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The Pentacyclic Triterpenoids in Herbal Medicines and Their Pharmacological Activities in Diabetes and Diabetic Complications A. Alqahtania, K. Hamida, A. Kama, K.H. Wonga, Z. Abdelhaka, V. Razmovski-Naumovskia,b, K. Chana,b, K.M. Lic, P.W. Groundwatera and G.Q. Lia,* a Faculty of Pharmacy, University of Sydney, NSW 2006, Australia; bCentre for Complementary Medicine Research, University of Western Sydney, NSW 2560, Australia; cSydney Medical School, University of Sydney, NSW 2006, Australia

Abstract: Pentacyclic triterpenoids including the oleanane, ursane and lupane groups are widely distributed in many medicinal plants, such as Glycyrrhiza species, Gymnema species, Centella asiatica, Camellia sinensis, Crataegus species and Olea europaea, which are commonly used in traditional medicine for the treatment of diabetes and diabetic complications. A large number of bioactive pentacyclic triterpenoids, such as oleanolic acid, glycyrrhizin, glycyrrhetinic acid, ursolic acid, betulin, betulinic acid and lupeol have shown multiple biological activities with apparent effects on glucose absorption, glucose uptake, insulin secretion, diabetic vascular dysfunction, retinopathy and nephropathy. The versatility of the pentacyclic triterpenes provides a promising approach for diabetes management.

Keywords: Diabetes, diabetic complications, herbal medicines, pentacyclic triterpenoids, phytochemicals, structure-activity relationship. 1. INTRODUCTION Diabetes mellitus (DM) is a chronic metabolic disorder associated with defects in insulin secretion and/or sensitivity [1]. DM is classified as type 1 or type 2 based on the pathogenic process that leads to hyperglycaemia. The precise underlying mechanisms for the development of insulin resistance are still incomplete, however, increasing evidence has suggested that low-grade chronic inflammation, as well as multiple defects in intracellular insulin signalling and glucose uptake in skeletal and adipose tissues, plays a pivotal role in the manifestation of insulin resistance [2]. Herbal medicines have been used for thousands of years in many ethnic cultures such as Chinese, Korean, Indian and Mexican to treat and manage diabetes and its complications [3-6]. In the last few decades, modern science has uncovered the benefits of using herbal medicines in the management of particular diabetic complications, such as vascular inflammation, nephropathy and retinopathy. Many traditional herbs that have been comprehensively studied and show promising clinical applications in regards to diabetes contain pentacyclic triterpenoids as their active components. Some examples of these herbs are: huangqi (the root of Astragalus membranaceus), baical skullcap (the root of Scutellaria baicalensis), bitter melon (the fruit of Momordica charantia), fenugreek (the seed of Trigonella foenum graecum), ginseng (the root of Panax ginseng), green tea (the flower buds of Camellia sinensis), gymnema (the leaves of Gymnema sylvestre, G. montanum, G. inodorum), hawthorn (the fruit of Crataegus monogyna), licorice (the root of Glycyrrhiza glabra), oats (the seeds of Avena sativa), olive (the fruit of Olea europaea), yam (the rhizome of Dioscorea opposita), ashwagandha (the root of Withania somnifera), gotu kola (the leaves of Centella asiatica) and kudzu (the root of Pueraria lobata) [7]. Triterpenoids have become a topic of intense interest due to their numerous biological and pharmacological properties, as evidenced by the number of increased citations from the PubMed database, which was 15,832 for triterpenes, as of March 18, 2012 compared to 8,054 on January 13, 2006 [8]. The structures of newly discovered triterpenoids are regularly reviewed by Hill and Connolly, and others [9-12]. Triterpenes are widely distributed in the plant and marine animal kingdoms, where they occur either in the free state, as esters, or as glycosides (saponins). They are composed of six isoprene units (C5H8)6 from mevanolic acid or deoxyxylulose phosphate, and *Address correspondence to this author at the Faculty of Pharmacy, the University of Sydney, NSW 2006, Australia; Tel: +61 2 9351 4435; Fax: +61 2 9351 4391; Email: [email protected] 0929-8673/13 $58.00+.00

are derived from the reductive coupling of two molecules of farnesyl pyrophosphate by squalene synthase. Triterpenoids are usually classified into three groups: acyclic, tetracyclic and pentacyclic [13, 14]. Pentacyclic triterpenes have received much attention, and several of them are being marketed as therapeutic agents, including oleanolic acid and glycyrrhizic acid as drugs for the treatment of liver diseases, asiaticoside for wound healing, corosolic acid and gymnemic acids for diabetes [15]. The pentacyclic triterpenes can be divided into three main classes: oleanane, ursane and lupane (Fig. 1). The oleanane skeleton is the most frequently occurring type of triterpene-over 50%; the most common aglycone in this class is oleanolic acid which is present in legume forages. Rings A/B, B/C, C/D of both oleanane and ursanes are generally trans-linked, while rings D/E are cis-linked. All the rings ABCDE in lupanes are trans-fused with a five- membered E ring. These structures can undergo rearrangements to form taraxeranes, taraxastanes, friedelanes, glutinanes and multiforanes, whilst hopanes are from squalene cyclisation. The important structural elements of these classes are: the unsaturation at C-12(13); the functionalisation of the methyl groups at C-23, C-28 or C-30 (hydroxymethyl, aldehyde or carboxyl); polyhydroxylation at C-2, C-7, C-11, C-15, C-16, C-19 (21, or 22) etc. The oxidation of one of these hydroxyl groups to a ketone is not uncommon (especially in the 11 position) and through etherification or lactonisation, formation of an additional ring is possible. The esterification of the pentacyclic triterpenoid by aliphatic acids sometimes occurs (generally by low molecular weight aliphatic acids). Many pentacyclic triterpenoids have acidic properties, due to the presence of one or two carboxyl groups in the aglycone and/or sugar moiety. A recent review by Sheng and Sun (2011) described mainly the potentials of synthetic modifications on pentacyclic triterpenes in enhancing their biological activities in metabolic and cardiovascular diseases. This review will specifically highlight the biological activities of pentacyclic triterpenes found in medicinal plants for diabetes and diabetic complications. By covering in vitro, in vivo and clinical evidence, including the possible molecular mechanisms, this review offers new insight into the use of medicinal plants which are rich in pentacyclic triterpenes for the management of diabetes and its complications as well as supports the development of new therapeutic agents. We will first address the distribution of pentacyclic triterpenes in medicinal plants in terms of their potential bioactivity in diabetes and diabetic complications, followed by detailed inclusion of bioactivities and structure-activity relationships of the main pentacyclic triterpenoids. © 2013 Bentham Science Publishers

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Current Medicinal Chemistry, 2013, Vol. 20, No. 4

Alqahtani et al.

E D

C A 29

B 29

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19 12 13

11 25 1 2

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18

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Oleanane

13

26 9

21

19

23

Ursane

24

Lupane

Fig. (1). Basic structure of the main bioactive pentacyclic triterpenoids.

2. PENTACYCLIC PLANTS

TRITERPENES

IN

MEDICINAL

2.1 The Oleanane Group The oleananes have a gem-dimethyl group at C-20. They are widely distributed in common medicinal plants such as Glycyrrhiza species, Aralia species, Panax ginseng and Ligusticum lucidum, which have ‘heat’ clearing, cardiotonic and diuretic properties, and are often used for treating hepatitis in traditional Chinese medicine (TCM). Oleananes are the active compounds in the Indian medicinal plant, Gymnema sylvestre, which is commonly used for reducing blood glucose levels in diabetic patients. The following section focuses on medicinal plants containing oleanane compounds which show antidiabetic activity, and thus potential in the treatment of diabetes and its complications. (Fig. 2, Table 1). 2.1.1 Gymnema sylvestre and Gymnema inodorum Gymnema sylvestre R.Br. (Asclepiadaceae) has been used in Ayurvedic medicine for the treatment of diabetes in India [16]. Mhasker and Caius studies observed the glucose-lowering effect of G. sylvestre leaves in alloxan-induced diabetic rabbits and dogs. In pancreatectomised animals, they did not find any hypoglycaemic effect and it was concluded that some residual pancreatic endocrine tissue was necessary for this plant to be effective [17]. Shanmugasundaram et al. (1981) reported the hypoglycaemic effect of G. sylvestre after administering dry leaf powder to a diabetic patient. They observed that prolonged administration (24 weeks) of 250 mg of dried leaf per day in alloxan-induced diabetic rabbits increased serum insulin both at fasting and after glucose load [18]. An alcoholic extract of G. sylvestre has been reported to stimulate insulin release from HIT-T15, MIN6 and RINm5F -cells, and from rat islets in the absence of any other stimulus. Two gymnemic acidenriched fractions have been shown to increase insulin secretion, with concomitant trypan blue uptake, confirming the stimulatory effect of G. sylvestre on insulin release [19]. Gymnemic acids, which are triterpene glycosides extracted from the leaves of G. sylvestre, have been reported to improve glucose tolerance and decrease the blood glucose level in diabetic patients [20-22]. The significant regeneration of -cells (in diabetic Wistars rats) by gymnemic acid from leaf and callus extracts has also been reported [23]. In particular, Gymnemic acid IV was found to reduce blood glucose levels by 13.5-60.0 % in the dose range 3.4-13.4 mg/kg. At a dose of 13.4 mg/kg, plasma insulin levels in

STZ-diabetic mice were increased [24]. A novel compound dihydroxy gymnemic triacetate, which is derived from the basic structure of gymnemic acid, has been isolated from the leaves of G. sylvestre. Dihydroxy gymnemic triacetate (optimal dose 20 mg/kg, orally administered for 45 days) was shown to decrease plasma glucose (by more than 50%) and HbA1c (39.56%) in diabetic rats. The compound increased the level of plasma insulin (50%), muscle glycogen (77.1%) and liver glycogen (59.09%) in diabetic rats [25]. The hypoglycaemic effect of G. sylvestre has been shown in several animal and human studies. The use of gymnemic acid IV and dihydroxy gymnemic triacetate as antidiabetic agents warrant further studies in animals to investigate the molecular mechanism of action, and large-scale clinical trials in humans. Gymnema inodorum (Lour.) Decne belongs to the same family as G. sylvestre and has similar therapeutic effects in DM. The main difference between G. sylvestre and G. inodorum is that the latter lacks the bitter taste or the ability to suppress the sweetness of food [26, 27]. Four saponin containing fractions (FI-FIV) obtained by HPLC from the leaves of G. inodorum were studied in high K+induced contraction of intestinal smooth muscle of guinea pig, glucose evoked transmural potential difference (PD) in an everted intestine isolated from guinea pig, O2 consumption by guinea pig ileum, and glucose level in glucose tolerance tests on rats. The increased PD with glucose, as well as high K+-induced contraction was suppressed by three of the fractions (F-I, F-II and F-III) and recovered by the application of pyruvate. These results suggest that some components of G. inodorum may have an inhibitory effect on the Na+-glucose co-transport system. The administration of glucose solution containing F-II (300 mg/kg) demonstrated an approximate 10% decrease in comparison with the control within 15 minutes. In contrast, F-III (60 mg/kg) resulted in blood glucose levels of approximate by 60% and 40% of control at 15 min and 30 min respectively. F-I and F-IV did not result in any significant change in blood glucose in comparison with control [27]. Four pentacyclic triterpenes (GiA-1, GiA-2, GiA-5 and GiA-7) from the leaves of G. inodorum have been isolated by Shimizu et al. (2001) (Fig. 3). GiA-2, GiA-5 and GiA-7 inhibited the high K+induced contraction of the intestinal smooth muscle, and suppressed an increase in PD in guinea pig. GiA-1 had no effect on the smooth muscle contraction, and did not change the increased PD level. This suggests that GiA-2, GiA-5 and GiA-7 have an inhibitory action on the Na+ glucose co-transport system. In the glucose

The Pentacyclic Triterpenoids in Diabetes


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R10 R8 R5 R7

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R2

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R4

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R6

R7

R8

R9

R10 CH3

Oleanolic acid

H

H

CH3

CH3

H

H

COOH

H

H

Maslinic acid

OH

H

CH3

CH3

H

H

COOH

H

H

CH3

Glycyrrhizic acid

H

GlucUA

CH3

CH3

C=O

H

CH3

H

H

COOH

Glycyrrhetinic acid

H

H

CH3

CH3

C=O

H

CH3

H

H

COOH

Gymnemic acid IV

H

GlucUA

CH2OH

CH3

H

OH

CH2OH

O-Tig

OH

CH3

Arjunolic acid

OH

H

CH2OH

H

H

H

COOH

H

H

CH3

GlucUA: glucuronic acid; Tig: tigloyl

Fig. (2). Pentacyclic triterpenoids from herbal medicines - oleanane group.

