Review Article Recent Advances in Astragalus membranaceus...

Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2013 Article ID 654643 9 pageshttpdxdoiorg1011552013654643

Review ArticleRecent Advances in Astragalus membranaceusAnti-Diabetic Research Pharmacological Effectsof Its Phytochemical Constituents

Kojo Agyemang12 Lifeng Han1 Erwei Liu1 Yi Zhang1 Tao Wang1 and Xiumei Gao1

1 Tianjin State Key Laboratory of Modern Chinese Medicine 312 Anshanxi Road Nankai District Tianjin 300193 China2Noguchi Memorial Institute for Medical Research PO Box LG 581 Legon Accra Ghana

Correspondence should be addressed to Tao Wang wangt263net

Received 29 August 2013 Revised 4 November 2013 Accepted 5 November 2013

Academic Editor Tong Ho Kang

Copyright copy 2013 Kojo Agyemang et alThis is an open access article distributed under theCreative CommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

The disease burden of diabetes mellitus is increasing throughout the world The need for more potent drugs to complement thepresent anti-diabetic drugs has become an imperative Astragalus membranaceus a key component of most Chinese herbal anti-diabetic formulas has been an important prospect for lead anti-diabetic compounds It has been progressively studied for its anti-diabetic properties Ethnopharmacological studies have established its potential to alleviate diabetes mellitus Recent studies havesought to relate its chemical constituents to types 1 and 2 diabetes mellitus Its total polysaccharides saponins and flavonoidsfractions and several isolated compounds have been the most studied The total polysaccharides fraction demonstrated activityto both types 1 and 2 diabetes mellitus This paper discusses the anti-diabetic effects and pharmacological action of the chemicalconstituents in relation to types 1 and 2 diabetes mellitus

1 Introduction

Diabetesmellitus (DM) has been reported as an epidemic andan increasing disease burden throughout the world [1 2] It isa chronic disease characterized by high blood glucose levelsresulting fromdefects in insulin production and action Types1 and 2 are the most prevalent Type 1 is characterized bylack of insulin production caused by autoimmunedestructionof pancreatic beta cells Type 2 results from the ineffectiveuse of insulin due to insulin resistance and deficient glucosemetabolism [1 3 4] Research for novel anti-diabetic drugs tocomplement those in present clinical use has intensified overthe years

Plant medicine has been important in present anti-diabetic drug research The prospects of a number of medic-inal plants herbal formulations and natural products withanti-diabetic effects have been reported [5ndash7]Notable amongsuch isAstragalus membranaceus (AM) It is a Fabaceae flow-ering plant recorded in various pharmacopoeias as a herbalimmunomodulator and an anti-diabetic drug Its roots have

been used in many state-approved Chinese herbal formulasfor the treatment of diabetes [6 7] A recent publicationby Wei et al (2011) [7] identified it as the most frequentlyprescribed herbal medicine for diabetes treatment in ChinaSeveral ethnopharmacological studies have established itspharmacological significance [6 8] Recent studies haveprogressively sought to identify the lead compounds involvedin inducing its anti-diabetic effects Its polysaccharidessaponins and flavonoids fractions and a number of singleisolated compounds have been studiedThe pharmacologicalprocesses and mechanism of action of these constituentshave also been studied [9ndash11] This paper considers it asan important anti-diabetic drug prospect Thus we reviewadvances in its anti-diabetic research with emphasis on thepharmacological prospects of its chemical constituents inrelation to types 1 and 2 DMThe following database systemswere considered for data collection PubMed SpringerLinkWiley Online Library Science Direct and China NationalKnowledge Infrastructure (CNKI)-China Academic JournalNetwork Publishing Database (CAJD)

