Evidence-Based Complementary and Alternative Medicine
Volume 2016 (2016), Article ID 9425714, 12 pages
http://dx.doi.org/10.1155/2016/9425714

Review Article

Euonymus alatus: A Review on Its Phytochemistry and Antidiabetic Activity

Xifeng Zhai,1,2 George Binh Lenon,¹ Charlie C. L. Xue,¹ and Chun-Guang Li1,3

¹Traditional & Complementary Medicine Program, School of Health Sciences, RMIT University, Bundoora, VIC 3083, Australia
²School of Pharmaceutical Sciences, Xi’an Medical University, Xi’an 710021, China
³National Institute of Complementary Medicine, Western Sydney University, Penrith, NSW 2751, Australia

Received 19 May 2016; Accepted 10 July 2016

Academic Editor: Bashar Saad

Copyright © 2016 Xifeng Zhai 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.

Euonymus alatus (E. alatus) is a medicinal plant used in some Asian countries for treating various conditions including cancer, hyperglycemia, and diabetic complications. This review outlines the phytochemistry and bioactivities of E. alatus related to antidiabetic actions. More than 100 chemical constituents have been isolated and identified from E. alatus, including flavonoids, terpenoids, steroids, lignans, cardenolides, phenolic acids, and alkaloids. Studies in vitro and in vivo have demonstrated the hypoglycemic activity of E. alatus extracts and its certain constituents. The hypoglycemic activity of E. alatus may be related to regulation of insulin signaling and insulin sensitivity, involving PPARγ and aldose reductase pathways. Further studies on E. alatus and its bioactive compounds may help to develop new agents for treating diabetes and diabetic complications.

1. Introduction

Euonymus alatus (E. alatus) is a medicinal plant used traditionally in many Asian countries, including China and Korea, for treating various conditions. It has long been used in China as a Chinese Materia Medica for pain and menstrual disorders. The first record of its clinical use in China was documented in Shen Nong Ben Cao Jing (The Classic of Herbal Medicine) written between 300 BC and 200 AD. Ben Cao Gang Mu (Compendium of Materia Medica, AD1578, written by Li Shizhen) later recorded its applications for vaginal bleeding, abdominal distention, and detoxification, and Ben Cao Jing Ji Zhu (Collective Notes to Canon of Materia Medica) recorded its use for abdominal pain, killing worms, and eliminating skin swelling caused by various reasons [1]. The interest in E. alatus has been increased recently largely due to the research on its bioactivities against cancer and diabetes. Recent studies have demonstrated a wide range of bioactivities of E. alatus, including hypoglycemic, antihypertensive [2], antitumor [3, 4], sedative [2], and regulation of blood lipid [5, 6] and immune functions [7]. There is also clinical evidence for its efficacy against hyperglycemia [8], chronic nephropathy [9], rheumatoid arthritis [10], cor pulmonale [11], bronchial asthma [12], anaphylactic disease [13, 14], urinary tract infection, and prostate diseases [15]. This short review outlines the phytochemistry of E. alatus and its pharmacology related to antidiabetic actions.

2. Phytochemistry

More than 128 chemical constituents have been isolated and identified from E. alatus. The main chemical classes include flavonoids, terpenoids, steroids, lignans, cardenolides, phenolic acids, and alkaloids.

2.1. Flavonoids

A total of 26 flavonoids have been isolated and identified from E. alatus. The main structure types include flavonoid, flavanone, and flavonol. The aglycones of flavonoid glycosides isolated from E. alatus include quercetin, kaempferol, naringenin, aromadendrene, and dihydroquercetin. The flavonoids are mainly distributed in the leaves and wings of E. alatus [16]. The structures of main flavonoids identified in E. alatus are listed in Tables 1–4.

Table 1: Quercetin and glycosides in E. alatus.

Skeleton
Number
Name
R₁
R₂
Reference

1
Quercetin
H
H
[24, 39, 48–50]

2
Quercitrin
α-L-Rhamnose
H
[17, 49]

3
Quercetin-7-O-α-L-rhamnoside
H
α-L-Rhamnose
[50]

4
Quercetin-3,7-O-α-L-dirhamnoside
α-L-Rhamnose
α-L-Rhamnose
[17, 50]

5
Quercetin 3-D-galactoside (hyperin)
3-D-Galactose
H
[17, 20]

6
Rutin
α-L-Rhamnopyranosyl-(1 → 6)-β-D-glucopyranose
H
[39]

Table 2: Kaempferol and the glycosides in E. alatus.

