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Astragalin: A Bioactive Phytochemical with Potential Therapeutic Activities.

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 [greater than or equal to] 2 benzene rings and [greater than or equal to] 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, antiinflammatory, 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-[beta]-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], antiinflammatory [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.

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.

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-1[beta], IL-6, and TNF-[alpha]. Astragalin's anti-inflammatory response proceeds via inhibition of LPS-induced activation of NF-[kappa]B, as it is actively involved in alleviating the deterioration of IkB[alpha] and restricting the nuclear translocation of NF-[kappa]B [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-[kappa]B signaling pathway [123]. Astragalin has been known to halt the MAPK and NF-[kappa]B 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.

3.2. Antioxidant Activity. In living systems, free radicals such as hydroxyl radicals (OH x), superoxide anion ([O.sub.2] x -), singlet oxygen ([sup.1][O.sub.2]), 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).

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 SpragueDawley rats as its mechanism of action precedes via diminishing intracellular oxidative stress and apoptosis. The associated mechanism involves decreased expression of MDA, TNF-[alpha], 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 norepinephrine, 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 ^-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 [Ca.sup.2+] 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-1[beta], and TNF-[alpha]. 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).

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-[kappa]B 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 1/2 [15]. Astragalin also prohibits TNF-[alpha]-induced NF-[kappa]B 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, [gamma]-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).

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-[kappa]B, iNOS, cytokines/chemokines (COX-2, TNF-[alpha], IL-10, and IL-6), MAPK signaling pathways (PGE2, IgE, IL-4, IL-5, IL-13, IL-1[beta], 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, cardio-protective, 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.
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-[gamma]:         Interferon gamma
IgE:                 Immunoglobin E
IL-1[beta]:          Interleukin-13
IL-1A:               Interleukin-1 beta
IL-4:                Interleukin-4
IL-6:                Interleukin-6
IL-8:                Interleukin-8
iNOS:                Inducible nitric oxide synthase
I[kappa]B[alpha]:    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-1[alpha]:        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
PKC[beta]2:          Protein kinase C beta-2
PLC[gamma]1:         Phosphoinositide phospholipase C [gamma]1
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-[beta]1:         Transforming growth factor beta 1
TLR-4:               Toll-like receptor 4
TNF-[alpha]:         Tumor necrosis factor alpha.


https://doi.org/10.1155/2018/9794625

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. 17180 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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[143] S. Y. Jung, W. S. Jung, H. K. Jung et al., "The mixture of different parts of Nelumbo nucifera and two bioactive components inhibited tyrosinase activity and melanogenesis," Journal of Cosmetic Science, vol. 65, no. 65, pp. 377-388, 2014.

[144] A. Svobodova, J. Psotova, and D. Walterova, "Natural phenolics in the prevention of UV-induced skin damage. A review," Biomedical Papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia, vol. 147, no. 147, pp. 137-145, 2003.

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[149] J. Sun, F. Li, Y. Zhao et al., "LZ-207, a newly synthesized flavonoid, induces apoptosis and suppresses inflammation-related colon cancer by inhibiting the NFkB signaling pathway," PloS One, vol. 10, no. 10, article e0127282, 2015.

[150] W. Li, J. Hao, L. Zhang, Z. Cheng, X. Deng, and G. Shu, "Astragalin reduces hexokinase 2 through increasing miR125b to inhibit the proliferation of hepatocellular carcinoma cells in vitro and in vivo," Journal of Agricultural and Food Chemistry, vol. 65, no. 65, pp. 5961-5972, 2017.

[151] O. H. You, E. A. Shin, H. Lee et al., "Apoptotic effect of astragalin in melanoma skin cancers via activation of caspases and inhibition of Sry-related HMg-box gene 10," Phytotherapy Research, vol. 31, no. 31, pp. 1614-1620, 2017.

[152] J. Zhang, N. Li, K. Zhang et al., "Astragalin attenuates UVB radiation-induced actinic keratosis formation," Anti-Cancer Agents in Medicinal Chemistry, 2017, In Press.

