL-4, IL-6, IL-8, IL-13, MCP-1, CXCL-1, CXCL-2, and IFN-γ). Although researchers have reported multiple pharmacological applications of astragalin in various diseased conditions, further experimental investigations are still mandatory to fully understand its mechanism of action. It is contemplated that astragalin could be subjected to structural optimization to ameliorate its chemical accessibility, to optimize its absorption profiles, and to synthesize its more effective analogues which will ultimately lead towards potent drug candidates.

1. Introduction

Medicinal plants have been an infinite source of therapeutic agents since millions of years. Most of the discovered drugs either belong to natural products or derivatives of natural compounds [1, 2]. The actual fact is that nature is the creator of seemingly limitless series of molecular structures. These structures can serve as unlimited sources for the development of drugs, robust chemotypes, and pharmacophores which are able to be amplified into scaffolds of novel drugs for the cure of various ailments [3]. Before the advent of the postgenomic era with high throughput screening, approximately 80% of drugs were either pure extracts of medicinal plants or the semisynthetic analogues of various compounds from natural sources [4]. After the second world war, the pharmaceutical research expanded to massive screening of plant extracts in search of new drugs from natural resources [5]. To date, about 61% of anticancer and 49% of anti-infective compounds have been discovered from natural products [6].

The term “natural products” encompasses chemical entities derived from plants, bread molds, microorganisms, terrestrial vertebrates as well as invertebrates, and marine organisms [7]. These chemical entities are known to have immense chemical diversity with outstanding drug-like properties that contribute towards their multitargeted action [8]. A lot of plant-derived bioactive compounds are used for the cure as well as for the prevention of several diseases. Among these compounds are the polyphenols consisting of alcohols with ≥2 benzene rings and ≥1 hydroxyl group. These polyphenols have a range from simple structural molecules (flavonoids and phenylpropanoids) to highly complex compounds (lignins and melanins). Reports have suggested that polyphenols in general and flavonoids in particular exhibit various biological effects like antiallergic, antibacterial, anti-inflammatory, antiviral, antithrombic, hepatoprotective, antibacterial, and antioxidant activities [9].

Flavonoids are structurally diverse and most abundantly found polyphenols in the human diet [10]. They are mostly found in the form of glycosides and acylglycosides. Flavonoids have been divided into various classes such as flavones, flavonols, flavanones, flavanonols, flavanols or catechins, and anthocyanins. They are the essential constituents of our food and are found in onions, parsley, berries including blue berries, black tea, green tea, bananas, red wine, all citrus fruits, sea blackthorns, and dark chocolates with the contents of 70% or more [11].

Astragalin (kaempferol-3-O-β-D-glucoside), a bioactive natural flavonoid, has been well known for its medicinal importance. It has been reported to exhibit multiple pharmacological properties including antioxidant [12, 13], anti-inflammatory [14], anticancer [15], neuroprotective [16], and cardioprotective property [16].

2. Natural Sources of Astragalin

Astragalin, a naturally occurring flavonoid, has been identified in a variety of plants (Figure 1 and Table 1) such as Cuscuta chinensis Lam., a member of the Convolvulaceae family, which consists of about 60 genera and 1,650 species. The seeds of the genus Cuscuta are a rich source of astragalin and are utilized as a traditional folk medicine to cure osteoporosis in various Asian countries including Pakistan [17]. C. chinensis has high contents of astragalin, that is, 29–34% of total phenolics as compared to other species [18]. Cassia alata belongs to the family Fabaceae (the largest family among angiosperms) that comprises of ∼700 genera and 20,000 species. The leaves of C. alata are found to be effective against skin diseases including eczema and chronic skin impurities in tropical regions of the world (Malaysia, Brazil, and Indonesia) [19]. Astragalin has also been isolated from the plants of Ebenaceae, Rosaceae, and Eucommiaceae families. The summary of plants containing astragalin, parts utilized, and biological features are enlisted in Table 1.

Figure 1: Natural sources of astragalin.

Table 1: Plants containing astragalin as an important constituent with its biological properties.