tolerance test in rats, GiA-2, GiA-5 and GiA-7 significantly suppressed the blood glucose level 15 and 30 minutes post administration. In contrast, GiA-1 did not exhibit any effects on increased blood glucose levels [28]. G. inodorum and its pure components may be a potential treatment for diabetes, but clinical studies are necessary. 2.1.2 Glycyrrhiza species Glycyrrhiza species (Fabaceae) extracts have been shown to be effective in preventing and ameliorating diabetic complications [29]. Glycyrrhizin, and its aglycone glycyrrhetinic acid, are the most studied bioactive triterpenes from licorice. G. uralensis Fisch. extract was found to improve glucose tolerance in pancreatectomised diabetic mice, and enhance insulin-stimulated glucose uptake through peroxisome proliferation-activated receptor (PPAR)- activation in 3T3-L1 adipocytes. In the same study, glycyrrhetinic acid enhanced glucose-stimulated insulin secretion in isolated islets and induced mRNA levels of insulin receptor substrate-2, pancreas duodenum homeobox-1, and glucokinase in the islets, which contributed to improved beta-cell viability [30]. Licorice and its triterpene constituents may be effective in the prevention and treatment of diabetes nephropathy as it has been shown that licorice extract alleviated blood glucose levels, restored renal function, and attenuated body-weight loss in STZ-induced diabetes in rats. In addition, the extract modulated renal malondialdehyde, glutathione, superoxide dismutase (SOD) and catalase (CAT) activity and restored kidney total antioxidant capacity. The histological investigations of focal segmental glomerulosclerosis, tubular damage and hyperaemic kidney were seen in diabetic, but not in licorice-treated rats [31]. In addition, the extract reduced sorbitol levels in erythrocytes of diabetic rats [32]. The increased collagen IV secretion and CTGF expression associated with high glucose treatment in human renal mesangial cells was appeased by licorice extract. The non-polar glycyrrhetic acid retarded high glucose-stimulated mesangial matrix deposition through diminishing CTGF expression [33]. On the contrary, glycyrrhizin and glycyrrhetinic acid from G. uralensis did not affect rat lens aldose reductase and human recombinant aldose reductase activity [34]. 2.1.3 Olea europaea Olea europaea L. (Oleaceae) has been widely used in traditional remedies in European and Mediterranean countries. The leaves of this plant have been used as extracts, herbal teas and pow-

der, and contain several potentially bioactive compounds that may have hypoglycaemic, antioxidant, antihypertensive, antiatherogenic, anti-inflammatory and hypocholesterolaemic properties [35]. The oral administration of an alcoholic extract of O. europaea at a dose of 0.5 g/kg body weight, significantly reduced serum glucose, total cholesterol, TG, urea, uric acid, creatinine, aspartate amino transferase (AST) and alanine amino transferase (ALT) in STZ-induced diabetic rats. The extract significantly increased the serum insulin in diabetic rats but not in normal rats (p < 0.05), and was found to be more active than glibenclamide (600 μg/kg) [36]. The antidiabetic effect of this plant has also been tested in humans. In a randomised clinical trial on 79 patients with type 2 diabetes (18-79 years of age), the oral administration of 500 mg tablet of the residue from the 80% aqueous ethanol extract of olive leaves for a period of 14 weeks significantly reduced HbA1c levels and fasting plasma insulin [37]. The effect of olive leaf extract in diabetic complications such as neuropathic pain is also promising. Olive leaf extract (200, 400 and 600 g/mL) inhibited high glucose-induced neuronal damage (when incubated with nerve growth factor-treated PC12 cells). Treatment with olive leaf extract (300 and 500 mg/kg per day) has been reported to suppress diabetes-induced thermal hyperalgesia [38]. Maslinic acid, a natural pentacyclic triterpene derived from O. europaea exhibits promising antidiabetic effect through the inhibition of glycogen phosphorylase. These enzymes, which catalyse the first step of glycogen breakdown, play an important role in glucose metabolism, especially in the glycogenolytic pathway, and it is well known that liver glycogen phosphorylase is the major enzyme controlling hepatic glucose output [39-42]. Liu et al. (2007) reported that the oral administration of maslininc acid (30 mg/kg body weight) reduced blood glucose levels in KK-Ay mice at 4 h and 7 h compared to control. The compound decreased plasma insulin and increased hepatic glycogen content which may contribute to a reduction in the glucose supply to the blood [43]. After intragastric administration of maslinic acid (5 mg/kg or 50 mg/kg) for 14 consecutive days in STZ-induced diabetic rats, Guan et al., (2011) reported lower blood glucose levels, as well as a reduction in infarct volumes, and improved neurological scores for both doses. Glutamate overflow in maslininc acid-treated rats after two hours of ischaemia followed by 24 hours and 72 hours reperfusion was also observed. In addition, maslininc acid treatment enhanced the glial glutamate transporter GLT-1 expression at the protein and mRNA

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Table 1.

Alqahtani et al.

Pharmacological Activities of Oleanane Compounds Presented in Popular Herbal Medicines. Plant name

Active compounds

Pharmacological activity

Ref.

Gymnemic acid IV

Reduces blood glucose levels by 13.5 -60.0% 6 h after administration at doses of 3.4- 13.4 mg/kg. At 13.4 mg/kg, plasma insulin levels were increased in streptozocin induced (STZ)-diabetic mice.

[24]

Dihydroxy gymnemic triacetate

At 20 mg/kg, decreases plasma glucose (> 50%), HbA1c (39.56%) in diabetic rats. Increases plasma insulin (50%), muscle glycogen (77.1%) and liver glycogen (59.09%) in diabetic rats.

[25]

Gymnema inodorum

GiA-2, GiA-5 and GiA-7

Inhibits high K+-induced contraction of guinea ileal smooth muscle, and suppresses the increase in glucose evoked transmuralpotential difference (PD) in inverted intestine of guinea pig. Suppresses blood glucose level significantly after 15 and 30 minutes in glucose tolerance test in male Sprague Dawley (SD) rats.

[28]

Glycyrrhiza inflate

Glycyrrhetic acid

Retards high glucose-stimulated mesangial matrix deposition through diminishing connective tissue growth factor (CTGF) expression.

[33]

Olea europaea

Maslinic acid

Exhibits antidiabetic effect by inhibiting glycogen phosphorylase and reduces blood glucose levels in KK-Ay mice at 4 h and 7 h compared to control. Intragastric administration of maslinic acid (5 or 50 mg/kg) for 14 consecutive days in STZ-diabetic rats lowers blood glucose levels, reduces infarct volumes and improves neurological scores for both doses.

[39, 43]

Terminalia arjuna

Arjunolic acid

At 20 mg/kg, reduces hyperglycaemia, membrane disintegration, oxidative stress, vascular inflammation and prevents oxidative stress-induced signalling cascades, leading to cell death in STZ-induced diabetic rats. At 20 mg/kg for 14 days, has a beneficial role against diabetic nephropathy.

[46-48]

Mangifera indica

3-Taraxerol

Produces a time-dependent increase in glucose transporter type 4 (GLUT4) with a maximum increase observed at 18 h, which was sustained until 24 h, maximum translocation of GLUT4 from cytosolic fraction to the plasma membrane fraction, increases glycogen synthesis involving the activation of PKB and suppression of GSK3 in 3T3-L1 adipocytes.

[51]

Camellia sinensis

Chakasaponins I–III

Inhibits gastric emptying time, which is partly responsible for significantly inhibiting an increase in plasma triglycerides (TG) and glucose levels in olive oil or sucrose loaded mice.

[53]

Aralia elata

Elatoside E, elatoside A, tarasaponin VI, stipuleanoside R1, chikusetsusaponin IV, stipuleanoside R2, Elatosides G, H and I

100 mg/kg of each compound shows hypoglycaemic activity in oral glucose/sucrose tolerance test in rats.

[54, 55]

Platycodon grandiflorum

Platycodin D

Inhibits intracellular TG accumulation in 3T3-L1 cells with IC50 value of 7.1 μM. Significantly down-regulates gene expression levels involved in lipid metabolism, such as fatty-acid-binding protein 4 and lipoprotein lipase.

[58]

Salacia species

Kotalagenin 16-acetate, Maytenfolic acid, 3, 22-dihydroxyolean-12-en-29-oic acid, 3, 22-dihydroxyolean-12-en-29-oic acid, amyrin, 22-hydroxy-3-oxoolean-12-en-29-oic acid, and -amyrenone

Inhibits rat lens aldose reductase at 30 and 100 M.

[60, 91]

Polygala senega

Sengins II and III

Reduces blood glucose level of normal mice 4 h after intraperitoneal administration and significantly lowers the glucose level of KK-Ay mice.

[66]

Pueraria thunbergiana

Kaikasaponin III

At 5 and 10 mg/kg, exhibits significant hypoglycaemic activity in STZ-induced diabetic rats.

[71]

Acanthopanax senticosus

3-O-[(-L-Rhamnopyranosyl) (12)]-[-Dglucuronopyranosyl-6-O-methyl ester]-olean12-ene-28-olic acid

Inhibits -glucosidase (EC.3.2.1.20) from Saccharomyces sp. with IC50 value of 908.5 M.

[75]

Beta vulgaris

Betavulgarosides II, III and IV

At 100 mg/kg, a single oral administration produces hypoglycaemic activity in oral glucose tolerance tests in rats

[77]

Fagus hayatae

1,10-seco-3,10, 23-trihydroxyolean-12-ene1,28-dioic acid 1,23-lactone

Inhibits -glucosidase type IV (Bacillus stearothermophilus) with IC50 value of 96.2 ± 0.08 M.

[81]

Kalopanax pictus

Kalopanaxsaponin A

At 25 mg/kg, decreases serum glucose by 93% in STZ-induced diabetic rats.

[82]

3-O-Acetyloleanolic acid

At 31 mg/kg, decreases (26.3 ± 3.7%) in the glucose level of STZ-induced diabetic rats after 7 h of treatment.

[83]

Gymnema sylvestre

Eysenhardtia platycarpa

levels. Maslininc acid pretreatment also attenuated ischaemiainduced translocation of the nuclear factor-kappa B (NF-B) p65 subunit to the nucleus. In addition to showing promising antidiabetic properties, it was concluded that maslininc acid had a direct beneficial effect in cerebral ischaemic injury, which may be correlated with the promotion of glutamate clearance by NF-Bmediated GLT-1 up-regulation [39]. Taken together, maslinic acid

shows promise as a natural therapeutic agent for the treatment of type 2 diabetes and potentially lowering the risk of stroke [39, 43]. 2.1.4 Terminalia arjuna Terminalia arjuna Roxb. (Combretaceae), commonly known as Arjuna, is a large tree grown throughout India and used traditionally for several medicinal purposes [44]. The use of carbohydrate-



5

R1

H

R4

H HOOC

O

HO

R2 CH2R3

O CH2R6CH2R5

R8O

R7O H

Triterpene compound

R1

R2

R3

R4

R5

R6

R7

R8

GiA-1

H

H

OH

OH

H

H

-Glu

H

GiA-2

H

H

OH

OH

OH

H

H

H

GiA-5

H

O – NMAt

OH

OH

OH

H

H

-Glu

GiA-7

H

O – NMAt

OH

OH

OH

H

H

H

-Glu: -glucopyranosyl; NMAt: N-methylanthraniloxy.

Fig. (3). Pentacyclic triterpenoids from Gymnema inodorum.

hydrolysing enzyme inhibitors has proven to be an important strategy for the management of postprandial hyperglycaemia through delaying the carbohydrate hydrolysis and absorption. A 50% methanol extract of T. arjuna was reported to inhibit -amylase activity, with IC50 of 302 ± 0.55 g/mL [45]. In another study, the methanolic extract of T. arjuna leaves at a dose of 100 and 200 mg/kg significantly (P < 0.001) reduced and normalised blood glucose levels in a dose-dependent manner in STZ-induced diabetic rats [44]. Manna et al. (2009) reported that arjunolic acid (2,3,23trihydroxyolean-12-en-28-oic acid), a natural pentacyclic triterpenoid saponin isolated from the bark of T. arjuna was beneficial against STZ-induced diabetes in Swiss albino rats at an oral dose of 20 mg/kg bodyweight. The compound inhibited the excessive formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and down-regulated the activation of phosphoERK1/2, phospho-p38, NF-B and mitochondrialdependent signal transduction pathways, leading to apoptotic cell death [46]. Vascular inflammation and cardiac dysfunction are the leading causes of mortality and morbidity among diabetic patients. It has been reported that treatment with arjunolic acid (20 mg/kg) in STZinduced diabetic rats reduced hyperglycaemia, membrane disintegration, oxidative stress and vascular inflammation, and prevented the activation of oxidative stress-induced signalling cascades leading to cell death, suggesting that arjunolic acid has the potential to be a beneficial therapeutic agent in diabetes and its associated cardiac complications [47]. Diabetic nephropathy is a common cause of end-stage renal disease. Manna et al. (2009) reported the beneficial role of arjunolic acid against STZ-induced diabetic nephropathy in rats. The administration of arjunolic acid at a dose of 20 mg/kg in the rats for 14 days reduced the increased production of intracellular ROS and NO. Treatment with arjunolic acid decreased the level of serum pro-inflammatory tumour necrosis factor- (TNF-) in STZinduced hyperglycaemic rats. It has been found that treatment with arjunolic acid can increase the antioxidant enzymes activities in diabetic renal dysfunction, ameliorate the alteration in the thiol parameters in diabetic renal tissue, down-regulate the activation of PKC, PKC, phospho-p38, phospho-ERK1/2, phospho-JNK and NF-B. From immunoblotting studies, it was observed that STZ treatment leads to the upregulation of pro-apoptotic (bcl-2associated death promoter) and downregulated anti-apoptotic (cell lymphoma 2, -cell lymphoma-extra large) proteins in kidney tissue initiating mitochondrial events such as the reduction in mito-