Skeleton
Number
Name
R₁
R₂
Reference

7
Kaempferol
H
H
[18, 21, 48, 49]

8
Kaempferol-7-O-α-L-rhamnoside
H
α-L-Rhamnose
[50]

9
Kaempferol-3,7-O-α-L-rhamnoside (kaempferitrin)
α-L-Rhamnose
α-L-Rhamnose
[17, 50]

10
Kaempferol-7-O-β-D-glucoside
H
α-L-Glucose
[50]

11
Apigenin-3-O-L-rhamnopyranoside
α-L-Rhamnose
H
[49]

Table 3: Apigenin and glycoside in E. alatus.

Skeleton
Number
Name
R₁
R₂
Reference

12
Apigenin
H
H
[48]

13
Acacetin-7-O-rutinoside (Linarin)
Rutinose
H
[18]

Table 4: Flavanone and the glycoside in E. alatus.

Skeleton
Number
Name
R₁
R₂
R₃
R₄
Reference

14
Dihydroquercetin
OH
H
OH
H
[49, 50]

15
Aromadendrene
OH
H
H
H
[19, 39, 49, 50]

16
Naringenin
H
H
H
H
[48–50]

17
Naringin
H
Neohesperidose
H
H
[18]

18
Hesperidin
H
Rutinose
OH
CH₃
[50]

Other flavonoids include catechin (19) [17–21], symplocoside (20) [17], quercetin-3-galactosyl-xyloside (21) [20], catechin lactone A (22) [17], dehydrodicatechin A (23) [17–21], 3-hydroxycoumarinflavanol (24), 7,4′-dihydroxy-8-C-glucoxylisoflavone (25) [22], and 5-hydroxy-6,7-dimethoxyflavone (26) [23].

2.2. Steroids

Eight steroids including sterols and sterones have been isolated and identified from E. alatus. The main structures of the steroids are shown in Table 5. Other steroids include 24R-methyllophenol (34) and α-spinasterol (35) [22].

Table 5: Steroids in E. alatus.

Skeleton
Number
Name
R
References

28
β-Sitosterol
OH
[18, 20, 24, 39, 51, 52]

29
β-Sitosterone
=O
[51]

30
Daucosterol
Glucose
[21, 48]

31
Stigmast-4-en-3-one (sitostenone)
H
[51, 52]

32
6β-Hydroxy-stigmast-4-en-3-one
OH
[51, 52]

33
Stigmast-4-en-3,6-dione
=O
[51]

2.3. Terpenoids

The main terpenoids isolated from E. alatus include triterpenes and sesquiterpenes.

2.3.1. Triterpenes

Multiple types of triterpenes were found in E. alatus. Most of the triterpenes in E. alatus belong to lupane type and oleanane type. Other types include hopane, ursane, and friedelane. Table 6 shows the lupane type and friedelane type triterpenes isolated from E. alatus.

Table 6: Lupane type and friedelane type triterpenes in E. alatus.

Lupane type
Number
Name
R₁
R₂
R₃
R₄
R₅
References

36
Lupeol
OH
H
H
CH₃
CH₂
[21, 48]

37
Lupenone
=O
H
H
CH₃
CH₂
[24]

38
Betulin
OH
H
H
CH₂OH
CH₂
[24]

39
Betulone
=O
H
H
CH₂OH
CH₂
[26]

40
Betulinic acid
OH
H
H
COOH
CH₂
[23]

41
Messagenin
OH
H
H
CH₂OH
O
[26]

42
(−)-Nepetidone
OH
OH
OH
CH₃
O
[48]