Name of the plant
Parts used/extract
Biological activities
References

Botanical name
Common name

Acer truncatum
Shantung maple
—
—
[21]

Aceriphyllum rossii
Mukdenia
Aerial parts
Antioxidant
[22]

Agrimonia pilosa
Hairy agrimony
Aerial parts
Antihemorrhagic, antiplatelet, antioxidant, and acetylcholinesterase inhibitory
[23]

Allium ursinum
Wild garlic
Flowers
Antimicrobial
[24]

Allium victorialis
Alpine leek
—
Antitumor
[25]

Alsophila spinulosa
Hook tryon
Leaves
Antixanthine oxidase
[26]

Apocynum venetum
Luobuma
Leaves
Lower blood pressure, antidepressant, antinephritis, and antineurasthenia
[27]

Jasminum subtriplinerve Blume
—
Aerial parts
—
[28]

Astragalus hamosus
Dwarf yellow milk vetch
Aerial parts
—
[29]

Caesalpinia decapetala
Mysore thorn
Leaves
—
[30]

Calligonum polygonoides
Phog
Aerial parts
Antiulcer, anti-inflammatory, hypoglycemic, and antioxidant
[31]

Camellia sinensis
Tea
Leaves and seeds
Antidysentery, antihyperlipidemia, antihyperglycemia, and anti-inflammatory
[32–35]

Carthamus lanatus L.
Downy safflower
Aerial parts
Antioxidant
[35]

Cassia alata
Ringworm bush
Leaves
Antioxidant, anti-infectious, and DNA repair
[19]

Celastrus gemmatus Loes
Chinese bittersweet
Leaves
—
[36]

Centella asiatica
Asiatic pennywort
Leaves
Anti-inflammatory
[37]

Clerodendrum philipinum
Chinese glory bower
Roots
—
[38]

Conyza filaginoides
Laennecia filaginoides
Aerial parts
Antiprotozoal
[39]

Corchorus olitorius L.
Moroheiya
Leaves
Inhibits the histamine
[40]

Cuscuta chinensis
Chinese dodder
Seeds
Antiosteoporotic
[17, 41–43]

Cuscuta australis
Australian dodder
Seeds
—
[17, 41–43]

Diodia teres
Buttonweed
Whole plant
—
[44]

Drosera peltata
Sundew

Antitussive
[45]

Dianthus barbatus cv
Sweet William
Aerial parts
Anti-inflammatory
[46]

Eucommia ulmoides
Hardy rubber tree
Leaves
Antidiabetic, antioxidant, and hypnotic effect
[47–49]

Eupatorium cannabinum L.
Hemp agrimony
Aerial parts
—
[50]

Eupatorium lindleyanum

Aerial parts
—
[51]

Exochorda racemosa
Pearlbrush
—
—
[52]

Flaveria bidentis (L.) Kuntze
Coastal plain yellow tops
Leaves
—
[53, 54]

Flos gossypii
—
Flowers
—
[55]

Gladiolus gandavensis
Gladiolus
Aerial parts
—
[56]

Glycyrrhiza glabra
European licorice
Leaves
—
[57]

Glycyrrhiza uralensis Fisch
Chinese licorice
Leaves
—
[58]

Gynura procumbens
Longevity spinach
—
Antidiabetic
[59]

Hedera helix
English ivy
—
—
[60]

Helianthemum glomeratum
Island rushrose
Aerial parts
—
[61]

Hemistepta lyrata Bunge
—
Whole plant
—
[62]

Hippophae rhamnoides L.
Sea buckthorn
Leaves
—
[63]

Ipomoea batatas
Sweet potato
Leaf
—
[64]

Koelreuteria paniculata
Golden rain tree
Flowers
Antioxidant
[65]

Allium ampeloprasum
Wild leek
Leaves
Antioxidant
[66]

Ligusticum chuanxiong
—
Aerial parts
—
[67]

Lindera aggregate
Evergreen lindera
Leaves
—
[68]

Litsea coreana
—
Leaves
Antioxidant
[69]

Magnolia fargesii
—
Flowers
Anticomplement
[70]

Moringa oleifera Lam.
Drumstick tree
Leaves
Antioxidant
[71]

Morus alba L.
White mulberry
Leaves
Hypoglycemic and antioxidant
[72–78]

Mussaenda arcuate
Forest star
Leaves

[79]

Nelumbo nucifera
Sacred lotus
Leaves
Lipolytic activity
[80–84]

Ochradenus baccatus
Taily weed
Aerial parts
—
[85]

Orostachys japonica
Rock pine
—
Calpain inhibitory activity
[86]

Diospyros kaki
Japanese persimmon
Leaves
Angiotensin converting enzyme activity, and inhibition of atopic dermatitis (AD)
[12, 87–89]

Rosa agrestis
Field briar
Leaves
Anti-inflammatory and antioxidant
[13, 90–92]

Peucedanum alsaticum
—
Fruits
—
[93]

Phaseolus vulgaris L.
Common bean

—
[94]

Phlomis spinidens
—
Aerial parts
Antiallergic
[95]

Phyllanthus muellerianus
—
Leaves
Antibacterial and anti-inflammatory
[96]

Polygala cyparissias
—

Antiulcer
[97]

Polygonum salicifolium
Knotweed
Aerial parts
DPPH-free radical scavenging activity
[98]

Prunus padus L.
European bird cherry
Flowers and leaves
Antioxidant
[99]