chondrial membrane potential, and the release of cytochrome C followed by the activation of caspase-dependent cell death. Treatment with arjunolic acid both pre- and post STZ administration significantly repressed STZ-induced alterations in these parameters [48]. Arujunolic acid has shown promising beneficial effects in STZinduced diabetes, nephropathy and cardiac complications associated with diabetes. To confirm these results, human trials are necessary. 2.1.5 Mangifera indica Mangifera indica L. (Anacardiaceae) is used medicinally in tropical Africa as an astringent, for bronchitis, catarrh, internal haemorrhage, skin diseases and toothache. The hypoglycaemic effect of an ethanol extract (250 mg/kg) and an aqueous extract of leaves (1 g/kg) in STZ-induced diabetic rats and mice, respectively, have been reported [49, 50]. Glucose transport by insulin stimulation is mediated through translocation of GLUT4 which is subsequently followed by its activation. 3-Taraxerol, a triterpenoid that has been isolated from M. indica, instigated a time-dependent increase in GLUT4, with the maximum increase observed at 18 h (which was sustained until 24 h). The increase in the GLUT4 expression levels was comparable with the positive controls insulin (100 nM, 15 min) and rosiglitazone (50 μM, 24 h). 3-Taraxerol facilitated the translocation of GLUT4 from cytosol to the plasma membrane. In comparison, untreated cells exhibited very minimal GLUT4 expression in the plasma membrane (23.1 ± 5%). The increase in translocation was comparable to that of rosiglitazone (50 μM) and insulin (100 nM) which also showed maximum translocation of GLUT4. It can be concluded that 3taraxerol activates glucose transport by inducing the activation of GLUT4 preceded by its translocation to the plasma membrane. After insulin-stimulated glucose transport, 3-taraxerol has been shown to increase glycogen synthesis through the activation of PKB and suppression of GSK3 [51]. 3-Taraxerol from M. indica is thus a potent candidate for the management of the hyperglycaemic state [51]. However, more studies are required to support its use as a hypoglycaemic agent. 2.1.6 Camellia sinensis Tea from the plant Camellia sinensis L. (Theaceae) is one of the most widely consumed drinks worldwide. Although the beneficial

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Alqahtani et al.

therapeutic advantages of tea leaves have been extensively studied, recent studies have attracted increasing interest in green tea flowers with affirmative bioactivities.

rats [55]. Chemical structures of the main pentacyclic triterpenes from A. elata are listed in (Fig. 4). 2.1.8 Platycodon grandiflorum

The isolation of chakasaponins I–III and a new acylated oleanane-type triterpene oligoglycoside, chakasaponin IV from the flower buds of C. sinensis cultivated in Fujian province, China has been reported by Matsuda et al. (2012). Chakasaponins I–III at dose of 50 and 100 mg/kg were examined on plasma TG and glucose levels in olive oil or sucrose-loaded mice. It was found that the compounds significantly inhibited increases in plasma TG and glucose levels. The compounds inhibited the gastric emptying time which may be partly responsible for their inhibitory effects on serum glucose and TG [53].

Platycodi radix, the root of Platycodon grandiflorum A. DC. (Campanulaceae), has been used in folk medicine in Korea for the treatment of hyperlipidaemia, hypertension and diabetes [56]. When a diet containing 5% (wt/wt) P. grandiflorum powder was fed to obese (fa/fa) Zucker rats (OZR), it led to a marked decrease in fasting plasma insulin levels, and significantly decreased the postprandial glucose level. In another study, the administration of an aqueous-ethanol extract of P. grandiflorum (150 and 300 mg/kg) to STZ-induced diabetic mice for 3 h (single oral administration) and for 4 weeks (repeated oral administration) produced a significant decrease in blood glucose levels. It was observed that the plasma insulin levels of the mice did not change indicating that the root of P. grandiflorum induced hypoglycaemic effects without stimulating insulin secretion [57].

2.1.7 Aralia elata The bark and root cortex of Aralia elata (Miq) Seem., (Araliaceae) is used as a tonic, antiarthritic and antidiabetic agent in TCM, and the root cortex of this plant is said to be useful in the treatment of diabetes in Japanese folk medicine.

Platycodin D, a triterpene saponin from the plant P. grandiflorum has been found to inhibit intracellular TG accumulation in 3T3-L1 cells, with an IC50 of 7.1 μM. The compound significantly down-regulated the expression levels of genes involved in lipid metabolism such as fatty-acid-binding protein 4 and lipoprotein lipase. It is suggested that the antiadipogenic effect of Platycodin D is due to the upregulation of an anti-adipogenic factor Kruppel-like factor (KLF)2 and subsequent down-regulation of PPAR- expression, and its binding to target DNA sequence [58]. TG accumulation is linked to obesity and low grade chronic inflammation, which, in turn can cause diabetes complications [7, 59].

Elatosides E, F, oleanolic acid and some oleanolic acid glycosides (elatoside A, elatoside C, tarasaponin VI, stipuleanoside R1, chikusetsusaponin IV and stipuleanoside R2) isolated from the root cortex of A. elata have been tested for hypoglycaemic activity using the oral sucrose tolerance test in rats. The potent hypoglycaemic activity was observed for elatoside E and tarasaponin VI, while oleanolic acid 3,28-O-bisdesmosides having a 2', 3'-O-diglycoside moiety (elatoside C and elatoside F) and oleanolic acid showed little activity. Oleanolic acid 3-O-monodesmosides and 3,28-Obisdesmosides, having an 4'-O-arabinosyl moiety, exhibited hypoglycaemic activity [54].

2.1.9 Salacia species

After observing the potent hypoglycaemic effect of the saponin fractions from the young shoots of A. elata, five new saponins, named elatosides G, H, I, J and K have been reported by the same research group. Elatosides G, H and I at a dose of 100 mg/kg showed hypoglycaemic activity in the oral glucose tolerance test in

Salacia oblonga Wall. (Celastraceae) known as ‘chundan’ in Tamil and ‘ponkoranti’ in Malayalam, is distributed throughout the southern region of India. The root of S. oblonga has been used in the treatment of gonorrhoea, rheumatism, itching, asthma and diabetes in the Ayurvedic system of traditional Indian medicine [60].

H

COOR7 R6

H O

R4 R3O

Triterpene compound

R1

Elatoside A

-D-Xyl

Elatoside E

-D-Xyl

O R5

R2O

OR1

R2

R3

R4

R5

R6

R7

-D-Gal

H

COOH

CH3

H

H

-D-Glu

H

H

CH3

H

H

Elatoside G

H

H

H

COOH

CH2OH

OH

H

Elatoside H

H

-D-Glu

H

COOH

CH3

OH

H

Elatoside I

-D-Glu

-D-Glu

H

COOH

CH3

H

H

Chikusetsusaponin IV

H

H

-L-Ara(f)

COOH

CH3

H

-D-Glu

Stipuleanoside R1

H

-D-Glu

-L-Ara(f)

COOH

CH3

H

H

Stipuleanoside R2

H

-D-Glu

-L-Ara(f)

COOH

CH3

H

-D-Glu

Tarasaponin VI

H

H

-L-Ara(f)

COOH

CH3

H

H

-D-Glu: -D-glucopyranosyl; -D-Gal: -D-galactopyranosyl -D-Xyl: -D-xylopyranosyl; -L-Ara(f): -L-arabinofuranosyl

Fig. (4). Oleanane-type triterpenes from Aralia elata SEEM.


A petroleum ether extract of the root bark of S. oblonga has been reported to prevent hyperglycaemia in STZ-induced diabetic rats, followed by an amelioration of lipid peroxidation in renal tissue [61]. The chronic administration of the water extract markedly improved interstitial and perivascular fibrosis of OZR heart and markedly suppressed the over-expression of mRNAs encoding transforming growth factor hs 1 and 3 in the OZR heart. A dosedependent inhibition of the increase of plasma glucose in sucrose-, but not in glucose-loaded mice, has also been observed. S. oblonga demonstrated the strong inhibition of -glucosidase activity in vitro, which suggests its contribution to the improvement of postprandial hyperglycaemia [62]. This finding supports other studies which demonstrated that S. oblonga decreases cardiac hypertrophy in ZDF rats, at least in part by inhibiting cardiac AT1 overexpression [63]. S. oblonga lowers postprandial glycaemia in patients with type 2 diabetes, [64] and may prevent or delay the onset of complications caused by diabetes such as cardiovascular diseases [62]. In a two-centre, randomised, double-blinded, three-period, threetreatment crossover study on sixty-six patients with diabetes, S. oblonga (at a dose of 240 mg and 480 mg, with control meal) lowered acute glycaemia and insulinaemia after a high carbohydrate meal [64]. Kotalagenin 16-acetate, maytenfolic acid and 3, 22dihydroxyolean-12-en-29-oic acid isolated from the roots of S. oblonga have been found to inhibit rat lens aldose reductase, a key enzyme in the polyol pathway. This enzyme is reported to catalyse the reduction of glucose to sorbitol, the accumulation of which has been implicated in the chronic complications of diabetes [60].


7

Kaikasaponin III isolated from the flower of P. thunbergiana exhibited significant hypoglycaemic activity in STZ-induced diabetic rats. The compound protected the Vero cell line (normal monkey kidney) from hydrogen peroxide injury [71]. In an another study, it has been reported that the hypoglycaemic and hypolipidaemic effects exhibited by Kaikasaponin III may be either by upregulating or down-regulating antioxidant mechanisms via the changes in Phase I and II enzyme activities [70]. Kaikasaponin III from the flowers of P. thunbergiana may treat or prevent DM by regulating the hepatic phase I and II enzymes associated with the disease [70]. However, more studies are needed to explore the underlying molecular mechanism. 2.1.12 Acanthopanax senticosus Acanthopanax senticosus Harms. (Araliaceae) is known as Ciwujia in China and is predominantly cultivated for medicinal use. The root and stem barks of A. senticosus have been used traditionally as a tonic, antirheumatic and prophylactic for chronic bronchitis, hypertension and ischaemic heart disease [72, 73]. The aqueous extract of A. senticosus root (150 mg/kg, three times daily) has been reported to improve insulin sensitivity and delay the development of insulin resistance in fructose rich chow-fed rats [72]. The ethanol extract reversed the hepatomegaly in insulin resistant ob/ob mice with fatty liver after 8 weeks of treatment, and lowered circulating glucose, lipids and enhanced insulin action in the liver with a reduction in liver glucose 6-phosphatase and lipogenic enzymes [74].

Salacia chinensis L. is widely distributed in Thailand, Myanmar and India. The stems of S. chinensis have been extensively used for the treatment of several illnesses including diabetes. 3, 22Dihydroxyolean-12-en-29-oic acid, maytenfolic acid, -amyrin, 22-hydroxy-3-oxoolean-12-en-29-oic acid, and -amyrenone isolated from the 80% aqueous methanolic extract of the stems of S. chinensis have been reported to inhibit rat lens aldose reductase [65].

A triterpene glycoside, 3-O-[(-L-rhamnopyranosyl) (12)][-D-glucuronopyranosyl-6-O-methyl ester]-olean-12-ene-28-olic acid, a new indole alkaloid, 5-methoxy-2-oxoindolin-3-acetic acid methyl ester, and six known compounds have been isolated from the leaves of A. senticosus. 3-O-[(-L-rhamnopyranosyl) (12)][-D-glucuronopyranosyl-6-O-methyl ester]-olean-12-ene-28-olic acid and (+)-afzelechin inhibited -glucosidase, with an IC50 value of 908.5 ± 67.29 and 186.0 ± 12.01 M, respectively [75]. A. senticosus has the potential to improve insulin resistance and thus, it can be considered as a candidate for improving insulin sensitivity, however, isolated pure compounds from this plant would require extensive in vivo testing.

2.1.10 Polygala senega

2.1.13 Beta vulgaris

Polygala senega var. latifolia has been traditionally used for the treatment of cough [66]. The n-butanol extract of senega rhizomes (5 mg/kg) has been reported to reduce the blood glucose levels of normal mice (from 191 ± 3 to 120 ± 3 mg/dL) four hours after intra-peritoneal administration (P < 0.001), and also produced a significant decrease in the glucose level of KK-Ay mice (from 469 ± 38 to 244 ± 14 mg/dL) under similar conditions (P < 0.001). In STZ-induced diabetic mice, the extract did not change blood glucose levels. It has been proposed that the hypoglycaemic effect of senega rhizomes extract occurs without altering the insulin concentration, and it needs the presence of insulin for its action [67].

Beta vulgaris L. var. cicla (Chenopodiaceae), is used in traditional medicine in Turkey as an antidiabetic agent [76]. The fresh root and leaves of this plant are used in TCM for its sedative and emmenagogue-like effects [77].

