# Euonymus alatus: A Review on Its Phytochemistry and Antidiabetic Activity

Authors: Xifeng Zhai; George Binh Lenon; Charlie C. L. Xue; Chun-Guang Li
Journal: Evidence-Based Complementary and Alternative Medicine
 (2016)

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## 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 ofE. alatus related to antidiabetic actions. More than 100 chemical constituents have been isolated and identified fromE. alatus, including flavonoids, terpenoids, steroids, lignans, cardenolides, phenolic acids, and alkaloids. Studiesin vitro andin vivo have demonstrated the hypoglycemic activity ofE. alatus extracts and its certain constituents. The hypoglycemic activity ofE. alatus may be related to regulation of insulin signaling and insulin sensitivity, involving PPARγ and aldose reductase pathways. Further studies onE. alatus and its bioactive compounds may help to develop new agents for treating diabetes and diabetic complications.


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## Body

## 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 inShen 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, andBen 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 inE. 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 ofE. 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 ofE. alatus and its pharmacology related to antidiabetic actions.


## 2. Phytochemistry

More than 128 chemical constituents have been isolated and identified fromE. 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 fromE. alatus. The main structure types include flavonoid, flavanone, and flavonol. The aglycones of flavonoid glycosides isolated fromE. alatus include quercetin, kaempferol, naringenin, aromadendrene, and dihydroquercetin. The flavonoids are mainly distributed in the leaves and wings ofE. alatus [16]. The structures of main flavonoids identified inE. alatus are listed in Tables 1–4.Table 1
Quercetin and glycosides inE. 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 inE. 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 inE. 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 inE. 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 fromE. 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 inE. 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 fromE. alatus include triterpenes and sesquiterpenes.


#### 2.3.1. Triterpenes

Multiple types of triterpenes were found inE. alatus. Most of the triterpenes inE. 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 fromE. alatus.Table 6
Lupane type and friedelane type triterpenes inE. 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 fromE. alatus.


#### 2.3.2. Sesquiterpenes

Two new sesquiterpenes (65, 66) and two known ones were isolated from 95% ethanol extract of the stems ofE. 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 fromE. alatus are shown in Figure 2.Figure 2
Structures of sesquiterpenes (compounds 65–68) isolated fromE. alatus.


### 2.4. Alkaloids

Five alkaloids have been isolated fromE. 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 fromE. alatus are shown in Figure 3.Figure 3
Structures of alkaloids (compounds 69 and 71–74) isolated fromE. alatus.


### 2.5. Cardenolides

Kitanaka et al. [3] isolated three cytotoxic cardenolides from the woods ofE. 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 ofE. 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 ofE. 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 inE. 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 fromE. alatus. In a study of essential oil fromE. 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].


## 2.1. Flavonoids

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


### 2.3.1. Triterpenes

Multiple types of triterpenes were found inE. alatus. Most of the triterpenes inE. 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 fromE. alatus.Table 6
Lupane type and friedelane type triterpenes inE. 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 fromE. alatus.


### 2.3.2. Sesquiterpenes

Two new sesquiterpenes (65, 66) and two known ones were isolated from 95% ethanol extract of the stems ofE. 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 fromE. alatus are shown in Figure 2.Figure 2
Structures of sesquiterpenes (compounds 65–68) isolated fromE. alatus.


## 2.3.1. Triterpenes

Multiple types of triterpenes were found inE. alatus. Most of the triterpenes inE. 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 fromE. alatus.Table 6
Lupane type and friedelane type triterpenes inE. 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 fromE. alatus.


## 2.3.2. Sesquiterpenes

Two new sesquiterpenes (65, 66) and two known ones were isolated from 95% ethanol extract of the stems ofE. 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 fromE. alatus are shown in Figure 2.Figure 2
Structures of sesquiterpenes (compounds 65–68) isolated fromE. alatus.


## 2.4. Alkaloids

Five alkaloids have been isolated fromE. 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 fromE. alatus are shown in Figure 3.Figure 3
Structures of alkaloids (compounds 69 and 71–74) isolated fromE. alatus.


## 2.5. Cardenolides

Kitanaka et al. [3] isolated three cytotoxic cardenolides from the woods ofE. 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 ofE. 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 ofE. 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 inE. 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 fromE. alatus. In a study of essential oil fromE. 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 ofE. alatus extracts have been testedin vivo. In streptozotocin (STZ) treated diabetic rats, an aqueous extract ofE. 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 thatE. 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 thatE. alatus can improve the glucose-lipid metabolism and insulin resistance in diabetic conditions [32]. Park et al. also demonstrated that an ethanol extract ofE. alatusreduced 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 ofE. alatusmay involve a protection of functional islet β cells sinceE. 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 thatE. alatusmay 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 ofE. alatus extract is illustrated in Figure 5 [33].Figure 5
Possible mechanism of hypoglycemic and hypolipidemic actions ofE. alatus ethanol extract, modified from [33].In addition, a study showed thatE. alatus protected rats from experimental diabetic nephropathy induced by uninephrectomy plus STZ treatment, with 12-week administration ofE. 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 β1 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 ofE. 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 ofE. 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 ofE. 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 ofE. 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 ofE. 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 ofE. 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 fromE. 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, andp-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 ofE. 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 ofE. 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 inE. 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 ofE. alatuscontaining 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 plusE. alatusformula 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 theE. alatustreatment group, compared to that of 55% in the control group [47]. It should be pointed out in most of these studies thatE. alatuswas not used lone, but in combination with other herbs; thus it is not clear if the observed effects are due toE. alatusor 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 ofE. alatus fordiabetic 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 levels30 cases with marked improvement 19 cases improved8 cases no effectTotal effective rate: 86% [55]  58 E. alatus formula containing other herbs Oral, daily per dose, average medication for 37.2 days. Fasting blood glucose level21 cases remarkable effect28 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 symptoms40 cases showed remarkable effect 51 cases effective 9 cases failedTotal effective rate: 91% [57].  1 E. alatusdecoction Oral, daily per dose, for 20 days Hypoglycemic effectsReduced 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 valuesTreatment group: 32 cases effective (80%) and 8 cases no effect (20%)Control group: 22 cases effective (55%) and 18 cases no effect (45%) [47]


## 3.1. Clinical Evidence

There have been limited clinical studies, mostly case reports, on the antidiabetic actions ofE. alatuscontaining 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 plusE. alatusformula 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 theE. alatustreatment group, compared to that of 55% in the control group [47]. It should be pointed out in most of these studies thatE. alatuswas not used lone, but in combination with other herbs; thus it is not clear if the observed effects are due toE. alatusor 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 ofE. alatus fordiabetic 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 levels30 cases with marked improvement 19 cases improved8 cases no effectTotal effective rate: 86% [55]  58 E. alatus formula containing other herbs Oral, daily per dose, average medication for 37.2 days. Fasting blood glucose level21 cases remarkable effect28 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 symptoms40 cases showed remarkable effect 51 cases effective 9 cases failedTotal effective rate: 91% [57].  1 E. alatusdecoction Oral, daily per dose, for 20 days Hypoglycemic effectsReduced 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 valuesTreatment 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 inE. alatus as a potential antidiabetic agent. More than 100 chemical constituents have been isolated and identified fromE. alatus. The main chemical classes include flavonoids, terpenoids, steroids, phenylpropanoids, cardenolides, phenolic acids, and alkaloids.E. alatus has been demonstrated with hyperglycemic activityin vivo. The hypoglycemic activityE. 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 ofE. alatus and its pharmacology may help to develop new agents for treating diabetes and diabetic complications.



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*Source: 9425714-2016-08-25.xml*