Prunus serotina Ehrh
Black cherry
Leaves and flowers
—
[100]

Pseudotsuga menziesii
Oregon pine
Needles
Cytotoxic
[101]

Radix astragali
Milk vetch root
Roots
Antidiabetic
[102–104]

Rhus sylvestris
Sumach
Stems and leaves
Antiosteoporotic
[105]

Rosa soulieana
Shrub rose
Flowers
Antioxidant
[106]

Rubus rigidus var. camerunensis
Ronce blanche
Aerial parts
Antioxidant
[107]

Sapium sebiferum
Chinese tallow
Leaves
—
[108]

Solenostemma argel
Arghel
Aerial parts
Antibacterial
[109]

Solidago canadensis L.
Canada goldenrod
—
Antioxidant
[110]

Sorbus aria (L.)
Lutescens
Leaves
—
[111]

Tadehagi triquetrum
—
Whole plant
Antimicrobial and anti-inflammatory
[112]

Tiarella polyphylla
Foam flower
Whole plant
—
[113]

Trachelospermum jasminoides
Confederate jasmine
Leaves
Antifungal
[114]

Urtica cannabina
—
Fruits
—
[115]

Vahlia capensis
—
—
Antibacterial
[116]

Vicia calcarata
Few flowered vetch
Aerial parts
Hepatoprotective
[117]

Wedelia chinensis
—
Whole plant
Inhibitor of the complement system
[118]

Astragalin can also be produced in vivo by glycosylation of kaempferol at the 3C-O position [20]. UDP-dependent glycosyltransferases (UGT) were used as biocatalysts in the synthesis of astragalin. A recombinant strain of Arabidopsis thaliana was used to construct an efficient UDP-glucose synthesis pathway by use of enzymes such as uridylyltransferase, sucrose phosphorylase, and sucrose permease. BL21-II was a recombinant strain designed to scale up the production of astragalin by using a fed-batch fermentator.

3. Biological Activities of Astragalin and Their Mechanisms of Action

The biologically active and therapeutically effective compound “astragalin” has been known to possess broad spectrum of pharmacological features such as anticancer, anti-inflammatory, antioxidant, neuroprotective, antidiabetic, cardioprotective, antiulcer, and antifibrotic as shown in Figure 2. Various in vivo and in vitro investigations on astragalin have elucidated its medicinal characteristics and mechanism of actions.

Figure 2: Biological activities of astragalin.

3.1. Anti-inflammatory Activity

Inflammation is an immediate response of a body to tissue damage caused by pathogens and toxic stimuli such as physical or chemical injury. Although inflammatory response is a defense mechanism, but if persistent, it can lead to multiple pathological conditions such as cancer, allergy, atherosclerosis, and autoimmune diseases [119]. Negative after effects associated with nonsteroidal type anti-inflammatory drugs (NSAIDs) arouse a need among researchers to find out effective and safe alternatives [120]. Plant extracts enriched with flavonoids have been known to possess anti-inflammatory activity [121].

Astragalin, a bioactive natural flavonoid, has been known to mitigate inflammation in LPS-induced murine model of mastitis and lung injury model via reducing the activity of myeloperoxidase and the expression of IL-1β, IL-6, and TNF-α. Astragalin’s anti-inflammatory response proceeds via inhibition of LPS-induced activation of NF-κB, as it is actively involved in alleviating the deterioration of IkBα and restricting the nuclear translocation of NF-κB [92, 122]. Another investigation on LPS-stimulated expression of inflammatory mediators in macrophages has declared the fact that astragalin actively inhibited the expression of proinflammatory mediators via inhibiting NF-κB signaling pathway [123]. Astragalin has been known to halt the MAPK and NF-κB pathways in leptospira-induced uterine and epithelial inflammation in mice [124]. Astragalin has capability to inhibit the production of prostaglandin E2 (PGE2) in periodontal pathogen-induced periodontitis, a destructive inflammatory pathological condition, in human gingival epithelial cells [125]. Astragalin has been investigated to determine the underlying mechanism for its protective effect against ovalbumin-stimulated allergic reactions in mouse models of allergic asthma. Results have declared that it effectively lowers the eosinophil count in lung tissues and inhibited eosinophilia induced by ovalbumin. As a result, IgE, IL-4, IL-5, and IL-13 were retrieved in bronchoalveolar lavage fluid [126]. Purely prepared astragalin inhibited the activity of PGE2 and downregulated the production of cellular nitrite oxide and IL-6 in LPS-stimulated RAW 264.7 cells [33]. Astragalin treatment leads to the inhibition of alveolar destruction, allergic inflammation, and thickening of airways in the ovalbumin-induced inflammatory mouse model [14]. Anti-inflammatory activities of astragalin in different animal models are recorded in Table 2.