[153] Y. Y. Chiang, S. L. Wang, C. L. Yang et al., "Extracts of Koelreuteria henryi Dummer induce apoptosis and autophagy by inhibiting dihydrodiol dehydrogenase, thus enhancing anticancer effects," International Journal of Molecular Medicine, vol. 32, no. 32, pp. 577-584, 2013.

[154] O. Ammar, "In silico pharmacodynamics, toxicity profile and biological activities of the Saharan medicinal plant Limoniastrum feei," Brazilian Journal of Pharmaceutical Sciences, vol. 53, no. 53, pp. 1-10, 2017.

Ammara Riaz, (1) Azhar Rasul (ID), (1) Ghulam Hussain, (2) Muhammad Kashif Zahoor (ID), (1) Farhat Jabeen, (1) Zinayyera Subhani, (3) Tahira Younis, (1) Muhammad Ali, (1) Iqra Sarfraz, (1) and Zeliha Selamoglu (4)

(1) Department of Zoology, Faculty of Life Sciences, Government College University, Faisalabad 38000, Pakistan

(2) Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad 38000, Pakistan

(3) Department of Biochemistry, University of Agriculture, Faisalabad 38000, Pakistan

(4) Department of Medical Biology, Faculty of Medicine, Nigde Omer 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

Caption: Figure 1: Natural sources of astragalin.

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

Name of the plant                                       Parts
Botanical name                 Common name          used/extract

Acer truncatum                Shantung maple             --
Aceriphyllum rossii              Mukdenia           Aerial parts
Agrimonia pilosa              Hairy agrimony        Aerial parts
Allium ursinum                 Wild garlic             Flowers
Allium victorialis             Alpine leek               --
Alsophila spinulosa             Hook tryon             Leaves
Apocynum venetum                 Luobuma               Leaves
Jasminum subtriplinerve                             Aerial parts
  Blume
Astragalus hamosus          Dwarf yellow milk       Aerial parts
                                  vetch
Caesalpinia decapetala         Mysore thorn            Leaves
Calligonum polygonoides            Phog             Aerial parts
Camellia sinensis                  Tea            Leaves and seeds
Carthamus lanatus L.         Downy safflower        Aerial parts
Cassia alata                  Ringworm bush            Leaves
Celastrus gemmatus Loes    Chinese bittersweet         Leaves
Centella asiatica           Asiatic pennywort          Leaves
Clerodendrum philipinum    Chinese glory bower          Roots
Conyza filaginoides       Laennecia filaginoides    Aerial parts
Corchorus olitorius L.          Moroheiya              Leaves
Cuscuta chinensis             Chinese dodder            Seeds
Cuscuta australis           Australian dodder           Seeds
Diodia teres                    Buttonweed           Whole plant
Drosera peltata                   Sundew
Dianthus barbatus cv          Sweet William         Aerial parts
Eucommia ulmoides           Hardy rubber tree          Leaves
Eupatorium cannabinum L.      Hemp agrimony         Aerial parts
Eupatorium lindleyanum                              Aerial parts
Exochorda racemosa              Pearlbrush               --
Flaveria bidentis (L.)     Coastal plain yellow        Leaves
  Kuntze                           tops
Flos gossypii                       --                 Flowers
Gladiolus gandavensis           Gladiolus           Aerial parts
Glycyrrhiza glabra          European licorice          Leaves
Glycyrrhiza uralensis        Chinese licorice          Leaves
  Fisch
Gynura procumbens           Longevity spinach            --
Hedera helix                   English ivy               --
Helianthemum glomeratum      Island rushrose        Aerial parts
Hemistepta lyrata Bunge             --               Whole plant
Hippophae rhamnoides L.       Sea buckthorn            Leaves
Ipomoea batatas                Sweet potato             Leaf
Koelreuteria paniculata      Golden rain tree          Flowers
Allium ampeloprasum             Wild leek              Leaves
Ligusticum chuanxiong               --              Aerial parts
Lindera aggregate           Evergreen lindera          Leaves
Litsea coreana                      --                 Leaves
Magnolia fargesii                   --                 Flowers
Moringa oleifera Lam.         Drumstick tree           Leaves
Morus alba L.                 White mulberry           Leaves
Mussaenda arcuate              Forest star             Leaves
Nelumbo nucifera               Sacred lotus            Leaves
Ochradenus baccatus             Taily weed          Aerial parts
Orostachys japonica             Rock pine                --
Diospyros kaki              Japanese persimmon         Leaves
Rosa agrestis                  Field briar             Leaves
Peucedanum alsaticum                --                 Fruits
Phaseolus vulgaris L.          Common bean
Phlomis spinidens                   --              Aerial parts
Phyllanthus muellerianus            --                 Leaves
Polygala cyparissias                --
Polygonum salicifolium           Knotweed           Aerial parts
Prunus padus L.            European bird cherry      Flowers and
                                                       leaves
Prunus serotina Ehrh           Black cherry          Leaves and
                                                       flowers
Pseudotsuga menziesii          Oregon pine             Needles
Radix astragali              Milk vetch root            Roots
Rhus sylvestris                   Sumach          Stems and leaves
Rosa soulieana                  Shrub rose             Flowers
Rubus rigidus var.                                  Aerial parts
camerunensis
Sapium sebiferum              Chinese tallow           Leaves
Solenostemma argel                Arghel            Aerial parts
Solidago canadensis L.       Canada goldenrod            --
Sorbus aria (L.)                Lutescens              Leaves
Tadehagi triquetrum                 --               Whole plant
Tiarella polyphylla            Foam flower           Whole plant
Trachelospermum            Confederate jasmine         Leaves
jasminoides
Urtica cannabina                    --                 Fruits
Vahlia capensis                     --                   --
Vicia calcarata             Few flowered vetch      Aerial parts
Wedelia chinensis                   --               Whole plant