2 Evidence-Based Complementary and Alternative Medicine

2 Ethnopharmacology Effects ofAM on Diabetes Mellitus

The roots of AM have a long history for the treatment ofdiabetes-related symptoms in China In traditional Chinesemedicine it is used to reinforce Qi in order to induceurination consolidate the exterior express toxins outwardand make new tissues grow [7 12] A number of studieshave emphasized its pharmacological relation to diabetesmellitus Earlier ethnopharmacological studies analyzed var-ious crude extracts for their anti-diabetic activities and theirpossible pharmacological processes They were studied asa single extract or as part of a compound formula andwere reported to have demonstrated potentials of attenuatingDM and their associated complications They were generallyobserved to have lowered increasing blood glucose andlipid levels improved insulin sensitivity and also correctedseveral pathological indicators of DM and its complications[6 13ndash16] In a clinical study of the effect of AM on insulinsensitivity AM decoction reduced fasting blood glucose andhomeostatic model assessment (HOMA) levels in type 2DM patients [14] Anti-diabetic studies onQilan Tangzhiningcapsule a Chinese herbal anti-diabetic formula containingAM showed its potential to reduce blood glucose levels andimprove lipid profiles in streptotozocin-induced diabetic rats[16] A number of pharmacological processes for inducingthese anti-diabetic effects have been suggested Some ofwhich include the suppression of macrophage- and cytokine-induced inflammatory responses stimulation of insulin sig-nal transduction and lowering of the hyperglycemic effects ofglucagon in experimental animals Its mechanism of actionhas been associated with several enzymes proteins andmolecularmarkers such as peroxisome-proliferator-activatedreceptor gamma (PPAR120574) phosphatidylinositide-3-kinase(PI-3-K) and Na+ K+-ATPase among others [10 14 16ndash18]Further studies have sought to elucidate the phytochemicalconstituents inducing these anti-diabetic effects

3 Phytochemical Constituents

Several classes of organic compounds namely Astragaluspolysaccharides saponins flavonoids isoflavonoids sterolsamino acids and volatile oils have been isolated from AMThe polysaccharides saponins and flavonoids are the majorchemical constituents demonstrating biological activity toDM [19 20]

31 Polysaccharides The polysaccharides of AM are byextractionmethods water-soluble and -insoluble glucans andheteropolysaccharides Astragalans I II and III are polysac-charides extracted by hot water Astragalan Ι was elucidatedas a neutral heteropolysaccharide containing D-glucose D-galactose and L-arabinose in the ratio of 175 163 1 It hasa molecular weight of 36 kD Astragalans ΙΙ and ΙΙΙ were120572-(14)-glucans with molecular weights of 12 kD and 34 kDrespectively [21 22] APS I and APS II were isolated by waterextraction and alcohol precipitation technique Structural

and content analyses showed that APS I consisted of arabi-nose and glucose in the ratio of 1 345 ASP II consisted ofrhamnose arabinose and glucose in the ratio of 1 625 1786[22 23] Acidic polysaccharides such as AMem-P AH-1and APSID3 have also been isolated [24ndash27] AMem-P is acomplex acidic polysaccharide with a molecular weight of60 kD It consists mainly of hexuronic acid and has terminaland 120572-15-linked-arabinofuranose terminal and120573-13-120573-14- 120573-16-linked 36-branched-D-galactose and 24-branched-L-rhamnose residue groups attached [24] Other Astragaluspolysaccharides include AH-2 AE AEF-1 and AEF-2 andastroglucans A B and C [27ndash29]

32 Saponins The saponin content of AM consists mainly oftriterpene saponins Structurally they are cycloartane triter-pene glycosides with one-to-three sugars attached at the 3-6- and 25-positions Kitagawa (1983) reported the isolation ofseveral cycloartane triterpenoids such as astragaloside IndashVIII[30ndash32] and isoastragalosides I and II [30] AstragalosidesVIIand VIII were elucidated as saponins with oleanane skeleton[32] Azukisaponin V methyl ester has been isolated andidentified as an oleanane-type triterpene saponin [33] Anastragaloside malonate has also been identified as malonylas-tragaloside [34] Several other astragalus saponins includingisoastragalosides III and IV astramembrannin II cyclogalegi-noside B cycloaraloside A brachyoside B cyclocanthoside Ecyclounifolioside B [27 35 36] and astramembranosides Aand B [33] have also been isolated

33 Flavonoids Flavonoids of varying structures have beenisolated from AM They are mainly in structural groupsof flavones isoflavones isoflavanones and pterocarpansKaempferol isorhamnetin rhamnocitrin kumatakeninand rhamnocitrin-3-glucoside and quercetin-3-glucosidehave been isolated as flavones [27] Formononetin ononincalycosin calycosin-7-O-120573-D-glucoside-610158401015840-O-malonate 31015840-methoxy-51015840-hydroxy-isoflavone-7-O-120573-D-glucoside and(3R)-2101584031015840-dihydroxy-410158407-dimethoxyisoflavone have beenisolated as isoflavones [27 37 38] The isoflavanones include21015840-hydroxy-3101584041015840-dimethoxyisoflavone-7-O-120573-D-glucopyra-noside 21015840-hydroxy-31015840410158407-trimethoxyisoflavone 210158407-dihy-droxy-31015840410158407-trimethoxyisoflavone 3101584041015840-dimethoxyisofla-vone-7-O-120573-D-glucoside 821015840-dihydroxy-410158407-dimethoxyis-oflavone and 21015840310158407-trihydroxy-41015840-methoxyisoflavone[27] The reported pterocarpans include 3910-trimethox-ypterocarpan (6aR11aR)-10-hydroxy-39-dimethoxyptero-carpan and 910-dimethoxypterocarpan-7-O-120573-D-glucopy-ranoside [27 38 39]