Table 2: Anti-inflammatory activities of astragalin in vitro and in vivo.

Assay
Organism tested
Dose/concentration
Molecular targets
References

LPS-induced mouse mastitis
Mouse mastitis
10, 25, and 50 mg/kg
TNF-α↓, IL-1β↓, IL-6↓, p65┴, and IκBα┴
[92]

LPS-induced endotoxemia and lung injury in mice
Mice (lung)
25, 50, and 75 mg/kg
TNF-α┴, IL-1β┴, and IL-6┴
[122]

LPS-induced macrophages in mice
Mouse cells
1–100 µg/mL
iNOS↓, COX-2↓,TNF-α↓, IL-1β↓, IL-6↓, MIP-1α↓, MCP-1↓, NF-κB p65┴, IκBα┴, and NO┴
[127]

LPS-induced RAW 264.7 cells.
Mice (RAW 264.7 cells)
1, 10, and 100 M
NO↓ and TNF-α↓
[37]

Inhibitory activity on the histamine release by KU812 cells
KU812 cells
10 to 30 mol/L
IL-4↓, IL-13↓, and (IFN-γ) no effect
[12]

LPS-induced inflammation in RAW 264.7 cells
Mice (RAW 264.7 cells)

NO┴, IL-6┴, and PGE2┴
[33]

P. gingivalis-induced human gingival epithelial (HGE) cells
Human gingival epithelial cells

COX-2┴, IL-6┴, IL-8┴, MMP-1┴, MMP-3┴, PGE-2┴, and IL-4┴
[125]

Anti-inflammatory effects on Leptospira interrogans-induced inflammatory response
Uterine and endometrial epithelial cells of mice
100 g/mL
TNF-α┴, IL-1β┴, IL-6┴, NF-κB↓, p38┴, p-p38 MAPK↓, ERK┴, JNK┴, and p-p65↓
[124]

Protective effects against ovalbumin- (OVA-) induced allergic inflammation
Mouse model of allergic asthma
0.5 mg/kg and 1 mg/kg
SOCS-3┴, SOCS-5┴, and IFN-γ↑
[126]

Alleviation in hepatic fibrosis function
Diabetic rats and nondiabetic rats

PAR2┴, IL-1β↓, IL-6↓, TNF-α↓, and TGF-β1┴
[128]

Prevention from atopic dermatitis
NC/Nga mice
1.5 mg/kg
IgE↓
[87]

↑Upregulation; ↓downregulation; ┴inhibition.

3.2. Antioxidant Activity

In living systems, free radicals such as hydroxyl radicals (OH⋅), superoxide anion (O₂⋅−), singlet oxygen (¹O₂), and ROS are reported to have deleterious impacts on cellular functions. Excessive production of free radicals may affect the balance of prooxidant and antioxidant systems in the body, thus causing various pathological conditions such as arterial hypertension, rheumatism, inflammation, diabetes, cancer, neurodegenerative disorders, and genetic mutations [120]. Researchers have affirmed various plant extracts as natural and infinite treasure of antioxidants. These antioxidants act as free radical scavengers, electron donors, and chelating agents for free catalytic metals in biological systems [75].

Astragalin also inhibits the endotoxin-induced oxidative stress, which can lead to epithelial apoptosis and eosinophilia. It can also act as an antagonizing agent against endotoxin-induced oxidative stress via modulation of LPS-TLR signaling network [129]. Astragalin causes the suppression of 6-hydroxydopamine-stimulated neurotoxicity in Caenorhabditis elegans via modulation of apoptosis-related pathways and alleviation of oxidative stress [130]. Astragalin has capability to improve neural function in the ischemia brain injury model of rats via blocking the apoptosis in the hippocampus region by enhancing the expression of NCam [131] (Table 3).

Table 3: Antioxidant activity of astragalin in vitro and in vivo.

Assay
Organism tested
Dose/concentration
Molecular targets
References

Free radical-scavenging activity

1, 3, 10, 30, 100, or 300 µg/mL

[107]

Inhibitory activity against autophagy-associated airway epithelial fibrosis
Mice
1–20 M
E-cadherin┴, vimentin┴, Beclin-1↓, LC3A/B↓, EMT↓, and TGF-β1┴
[132]

Apoptotic and eosinophilia amelioration
BEAS-2B cells
1–20 M
TLR-4↓, Eotaxin-1↓, PLCγ1↓, PKCβ2↓, p-p22↓, p-47↓, JNK↓, p38 MAPK↓, Akt↑, and ERK↑
[129]

Suppression of 6-hydroxydopamine-induced neurotoxicity in Caenorhabditis elegans
C. elegans
2.0 mg/mL
egl-1↓, SOD↑, GPX↑, AChe↑, and p38 MAPK↓
[130]

Neuroprotective effect against ischemic brain injury
Wister rats
5 mg/kg and 15 mg/kg
NCam↑
[131]

↑Upregulation; ↓downregulation; ┴inhibition.