Name of the plant              Biological activities       References
Botanical name

Acer truncatum                          --                    [21]
Aceriphyllum rossii                 Antioxidant               [22]
Agrimonia pilosa          Antihemorrhagic, antiplatelet,      [23]
                                 antioxidant, and
                          acetylcholinesterase inhibitory
Allium ursinum                     Antimicrobial              [24]
Allium victorialis                   Antitumor                [25]
Alsophila spinulosa            Antixanthine oxidase           [26]
Apocynum venetum               Lower blood pressure,          [27]
                          antidepressant, antinephritis,
                               and antineurasthenia
Jasminum subtriplinerve                 --                    [28]
  Blume
Astragalus hamosus                      --                    [29]
Caesalpinia decapetala                  --                    [30]
Calligonum polygonoides    Antiulcer, anti-inflammatory,      [31]
                           hypoglycemic, and antioxidant
Camellia sinensis                 Antidysentery,             [32-35]
                                antihyperlipidemia,
                           antihyperglycemia, and anti-
                                   inflammatory
Carthamus lanatus L.                Antioxidant               [35]
Cassia alata               Antioxidant, anti-infectious,      [19]
                                  and DNA repair
Celastrus gemmatus Loes                 --                    [36]
Centella asiatica                Anti-inflammatory            [37]
Clerodendrum philipinum                 --                    [38]
Conyza filaginoides                Antiprotozoal              [39]
Corchorus olitorius L.        Inhibits the histamine          [40]
Cuscuta chinensis                Antiosteoporotic          [17, 41-43]
Cuscuta australis                       --                 [17, 41-43]
Diodia teres                            --                    [44]
Drosera peltata                     Antitussive               [45]
Dianthus barbatus cv             Anti-inflammatory            [46]
Eucommia ulmoides         Antidiabetic, antioxidant, and     [47-49]
                                  hypnotic effect
Eupatorium cannabinum L.                --                    [50]
Eupatorium lindleyanum                  --                    [51]
Exochorda racemosa                      --                    [52]
Flaveria bidentis (L.)                  --                  [53, 54]
  Kuntze
Flos gossypii                           --                    [55]
Gladiolus gandavensis                   --                    [56]
Glycyrrhiza glabra                      --                    [57]
Glycyrrhiza uralensis                   --                    [58]
  Fisch
Gynura procumbens                  Antidiabetic               [59]
Hedera helix                            --                    [60]
Helianthemum glomeratum                 --                    [61]
Hemistepta lyrata Bunge                 --                    [62]
Hippophae rhamnoides L.                 --                    [63]
Ipomoea batatas                         --                    [64]
Koelreuteria paniculata             Antioxidant               [65]
Allium ampeloprasum                 Antioxidant               [66]
Ligusticum chuanxiong                   --                    [67]
Lindera aggregate                       --                    [68]
Litsea coreana                      Antioxidant               [69]
Magnolia fargesii                 Anticomplement              [70]
Moringa oleifera Lam.               Antioxidant               [71]
Morus alba L.              Hypoglycemic and antioxidant      [72-78]
Mussaenda arcuate                                             [79]
Nelumbo nucifera                Lipolytic activity           [80-84]
Ochradenus baccatus                     --                    [85]
Orostachys japonica         Calpain inhibitory activity       [86]
Diospyros kaki             Angiotensin converting enzyme   [12, 87-89]
                            activity, and inhibition of
                              atopic dermatitis (AD)
Rosa agrestis                  Anti-inflammatory and       [13, 90-92]
                                    antioxidant
Peucedanum alsaticum                    --                    [93]
Phaseolus vulgaris L.                   --                    [94]
Phlomis spinidens                  Antiallergic               [95]
Phyllanthus muellerianus      Antibacterial and anti-         [96]
Polygala cyparissias          inflammatory Antiulcer          [97]
Polygonum salicifolium     DPPH-free radical scavenging       [98]
                                     activity
Prunus padus L.                     Antioxidant               [99]