4 Pharmacological Effects of AstragalusChemical Constituents on Diabetes Mellitus

The polysaccharides (APS) saponins (ASS) and flavonoids(ASF) fractions of AM have been the most studied fortheir anti-diabetic effects on types 1 and 2 DM Several sin-gle isolated compounds including astragalin formononetinastragalosides I II and IV and isoastragaloside I (Figure 1)have also been analyzed Their pharmacological processes

Evidence-Based Complementary and Alternative Medicine 3

OHO

HO

OH OH

OH

O

HO

O

O

OH

Astragalin

(a)

O

OHO

OFormononetin

(b)

O O

HO

OH

OH

OH

O

O

OHO

OH

O

HO

HO

O

O

Astragaloside II

(c)

O

HO

OH

OH

OHO

O

OH

O

OH

OHO

HO

OH

Astragaloside IV

(d)

O

HO

OH

OH

OHOO

OH

O

OH

OO

O

HO O

O

Isoastragaloside I

(e)

Figure 1 Phytocompounds of Astragalus membranaceus demonstrating anti-diabetic effects

and mechanism of action on types 1 and 2 DM have beenreported

41 Type 1 DiabetesMellitus Type 1 DM is caused by autoim-mune destruction of pancreatic beta cells The polysaccha-rides fraction (APS) has been the only constituent demon-strating activity to type 1 DM It lowered the incidence rateand postponed the onset of type 1 DM in nonobese type1 diabetes mellitus (NOD) mice [40ndash42] It also attenuatedautoimmunal insulitis increased the proliferation of pancre-atic beta cells and decreased apoptotic beta cell mass [43ndash45] APS was postulated to have induced immunoprotectiveeffects in type 1 diabetic NODmodelsThis potential has beenwidely investigated Chen et al (2001) and others evaluatedthe immunomodulatory effect of APS on CD4+ and CD8+T cells APS was observed to have decreased lymphocyticinflammation of pancreatic islets in type 1 noobese diabetic

(NOD) mice It was also reported to have lowered theproliferation of CD4+ and CD8+ T cells [41 42 46] TheCD4+ and CD8+ T cells have been implicated in inflam-matory response apoptosis and autoimmunity leading totype 1 DM [47 48] APS may protect pancreatic beta cellsfrom autoimmune destruction through the regulation ofinflammatory and apoptotic responses

411 Immunomodulation of Inflammatory Response Theanti-inflammatory effect of APS was studied mainly on thesecretory cytokines of CD4+ T helper cells Naive CD4+ Tcells differentiate into T helper cells 1 (Th1) and 2 (Th2) forinflammatory response and autoimmunityTheTh1 expressessecretory cytokines such as interferon gamma (IFN120574) tumornecrosis factor-alpha (TNF-120572) interleukin-2 (IL-2) and IL-I120573 that induce inflammation and intracellular autoimmuneresponses The Th2 is noted for IL-4 IL-5 IL-10and IL-13