Friedelane type
Number
Name
R₁
R₂
Reference

43
Epifriedelanol
OH
CH₃
[18, 24, 39, 52]

44
Friedelin
=O
CH₃
[20, 24]

Other triterpenes include oleanic acid (45), wilforlide A (46) [24], hop-(22)-29-en-3β-ol (47) [25], 3β-hydroxy-21αH-hop-22(29)-en-30-ol (48), 2α,3β-dihydroxyurs-12,19-dien-23,28-oic acid (49) [21], arborinone (50), taraxerol (51) and germanicol (52) [22], 11-keto-β-boswellic acid (53), acetyl 11-keto-β-boswellic acid (54), camaldulenic acid (55) [23], 3β,28,30-lup-20(29)-ene triol (56), 28,30-dihydroxy-3-oxolup-20(29)-ene (57), glut-5-en-3β-ol (58), maslinic acid (59), hederagenin (60), 3-oxo-11alpha-methoxyolean-12-ene (61), 3β-hydroxy-1-oxo-olean-12-en-28-oic acid (62), ursolic acid (63), and 2α-hydroxy-ursolic acid (64) [26]. The structures of compounds 45–64 are shown in Figure 1.

Figure 1: The structures of compounds 45–64 isolated from E. alatus.

2.3.2. Sesquiterpenes

Two new sesquiterpenes (65, 66) and two known ones were isolated from 95% ethanol extract of the stems of E. alatus. The known ones were identified as 6α,12-diacetoxy-2b,9α-di(b-furancarbonyloxy)-4α-hydroxyl-1β-(2-methylbutanoyloxy)-β-dihydroagarofuran (67), 1α,2α,6β-triacetoxy-4β-hydroxy-9β-(β-) furancarboxy-15-[(amethyl) butyroyloxy]-β-dihydroagarofuran (68) [27]. The structures of sesquiterpenes isolated from E. alatus are shown in Figure 2.

Figure 2: Structures of sesquiterpenes (compounds 65–68) isolated from E. alatus.

2.4. Alkaloids

Five alkaloids have been isolated from E. alatus and identified as alatamine (69), alatusamine (70) and alatusinine (71) [28], 1β,2β,5α,8β,11-pentaacetoxy-4α-hydroxy-3α-(2-methylbutanoyl)-15-nicotinoyl-7-oxo-dihydroagarofuran (72), evonine (73), and neoevonine (74) [27]. The structures of alkaloids isolated from E. alatus are shown in Figure 3.

Figure 3: Structures of alkaloids (compounds 69 and 71–74) isolated from E. alatus.

2.5. Cardenolides

Kitanaka et al. [3] isolated three cytotoxic cardenolides from the woods of E. alatus and identified them as acovenosigenin A 3-O-α-L-rhamnopyranoside (75), euonymoside A (76), and euonymusoside A (77).

2.6. Lignans

Jeong et al. [29] identified three new lignans from 80% methanolic extract of E. alatus leaves and twigs, including (−)-threo-4,9,4′,9′-tetrahydroxy-3,7,3′,5′-tetramethoxy-8-O-8′-neolignan (78), (−)-threo-4,9,4′,9′-tetrahydroxy-3,5,7,3′-tetramethoxy-8-O-8′-neolignan (79), and (7R,8R,7′R)-(+)-lyoniresinol (80). The other known compounds identified include (+)-simulanol (81), (+)-dehydrodiconiferyl alcohol (82), (−)-simulanol (83), (−)-dehydrodiconiferyl alcohol (84), (+)-dihydrodehyrodiconiferyl alcohol (85), 7R,8S-guaiacylglycerol-8-O-4′-(coniferyl alcohol) ether (86), 7S,8R-guaiacylglycerol-8-O-4′-(coniferyl alcohol) ether (87), 7S,8R-syringylglycerol-8-O-4′-(sinapyl alcohol) ether (88), 7S,8S-guaiacylglycerol-8-O-4′-(sinapyl alcohol) ether (89), 7S,8S-4,9,9′-trihydroxy-3,3′-dimethoxy-8-O-4′-neolignan (90), 7R,8R-4,9,9′-trihydroxy-3, 3′-dimethoxy-8-O-4′-neolignan (91), (+)-syringaresinol (92), de-4′-methylyangabin (93), hedyotol C (94), threo-buddlenol B (95), hedyotisol C (96), and hedyotisol B (97). The structures of compounds 78–97 are shown in Figure 4.

Figure 4: Structures of compounds 78–97 isolated from leaves and twigs of E. alatus, modified from [29].

2.7. Other Constituents

E. alatus also contains organic acids, esters, and aldehydes, as illustrated examples in Table 7.

Table 7: Illustrated examples of other constituents in E. alatus.