3.3. Neuroprotective Activity

Disturbance in cerebral redox homeostasis is the main cause of neurodegenerative diseases in humans. Cerebral oxidative stress leads to dopaminergic neuronal cell death and dysfunction. Neuroprotective mechanism of naturally occurring bioactive entities is associated with their free radical scavenging capability generated by neurotoxins and oxidative stress-induced processes in neuronal cells of the brain [133].

Astragalin has been reported to decrease the neurodegeneration in C. elegans stimulated by 6-OHDA and increase lifespan of astragalin-treated nematode. It also reduces the ROS levels, inhibits lipid peroxidation, and increases SOD and GPx activities. Furthermore, it is capable of enhancing AChE and reducing the transcript level of proapoptotic gene egl-1 associated with neuronal cell death [130]. In another attempt, the effects of astragalin on CNS were assessed by the application of the leaves extract of Eucommia ulmoides. The extract with high percentage of astragalin had a significant effect on metabolism of mice. Moreover, it effectively prolonged the convulsion latency and diminished the convulsion rate. These results strengthen the fact that E. ulmoides has a very good hypnotic effect on CNS [49]. Astragalin also suppressed carrageenan-stimulated paw edema in rats. Neural function is also reported to be improved by the use of astragalin in ischemic brain injury rat models [131].

3.4. Cardioprotective Activity

Myocardial infarction and ischemic heart failure are the leading causes of mortality in the developing countries, and their number is increasing day-by-day. They may result in reperfusion arrhythmias, myocardial stunning, and similar other cardiovascular disorders [16]. An enhanced perception of ischemia reperfusion (I/R) damage provides an innovative approach for new cardioprotective administrations [134]. Regulation of bradykinin, adenosine, opioid, adrenergic, and other G-protein connected receptors have been known to be associated with myocardial protection [135].

Certain epidemiological studies have confirmed that flavonoids stimulate cardioprotective effects against myocardial ischemia [136]. Astragalin, a bioactive flavonoid, was proved to be effective against acute I/R injury in Sprague-Dawley rats as its mechanism of action precedes via diminishing intracellular oxidative stress and apoptosis. The associated mechanism involves decreased expression of MDA, TNF-α, IL-6, ROS, and Bax along with the increased ratio of GSH/GSSG, respectively [137].

3.5. Antiobesity Activity

The term “obesity” can be defined as impaired energy balance that usually results from either enhanced caloric intake and/or reduced energy consumption. Currently, much attention has been given to several nutritional aspects that may be useful for inhibiting body fat accumulation and decreasing the risk of diseases related to obesity. In case of mammals, energy metabolism is maintained by lipolytic action in adipose tissues which is generally stimulated by some pharmacologically important lipolytic hormones such as nor-epinephrine, epinephrine, and catecholamines [80]. Many cellular investigations have determined that dietary polyphenols decrease viability of adipocytes and growth of preadipocytes, downregulate triglyceride accumulation and adipocyte differentiation, and induce fatty acid beta-oxidation and lipolysis [138].

Astragalin along with other known flavonoids isolated from N. nucifera showed inhibitory effect on diet-induced obesity and also activated β-adrenergic receptor pathway, but additional experimentation is required to fully elucidate its possible mechanism of action [80].

3.6. Antiulcer Activity

Ulcer is a chronic lesion which usually develops due to an imbalance between numerous protective and aggressive factors. Gastric ulcers being represented by repeated incidents of healing and reexacerbation contribute towards chronic inflammation which may persist for 10–20 years. It is a well-known fact that naturally occurring phenolic entities have capability to shield gastric mucosa from injury due to their cytoprotective and antioxidant features. Furthermore, flavonoids stimulate mucus secretion, block pepsinogen, prohibit Ca²⁺ influx, and also change GSH metabolism. Astragalin, a pharmacologically active flavonoid isolated from C. cyparissias, has been examined for its antiulcer activity. Results demonstrated that 30 mg/kg dosage of astragalin effectively decreases percentage of lesion area, total area of lesion, and ulcer index in the mice model of gastric secretion [97].

3.7. Antidiabetic Activity

Diabetes mellitus is characterized by hyperglycemia which is caused by deficit in insulin action or production [139]. Currently available antidiabetic therapeutics such as hypoglycemic drugs and insulin have limitations of their own. Natural products and herbal medicines have been suggested as one of the treatment options for diabetes since ancient times. Naturally occurring bioactive chemical entities such as flavonoids, terpenoids, alkaloids, and phenolics have been reported as antidiabetic agents [140].