production for extracellular immunity and counteraction ofTh1 inflammatory response [49 50] APS has demonstratedthe potential to lower the expression ofTh1 cells and regulateTh1 and Th2 imbalance in in vivo diabetic models Chenand Yu (2004) in molecular immunomodulatory studiesreported a possible correction of genetic imbalance of Th1and Th2 genes and proteins in APS-treated type 1 DMNOD mice Their studies observed about 547 changesin gene expression of which 17 genes were of functionalrelation to immunity [51] Further studies showed thatAPS demonstrates immunomodulatory effects on Th1 andTh2 cytokines It was reported to have downregulated theexpression levels of Th1 cytokines such as IL-12 TNF-120572and IFN120574 and enhanced Th2 cytokines such as IL-4 IL-5 IL-6 and IL-10 [42 45 52] APS also demonstrated asignificant lowering effect on Th1Th2 ratio [44 53] animportant apoptotic index that measures relatively loweredlevels of Th1 per Th2 cytokines as an indication for reducedintracellular autoimmunity and inflammatory response [54]The effect of APS on other inflammatory markers such asperoxisome-proliferator-activated receptor gamma (PPAR-120574) superoxide dismutase (SOD) and nitric oxide (NO)has also been studied APS significantly enhanced the geneexpression of PPAR-120574 in a time- and dose-dependentmanner[53] and promoted SOD anti-oxidation in type 1 DMmodels[42 55] It also lowered the expression of inducible nitricoxide synthase (iNOS) [42 55] PPAR-120574 NO iNOS andSOD among a variety of functions also play various rolesin the stimulation and regulation of inflammatory response[56]

The effect of astragalin a flavonoid isolate of AMon apoptotic cytokines has also been studied It showedan inhibitory effect on the production levels of TNF-120572IL-1 and IL-6 [57] It was reported to have repressed theexpression of these Th1 cells via NF-120581B inhibition It hasalso been shown as exhibiting inhibitory effects on proin-flammatory mediators similar to quercetin It was shown tohave attenuated the production of nitric oxide (NO) andrepressed the expression and production levels of iNOS andcyclooxygenase-2 (COX-2) in J774A1 mice macrophages[57 58]

412 Promotion of Antiapoptotic Response APS has exhib-ited the potential to regulate a number of apoptosis-relatedproteins and enzymes It demonstrated significant inhibitoryeffect on caspase-3 enzyme [45 59] while enhancing theexpression of B-cell lymphoma-2 (Bcl-2) [55] in type 1 DMmodels Caspase-3 is noted for apoptosis execution whereasBcl-2 has apoptosis regulatory effects APS was also positivelycorrelated to increased galectin-1 levels in the muscles oftype 1 DM mice Its correlation with galectin-1 was furthershown to have a negative regulatory effect onCD8+ T cells anapoptosis-enhancing T cell [60] APS has also been reportedto have lowered the expression of Fas [42 61 62] Fas is amember of the TNF family of receptors that expresses on cellsto trigger their apoptosis

Formononetin an O-methylated isoflavone has beenreported as inhibiting the activity of caspase-3 It was shown

to have reduced caspase-3 levels in INS-1 cells [63] It alsolowered in vitro nitric oxide production and apoptotic sig-naling via a demonstrated inhibition of IL-1120573 and reductionof BaxBcl-2 ratio It was also shown to have inhibited theactivation of nuclear factor-kappaB (NF-120581B) [63]

42 Type 2 Diabetes Mellitus Type 2 of DM is caused byinsulin resistance and deficient glucosemetabolismAll of themajor constituents of AM have been shown to differentiallylower high blood glucose levels and body weight and improveimpaired glucose tolerance in type 2 diabeticmodels [64ndash67]The postulated pharmacological processes include variousglucose transportation and insulin signaling pathways thatlead to insulin sensitivity and restoration of the proliferativeability of the pancreatic beta cells

421 Promotion of Intracellular Glucose Transportation Thepolysaccharides fraction has exhibited potentials of reducinghyperglycemia through the induction of glucose transloca-tion enzymes and proteins It has been studied as a promoterof increased glucose transporter protein-4 (GLUT4) levelsIn a molecular expression study of the effect of APS onGLUT4 APS increased the expression and translocation ofGLUT4 in skeletal muscle and adipose tissues [64 68] TheGLUT4 is an insulin-regulated intracellular transporter notedfor the mediation of glucose translocation into muscle andfat cells Liu et al (2010) analyzed the effect of APS onthe GLUT4protein kinase B (PKB) glucose transportationpathway in the skeletal muscles of insulin-resistant KKAymice APS was reported to have partially restored loweredactivation levels of PKB and GLUT4 translocation [64]