Number
Name
Chemical structure
Reference

98
Usnic acid

[24, 48]

99
Protocatechuic acid

[18, 39]

100
2-Hydroxy-4-methoxy-3,6- dimethylbenzoic acid

[48]

101
Benzoic acid

[24, 48]

102
Methyl 2,4-dihydroxy-6-methyl benzoate

[52]

103
2,4-Dihydroxy-3,6-dimethylbenzoate

[21, 52]

104
7-Methoxy-4-methyl phthalide

[52]

105
Caffeine

[25]

106
Caffeic acid

[49, 53]

107
Chlorogenic acid

[54]

108
Vanillin

[52]

109
5-Hydroxymethyl furfural

[25]

110
Dulcitol

[20]

111
Grasshopper ketone

[49]

112
Suberone

[18]

113
Syringin

[49]

In addition, 3,4-dihydroxybenzoic acid (114), p-propoxybenzoic acid (115), p-coumaric acid (116), ferulic acid (117), 1-feruloyl-β-D-glucoside (118), tetradecyl (E)-ferulate (119) [22], ethyl 2,4-dihydroxy-6-methylbenzoate (120), 4,4′-dimethoxy-1,1′-biphenyl (121) [23], squalene (122) [25], 1-octacosanol (123) [24], n-hexacosanoic acid (124) [18, 24], 1,30-triacontanediol (125), tetracosanoic acid (126), n-octane (127), and n-nonane (128) [21] were also isolated from E. alatus. In a study of essential oil from E. alatus by using GC-MS, 56 volatile components were identified. The main volatile components include carboxylic acid, aldehyde, ketone, terpenoid, and derivatives of oxygenated terpenoid. Among these the highest content is hexadecanoic acid (39.69%), followed by wintergreen (5.02%) [30].

3. Antidiabetic Activity

The effects of E. alatus extracts have been tested in vivo. In streptozotocin (STZ) treated diabetic rats, an aqueous extract of E. alatus reduced the body weight, the fasting plasma glucose level, and glucose tolerance. The serum levels of insulin, glucagon, cholesterol, and triglyceride were also reduced [31]. Similar results were obtained in high-fat plus low dose STZ diabetic rats, showing that E. alatus treated rats had lower levels of fasting blood glucose and insulin and decreased levels of blood lipids and inflammatory mediators (TNF-α, C-reactive protein), indicating that E. alatus can improve the glucose-lipid metabolism and insulin resistance in diabetic conditions [32]. Park et al. also demonstrated that an ethanol extract of E. alatus reduced the body weight, increased insulin sensitivity, and corrected the associated hyperinsulinemia and hyperlipidemia in high-fat diet-induced hyperglycemic and hyperlipidemic ICR mice [33].

The antihyperglycemic effect of E. alatus may involve a protection of functional islet β cells since E. alatus treated animals were shown with more positive staining of islet β cells than those in diabetic controls [34]. Other studies in ICR mice indicate that E. alatus may affect glucose and lipid homeostasis via a regulation of hepatic lipogenesis related genes (SREBPla, FAS, and GAPT) and PPARγ gene expressions in periepididymal fat. The plausible mechanism of hypoglycemic and hypolipidemic actions of E. alatus extract is illustrated in Figure 5 [33].

Figure 5: Possible mechanism of hypoglycemic and hypolipidemic actions of E. alatus ethanol extract, modified from [33].

In addition, a study showed that E. alatus protected rats from experimental diabetic nephropathy induced by uninephrectomy plus STZ treatment, with 12-week administration of E. alatus extract and irbesartan (positive control) decreased HbA1c and pathological changes (extracellular matrix expansion and glomerulosclerosis) in kidney and improved blood lipids profile and kidney function; the effect was associated with a downregulation of transform growth factor expression [35]. In addition, E. alatus was shown to inhibit polyol pathway, which is known to be associated with chronic diabetic complications such as neuropathy, nephropathy, and retinopathy [36].