Diabetic retinopathy (DR) arises due to diabetes mellitus and is one of the most common causes of vision loss. Hyperglycemia leads to overexpression of many biological effectors such as vascular endothelial growth factor (VEGF) which is very crucial for the development of DR. Astragalin derived from A. membranaceus has beneficial effects against hyperglycemia. It helps to prevent DR by decreasing the overexpression of VEGF in cultured muller cells and alleviating the effects caused by high concentration of glucose in the blood [141].

3.8. Antifibrotic Activity

Environmental factors like air pollutants may result in considerable production of reactive oxygen species in the airways. Astragalin isolated from leaves of persimmon and green tea can be effectual in allaying ROS-prompted bronchial fibrosis as it has capability to inhibit auto phagosome formation in the airways [132]. It also alleviates hepatic fibrosis by regulating PAR2 (protease-activated receptor 2) mechanism. AGS regulates proinflammatory cytokines namely IL-6, IL-1β, and TNF-α. It also attenuates the PAR2 signaling expression, and its protective effects are especially prominent in diabetic animal models [128].

3.9. Cosmetic Use

Astragalin glucosides can be used as valuable agents in cosmetics due to their important chemical characteristics. First of all, it inhibits collagenase activity. Collagenase is involved in the hydrolyzation of dermal matrix protein formation as well as wrinkle formation. Secondly, astragalin has an antioxidant activity as it alleviates the free radical species. Thirdly, astragalin controls the pigmentation in the skin caused by melanin [142]. Melanin pigment causes darkening of complexion in skin, eyes, and hair in humans. Nelumbo nucifera (lotus) contains bioactive compounds astragalin and hyperoside in the receptacles which are known to be the melanogenesis inhibitor, thus possibly decreasing the skin darkness [143]. Astragalin along with quercetin is known to possess protective effect against the UV radiations. UV radiations can make the skin of animals prone to various biological responses such as DNA damage, formation of sunburn cells, melanogenesis, photoaging, skin cancer, hyperplasia, immune suppression, and edema. UV radiations from the sun can also damage macromolecules in the epidermal layer of animals creating specific changes in the skin, for example, mutations in genes and changes in the immune system. Expression of major CXC chemokines, that is, chemokine ligand 1 (CXCL1) and chemokine ligand 2 (CXCL2), at sites of inflammation within the skin are upregulated after the exposure of skin to UV radiations. These chemokines are the potent stimulators of neutrophil activation which later on produce ROS and leads to oxidative stress. Astragalin, a major flavonoid, can be used as a barrier against UV-induced damage as it is associated with downregulation of CXCL-1 and CXCL-2 in the skin and thus can be used as a photoprotective agent [144] (Table 4).

Table 4: Cosmetic uses of astragalin.

Assay
Organism tested
Dose/concentration
Molecular targets
References

Inhibition of melanin secretion
Leuconostoc mesenteroides
10 mM
MMP-1┴
[142]

Protection against UV damage
Mice (BalB/c) and human keratinocyte cells (HaCaT cells)
2.5 mg/kg and 0.25 µM/ml
CXCL-1↓ and CXCL-2↓
[144]

↓Downregulation; ┴inhibition.

3.10. Antiosteoporotic Activity

Osteoporosis is characterized by structural deterioration of tissues in the bone along with lower bone mass and bone fragility. The main causes of osteoporosis include estrogen deficiency, excess of glucocorticoids, and oxidative stress. Astragalin, an active compound, isolated from crude methanolic extract of the seeds of C. chinensis showed estrogenic activity against osteoporosis, and it is responsible for significant osteoblastic cell proliferation in UMR-106 osteoblastic cells [17].

3.11. Anticancer Activity

Currently, cancer is the second leading cause of mortality worldwide. In spite of advances in the development of new therapeutic preferences for cancer, its ratio is increasing day by day. Every year, almost 7 million people die due to cancer. Lung cancer particularly non-small cell lung cancer (NSCLC) accounts for more than 80% of deaths all around the world today. Therefore, it is necessary to discover new cheap and inexpensive drugs that can ameliorate the antitumor effects and reduce the side effects of generally recommended chemotherapy drugs [145].