422 Regulation of Glucose and Lipid Metabolism Increasedlevels of circulating glucose free fatty acids and accumu-lation lipids in nonadipose tissues have been implicated inthe development of insulin resistance and type 2 DM [69]APS ASS and ASF have all shown differential regulatoryeffects on several glucose- and lipid-metabolizing enzymesproteins and receptors The polysaccharides fraction hasbeen the most widely studied It has been shown to haveenhanced the phosphorylation and activation of hepaticglycogen synthase and regulated the expression and acti-vation of adenosine monophosphate-alpha (AMP-120572) andacetyl-CoA carboxylase to alleviate glucose accumulationin in vitro skeletal muscle cells and KKAy mice models[65] It also exhibited an upregulatory effect on the levelsof adiponectin [70] and its receptor adipo-R1 [71] in type2 DM rats It promoted the expression and activation ofadenosine monophosphate protein kinase (AMPK) and itsalpha-subunit AMPK-alpha [65 71 72] Adiponectin andAMPK are important activating factors for glucose and lipidmetabolism in the liver muscles and adipocytes Increasedlevels of their activity have been associated with reduced riskfor type 2 DM [73 74] Other studies have demonstratedAPS as regulating glucose and lipid metabolism throughthe promotion of peroxisome proliferator-activated receptor-(PPAR-) alpha activity and inhibition of the autonomicneurotransmitter neuropeptide-Y (NPY) The PPARs are


a family of ligand-dependent transcription factors that con-trol energy homeostasis through the regulation of carbo-hydrate and lipid metabolism PPAR-alpha potentiates fattyacid catabolism and reduces circulating lipids [75] APSenhanced the gene and protein expression of PPAR-120572 andimproved the lipoprotein profiles of streptozotocin-induceddiabetic hamsters [76] Neuropeptide-Y is an autonomicneurotransmitter that induces increased food intake leadingto obesity and type 2 DM Chen et al (2011) reported loweredlevels of increased blood glucose and body weight in relationto neuropeptide-Y in streptozotocin-induced diabetic ratsAPS was reported to have reduced the mRNA expressionlevels of neuropeptide-Y and its receptor neuropeptide-Y2 protein [77] The effect of APS on aldose reductasea glucose-metabolizing enzyme target implicated in high-glucose-induced diabetes complications [78] has also beenstudied APS had no significant inhibitory effect on aldosereductase [79]

The saponins (ASS) and flavonoids (ASF) fractions exhib-ited their antagonizing effects on ascending blood glucoselevels in type 2 DM rats through a common adiponectinand AMPK-metabolizing pathway They increase the geneticand cellular expression of AMPK adiponectin and adipo-R1levels in the liver and skeletal muscle of diabetic rats [70 71]The expression levels of AMPK and adipo-R1 induced by thesaponinswere reported to bemore pronounced in the skeletalmuscles than in the liver whereas the flavonoids showed anincreased effect in the liver than in the skeletal muscle [71]

Several Astragalus saponins isolates have been studiedAstragaloside II and isoastragaloside I exhibited regulatoryeffects on adiponectin and AMPK action They significantlyincreased adiponectin levels and promoted the activation ofAMPK in type 2 DM mice Their induction of increasedadiponectin levels was reported to be independent of PPAR120574an adiponectin agonist [75 80] The Astragalus saponinsastragalosides I and IV have demonstrated inhibitory effecton aldose reductase They downregulated its activation levelsto ameliorate accumulation of advanced glycation endprod-ucts in both erythrocytes and nerve cells of diabetic rats [81]

The comparative effects of formononetin and caly-cosin isoflavonoids on the peroxisome-proliferator-activatedreceptors activation system have also been studied For-mononetin was reported to be more potent activator ofPPAR120574-induced differentiation of 3T3-L1 preadipocyte thancalycosin [18] PPAR120574 plays crucial role in the differentiationand maturity of fat cells [75]

423 Alleviation of ER Stress and Induction of Insulin SignalTransduction Stress responses in the endoplasmic reticulum(ER) have been associated with increased 120573-cell apoptosisrates reduced beta cell mass lowered insulin production andincreased insulin resistance in type 2 DM patients APS hasbeen reported as a negative regulator of key ER stress indica-tors such as phosphorylated protein kinase-like endoplasmicreticulum kinase (PERK) activating transcription factor-6(ATF-6) glycogen synthase kinase 3 beta (GSK3120573) and XhoIsite-binding protein 1 (XBP1) in type 2 diabetes models Itrelieved ER stress in type 2 DM SD rats through a significant