Triterpenoid glycosides from the rhizomes of P. senega, including senegins II-IV and desmethoxysenegin II, have been isolated. Sengins II (the main component of P. senega) and III (5 mg/kg) reduced the blood glucose of normal mice four hours after intraperitoneal administration, and also significantly lowered the glucose level of KK-Ay mice [66]. At 2.5 mg/kg, Senegin-II reduced the blood glucose level in normal mice from 220 ± 8 to 131 ± 5 mg/dL 4 hours after intraperitoneal administration (P < 0.001), and also significantly lowered the blood glucose of KK-Ay mice from 434 ± 9 to 142 ± 6 mg/dL [68]. 2.1.11 Pueraria thunbergiana The flowers of Pueraria thunbergiana (Leguminosae) have been used as an ‘anti-thirst’ drug for the treatment of DM [69]. The traditional medicinal term, ‘anti-thirst’ drug, mainly implies to crude anti-diabetic drug in Korea [70].

The hypoglycaemic effect of chard leaves of B. vulgaris in normal and alloxan-induced diabetic rabbits has been investigated. It was found that the aqueous extract had significant hypoglycaemic effect on normal rabbits four hours after administration. This aqueous extract also showed an antihyperglycaemic effect in diabetic rabbits [76]. In diabetic rats treated with the aqueous extract of B. vulgaris leaves (at a dose of 2 g/kg for a period of 28 days), the morphology of the kidney tissue was similar to that of controls. In contrast, significant degenerative changes in the kidney tissue of diabetic rats were observed. Chard extract also reduced serum urea and creatinine significantly, in comparison with the diabetic group [78]. In another study, the effect of feeding chard leave extract on diabetesinduced free radical–mediated injury in rat aorta and heart tissues was investigated by the same research group. It was found that treatment with chard extract (2 g/kg) given for 28 days decreased lipid peroxidation and increased glutathione in both aorta and heart tissue in comparison with diabetic controls [79]. The protective effect of chard extract on the liver of diabetic rats has been investigated both morphologically and biochemically. At a dose of 2 g/kg for 28 days in diabetic rats, there was slight or no changes in the liver tissue in comparison with the untreated group, which showed some degenerative changes. Chard extract has

8


decreased serum alanine, aspartate transaminase, alkaline phosphatase activities, as well as the total lipid, sialic and uric acid, blood glucose and liver lipid peroxidation and nonenzymatic glycosylation levels, and increased blood and liver glutathione levels [80]. The isolation of betavulgarosides I, II, III, IV, VI, VII, VIII and oleanolic acid oligoglycosides, having an unique acidic substituent, have been reported from the root of B. vulgaris. Among them, betavulgarosides II, III and IV (at a dose of 100 mg/kg, single oral administration) were found to have hypoglycaemic activity in oral glucose tolerance tests in rats [77]. In addition to having hypoglycaemic effects, B. vulgaris also shows protective effects on the kidney, and ameliorating effects on liver injury caused by diabetes. Isolated triterpenes were also found to have antidiabetic activity suggesting that B. vulgaris could be a prominent source of new antidiabetic agents.

Alqahtani et al.

2.2 The Ursane Group The ursanes have methyl groups on C-19 and C-20. They are widely distributed in common medicinal plants which have ‘heat’ clearing properties in traditional medicine, such as Crataegus species, Cornus officinalis, Boswellia carterii [89, 90], Centella asiatica [91], Glycyrrhiza species [30] and Terminalia arjuna [92]. They have shown potent apoptosis-inducing activity [93], antiinflammatory and cancer chemoprotective activity [94]. The following section focuses on medicinal plants containing ursane compounds as active compounds for diabetes and its complications (Fig. 5, Table 2). R6

2.1.14 Miscellaneous Herbs An oleanane-type triterpenoid (1,10-seco-3 ,10,23trihydroxyolean-12-ene-1,28-dioic acid 1,23-lactone) possessing a hitherto unknown 1,10-seco-oleanane skeleton, isolated from the leaves of the plant Fagus hayatae Palib., has been reported to inhibit -glucosidase, with an IC50 of 96.2 ± 0.08 M [81]. The stem bark of Kalopanax pictus Nakai. has been used in traditional herbal medicine as a tonic, analgesic and antidiabetic agent. Kalopanaxsaponin A isolated from this plant exhibited potent antidiabetic activity in STZ-induced diabetic rats [82]. The methanolic extracts from the branches and leaves of Eysenhardtia platycarpa have been reported to significantly decrease blood glucose levels in normal and STZ-induced diabetic rats. 3-OAcetyloleanolic acid, which has been identified as the major constituent of branches of E. platycarpa, produces a significant decrease (26.3 ± 3.7%) in the glucose level of STZ-induced diabetic rats after 7 hours of treatment [83]. A fraction containing three new oleanane-derived triterpenes, (3-O--D-glucopyranosyl-(1-4)--D-glucuronopyranosyl siaresinolic acid-28-O--D-glucopyranosyl ester, macranthoside B and its isomer) separated from the Ilex kudingcha, have been found to significantly reduce the elevated levels of serum glycaemic and lipids in type 2 diabetic mice. 3-Hydroxy-3-methylglutaryl coenzyme A reductase and glucokinase were significantly upregulated, while fatty acid synthetase and glucose-6-phosphatase catalytic enzyme were down-regulated after treatment [84]. Olean-12-en-28-oic acid 3-O-monodesmoside based saponins have been isolated from many natural medicines and exhibit inhibitory activity on the increased serum glucose levels in oral glucoseloaded rats. Two of these saponins, momordine Ic and oleanolic acid 3-O-glucuronide significantly suppressed gastric emptying at the dose of 25 mg/kg and 50 mg/kg, respectively. They also inhibited the glucose uptake in rat small intestine in a dose-dependent manner [85]. Bumelia sartorum Mart has been used by Brazilian folklore in the treatment of diabetes mellitus and inflammatory disorders. Bassic acid isolated from this medicinal plant in a dose of 50 mg/kg per day or 100 mg/kg per day exhibited significant hypoglycaemic effect equal to chlorpropamide in alloxan-induced diabetic rats but not normal rats. It favourably altered the glucose tolerance and increased plasma insulin levels and also increased the glucose uptake in isolated rat diaphragm. It was suggested that the activity is mediated through enhancing insulin secretion from pancreatic cells [86]. A bioassay-guided study of the Spondias mombin, a medicinal plant used traditionally to manage diabetes in South West Nigeria, led to the isolation of 3-olean-12-en-3-yl (9Z)-hexadec-9-enoate from the diethyl ether fraction with 57% -amylase inhibitory activity at a dose of 20 mg/mL [87, 88].

H

R1

R5

H R2 R3 Triterpene compound

R4

R1

R2

Ursolic acid

H

-OH

Asiatic acid

-OH

H

R3

R4

R5

R6

CH3

H

COOH

H

CH2OH

OH

COOH

H

-Amyrin

H

-OH

CH3

H

CH3

H

Corosolic acid

-OH

-OH

CH3

H

COOH

H

3-Epicorosolic acid

-OH

-OH

CH3

H

COOH

H

Uvaol

H

-OH

CH3

H

CH2OH

H

Pomolic acid

H

-OH

CH3

H

COOH

OH

Euscaphic acid

-OH

-OH

CH3

H

COOH

OH

Tormentic acid

-OH

-OH

CH3

H

COOH

OH

Fig. (5). Pentacyclic triterpenoids from herbal medicines - Ursane group.

2.2.1 Eriobotrya japonica Eriobotrya japonica Lindl. (Rosaceae), known as Loquat, is a medicinal plant that has been used in China and India for the treatment of DM. Triterpene saponins are known to be abundant in this plant and responsible for its anti-inflammatory activity [95, 96]. Total triterpene fraction of the leaves extract showed significant hypoglycaemic and anti-diabetic activities in animal studies [97]. The ethanolic extract showed significant hypoglycaemic effect in normal rabbits similar to the drug tolbutamide [98]. Pentacyclic triterpenoids, mainly of ursolic and oleanolic groups, have been isolated from the leaves of this plant and considered as the most bioactive constituents in E. japonica. The composition of main compounds in intact leaves reached 16.0 mg/g and 5.4 mg/g (dry weight) of ursolic acid and corosolic acid respectively, while maslinic acid was reported much higher in callus tissues than in the intact leaves [99, 100]. Polyhydroxylated triterpenoids, 2-hydroxyursolic acid and pomolic acid are thought to promote insulin release by stimulating pancreatic beta-cells in genetically-altered diabetic mice as well as normoglycaemic rats [101]. Tormentic acid is also found in Loquat and was reported previously as a hypoglycaemic agent [99, 102]. 2.2.2 Centella asiatica The triterpenoid glycosides represent the main pharmacologically active constituents in Centella asiatica L. (Umbelliferae/Apiaceae). The major components are pentacyclic triterpenes


Table 2.


9

Pharmacological Activities of Ursane Compounds Presented in Popular Herbal Medicines.

Plant name

Eriobotrta japonica

Centella asiatica

Lagerstroemia speciosa

Active compounds


Ref.

Corosolic acid

Promotes 3H-glucose uptake, suppresses the differentiation and down-regulates the expression of PPAR- and C/EBP- mRNA in 3T3-L1 adipocytes. Inhibits 11-Hydroxysteroid dehydrogenase 1 activity.

[232], [233]

3-Epicorosolic acid methyl ester

Inhibits 11-Hydroxysteroid dehydrogenase 1 activity. Exhibits hypoglycaemic activity and stimulates insulin release.

[233] [102]

2-Hydroxy-3-oxo urs12-en-28-oic acid. Tormentic acid.

Inhibits 11-Hydroxysteroid dehydrogenase 1 activity. Tormentic acid inhibits glycosuria.

[233]

2-Hydroxyursolic acid. Pomolic acid.

Exhibits hypoglycaemic activity

[101]

Total triterpene acid fraction

Exhibits hypoglycaemic and hypolipidaemic effects

[97]

Euscaphic acid

Exhibits hypoglycaemic effect in alloxan-diabetic mice

[234]

Asiatic acid

Preserves pancreatic beta cell mass and mitigates hyperglycaemia in STZ-induced diabetic rats at dose of 25 mg/kg for two weeks.

[103]

Asiaticoside

Promotes wound healing in STZ diabetic rats

[106]

Madecassoside

Exhibits cardioprotective effect through suppression of inflammatory mediators in cardiomyocytes and protection against myocardial ischemia-reperfusion injury in vivo

[107, 108]

Ursolic acid

Ameliorates obesity and glucose intolerance in high-fat-fed C57BL/6 mice

[140]

Corosolic acid 23-Hydroxyursolic acid

Exhibits -glucosidase inhibiting activity. Exhibits hypoglycaemic activity.

[147], [100]

2-Oxopomolic acid

Exhibits -glucosidase inhibiting activity. Exhibits antioxidant activity.

[149], [150]

Exhibits -glucosidase inhibiting activity.

[149]

Inhibits PTP1B.

[153]

Corosolic acid Pomolic acid

Stimulates glucose uptake in basal- and insulin-stimulates L6 muscle cells.

[152]

Ilekudinol A

Inhibits PTP1B, with IC50 values of 29.1 M.

[151]

Ilekudinol B

Inhibits PTP1B, with IC50 values of 5.3 M. Stimulates glucose uptake in basal- and insulin-stimulated L6 muscle cells.

[151, 152]

Ursolic acid Sanguisorba tenuifolia

Euscaphic acid p-Coumaroylursolic acid 2,19-Dihydroxy-3oxo-12-ursen28-oic acid

Symplocos paniculata

Weigela subsessilis

Ursolic acid Corosolic acid

including asiaticoside, madecassoside and their corresponding aglycones asiatic acid and madecassic acid. Asiatic acid significantly reduced the blood glucose levels and concomitantly increased serum insulin levels in STZ-induced diabetic rats with marked preservation of pancreatic beta cells [103]. The compound decreased the level of inflammatory mediators in mice serum after 5 hours of carrageenan (Carr) administration, and decreased Carr-induced inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), and nuclear factor-kappaB (NF-B) expressions in the oedema paw [104]. In vitro, asiatic acid showed more activity than asiaticoside in inhibiting the lipopolysaccharide (LPS)-induced NO and PGE2 production via NF-B inactivation [105]. Asiaticoside at 0.4% solution applied over wounds in STZ-diabetic rats increased hydroxyproline content, wound tensile strength, collagen accumulation and epithelisation in the wound area [106]. The cardioprotective ability of madecassoside has been observed by suppressing the LPS-induced TNF- production in cardiomyocytes through inhibition of ERK, p38 and NF-B activity in vitro, and protection against myocardial ischaemia-reperfusion injury in vivo [107, 108]. Recently, a new ursane-type triterpenoid glycoside, asiaticoside G, has been isolated and found to modulate the production of NO and

secretion of TNF- in LPS-stimulated RAW 264.7 cells [109]. The triterpene components from Centella have shown activities related to diabetes and its complications in humans. In a randomisedcontrolled clinical trial of two hundred diabetic patients, Centella extract at an oral dose (300 mg/kg) shortened the duration of healing in diabetic wounds [110]. In a randomised clinical study, total triterpene fraction of C. asiatica (TTFCA), (containing approximately 40% asiaticoside and 60% of asiatic and madecassic acids) improved microcirculation and decreased capillary permeability in diabetic microangiopathy when administered in a dose of 60 mg twice daily [111, 112]. 2.2.3 Ilex species The leaves of Ilex plant (Aquifoliaceae), consumed as herbal tea beverages, are used widely for numerous health disorders. I. paraguariensis St.-Hil. (mate), I. aquifolium L. (holly) and I. kudingcha C. J. Tseng (Kudingcha) are the main common Ilex species used medicinally. The majority of triterpenoidal saponins in ilex are from oleanane- and ursane-type aglycones. The ursane saponins from ilex are mainly ilekudinosides, ilexosides, ilexsaponins, latifolosides and ursolic acid [113-116]. Moreover, kudinosides and