Fang et al. studied the antidiabetic effects of different fractions of E. alatus extracts (including petroleum ether, diethyl ether, ethyl acetate, n-butanol, and water fraction) in alloxan-induced diabetic mice and high-fat diet diabetic mice and found that ethyl acetate fraction significantly reduced plasma glucose and glucose tolerance in both normal and diabetic mice [37] and also reduced total cholesterol and triglyceride contents and increased SOD activity in diabetic mice [37]. Further analysis revealed that the main components in the ethyl acetate fraction were flavonoids and phenolic acids, including quercetin and kaempferol, which were known for their antioxidant activities [37]. In another study, different extract fractions of E. alatus, including aqueous, diethyl ether, and ethyl acetate fractions, were tested in alloxan induced diabetic mice at a dose of 10 g/kg and it was found that the aqueous extract was the most active in decreasing blood glucose and lipid levels and improved glucose tolerance [6]. Thus, E. alatus may contain multiple active antidiabetic constituents. Similarly, a study on the hypoglycemic fractions of six fractions of E. alatus extracts (including petroleum ether, ethyl acetate, n-butanol, water, residue, and rectified polysaccharide) in diabetic rats found that the fractions of petroleum ether, water, and ethyl acetate had significant antidiabetic effects. Fractions of n-butanol and rectified polysaccharide reduced blood creatinine, and other fractions reduced urea level. The residue fraction decreased the low-density lipoprotein (LDL) and cholesterol contents. The body weight was increased by the treatment with all fractions except rectified polysaccharide. These results indicate that different active compounds in these fractions may be responsible for the observed effects of E. alatus, including antidiabetic, antihyperlipidemic, kidney function improvement, blood viscosity decrease, and body weight affecting [38], and the active antidiabetic compounds are likely to be from the petroleum ether, water, and ethyl acetate fractions. In another study, an ethyl acetate extract of E. alatus was shown with hypoglycemic effect, and four compounds were isolated from this fraction and identified as p-hydroxybenzoic acid (EA-1), protocatechuic acid (EA-2), 4-hydroxy-3-methoxybenzoic acid (EA-3), and 3, 5-dimethoxy-4-hydroxybenzoic acid (EA-4) [8]. Others reported identification of six compounds with hyperglycemic activity from the 90% ethanol extracts of E. alatus, including aromadendrin, epifriedelanol, protocatechuic acid, β-sitosterol, quercetin, and rutin [39]. The active components in protecting experimental diabetic nephropathy as mentioned above have also been suggested to be concentrated in ethyl acetate and n-butanol fractions [36, 40], though the nature of these compounds is still not identified.

Jeong et al. (2015) studied the inhibitory effects of 23 compounds isolated from E. alatus on protein tyrosine phosphatases 1B (PTP1B) and α-glucosidase activities and found that lupenone, lupeol, taraxerol, p-propoxybenzoic acid, 1-feruloyl-β-D-glucoside, and 3-hydroxycoumarinflavanol exhibited inhibitory activity against PTP1B with IC₅₀ values ranging from 5.6 to 18.4 μM. 24R-methyllophenol, arborinone, and p-propoxybenzoic acid were shown with a similar activity with IC₅₀ values of 15.1, 23.6, and 14.8 μM, respectively. On the other hand, p-propoxybenzoic acid, tetradecyl (E)-ferulate, and 3-hydroxycoumarinflavanol exhibited inhibition on α-glucosidase with IC₅₀ values of 10.5, 9.5, and 9.1 μM, respectively [22].

Studies on kaempferol and quercetin, the active constituents of E. alatus, demonstrated that these compounds improved insulin-stimulated glucose uptake in mature 3T3-L1 adipocytes [41]. kaempferol and quercetin were shown to act as weak partial agonists in the PPARγ reporter gene assay, without inducing differentiation of 3T3-L1 preadipocytes as traditional PPARγ agonists. When kaempferol and quercetin were added together with the PPARγ agonist rosiglitazone, the 3T3-L1 differentiation was inhibited in a dose-dependent manner. Competitive ligand-binding assay confirmed that kaempferol and quercetin competed with rosiglitazone at the same binding pocket site as PPARγ. These compounds were also shown with significant inhibitory effects on NO production in response to lipopolysaccharide treatment in macrophage cells in which the PPARγ was overexpressed. These findings suggest that kaempferol and quercetin may act on multiple targets to ameliorate hyperglycemia [41].