Natural phytochemicals that are active constituents of medicinal plants, seeds, fruits, and herbs including polyphenols (flavonoids, terpenoids, and carotenoids) have gained significant recognizance for their potential value as therapeutic agents [146, 147]. Much research work has been conducted towards the assessment of phenolic phytochemicals as potent prophylactic agents as they can act on multiple cellular targets. The mechanistic insight into chemoprevention incorporates induction of apoptosis and cell cycle arrest or prohibition of certain cell signaling pathways mostly protein kinases C (PKC), glycogen synthase kinase (GSK), mitogen-activated protein kinases (MAPK), and phosphoinositide 3-kinase (PI3K) leading to abnormal AP-1, COX-2, and NF-κB expressions. Efficacy of chemopreventive agents revert their capacity to counteract with certain up-stream signals that leads to redox imbalances, genotoxic injury, and other situations of cellular stress. Thus, targeting damaged molecules along with interrupted signal transduction pathways in cancer epitomize a rational strategy for chemoprevention, and phenolic compounds seem to be auspicious in this aspect [147, 148]. In recent years, flavonoids have drawn developing consideration as powerful anticancer agents against various cancer types [149].

Several investigations on astragalin have explained its anticancer effect due to its promising competency to inhibit proliferation in different cancer cell lines including leukemia (HL-60) [15], hepatocellular (HepG2, Huh-7, and H22) [150], skin (HaCaT, A375P, and SK-MEL-2) [151], and lung (A549 and H1299) cancerous cells [145].

Astragalin heptaacetate (AHA), a therapeutically active flavonoid, induces apoptosis in HL-60 cells through release of cytochrome c into the cytosol. The associated mechanism involves activation of Bax, caspase-3/-7, and p38MAPK and intracellular ROS generation along with inhibition of cell signaling pathways JNK/SAPK and ERK ½ [15]. Astragalin also prohibits TNF-α-induced NF-κB activation in A549 and H1299 cells. Moreover, AG-triggered cell death is affiliated with increased Bax : Bcl-2 ratio and enhanced cleavage of caspase-3/-9 and PARP in conjunction with blockage of PI3K/Akt, MAPK, and ERK 1/2 signaling cascades in a time- and dose-related manner [145]. In hepatocellular carcinoma cells, astragalin (AG) significantly suppressed proliferation both in vitro in HepG2 cells and in vivo in Huh-7 (nude mice) and H22 (Kunming mice) cells via mechanistically inhibiting hexokinase 2 and upregulating miR-125b expression, respectively [150].

Astragalin can be a novel anticancer agent for the cure and prevention of UVB-stimulated actinic keratosis skin lesion by suppressing phospho-MSK1, γ-H2AX, and p38MAPK activation in a time-and dose-related manner in human HaCaT cells in vitro and Babl/c mice in vivo. In another report, astragalin strongly exerted cytotoxic effects in A375P and SK-MEL-2 cancerous cells in a concentration-dependent way through induction of apoptosis. The underlying cell death mechanism involves activation of Bax and caspase-3/-9, cleavage of PARP, and downregulation of cyclin D1 and Mcl-1 along with inhibition of Sry-related HMg-Box Gene 10 (SOX10) signaling cascade [151, 152]. The reported data recommend astragalin’s multitargeted activity in preference to single effect that may perform an imperative role towards developing astragalin into potential anticancer drug in future (Table 5).

Table 5: Anticancer activities of astragalin in vitro and in vivo.

Type of cancer
Cell line
Dose/concentration
Molecular targets
References

Leukemia
HL-60
6 ± 1 µM
Bax↑, Bcl-2↓, caspase-3/-7Act, JNK/SAPK┴, and ERK 1/2┴
[15]

Hepatocellular
HepG2, Huh-7, and H22
—
HK2┴ and miR-125b↑
[150]

Skin
HaCaT, A375P, and SK-MEL-2
50 and 100 M/mL
p38 MAPK↓, phospho-MSK1↓, γ-H2AX↓, caspase-9/-3Act, BaxAct, PARP cleavage, cyclin D1↓, Mcl-1↓, and SOX10┴
[151, 152]

Lung
A549, H1299, H226, H838, H23, H1437, H125, H2009, and H2087
5, 40 µg/mL (A549) and 20 µg/mL (H1299)
Bax:Bcl-2↑, caspase-9/-3↑, p-IKK-β↓, NF-κB p65┴, TNF-α┴, ERK-1/2┴, JNK↑, PI3K/Akt┴, DDH┴, DRP-1↓, pro-caspase-3/-8↑, and Bax↑
[145, 153]

Breast
ZR-75-1, T47D, BT20, MCF-1, and MCF-7
—
DDH┴, DRP-1↓, pro-caspase-3/-8↑, and Bax↑
[153]

Gastric
AGS, SC-M1, NUGC-1, NUGC-3, and KOTA-III
—
DDH┴, DRP-1↓ pro-caspase-3/-8↑, and Bax↑
[153]

↑Upregulation; ↓downregulation; ┴inhibition.