10 Current Medicinal Chemistry, 2013, Vol. 20, No. 4

kudinlactones have been specifically found in I. kudingcha C. J. Tseng [117]. Metasaponin was isolated from I. paraguariensis, while 28-nor-ursolic acid, 3-O-acetylursolic acid and uvaol were isolated from the leaves of I. affinis and I. buxifolia [118, 119]. Published studies have highlighted their beneficial effects, including antioxidant [120, 121], antiglycation [122] anti-obesity [123] and cardioprotective activities [124]. They have been experimentally and clinically reported to ameliorate the oxidative stress and metabolic syndrome associated with obesity and dyslipidaemia [125-128]. The saponin fraction from the ethanolic extract of the roots of I. pubescens Hook. et Arn. showed anti-inflammatory effects on carrageenan-induced paw oedema in rats. Pubescenosides, ilexsaponins and chikusetsusaponin IV were identified in this fraction [129]. In a clinical pilot study, regular consumption of mate tea for 60 days was shown to significantly improve the glycaemic control and lipid profile of type-2 diabetes mellitus subjects [130]. The aqueous extract of I. paraguariensis was shown to reduce the development of atherosclerotic lesion in cholesterol-fed rabbits [131]. It has been shown to inhibit LDL oxidation both in vitro and in human subjects; this is likely due to its antioxidant capacity [132, 133]. 2.2.4 Crataegus species Crataegus species (Rosaceae) such as C. pinnatifida Bge., C. oxyacantha L. and C. microphylla C. Koch have shown antidiabetic activity. Ursolic acid and oleanolic acid contents have been detected in Chinese hawthorn (C. pinnatifida) fruits, up to 1177 g/g and 224 g/g (fresh weight), respectively [134]. The leaves extract of C. oxyacantha and C. microphylla has potent hypoglycaemic effect and preserved vascular function in STZ-induced diabetic rats [135, 136]. Chronic in vivo treatment with C. microphylla methanolic extract normalised the elevated aortic iNOS, TNF-, interleukin6 (IL-6), total nitrate/nitrite and malondialdehyde levels in diabetic rats [136]. The increased formation of advanced glycated end products in diabetic patients due to chronic hyperglycaemia may activate protein kinase C (PKC) which contributes to the pathogenesis of diabetic complications [137]. Corosolic acid isolated from the fruit of C. pinnatifida was shown to inhibit PKC in a dosedependent manner [138]. 2.2.5 Miscellaneous A phytochemical study on a methanol-soluble extract of the leaves of persimmon (Diospyros kaki) resulted in the isolation of two ursane-type triterpenoids, 3,19 -dihydroxyurs-12,20(30)dien-24,28-dioic acid and 3,19-dihydroxyurs-12-en-24,28-dioic acid, together with 12 known ursane- and oleanane-type triterpenoids. Those with a 3-hydroxy group were found to inhibit protein tyrosine phosphatase 1B (PTP1B) activity, which plays a pivotal role in insulin receptor activity and downstream signaling pathways, with IC50 values ranging from 3.1 ± 0.2 to 18.8 ± 1.3 M [139]. 12-Ursene was isolated from Agarista mexicana (Hemsl) Judd, and produced a significant glucose-lowering effect in normal and alloxman-diabetic CD1 mice (at a dose of 50 mg/kg) [140]. Ursolic acid has been isolated from Astianthus viminalis Baill. and showed hypoglycaemic effects in normoglycaemic and STZinduced diabetic mice [141]. It also has been isolated from Sambucus australis Cham. et. Schltdl. and found to ameliorate abdominal adiposity and to decrease blood glucose and plasma lipid levels in vivo [142]. 3-Acetyl-11-keto-beta-boswellic acid, isolated from Boswellia serrata Roxb., inhibits the expression of acid sphingomyelinase in intestinal cells [143]. The ether extract of Cornus officinalis Sieb. et Zucc., containing triterpene acids, mainly ursolic and oleanolic acids, attenuated diabetic cardiomyopathy by suppressing ROS production and normalising the endothelin-1 pathway and the expression of FKBP12.6 and SERCA2a in STZ-rats. It modulated the upregulated endothelin system in diabetic vascular dysfunction and early retinopathy [144, 145]. Ursolic acid isolated from Cornus ameliorated obesity and glucose intolerance in high-

Alqahtani et al.

fat-fed C57BL/6 mice [140]. Ursane-type triterpenes with glucosidase inhibitory activity include -amyrin-3-O--(5-hydroxy) ferulic acid, isolated from Euclea undulate Thunb. var. myrtina [146], and 23-hydroxyursolic acid, isolated from Lagerstroemia speciosa [147] [100]. Urs-12-en-3-ol-28-oic acid 3-Dglucopyranosyl-4'-octadecanoate isolated from Lantana camara reduced blood glucose levels in STZ-induced diabetic rats [148]. Several ursane-type triterpenes from Sanguisorba tenuifolia var. alba. were shown to have -glucosidase inhibitory activity, including ursolic acid, 2-oxopomolic acid, euscaphic acid, pcoumaroylursolic acid and 2,19-dihydroxy-3-oxo-12-ursen-28oic acid [149], [150]. The methanolic extract of the leaves and stems of Weigela subsessilis L. was found to inhibit PTP1B. In vitro bioassay-guided fractionation led to the isolation of two 24norursane triterpenes, ilekudinol A and ilekudinol B, which inhibited PTP1B, with IC50 values of 29.1 and 5.3 μM, respectively [151]. Ilekudinol B, corosolic acid and pomolic acid from W. subsessilis stimulate glucose uptake in basal- and insulin-stimulated L6 muscle cells [152]. Ursolic acid and corosolic acid were isolated from Symplocos paniculata Thunb., and were found to inhibit PTP1B [153]. 2.3 The Lupane Group Lupane-type triterpenes are widely distributed in medicinal plants, such as A. senticosus [154], Viburnum odoratissimum var. awabuki [155], Acacia mellifera (Benth) [156]. Lupane-type triterpenes, such as betulin, betulinic acid and lupeol, display antiinflammatory activity which often accompanies immunomodulation, antiproliferative and topoisomerase I and II inhibitory activity [157, 158]. The following section focuses on medicinal plants containing lupanes as active compounds for the treatment of diabetes and its complications (Fig. 6, Table 3).

H H R1

R3

R2

H

Triterpene compound

R1

R2

R3

Betulinic acid

-OH

CH3

COOH

Betulin

-OH

CH3

CH2OH

Lupeol

-OH

CH3

CH3

Lupenone

=O

CH3

CH3

Bacosine

-OH

-COOH

CH3

Fig. (6). Pentacyclic triterpenoids from herbal medicines - Lupane group.

2.3.1 Bacopa monniera The leaves of Bacopa monniera (L.) Wettst. (Scrophulariaceae), known as Brahmi, is a nerve tonic and anti-anxiety medicinal plant in Unani and Ayurvedic medicines. It has been used to help alleviate the symptoms associated with diabetes, especially those related to neuropathic disorders, due to the neuroprotective [159-162], antiinflammatory [163] and antioxidant [164, 165] potential of its bioactive constituents. An aqueous ethanolic extract of B. monnieri has been shown to modulate the antioxidant and lipid peroxidative status in diabetic models, suggesting a protective effect against diabetes induced-oxidative stress. The extract significantly in-


Table 3.


11

Pharmacological Activities of Lupane Compounds Presented in Popular Herbal Medicines.

Plant name

Active compounds


Ref.

Bacosine

In vivo hypoglycaemic effect.

[168]

Betulinic acid

Anti-inflammatory.

[169]

Lupeol

Antidyslipidaemic activity

[179]

Ethanolic extract

Hypoglycaemic and -cells regenerative effects of bark extract (contains 0.29% w/w lupeol) in STZ-induced diabetic rats.

[83]

Lupeol and lupenone

Reduces NO production, iNOS and COX-2 protein levels in LPS-stimulated RAW 264.7 cells, and inhibits intracellular ROS generation by tert-butylhydroperoxide.

[180]

Bacopa monnieri

Aegle marmelos

Pueraria lobata

creased the levels of antioxidant enzymes (SOD), CAT, and glutathione peroxidase (GPX)] and glutathione (GSH) in the brain and kidney tissues of STZ-induced diabetic rats [166]. Furthermore, 50 mg/kg of B. monniera extract showed significant ulcer-healing activities in normal and NIDDM rats [167]. Dammarane-type saponins (e.g. bacosides) are considered to be the main active components in brahmi, however, pentacyclic triterpenes have recently been isolated and shown to have potential activities. Bacosine, a new lupane-derived triterpene isolated from the ethyl acetate fraction of the ethanolic extract, significantly decreased blood glucose levels, by enhancing glucose utilisation, in alloxanised-diabetic rats. It also prevented haemoglobin glycosylation in vitro (IC50 = 7.44 g/mL), comparable to the activity of -tocopherol [168]. In addition, betulunic acid markedly suppressed LPS- stimulated IL-6 production through the modulation of NF-B in blood mononuclear cells both in vivo and in vitro [169]. In summary, a number of studies have shown the antioxidant, anti-inflammatory and neuroprotective potential of brahmi and its triterpene constituents.

Fagara tessmannii Engl.) [107] and 3 ,6-dihydroxylup-20(29)ene (from Periploca aphylla Decne.) [108] show -glucosidase inhibitory activity. The ethanolic crude extract from Sorbus decora C.K.Schneid has been reported to exhibit anti-hyperglycaemic and insulin-sensitising activities in vivo and increased glucose uptake in skeletal muscle cells in vitro [182, 183]. The bioassay-guided fractionation led to the isolation of 23,28-dihydroxylupan-12-ene-3caffeate as the antidiabetic compound. Other isolated pentacyclic triterpenes were not active in this assay [184].

2.3.2 Aegle marmelos

3.1 Oleanolic Acid

Aegle marmelos Corr. (Rutaceae), commonly known as beal fruit tree, is an Indian native species that has been used medicinally since ancient times and it is highly reputed in Ayurvedic medicine. The extracts of the different parts of A. marmelos have antidiabetic [170-172], beta-cell protection and regeneration [173-175], neuroprotection [176], cardioprotective [177] and antidyslipidaemic [178] activity. Lupeol is one of the active constituents of A. marmelos. The ethanolic extract of tree bark (dose of 200 mg/kg containing 0.29% w/w lupeol) resulted in a significant reduction in blood glucose levels (19.14%) in STZ-induced diabetic rats [175]. Lupeol has also been isolated from the plant leaves and found to normalise the lipid profile of dyslipidaemic hamster model. At a dose of 100 mg/kg, it lowered the TG level by 26%, cholesterol by 9%, glycerol by 10%, free fatty acids by 23%, and significantly improved the HDL–cholesterol level by 44%, with the HDL/cholesterol ratio being 63% [179].

Oleanolic acid has been shown to effectively improve diabetic parameters in various animal models. In STZ-induced diabetic mice, the oral administration of oleanolic acid (100 and 200 mg/kg) for 40 days resulted in reduced glucose blood levels, and an improvement in oral glucose tolerance tests compared to the nontreatment group. The level of TG, total cholesterol and LDL levels were significantly diminished, whereas HDL was markedly enhanced, and the serum insulin level was improved in the oleanolic treatment group compared to the control [185]. Similar hypoglycaemic and hypolipidaemic effects for oleanolic acid were observed in other studies. Ngubane et al. (2011) postulated that the hypoglycaemic effect of oleanolic acid was related to enhanced hepatic glycogen synthesis. In this study, 80 mg/kg oleanolic acid was given orally to STZ-induced diabetic mice for 5 weeks. In the oleanolic acid-treated group, the glycogen levels were restored to nearly normal through the increased glucokinase and hexokinase activity in both muscle and hepatic tissues [186]. In high-fat-dietinduced obese mice, continuous oral administration of oleanolic acid (10 mg/kg) daily for 15 weeks led to a significant enhancement in glucose tolerance, and reduction in body weights, visceral adiposity and plasma levels compared with the control group. Furthermore, oleanolic acid elevated plasma leptin level and reduced the level of plasma ghrelin, which modulate the metabolism of carbohydrate and fat [187].

2.3.3 Miscellaneous Herbs Lupeol and lupenone have been isolated from several medicinal plants, e.g. Pueraria lobata (Willd.) Ohwi., Sorbus commixta Hedl., Solanum xanthocarpum Schrad and Wendl and Terminalia sericea Burch. Ex. DC. Both lupeol and lupenone are able to reduce NO production, iNOS and COX-2 protein levels in LPS-stimulated RAW 264.7 cells, and inhibit the intracellular ROS generated by tert-butylhydroperoxide [180]. Lupeol and lupenone isolated from S. commixta also inhibited PTP1B, which plays a pivotal role in the inhibition of insulin activity [181]. Lupeol isolated from S. xanthocarpum and T. sericea has antioxidant properties [110], glucosidase and -amylase inhibitory activity [106]. The methanolic extract of the aerial parts of Tournefortia hartwegiana Steud., which contains lupeol, exerts anti-hyperglycaemic and glucosidase inhibition activity [142]. New isolated lupane-type triterpenes, 3-acetoxy-16-hydroxybetulinic acid (isolated from

3. IMPORTANT PENTACYCLIC TRITERPENOID FOR DIABETES AND ITS COMPLICATIONS Many bioactive pentacyclic triterpenoid have been identified from medicinal plants, with ursolic acid, oleanolic acid, glycyrrhetinic acid and betulinic acid the most studied for their activity and clinical applications in cancer. There is an increasing number of reports on their antidiabetic activities (Table 4).