Prunus serotina Ehrh                    --                    [100]

Pseudotsuga menziesii                Cytotoxic                [101]
Radix astragali                    Antidiabetic             [102-104]
Rhus sylvestris                  Antiosteoporotic             [105]
Rosa soulieana                      Antioxidant               [106]
Rubus rigidus var.                  Antioxidant               [107]
camerunensis
Sapium sebiferum                        --                    [108]
Solenostemma argel                 Antibacterial              [109]
Solidago canadensis L.              Antioxidant               [110]
Sorbus aria (L.)                        --                    [111]
Tadehagi triquetrum           Antimicrobial and anti-         [112]
                                   inflammatory
Tiarella polyphylla                     --                    [113]
Trachelospermum                     Antifungal                [114]
jasminoides
Urtica cannabina                        --                    [115]
Vahlia capensis                    Antibacterial              [116]
Vicia calcarata                  Hepatoprotective             [117]
Wedelia chinensis           Inhibitor of the complement       [118]
                                      system

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

Assay                    Organism tested       Dose/concentration

LPS-induced mouse         Mouse mastitis          10, 25, and
mastitis                                            50 mg/kg

LPS-induced                Mice (lung)            25, 50, and
endotoxemia and lung                                75 mg/kg
injury in mice

LPS-induced                Mouse cells         1-100 [micro]g/mL
macrophages in mice

LPS-induced RAW          Mice (RAW 264.7           1, 10, and
264.7 cells.                  cells)              100 [micro]M

Inhibitory activity        KU812 cells              10 to 30
on the histamine                                  [micro]mol/L
release by KU812
cells

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

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

Anti-inflammatory          Uterine and          100 [micro]g/mL
effects on                 endometrial
Leptospira             epithelial cells of
interrogans-induced            mice
inflammatory
response

Protective effects        Mouse model of         0.5 mg/kg and
against ovalbumin-       allergic asthma            1 mg/kg
(OVA-) induced
allergic
inflammation

Alleviation in          Diabetic rats and
hepatic fibrosis         nondiabetic rats
function

Prevention from            NC/Nga mice             1.5 mg/kg
atopic dermatitis

Assay                          Molecular targets            References

LPS-induced mouse       TNF-[alpha] ([down arrow]), IL-        [92]
mastitis                  1[beta] ([down arrow]), IL-6
                              ([down arrow]), p65
                            ([perpendicular to]) and
                        I[kappa]B[alpha] ([perpendicular
                                      to])

LPS-induced            TNF-[alpha] ([perpendicular to]),      [122]
endotoxemia and lung    IL-1[beta] ([perpendicular to]),
injury in mice           and IL-6 ([perpendicular to])