Ivorra et al. studied the effects of daucosterol (β-sitosterol 3-β-glucoside) and its aglycone (β-sitosterol) on plasma insulin and glucose levels in normo- and hyperglycemic rats and found that oral administration of daucosterol or β-sitosterol increased the fasting plasma insulin levels. In addition, both compounds improved the oral glucose tolerance and increased glucose-induced insulin secretion [42]. In addition, rutin, one of the constituents of E. alatus, has been shown to decrease the plasma levels of glucose and lipids and increase the expression of PPARγ mRNA and protein in skeletal muscles of db/db mice [43]. Rutin was also demonstrated with an AR inhibition activity (IC₅₀ 3.01 μM) [44]. Quercitrin, a flavonoid glycoside in E. alatus, was demonstrated as a noncompetitive AR inhibitor. It blocked polyol accumulation in intact rat lenses incubated in medium containing high concentration of sugars [45]. Other compounds, such as linarin (acacetin-7-O-β-D-rutinoside), have also been demonstrated with inhibitory activity against α-glucosidase [46].

3.1. Clinical Evidence

There have been limited clinical studies, mostly case reports, on the antidiabetic actions of E. alatus containing formulae (Table 8). In addition, a controlled trial, involving two groups of patients (40 patients in each group) with impaired glucose tolerance, showed that the group treated with diet and exercise intervention plus E. alatus formula for 1 month had significantly reduced blood glucose levels, compared to that in the diet and exercise control group. The effective rate was 80% in the E. alatus treatment group, compared to that of 55% in the control group [47]. It should be pointed out in most of these studies that E. alatus was not used lone, but in combination with other herbs; thus it is not clear if the observed effects are due to E. alatus or through interactions with other herbs. Thus, there may be potential bias in these findings. The current evidence for the clinical efficacy for treating diabetes is still weak. Nevertheless, these findings warrant further studies.

Table 8: Clinical studies of E. alatus for diabetic conditions.

Number of patients
Preparation/compound
Treatment
Outcome measures/outcome
Reference

57
E. alatus formula containing other herbs
Oral, daily per dose, for 3 months
Fasting blood glucose and 24 h urine glucose levels
30 cases with marked improvement
19 cases improved
8 cases no effect
Total effective rate: 86%
[55]

58
E. alatus formula containing other herbs
Oral, daily per dose, average medication for 37.2 days.
Fasting blood glucose level
21 cases remarkable effect
28 cases effective
9 cases no effect
Effective rate: 84.4%
[56]

100
E. alatus formula containing other herbs
Oral, daily per dose, for 4 months
Fasting blood glucose and urine glucose levels, clinical symptoms
40 cases showed remarkable effect 51 cases effective
9 cases failed
Total effective rate: 91%
[57].

1
E. alatus decoction
Oral, daily per dose, for 20 days
Hypoglycemic effects
Reduced blood and urine glucose and increased body weight
[58]

80
E. alatus formula containing other herbs
Oral, daily per dose, for 30 days
Fasting blood glucose, 2 h postprandial blood glucose values
Treatment group: 32 cases effective (80%) and 8 cases no effect (20%)
Control group: 22 cases effective (55%) and 18 cases no effect (45%)
[47]

4. Conclusion

There is an increasing interest in E. alatus as a potential antidiabetic agent. More than 100 chemical constituents have been isolated and identified from E. alatus. The main chemical classes include flavonoids, terpenoids, steroids, phenylpropanoids, cardenolides, phenolic acids, and alkaloids. E. alatus has been demonstrated with hyperglycemic activity in vivo. The hypoglycemic activity E. alatus may be related to its effects on insulin signaling and glucose metabolism, including stimulating insulin secretion, improving affinity of insulin and receptor, increasing insulin sensitivity and tolerance, and reducing insulin resistance. It may also act as PPARγ agonist and aldose reductase inhibitor. Further study on the bioactive compounds of E. alatus and its pharmacology may help to develop new agents for treating diabetes and diabetic complications.

Abbreviations

AR: | Aldose reductase
DPP-IV: | Dipeptidyl peptidase IV
E. alatus: | Euonymus alatus
GC-MS: | Gas chromatography-mass spectrometry
LDL: | Low-density lipoprotein
NO: | Nitric oxide
PPARγ: | Peroxisome proliferator activated receptor gamma
PTP1B: | Protein tyrosine phosphatase 1B
SOD: | Superoxide dismutase
STZ: | Streptozotocin
TNF-α: | Tumor necrosis factor-alpha.

Competing Interests

The authors declare that they have no competing interests.

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