decrease in the expression of PERK and inhibition of ATF-6 activity [82] It also reduced the levels of the transcriptionrepressor protein XBP1 and GSK3120573 in KKAy mice [83]The inhibitory effect of APS on ATF-6 was further studiedin relation to protein tyrosine phosphatase-1-B (PTP1B) anegative regulator of insulin-receptor signal transductionATF-6 inhibition was positively correlated with loweredexpression and activation levels of PTP1B in experimentalanimals [67 84 85] APS may have indirectly promotedinsulin signaling via ER stress alleviation Other insulinsignaling studies have reported the upregulatory effect ofAPS on insulin receptors APS was shown to have increasedthe levels of insulin receptor substrate-1 (IRS-1) and its betatransmembrane receptor (IR-120573) subunit in muscle cells [84]IRS-1 s key role in insulin signal transduction Lowered levelsof IRS-1 have been associated with increased susceptibility totype 2 DM [86 87] APS has also demonstrated regulatoryeffects on resistin an insulin-resistance protein [88 89] Itdecreased the mRNA and protein expression levels of resistinin type 2 DMWistar rats

5 Pharmacological Prospects andConcluding Remarks

The anti-diabetic potential of Astragalus membranaceus hasbeen progressively studied in the recent past Its crudeextracts have been reported in several ethnopharmacologicalstudies as potential prospect for further anti-diabetic studiesRecent studies have analyzed its phytochemical constituentsin elucidating its pharmacological significance to types 1 and2 DM Its polysaccharides saponins and flavonoids fractionsand several isolated compounds have been studied Theyall exhibited differential potentials of correcting the charac-teristic defects of inadequate insulin production secretionand action on target cells The total polysaccharides fractiondemonstrates significant activity to type 1 DM It protectspancreatic beta cells from intracellular (autoimmune) celldeath via the immunomodulation of several inflammatoryand apoptotic cytokines enzymes and proteins It demon-strated the potential tomodulate T helper cells 1 and 2 reduceinflammatory response and promote antioxidant activitiestowards antiapoptotic protection of pancreatic beta cellsAstragalin and formononetin also demonstrated regulatoryeffects on various inflammatory and apoptotic indicators

The polysaccharides saponins and flavonoids fractionsall exhibited significant activities to type 2 DM They gen-erally induce their hypoglycemic effects through variousinsulin sensitizing pathways They all demonstrated regu-latory effects on AMPK and adiponectin and its receptoradipo-R1 Astragaloside II and isoastragaloside I isolates werealso associated with this effect The polysaccharides fractionhas been most extensively studied in relation to type 2 DMIt promotes insulin sensitization through various coordi-nated pathways towards intracellular glucose transportationinsulin signal transduction and protection of pancreaticbeta cells from apoptotic death It promoted the PKBAktand -PPAR-120572 and -120574 systems activated insulin recep-tors and regulated ER stress-related proteins and enzymes


The PKBAkt system differentially coordinates PKB to glyco-gen synthase kinase 3 (GSK3) GLUT4 apoptotic caspasesIR and IRS-1 among others to induce glucose transportationand cell proliferation The phosphorylation and activationof PKB lead to increased IRS-1 and GLUT4 activity forglucose translocation and insulin signaling Its activation alsoresults in the inactivation of GSK3 and caspase proteases toinhibit apoptosis [90 91] Stress-induced apoptosis in theendoplasmic reticulum of pancreatic and liver cells has alsobeen related to reduced insulin production and increasedinsulin resistance [92 93] APS notably exhibited a negativelyregulatory effect on PERK ATF-6 and XBP1 ER stressindicators The PPAR are a family of ligand-dependent tran-scription factors that control energy homeostasis through theregulation of carbohydrate and lipid metabolism [94] Theyare also involved in the regulation of inflammatory responses[56 75] PPAR-alpha [75] and PPAR-gamma [94] have beenassociated with the regulation of DM APS demonstratedactivity to both of them to alleviate high blood glucose levelsThe demonstrated regulatory effects of APS on these systemssuggest its importance and prospects for further research anddevelopment for diabetes therapy

Further studies on more single-compound isolates areimportant to understand the overall mechanisms and pro-cesses of anti-diabetic effects as well as their structure-activityrelationships

Conflict of Interests

The authors have no conflict of interests in this paper

Acknowledgments

This paper was supported by the Program for New Cen-tury Excellent Talents in University (NCET-10-0958 and1069) the Important Drug Development Fund Ministry ofScience and Technology of China (nos 2011ZX09307-002-01 and 2012ZX09304007) and the National Natural ScienceFoundation of China (81173524)