LPS-induced            iNOS ([down arrow]), COX-2 ([down      [127]
macrophages in mice        arrow]),TNF-[alpha] ([down
                           arrow]), IL-1[beta] ([down
                       arrow]), IL-6 ([down arrow]), MIP-
                       1[alpha] [down arrow], MCP-1 [down
                              arrow], NF-[kappa]B

LPS-induced RAW            p65 ([perpendicular to]),           [37]
264.7 cells.            I[kappa]B[alpha] ([perpendicular
                       to]), and NO ([perpendicular to])
                       NO ([down arrow]) and TNF-[alpha]
                                 ([down arrow])

Inhibitory activity    IL-4 ([down arrow]), IL-13 ([down       [12]
on the histamine         arrow]), and (IFN-[gamma]) no
release by KU812                     effect
cells

LPS-induced              NO ([perpendicular to]), IL-6         [33]
inflammation in RAW      ([perpendicular to]), and PGE2
264.7 cells                   ([perpendicular to])

P. gingivalis-          COX-2 ([perpendicular to]), IL-6      [125]
induced human              ([perpendicular to]), IL-8
gingival epithelial       ([perpendicular to]), MMP-1
(HGE) cells               ([perpendicular to]), MMP-3
                          ([perpendicular to]), PGE-2
                         ([perpendicular to]), and IL-4
                              ([perpendicular to])

Anti-inflammatory      TNF-[alpha] ([perpendicular to]),      [124]
effects on              IL-1[beta] ([perpendicular to]),
Leptospira               IL-6 ([perpendicular to]), NF-
interrogans-induced      [kappa]B1 ([down arrow]), p38
inflammatory            ([perpendicular to]), p-p38 MAPK
response                      ([down arrow]), ERK
                           ([perpendicular to]), JNK
                        ([perpendicular to]), and p-p65
                                 ([down arrow])

Protective effects     SOCS-3 ([perpendicular to]), SOCS-     [126]
against ovalbumin-      5 ([perpendicular to]), and IFN-
(OVA-) induced                [gamma] ([up arrow])
allergic
inflammation

Alleviation in           PAR2 ([perpendicular to]), IL-       [128]
hepatic fibrosis          1[beta] ([down arrow]), IL-6
function               ([down arrow]), TNF-[alpha] ([down
                            arrow]), and TGF-[beta]1
                              ([perpendicular to])

Prevention from                IgE ([down arrow])              [87]
atopic dermatitis

([up arrow]) Upregulation; ([down arrow]) downregulation;
([perpendicular to]) inhibition.

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

                          Organism      Dose/concentration
Assay                      tested

Free radical-                          1, 3, 10, 30, 100, or
scavenging activity                       300 [micro]g/mL

Inhibitory activity         Mice           1-20 [micro]M
against autophagy-
associated airway
epithelial fibrosis

Apoptotic and             BEAS-2B         1-20 [micrio]M
eosinophilia               cells
amelioration

Suppression of 6-        C. elegans          2.0 mg/mL
hydroxydopamine-
induced neurotoxicity
in Caenorhabditis
elegans

Neuroprotective         Wister rats    5 mg/kg and 15 mg/kg
effect against
ischemic brain injury

                               Molecular targets           References
Assay

Free radical-                                                 [107]
scavenging activity

Inhibitory activity     E-cadherin ([perpendicular to]),      [132]
against autophagy-       vimentin ([perpendicular to]),
associated airway        Beclin-1 ([perpendicular to])
epithelial fibrosis        LC3A-B ([down arrow]), EMT
                         ([down arrow]), and TGF-[beta]
                              ([perpendicular to])

Apoptotic and           TLR-4 ([down arrow]), Eotaxin-1       [129]
eosinophilia              ([down arrow]), PLC[gamma]1
amelioration               ([down arrow]), PKC[beta]2
                          ([down arrow]), p-p22 ([down
                         arrow]), p-47 ([down arrow]),
                          JNK ([down arrow]), p38 MAPT
                            ([down arrow]), Akt ([up
                         arrow]), and ERK ([up arrow])

Suppression of 6-        egl-1 ([down arrow]), SOD ([up       [130]
hydroxydopamine-        arrow]), GPX ([up arrow]), Ache
induced neurotoxicity      ([up arrow]), and p38 MAPT
in Caenorhabditis                ([down arrow])
elegans

Neuroprotective                Ncam ([up arrow])              [131]
effect against
ischemic brain injury

([up arrow]) Upregulation; [down arro] downregulation;
([perpendicular to]) inhibition.