Apart from its lipid- and glucose-lowering effects, oleanolic acid modulates the secretion of insulin in both animal and cellular models. In diabetic mice induced by STZ, 100 mg/kg of oleanolic acid was given intraperitoneally for 1 week. The plasma insulin levels in the oleanolic acid treated group was elevated compared to the basal level of the control group, possibly via the promotion of the insulin signal transduction in mice hepatic cells. Indeed, oleanolic acid protected hepatic cell death by maintaining the mitochondrial membrane potential and the phosphylation of the


Table 4.

Alqahtani et al.

Bioactive Pentacyclic Triterpenoids for Diabetes and its Complications.

Compound

Glycyrrhizic acid

Model

Dose/duration

Effects

Ref.

STZ-induced diabetic rats

100 mg/kg for 2 weeks

Reduces blood glucose level, enhanced serum insulin level and pancreatic islet cell number. Reverses oxidative stress parameters such as serum SOD, catalase, malondialdehyde and fructosamine to their respective normal values.

[203]

Genetic diabetic KK-Ay mice

4.1g/kg for 7 weeks

Reduces blood glucose level and enhanced serum insulin level.

[204]

Wild type ddY mice

30 mM was given 30 mins before the administration of glucose solution

Restores postprandial glucose level.

[205]

High-fat-diet-induced dyslipidaemia


Reduces plasma total cholesterol and TG levels; reduces Apo B and cholesterol-ester-transport protein and enhances Apo A-1 level Decreases hepatic HMG-CoA reductase expression.

[208]


100 mg/kg for 28 days

Leads to the up-regulation of LDL expression in the kidney, heart, quadriceps femoris, abdominal muscle and visceral and subcutaneous adipose tissues.

[209]


Improves serum lipid parameters, including reductions in serum free fatty acid, TG, total cholesterol and LDL levels, whereas HDL levels were elevated. Reduces lipid deposition in both abdominal muscle and quadriceps femoris.

[210, 211].


Attenuates the increased plasma glucose and glycosylated haemoglobin (HbA1c) and reduces plasma insulin and haemoglobin. Enhances the activity of hepatic gluconeogenic enzymes such as glucose 6-phosphatase, fructose 1,6-biphosphatase, and diminishes the activity of glucokinase and glucose 6-phosphatase dehydrogenase.

[206]

100 mg/kg for one week

Reduces the postprandial plasma glucose level.

[207]

5 M for 30 mins

Enhances insulin secretion and cell viability in high glucose (20 mM) stimulated cells. Raises mRNA level of insulin receptor substrate-2, pancreas duodenum homeobox-1 and glucokinase.

[30]



Diminishes body weight, abdominal fat accumulation, blood glucose, plasma TG and total cholesterol level as compared with non-treatment group. Enhances the plasma insulin and leptin levels, and reduces the level of ghrelin.

[213]

L-NAME-induced hypertensive rats


Increases the ROS level and reduces the NO level, SOD and eNOS activities in rat aortic rings.

[215]

HUVEC and EA.hy926

Leads to the up-regulation of eNOS expression, and diminishes the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in both HUVEC and EA.hy926.

[196]

Human aortic smooth muscle cell

1 M for 24 hrs

Inhibits the proliferation of human aortic smooth muscle cell induced by high glucose. Diminishes the protein and mRNA expression of MMP-2 and MMP-9 levels in a dose-dependent manner. Reduces the levels of intracellular ROS; suppresses the nuclear translocation and phosphylation of IB- of NF-B induced by high glucose condition.

[217]


100 and 200 mg/kg for 40 days

Reduces glucose blood levels and improves oral glucose tolerance tests. Diminishes TG, total cholesterol and LDL levels, and enhances HDL. Improves serum insulin levels.

[185]



Restores glycogen level to near normal by enhancing the activity of glucokinase and hexokinase in muscle and hepatic tissues.

[186]


10 mg/kg daily for 15 weeks

Enhances the glucose tolerance and reduces body weights, visceral adiposity and plasma level. Elevates plasma leptin levels, and reduces the level of plasma ghrelin, which modulates the metabolism of carbohydrate and fat.

[187]


100 mg/kg for 1 week

Protects hepatic cell death by maintaining the mitochondrial membrane potential and the phosphylation of ERK pathway.

[188]

20 mg/kg for 90 mins

Enhances insulin levels. Abolishes the enhancement of insulin secretion when co-administered with hemicholinium-3 (synaptic choline uptake inhibitor) or vesamicol (vesiculat acetylcholine transporter). Increases the insulin secretion effect of oleanolic acid markedly with concomitant adminstration of physostigmine, an acetylcholinease inhibitor.

[189]


STZ-induced diabetic rats Glycyrrhetinic acid

Islet cells isolated from male C57BL6J mice

Betulinic acid

Oleanolic acid

Wistar rats



13

(Table 4) contd…. Compound

Ursolic acid

Betulin

Model

Dose/duration

Effects

Ref.

Alloxan-induced diabetic rats


Restores the serum levels of AST, ALT and alkaline phosphatase.

[193]

BALB/cA diabetic mice

0.2 % w/w for 10 weeks

Reduces renal N -(carboxymethyl)lysine, urinary glycated albumin and urinary albumin levels Reduces renal aldose reductase activity and down-regulates aldose reductase mRNA expression in a dose-dependent manner. Increases renal glyoxalase 1 activity and dose-dependently up-regulates the mRNA expression of glyoxalase 1 expression.

[194]



Enhances the creatinine clearance, with concomitant reduction of plasma creatinine concentration and renal mean arterial blood pressure.

[195, 216]

Dexamethasone-induced hypertensive rats

60mg/kg for 5days

Attenuates the rised systolic blood pressure and cardiac lipid peroxidation induced by dexamethasone. Reduces the plasma nitrite level compared to the non-treatment group.

[235]

INS-1 832/13 and islets cells isolated from Wistar rats

50 M for 1 hour

Enhances insulin scretion in both beta and islet cells.

[190]

PTP 1B

Inhibits the activity of PTP 1B, with an IC50 of 9.5 ± 0.5 M.

[192]

High-fat-diet-fed mice


Attenuates high fat-diet induced glucose intolerance and lipid accumulation in the liver Preserves the islet structure and insulin content in the pancreatic section.

[140]

STZ-induced diabetic rat fed with high fat diet

0.05% w/w for 4 weeks

Results in improved blood glucose levels, glucose intolerance and insulin sensitivity. Results in significant elevation in insulin levels and preserving pancreatic ß-cell function. Lowers the plasma total cholesterol, free fatty acid, and TG concentration, and normalises hepatic TG concentrations.

[196] [197]

STZ-nicotinamide induced diabetic mice

0.01% and 0.05% w/w for 4 weeks

Improves blood glucose, glycosylated haemoglobin, glucose and insulin tolerance, plasma leptin and aminotransferase activity. Increases plasma and pancreatic insulin concentration.

[198]

STZ- induced diabetic mice fed with high fat diet


Results in a 53% reduction in atherosclerotic lesion formation. Reduces monocyte recruitment into MCP-1 loaded Matrigel plugs.

[200]



Reduces blood glucose and glycated haemoglobin levels. Significantly reduces aortic arch injury and the accumulation of advanced glycated end products in the aorta.

[201]



Ameliorates the accumulation of type IV collagen in the kidneys and glomerular hypertrophy.

[202]

Chinese-hamster ovary cells expressing human insulin receptor

insulin-mimetic agent at 50 μg/ml and insulin-sensitizer at 1 μg/ml.

Enhances the activity of insulin on tyrosine phosphorylation of insulin receptor B-subunit.

[199]

3T3-L1 adipocyte

1 μg/mL for 20 min

Results in an increase in the number of insulin receptors activated by insulin, and enhanced the effect of insulin on the translocation of GLUT 4.

[199]

Rat hepatocytes CRL-1601

3 g/mL for 6 hr

Inhibits the maturation of sterol regulatory element-binding proteins (SREBP) and decreases the biosynthesis of cholesterol and fatty acid.

[218]

Western-type diet-fed mice with LDL receptorknockout. High-fat diet-fed mice.

30 mg/kg/day for 6 weeks

Ameliorates diet-induced obesity, decreases serum and tissue lipid contents, improves glucose tolerance and increases insulin sensitivity. Minimises the size and improves the stability of atherosclerotic plaques.

[218]

Male albino rats of Wistar strain

35 mg/kg/day for 21 days

Exhibits an antiperoxidative effect, resulting in the protection against peroxidative damage to the red-cell membrane through antioxidant activity.

[221]

Human hepatoma cell line HepG2

1 M for 24 h

Exhibits hepatoprotective activity through decreasing the production of superoxide anion against ethanol-induced cytotoxicity.

[219]

Rat liver stellate cell line CFSC-2G

1 and 10 M for 24 h

Exhibits hepatoprotective activity against ethanol toxicity Inhibits the production of TNF-, and TGF-1 and ROS. Results in the downregulation of the production of TIMP-TIMP-2 and MMP-2. Inhibits the activation of the p38 MAPK and the JNK transduction pathways. Inhibits the phosphorylation of IB and Smad 3 and attenuates the activation of TGF-1 and NFB/IB transduction signalling.

[220]

STZ- induced diabetic rats

20, 30 and 40 mg/kg/day

Reduces serum glucose, nitric oxide and glycated haemoglobin levels. Increases pancreatic antioxidants and reduces the level of thiobarbituric acid-ROS.

[104]

Ameliorates lipid profile by lowering the TG, cholesterol, glycerol and free fatty acid levels. Improves the HDL–cholesterol level and HDL/cholesterol ratio.

[179]

Lupeol Dyslipidaemic hamster model


Table 5.

Alqahtani et al.

Mechanism of Action of Pentacyclic Triterpenoids for Diabetes and its Complications. Hypoglycaemic activity

Glucose absorption by intestine

Insulin secretion from pancreas

Glucose uptake in adipose and muscle tissues

Macrovascular/ microvascular inflammation

Models

STZ-induced diabetic rat, STZinduced diabetic mice, genetic diabetic KK-Ay mice

-glucosidase and -amylase

Plasma insulin

Muscle and liver glycogen PTP1B

HbA1c HUVEC and EA.hy926 membrane disintegration oxidative stress vascular inflammation

Herbs

Gymnema sylvestre Glycyrrhiza species Crataegus species Centella asiatica Aegle marmelos Bacopa monnieri

Gymnema sylvestre Glycyrrhiza species Centella asiatica Aegle marmelos

Gymnema sylvestre Glycyrrhiza species Centella asiatica

Gymnema sylvestre Glycyrrhiza species Crataegus species Centella asiatica Cornus officinalis

Active compounds

Oleanolic acid Ursolic acid Lupeol

Oleanolic acid

Ursolic acid

Oleanolic acid Ursolic acid Lupeol

ERK pathway [188]. The in-depth mechanism of insulin modulation was investigated in another study conducted by Hsu et al. (2006), in which a single bolus of oleanolic acid (20 mg/kg) was given to Wistar rats intraperitoneally. After 90 mins, the plasma insulin level was significantly enhanced in the oleanolic acidtreated group. The enhancement of insulin secretion was completely abolished upon co-administration of hemicholinium-3 or vesamicol. In contrast, the insulin-secreting effect of oleanolic acid was markedly increased with concomitant adminstration of physostigmine, an acetylcholinease inhibitor. These results suggest that the hypoglycaemic effect of oleanolic acid is related to an increased synaptic acetylcholine level which, in turn, stimulates muscarinic M3 receptor on pancreatic cell and resulted in an increased insulin level in plasma [189]. The anti-diabetic effect of oleanolic acid on a pancreatic beta cell line (INS-1 832/13) and islets cells isolated from Wistar rats was investigated in vitro. The incubation with oleanolic aid (50 M) for 1 hour significantly enhanced insulin scretion in both beta and islet cells [190]. In another study, oleanolic acid was shown to dose-dependently inhibit the activity of PTP1B, with an IC50 of 9.5 ± 0.5 M [191]. The results from PTP1B knock-out mice suggested that the lack of PTP1B could activate the insulin receptor, improve insulin sensitivity and stimulate glucose uptake in muscle and hepatic tissues [192]. Oleanolic acid also showed hepatoprotective and renal protective effects associated with diabetes. In alloxan-induced diabetic rats, the serum levels of AST, ALT and alkaline phosphatase were noticeably increased. However, the administration of oleanolic acid (100 mg/kg) for 40 days reduced the levels to the normal. Additionally, oleanolic acid treatment reduced the malondialdehyde levels, and increased the levels of SOD, GPX in both liver and kidney in diabetic rats [193]. The oral administration of oleanolic acid (0.2 % w/w) for 10 weeks led to a significant reduction in renal N (carboxymethyl)lysine, urinary glycated albumin and urinary albumin levels in BALB/cA diabetic mice. Indeed, oleanolic acid reduced renal aldose reductase activity and down-regulated aldose reductase mRNA expression in a dose-dependent manner. Oleanolic acid increased renal glyoxalase 1 activity and led to the upregulation of the mRNA expression of glyoxalase 1 expression in a dose-dependent manner [194]. In another study, the oral administration of oleanolic acid (60 mg/kg for 5 weeks) substantially enhanced creatinine clearance, with concomitant reduction of plasma creatinine concentration and renal mean arterial blood pressure in STZ-induced diabetic mice [195]. Overall, oleanolic acid has been shown to possess promising anti-diabetic effects in various in vitro and in vivo models, as well