4. ADMET Profiles of Astragalin

ADMET profiles along with biological activity spectra were performed for astragalin based on in-silico tools. The results indicate that astragalin is a potential anticancer agent which is unlikely to present any acute hazard or toxicity. Furthermore, astragalin can be absorbed by human intestines, but it is incapable of penetration to Caco-2 cells. Astragalin has been validated as a novel substrate of p-glycoprotein which is crucial for the metabolism and clearance of the compounds and for the efflux of drugs [154].

5. Conclusions and Future Perspectives

Astragalin, a natural flavonoid, has been isolated from various traditional medicinal plants such as Cassia alata, Moringa oleifera, Nelumbo nucifera, Cuscuta spp., Radix astragali, Morus alba, and Eucommia ulmoides. Astragalin has been reported to modulate inflammatory responses by regulating the expression of NF-κB, iNOS, cytokines/chemokines (COX-2, TNF-α, IL-10, and IL-6), MAPK signaling pathways (PGE2, IgE, IL-4, IL-5, IL-13, IL-1β, and IL-6), and PAR2 signaling expression. It also has the capability to alleviate the production of ROS and inhibit the endotoxin-induced oxidative stress (Figure 3). Astragalin is also known to be an inhibitor of ERK-1/2 and Akt signaling; therefore, it is a significant compound against cancer proliferation. In this review paper, we have emphasized on various pharmacological properties of astragalin such as anti-inflammatory, antioxidant, neurological, cardioprotective, antidiabetic, and anticancer. Although several in vitro and in vivo investigations have demonstrated its diversified pharmacological applications, further experimentation along with medicinal chemistry approaches and preclinical trials is still obligatory to uncover the knowledge of its biological and pharmacological applications and their associated mechanisms of actions for the treatment and prevention of several diseases.

Figure 3: A diagrammatic representation of molecular targets and mechanism of action of astragalin. Astragalin has capability to modulate various transcriptional factors, enzymes, protein kinases, cell adhesion molecules, apoptotic and antiapoptotic proteins, and inflammatory cytokines resulting in anticancer, anti-inflammatory, antioxidant, and cardioprotective activities.

Abbreviations

Ache: | Acetylcholinesterase
Bax: | Bcl-2 associated protein
Bcl-2: | B-cell lymphoma-2
COX-2: | Cyclooxygenase-2
CXCL-1: | Chemokine-1
CXCL-2: | Chemokine-2
DAF-16: | Abnormal dauer formation
DDH: | Dihydrodiol dehydrogenase
DRP-1: | Dynamin-related protein-1
E-cadherin: | Epithelial cadherin
EMT: | Epithelial to mesenchymal transition
Eotaxin-1: | Eosinophil chemotactic protein
ERK: | Extracellular signal-regulated kinase
GPX: | Glutathione peroxide
GSH: | Glutathione
HK2: | Human kallikrein-related peptidase-2
IFN-γ: | Interferon gamma
IgE: | Immunoglobin E
IL-13: | Interleukin-13
IL-1β: | Interleukin-1 beta
IL-4: | Interleukin-4
IL-6: | Interleukin-6
IL-8: | Interleukin-8
iNOS: | Inducible nitric oxide synthase
IκBα: | Inhibitor of kappa B alpha
JNK: | c-Jun N-terminal kinase
LC3A/B: | Microtubule-associated protein 1 light chain 3A/B
MAPK: | Mitogen-activated protein kinase
Mcl-1: | Myeloid cell leukemia 1
MCP-1: | Monocyte chemoattractant protein-1
MIP-1α: | Macrophage inflammatory protein 2-alpha
miR-125: | MicroRNA-125
MMP: | Mitochondrial membrane potential
MMP-1: | Matrix metalloproteinase-1
MMP-3: | Matrix metalloproteinase-3
NCam: | Neutral cell adhesion molecule
NO: | Nitric oxide
PAR2: | Protease-activated receptor 2
PGE2: | Prostaglandin E2
PI3K: | Phosphoinositide-3
PKCβ2: | Protein kinase C beta-2
PLCγ1: | Phosphoinositide phospholipase C γ1
SAPK: | Stress-activated protein kinase
SOCS-3: | Suppressor of cytokine signaling 3
SOCS-5: | Suppressor of cytokine signaling 5
SOD: | Superoxide dismutase
SOD: | Superoxide dismutase
SOX10: | Sry-related HMg-Box gene 10
TGF-β1: | Transforming growth factor beta 1
TLR-4: | Toll-like receptor 4
TNF-α: | Tumor necrosis factor alpha.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

Acknowledgments

This study was supported by the research grant from The Nagai Foundation, Tokyo, Japan (NFT-R4-2017 and NFT-R4-2018) and TWAS-COMSTECH Research Grant (no. 17-180 RG/PHA/AS_C). The authors would also like to thank Higher Education Commission (HEC), Pakistan, for providing access to related papers from various journals.

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