Table 4: Cosmetic uses of astragalin.

Assay                         Organism tested              Dose/
                                                       concentration

Inhibition of melanin    Leuconostoc mesenteroides         10 mM
secretion

Protection against UV     Mice (BalB/c) and human      2.5 mg/kg and
damage                   keratinocyte cells (HaCaT   0.25 [micro]M/ml
                                  cells)

Assay                             Molecular            References
                                   targets

Inhibition of melanin    MMP-1 ([perpendicular to])       [142]
secretion

Protection against UV     CXCL-1 ([down arrow]) and       [144]
damage                      CXCL-2 ([down arrow])

([down arrow]) Thownregulation; ([perpendicular to]) inhibition.

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

Type of cancer            Cell line              Dose/concentration

Leukemia                    HL-60               6 [+ or -] 1 [micro]M

Hepatocellular      HepG2, Huh-7, and H22                --

Skin                HaCaT, A375P, and SK-      50 and 100 [micro]M/mL
                            MEL-2

Lung              A549, H1299, H226, H838,    5, 40 [micro]g/mL (A549)
                  H23, H1437, H125, H2009,       and 20 [micro]g/mL
                          and H2087                    (H1299)

Breast            ZR-75-1, T47D, BT20, MCF-              --
                        1, and MCF-7

Gastric           AGS, SC-M1, NUGC-1, NUGC-              --
                       3, and KOTA-III

Type of cancer              Molecular targets              References

Leukemia              Bax ([up arrow]), Bcl/2 ([down          [15]
                    arrow]), caspase-3/-7Act, JNK/SAPK
                    ([perpendicular to]), and ERK 1/2
                           ([perpendicular to])

Hepatocellular     HK2 ([down arrow]) and miR-125b ([up       [150]
                     arrow]) p38 MAPK ([down arrow]),
                       phospho-MSK1 ([down arrow]),

Skin                   [gamma]-H2AX ([down arrow]),        [151, 152]
                     caspase-9--3 Act, Bax Act, PARP
                   cleavage, cyclin D1 ([down arrow]),
                     Mcl-1 ([down arrow]), and SOX10
                   ([perpendicular to]) Bax:Bcl-2 ([up
                  arrow]), caspase-9--3 ([up arrow]), p-
                        IKK-[beta] ([down arrow]),

Lung              NF/[kappa]B p65 ([perpendicular to]),    [145, 153]
                    TNF/[alpha] ([perpendicular to]),
                  ERK-1/2 ([perpendicular to]), JNK ([up
                    arrow]), PI3K/Akt ([perpendicular
                  to]), DDH ([perpendicular to]), DRP/1
                  ([down arrow]), pro-caspase-3/-8 ([up
                      arrow]), and Bax ([up arrow])

Breast            DDH ([perpendicular to]), DRP/1 ([down      [153]
                      arrow]), pro-caspase-3/-8 ([up
                      arrow]), and Bax ([up arrow])

Gastric           DDH ([perpendicular to]), DRP/1 ([down      [153]
                  arrow]) pro-caspase-3/-8 ([up arrow]),
                           and Bax ([up arrow])

([up arrow]) Upregulation; ([down arrow]) downregulation;
([perpendicular to]) inhibition.

Figure 2: Biological activities of astragalin.

Astragalin

Antioxidantactivity
Neuroprotective effect
Cardioprotective activity
Antiobesity activity
Antiulcer activity
Antidiabetic activity
Cosmetic use
Antiosteoporotic activity
Anticancer activity
Anti-inflammatory activity
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Author:Riaz, Ammara; Rasul, Azhar; Hussain, Ghulam; Zahoor, Muhammad Kashif; Jabeen, Farhat; Subhani, Zinay
Publication:Advances in Pharmacological Sciences
Date:Jan 1, 2018
Words:10838
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