as the ability to reduce blood pressure, blood glucose levels, total cholesterol, TG, LDL, and increase the plasma insulin and HDL levels. In addition, oleanolic acid may be useful in the management of diabetic complications, as it has been shown to protect liver and kidney against damage induced by physiological diabetic conditions. 3.2 Ursolic Acid Ursolic acid is considered to be an important bioactive constituent in the mentioned medicinal plants for the treatment of diabetes and diabetic complications, while the antidiabetic effects of ursolic acid have been demonstrated in several in vivo diabetic models. Jayaprakasam et al. (2006) reported that the oral consumption of ursolic acid (500 mg/kg with high fat diet) for 8 weeks significantly attenuated high fat-diet induced glucose intolerance and lipid accumulation in the liver, as well as preserving the islet structure and insulin content in the pancreatic section [140]. Another study by Jang et al. (2009) utilised STZ-induced diabetic rats fed with a high fat diet, and showed that ursolic acid (0.05% w/w) for 4 weeks consumption significantly improved blood glucose levels, glucose intolerance and insulin sensitivity, together with a significant elevation in insulin levels and preservation of pancreatic -cell function [196]. It was further demonstrated that ursolic acid significantly lowered the plasma total cholesterol, free fatty acid and TG concentration, and led to the normalisation of the hepatic TG concentrations [197]. Similar protective effects against hyperglycaemia were demonstrated in STZ-nicotinamide induced diabetic mice [198]. It is interesting to note that the stearoyl glucoside derivative of ursolic acid, ur-12-en3-ol-28-oic acid 3-D-glucopyranosyl-4’-octadecanoate led to a significant reduction in blood glucose levels in STZ-induced diabetic rats [148]. It has been demonstrated that ursolic acid enhanced the activity of insulin on the tyrosine phosphorylation of insulin receptor B-subunit in Chinese hamster ovary/insulin receptor [199]. It also increased the number of activated insulin receptors, and enhanced the effects of insulin on the translocation of GLUT 4 in insulin-sensitive 3T3-L1 adipocytes [199]. In terms of diabetic complications and the protective effects of ursolic acid, Ullevig et al. (2011) reported that the dietary supplementation of ursolic acid (0.2%) for 11 weeks resulted in a 53% reduction in atherosclerotic lesion formation in STZ-induced diabetic mice fed with a high fat diet. This was accompanied by a reduction in monocyte recruitment into MCP-1-loaded Matrigel plugs implanted into these diabetic mice [200]. In another study by Xiang et al. (2012), ursolic acid (50 mg/kg) significantly reduced aortic arch injury and the accumulation of advanced glycated end products in the aorta of STZ-induced diabetic rats [201]. Ursolic acid also shows potential benefits in diabetic nephropathy. Zhou et al. (2010)


revealed that the oral consumption of ursolic acid (0.1% w/w in food for three months) ameliorated the accumulation of type IV collagen in the kidneys and glomerular hypertrophy in STZ-induced diabetic mice [202]. This was accompanied by the induction of STAT-3, ERK1/2, and JNK pathways, which may explain partly the molecular mechanisms which ursolic acid targets [202]. 3.3 Glycyrrhizinic Acid and Glycyrrhetinic Acid Glycyrrhizic acid, also known as glycyrrhizin, is a triterpenoid saponin commonly found in licorice root (Glycyrrhiza glabra L.), which has been shown to have anti-diabetic effects in various animal models. In STZ-induced diabetes Wistar rats, the intraperitoneal injection of glycyrrhizin (100 mg/kg for 2 weeks) substantially reduced blood glucose levels, enhanced serum insulin levels and pancreatic islet cell numbers. Furthermore, oxidative stress parameters such as serum SOD, catalase, malondialdehyde and fructosamine reverted to their respective normal values [203]. Apart from the chemically-induced diabetic model, glycyrrhizin demonstrated comparative hypoglycaemic effect in genetic diabetic KK-Ay mice. The oral administration of glycyrrhizin (4.1 g/kg for 7 weeks) reduced blood glucose levels and enhanced serum insulin levels [204]. Similar results were observed in wild type ddY mice, in which postprandial glucose levels were restored to near normal after glycyrrhizin (30 mM) was given 30 mins before the administration of glucose solution [205]. Glycyrrhetinic acid, the aglycone derivative of glycyrrhizinic acid, has shown potential beneficial effects in diabetes. The oral administration of glycyrrhetinic acid (100 mg/kg) for 45 days attenuated the increase in plasma glucose and glycosylated haemoglobin (HbA1c), and decreased plasma insulin and haemoglobin in STZ-induced diabetic mice. In addition, glycyrrhetinic acid enhanced the activity of hepatic gluconeogenic enzymes, such as glucose 6-phosphatase and fructose 1,6-biphosphatase, and diminished the activities of glucokinase and glucose 6-phosphatase dehydrogenase [206]. In another study, glycyrrhetinic acid (100 mg/kg) given orally to STZ-diabetic rats for one week resulted in a significant reduction in the postprandial plasma glucose levels [207]. In an in vitro study, primary pancreatic islet cells were isolated from male C57BL6J mice. The incubation of glycyrrhetinic acid (5 M) with islet cells for 30 mins enhanced insulin secretion and cell viability in high glucose (20 mM) stimulated islet cells. Additionally, glycyrrhetinic acid was reported to induce the mRNA levels of the insulin receptor substrate-2, pancreas duodenum homeobox-1 and glucokinase [30]. Male Syrian Golden hamsters were fed with a high fat diet for 8 weeks to induce dyslipidaemia. The oral administration of glycyrrhizic acid (100 mg/kg) for 4 weeks significantly reduced plasma total cholesterol and TG levels, reduced Apo B and cholesterolester-transport protein, and enhanced Apo A-1 levels. Glycyrrhizic acid treatment dramatically decreased hepatic HMG-CoA reductase expression [208]. In another study, glycyrrhizic acid (100 mg/kg) was given orally to high-fat-diet-induced, dyslipidaemic SD rats for 28 days, and LDL expression was found to be up-regulated in the kidney, heart, quadriceps femoris, abdominal muscle and visceral and subcutaneous adipose tissues [209]. Furthermore, glycyrrhizic acid improved serum lipid parameters, including serum free fatty acid, TG, total cholesterol and LDL levels, and elevated HDL levels. Lipid deposition was also dramatically decreased in both abdominal muscle and quadricep femoris after the administration of glycyrrhizin acid, possibly via the induction of PPAR- pathway [210, 211]. In conclusion, glycyrrhizic acid and its aglycone glycyrrhetinic acid show potential in the treatment and management of diabetes, having exhibited hypoglycaemic and anti-hypolipidaemic effects in various in vitro and in vivo models. Further investigation of the indepth mechanisms, however, is warranted.


15

3.4 Betulinic Acid Betulinic acid is a lupane-type pentacyclic triterpenoid initially isolated from the outer bark of the white-barked birch tree Betula alba, which has long been used as a folk medicine by native Americans and Russians for the treatment of stomach and intestinal aliments. Betulinic acid, and its precursor botulin, are widely distributed in a variety of plants, including: Diospyros species, Ziziphus species, Syzygium species, Sarracenia flava, Inga punctate and Vauquelinia corymbosa [212]. In Swiss obese rats fed with a high fat diet, the oral administration of betulinic acid (50 mg/kg for 15 weeks) significantly diminished body weight, abdominal fat accumulation, blood glucose, plasma TG and total cholesterol levels compared to the nontreatment group. Additionally, treatment with betulinic acid enhanced the plasma insulin and leptin levels, and reduced the levels of ghrelin [213]. Furthermore, betulinic acid selectively inhibited the activity of TGR5. TGR5 is a G protein-coupled receptor which is normally expressed in brown adipose tissue and muscle. The activation of this receptor triggers an increase in energy expenditure and may help attenuate diet-induced obesity [214]. Betulinic acid has demonstrated cardiovascular protective effects in both in vivo and in vitro models. In N-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive SD rats, intraperitoneal administration of betulinic acid (20 mg/kg) for 2 weeks led to a marked increase in the ROS levels, and reduction in the NO and SOD levels and eNOS activity in rat aortic rings [215]. Furthermore, betulinic acid upregulated eNOS expression, and diminished the expression of NADPH oxidase in both HUVEC and EA.hy926 human endothelial cells through an PKCindependent pathway. Betulinic acid enhanced the eNOS activity via the phosphorylation of serine [216]. In an in vitro study, the incubation of betulinic acid (1M for 24 hrs) resulted in the significant inhibition of the proliferation of human aortic smooth muscle cells, which was induced by high glucose (25 M). The increased expression of cell cycle regulatory proteins such as cyclins and CDKs induced by high glucose was markedly attenuated by co-incubation with betulinic acid. Betulinic acid also diminished the protein and mRNA expression of MMP-2 and MMP-9 levels in a dose-dependent manner. In addition betulinic acid reduced the intracellular ROS, suppressed the nuclear translocation and phosphylation of IB- of NF-B induced by high glucose condition [217]. In summary, the anti-diabetic and anti-hypertensive effects of betulinic acid may be employed in the treatment and management of diabetes and its complications, but once again more clinical trials are necessary to complement the preclinical data. 3.5 Betulin Betulin is an abundant, naturally-occurring pentacyclic triterpene, commonly isolated from the white outer bark of the birch tree B. alba which forms up to 34% (w/w) of the dry weight of the extract. Numerous reports have shown that betulin, and its synthetic derivatives, exhibit anti-cancer properties due to their cytotoxic and pro-apoptotic activity. Moreover, the application of betulin for hyperlipidaemia and various inflammatory and metabolic disorders is also finding widespread support in the scientific literature. Betulin has recently been found to specifically inhibit the maturation of sterol SREBP. This resulted in downregulating SREBP-2 expression by 40%, as well as other genes involved in the cholesterol, fatty acid and TG synthetic pathways, and also decreased the cellular levels of both cholesterol and natural lipids. In the same study, betulin significantly improved glucose tolerance and insulin resistance in Western-type diet-fed mice with impaired glucose and insulin tolerance, and in high-fat diet-fed mice. In


addition, betulin reduced atherosclerotic lesion formation and stabilised aortic plaques in Western-type diet-fed LDL receptorknockout mice [218]. The hepatoprotective activity of major pentacyclic triterpenes (betulin, betulinic acid and oleanolic acid) was examined and betulin was found to be the most active against ethanol-induced cytotoxicity in HepG2 and hepatic stellate cells (HSCs). Betulin acted as an antioxidant and an inhibitor of cytokine production, TGF- and NFB/IB transduction signaling [219, 220]. It was concluded that the antioxidant effects were not connected to its ROS scavenging activity, and were mainly dependent on the induction of the superoxide anion. The protective action of betulin against peroxidative damage to the cell membrane of rat erythrocytes was suggested by its ability to directly scavenge free radicals, and by preventing the attack of radicals on the membrane through increasing its negative surface charge [221]. In addition, betulin displayed moderate or less anti-inflammatory activity in comparison to its oxidised form, betulinic acid [222, 223]. It had no significant effect on eNOS expression in HUVEC and HUVEC-derived EA.hy 926 cells compared to betulinic acid which increased eNOS mRNA and protein expression [216]. 3.6 Lupeol Lupeol, as with the other main bioactive pentacyclic triterpenes, is known for its antioxidative potential. It acts mainly by increasing the activity of SOD, CAT, glutathione S-transferase and GPX [111]. The antidiabetic and antioxidant activity of lupeol has recently been shown in diabetes-induced oxidative damage in the pancreas of the Wistar rat model. Glycated haemoglobin, serum glucose and NO levels were reduced after lupeol treatment, with a concomitant increase in the serum insulin levels. In addition, lupeol administration significantly improved pancreatic antioxidants such as SOD and CAT, reduced GSH, glutathione-S-transferase and GPX, with a decrease in the levels of thiobarbituric acid-ROS, suggesting its ability to stimulate pancreatic regeneration through the improved synthesis of proteins and its antioxidant activity [224]. The nicotinic acid derivative of lupeol (50 mg/kg) normalised the lipid profile in the dyslipidaemic hamster model. Interestingly, in the STZ-induced diabetic rat model, this derivative (100 mg/kg) lowered the blood glucose levels by 18.2% and 25.0% at 5 h and 24 h, respectively [179]. 4. STRUCTURE-ACTIVITY RELATIONSHIPS Although the majority of studies in structure-activity relationships of pentacyclic triterpenes were targeting the anti-cancer molecular mechanisms, a detailed literature search on the structureactivity relationship studies related to diabetes have revealed a small number of publications summarised below. Following a detailed examination of the hypoglycaemic activity of oleanolic acid and its glucoronides from Aralia elata, it was suggested that the 3-O-glycoside moiety is essential for the activity; the 28-ester glucoside moiety significantly reduces the activity, and in the 3-O-oligoglycoside structure, the 3'-O- glucopyranosyl moiety decreases the activity, while the 4'-O-arabinofuranosyl moiety increases activity [54]. The 3-O-glucuronide moiety and the 28-carboxyl group in oleanolic acid glycosides are required for hypoglycaemic activity. Oleanolic acid glycosides have neither insulin-like nor insulinreleasing activity, however, they inhibit gastric emptying and glucose-uptake in the small intestine by stimulating the release and/or production of dopamine which acts through dopamine 2 receptors, resulting in the release of prostaglandins [225]. In a SAR study on the oleanolic acid core and different cinnamic amide ligands, the compounds with 3,28-disubstituted oleanolic acid exhibited stronger activity than 28-monosubstituted analogues. Cinnamic amide substitution increased inhibitory activity against glucosidase, resulting in greater efficacy than found for a typical glucosidase inhibitor such as acarbose [226].

Alqahtani et al.

After evaluation of twenty-five naturally-derived pentacyclic triterpenes on the inhibition of rabbit muscle glycogen phosphorylase, it was suggested that the diversity of the structure skeleton among the three groups (oleanane, ursane and lupane) did not interfere with their inhibitory activities on glycogen phosphorylase. However the number of hydroxyl groups and their positioning affected the potency. It was found that introducing a hydroxyl group at C-2 resulted in a loss of potency; both 2-hydroxyoleanolic acid (IC50 = 28 M) and 2-hydroxyoleanolic acid (IC50 = 34 M) were less potent than oleanolic acid (IC50 = 14 M). The same trend was observed in both 2-hydroxyursolic acid (IC50 = 20 M) and 2hydroxyursolic acid (IC50 = 116 M) compared to the parent compound, ursolic acid (IC50 = 9 M). Also, in madecassic acid, it was found that a hydroxyl group at C-6 was related to complete loss of activity. This study also suggested that the presence of a sugar moiety in the triterpene compounds resulted in a markedly decreased or loss in the activity comparing to their aglycones. Glycyrrhizic acid (IC50 = 822 μM) was 12-fold less potent than glycyrrhetinic acid (IC50 = 66 μM). Also, -D-pyranoglucosyl 3 -hydroxyolean-12-en28-oic acid (IC50 = 293 μM) was 20-fold less potent than its aglycone; oleanolic acid. The decrease in the activity was also observed in -D-pyranoglucosyl 3-hydroxyurs-12-en-28-oic acid and -Dpyranoglucosyl 2,3-dihydroxyurs-12-en-28-oic acid. In addition, asiaticoside and madecassoside were in-active (Fig. 7) [42]. The structures of oleanane pentacyclic triterpenes (GiA-1, GiA2, GiA-5 and GiA-7) from G. inodorum leaves (Fig. 3) are derivatives of (3, 4, 16)-16, 23, 28-dihydroxyolean-12-en-3-yl--D glucopyranosiduroic acid. GiA-1 has a -H at the C-21 position and CH3 at 4 position of the aglycone. GiA-2, GiA-5 and GiA-7 commonly have a -H at the C-21 position and -CH2OH at 4 position of the aglycone. It was shown that -CH2OH at the 4 position of the aglycone is necessary for the inhibition of glucose absorption from the intestinal tract [28]. PTP1B is a negative regulator in the process of insulin signaling and a promising drug target for the treatment of diabetes and obesity. Oleanolic acid derivatives were synthesised and evaluated as PTP1B inhibitors and several exhibited moderate to good activity against PTP1B, with compound 3-oxo-28-(phthaloyl-4)-erythrane displaying the most promising inhibition (IC50 = 3.12 M). A SAR analysis of these derivatives demonstrated that the integrity of the A ring and 12-ene moieties was important in the retention of PTP1B enzyme inhibitory activity [227]. Ursane-type triterpenoids from Diospyros kaki with a 3 -hydroxy group were found to inhibit PTP1B activity, with IC50 values ranging from 3.1 ± 0.2 to 18.8 ± 1.3 M, whereas those with a 3-hydroxy moiety were inactive [139]. The synthesis and biological evaluation of glucoconjugates of oleanolic acid, linked by either a triazole moiety or an ester function, as novel inhibitors of glycogen phosphorylase has been described. Oleanolic acid derivative (3-O-[1-(methyl-6-deoxy--Dglucopyranosid-6-yl)-1H-1,2,3-triazol-4-yl]methyl 3-hydroxyolean-12-en-28-oate) showed the best inhibition, with an IC50 of 1.14 M [228]. The G protein-coupled receptor TGR5 is known to be activated by bile acids and mediates some important cell functions. This work revealed that betulinic acid, oleanolic and ursolic acid also exhibited TGR5 agonist activity in a selective manner compared to bile acids (which also activate FXR, the nuclear bile acid receptor). Structural variations around the C-3 position of betulinic acid gave rise to major improvements in potency [229]. The structure-activity relationship findings related to antidiabetic activity have revealed some requirements for hypoglycaemic activity, PTP1B inhibition, glycogen phosphorylase inhibition and G protein-coupled receptor TGR5 activation. The 3-O-glucuronide moiety and the 28-carboxyl group in oleanolic acid glycosides are required for hypoglycaemic activity; 3-hydroxy group on the oleanolic acid and ursane structure inhibits PTP1B activity; -



17

Fig. (7). Naturally-derived pentacyclic triterpenoids with variation on the inhibition of glycogen phosphorylase.

CH2OH at the 4 position of the oleanane aglycone inhibits glucose absorption from the intestinal tract; C-3 position of betulinic acid improves in TGR5 agonist activity; therefore C-3 substitution on pentacyclic triterpenoids enhance their antidiabetic bioactivity.

5. SUMMARY AND FUTURE PERSPECTIVES Pentacyclic triterpenes are molecules with special properties. Some of the properties have already been well established. Many are found in common foodstuffs, especially in many diets, which


Alqahtani et al.

would make adherence to treatment protocol more likely. Oleananes, ursanes and lupanes are the major groups that produce a large variety of phytochemicals and active compounds for diabetes, while hopanes are rare in medicinal plants. There is now evidence that Glycyrrhiza species, Gymnema sylvestre, Centella asiatica, Camellia sinensis, Crataegus species and Olea europaea contain pentacyclic triterpenoids as their active components for the management of diabetes and its complications.

tion, diabetic vascular dysfunction, retinopathy and nephropathy. While the hypoglycaemic effects are not as strong as for antidiabetic pharmaceuticals, the multiple effects of the pentacyclic triterpenes on diabetes and diabetic complications provides a promising approach in diabetes management. Moreover, the structure-activity relationship studies have not been fully investigated for naturallyderived pentacyclic triterpenes, thus, future studies may also take this into account for developing potent therapeutic agents.

The oleanane group is widely distributed in common medicinal plants such as Glycyrrhiza species, Gymnema sylvestre, Camellia sinensis, Olea europaea, Beta vulgaris, Pueraria thunbergiana, Salacia chinensis, Ligustrum lucidum, Polygala senega var. latifolia and Terminalia arjuna, where the pentacyclic triterpenes active in diabetes have been identified. Gymnema sylvestre and Camellia sinensis are the most commonly used herbs in diabetes (Table 1). Oleanolic acid, glycyrrhizin and glycyrrhetinic acid are the most widely distributed oleananes-type interpenoids, and possess promising anti-diabetic activity in various in vitro and in vivo models (Table 4).

There is an increasing number of studies advocating the therapeutic potential of triterpenes in the prevention and treatment of diabetes and its complications. Here we propose pentacyclic triterpenes as natural multi-target agents which represent promising therapeutic agents. However, further studies are required to elucidate and verify the active compounds, activity-based quality standardardisation and detailed molecular mechanisms implicated in diabetes and diabetic complications as well as pharmacokinetics and the possible adverse reactions. Linking these with high level clinical trials will support the development of new therapeutic agents.

The ursane group are widely distributed in common medicinal plants such as Crataegus species, Cornus officinalis, Centella asiatica, Eriobotrta japonica, Ilex species, Boswellia carterii, Terminalia arjuna and Bacopa monniera, which are used for diabetes and its complications (Table 2). The most widely distributed ursane is ursolic acid which has been shown to be effective in the treatment of diabetes and its complications in a number of animal models (Table 4). These plants often contain both oleananes and ursanes, particularly oleanolic acid and ursolic acid.

CONFLICT OF INTEREST The author(s) confirm that this article content has no conflicts of interest. ACKNOWLEDGEMENT Declared none.

Lupane-type triterpenes have a narrower distribution in medicinal plants, with antidiabetic activity from Aegle marmelos and Bacopa monnieri (Table 3). Some of this activity may be related to the common active compounds betulin, betulinic acid and lupeol, which have shown antidiabetic effects in in vivo models (Table 4).

ABBREVIATIONS ALT

=

Alanine amino transferase

ANP

=

Atrial natriuretic peptide

The preclinical evidence supports the clinical usage of common herbal medicines such as Glycyrrhiza species, Gymnema sylvestre, Centella asiatica, Camellia sinensis, Crataegus species, Olea europaea and Cornus officinalis in the management of diabetes and its complications in TCM and Ayurveda medicine. Oleanane, ursane and lupane compounds are often found in the same plant, which is due to the presence of common biosynthetic enzymes, so the bioactivity of the herbal medicines may be due to the combinatory effects of a number of active compounds present in the extracts [230].

AST

=

Aspartate amino transferase

AT1

=

Angiotensin II receptor, type 1

CAT

=

Catalase

The antidiabetic activities of pentacyclic triterpenes have been studied in both in vivo and in vitro models.The pentacyclic triterpenes decrease plasma glucose, HbA1c, and increase plasma insulin, muscle and liver glycogen in diabetic rats [25]. The PTP1B, glucosidase and -amylase activity assays provide information on glucose absorption and metabolism, while cell lines such as HUVEC and EA.hy926 give information on the protective effects for vascular complications [231]. Diabetic complications include macrovascular inflammation, causing atherosclerosis, and microvascular inflammation, causing diabetic nephropathy, diabetic neuropathy, diabetic peripheral neuropathy and diabetic retinopathy. Treatment with pentacyclic triterpenes reduces hyperglycaemia, membrane disintegration, oxidative stress and vascular inflammation in vivo, suggesting that these agents have potential in the clinical treatment of diabetes and its associated cardiac complications [46-48]. A large number of studies in diabetic rats showed the protective effects of common pentacyclic triterpenes on the kidney, liver, eye and heart [78, 79]. Improvements in oxidative stress parameters and serum lipid parameters may play a role in diabetic complications [203, 210, 211]. The main mechanisms, herbs and active compounds are summarised in Table 5. The biological studies on the herbal extracts or active compounds include glucose absorption, glucose uptake, insulin secre-

CTGF

=

Connective tissue growth factor

DM

=

Diabetes mellitus

DNA

=

Deoxyribonucleic acid

eNOS

=

Endothelial nitric oxide synthase

ERK

=

Extracellular-signal-regulated kinases

ERK1/2

=

Extracellular signal-regulated kinase 1/2

GLT-1

=

Glutamate transporter 1

GLUT4

=

Glucose transporter type 4

GPX

=

Glutathione peroxidase

GSH

=

Glutathione

GSK3

=

Glycogen synthase kinase 3 beta

HbA1c

=

Hemoglobin A1c

HDL

=

High-density lipoprotein

HMG-CoA

=

3-Hydroxy-3-methyl-glutaryl-CoA

HUVEC

=

Human umbelicle vein cells

IB-

=

I-kappa-B-alpha

IL-6

=

Interleukin-6

iNOS

=

Inducible nitric oxide synthase

JNK

=

C-Jun N-terminal kinases

LDL

=

Low density lipoprotein

MCP-1

=

Monocyte chemotactic protein-1


MMP-2

=

Matrix metalloproteinase-2

NADPH

=

Nicotinamide adenine dinucleotide phosphate

NF-B

=

Nuclear factor kappa B

NIDDM

=

Non-insulin-dependent diabetes mellitus

NO

=

Nitric oxide

OZR

=

Obese zucker rat

Phospho-JNK =

Phospho c-Jun N-terminal kinase

PKB

=

Protein kinase B

PKC

=

Protein kinase C

PPAR

=

Peroxisome proliferation-activated receptor

PTP1B

=

Protein-tyrosine phosphatase 1B

ROS

=

Reactive oxygen species

SD

=

Sprague Dawley

SOD

=

Superoxide dismutases

SREBP

=

Sterol regulatory element-binding protein

STAT-3

=

Signal transducer and activator of transcription 3

STZ

=

Streptozocin

TCM

=

Traditional Chinese medicine

TG

=

Triglycerides

TGF-

=

Transforming growth factor beta

TGR5

=

G protein-coupled bile acid receptor


[16]

[17] [18]

[19] [20] [21]

[22]

[23] [24]

[25]

TNF-

=

Tumor necrosis factor alpha

[26]

ZDF rat

=

Zucker diabetic fatty rat

[27]

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