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[1] S Wild G Roglic A Green R Sicree and H King ldquoGlobalprevalence of diabetes estimates for the year 2000 and projec-tions for 2030rdquoDiabetes Care vol 27 no 5 pp 1047ndash1053 2004

[2] D Einhorn ldquoAdvances in diabetes for the millennium insulintreatment and glucose monitoring CMErdquo MedGenMed Med-scape General Medicine vol 6 supplement 3 p 8 2004

[3] M Rendell ldquoAdvances in diabetes for the millennium drugtherapy of type 2 diabetesrdquo Medscape General Medicine vol 6supplement 3 p 9 2004

[4] P Lambert and P J Bingley ldquoWhat is type 1 diabetesrdquoMedicinevol 30 no 1 pp 1ndash5 2002

[5] B M Berman J P Swyers and J Kaczmarczyk ldquoComplemen-tary and alternative medicine herbal therapies for diabetesrdquoJournal of the Association for Academic Minority Physicians vol10 no 1 pp 10ndash14 1999

[6] W Jia W Gao and P Xiao ldquoAntidiabetic drugs of plant originused in China compositions pharmacology and hypoglycemic

mechanismsrdquo Zhongguo Zhongyao Zazhi vol 28 no 2 pp 108ndash113 2003

[7] D X Wei N Z Yu and O Z Ya ldquoTraditional Chinesemedicines in treatment of patients with type 2 diabetes melli-tusrdquo Evidence-Based Complementary and Alternative Medicinevol 2011 Article ID 726723 13 pages 2011

[8] W L Li H C Zheng J Bukuru and N De Kimpe ldquoNaturalmedicines used in the traditional Chinese medical system fortherapy of diabetesmellitusrdquo Journal of Ethnopharmacology vol92 no 1 pp 1ndash21 2004

[9] S F Zang L Ning H X Ni Q L Zhang and Z J ChenldquoThe effect of Astragalus on PPAR-120574 mRNA expression inmacrophage with Type2 Diabetic Mellitusrdquo Chinese Archives ofTraditional Chinese Medicine vol 29 no 8 p 1853 2006

[10] X C Liang L Y Cui S S Guo et al ldquoClinical studyof Jinmaitong composita on diabetic peripheral neuropathyrdquoChinese Journal of IntegrativeMedicine vol 7 no 2 pp 103ndash1062001

[11] D Seely E Mills and B Rachlis ldquoPatients with diabetesusing alternative medicinerdquo in Contemporary Endocrinology(Evidence-Based Endocrinology) vol 4 pp 323ndash342 2006

[12] C Keji ldquoUnderstanding and treatment of diabetes mellitusby traditional Chinese medicinerdquo American Journal of ChineseMedicine vol 9 no 1 pp 93ndash94 1981

[13] Z Sang L Zhou X Fan and R J McCrimmon ldquoRadixzastragali (Huangqi) as a treatment for defective hypoglycemiacounterregulation in diabetesrdquo American Journal of ChineseMedicine vol 38 no 6 pp 1027ndash1038 2010

[14] S F Zang L Ning H X Ni Q L Zhang and Z J ChenldquoThe effect of Astragalus on PPAR-120574 mRNA expression inmacrophage with type2 diabetic mellitusrdquo Chinese Archives ofTraditional Chinese Medicine vol 29 no 8 pp 1853ndash1855 2011

[15] M Chao D Zou Y Zhang et al ldquoImproving insulin resistancewith traditional Chinese medicine in type 2 diabetic patientsrdquoEndocrine vol 36 no 2 pp 268ndash274 2009

[16] D Q Zhang J J Zhang J X Wang et al ldquoEffects of QilanTangzhining capsule on glucose and lipid metabolism in ratswith diabetes mellitus and hyperlipemiardquo Zhongguo ZhongyaoZazhi vol 30 no 10 pp 773ndash777 2005

[17] Q J Qin J Y Niu Z X Wang W J Xu Z D Qiao and Y GuldquoAstragalus membranaceus Inhibits Inflammation via Phospho-P38 Mitogen-Activated Protein Kinase (MAPK) and NuclearFactor (NF)-120581B Pathways in Advanced Glycation End Product-Stimulated Macrophagesrdquo International Journal of MolecularSciences vol 13 no 7 pp 8379ndash8387 2012

[18] P Shen M H Liu T Y Ng Y H Chan and E L Yong ldquoDiffer-ential effects of isoflavones fromAstragalus membranaceus andPueraria Thomsonii on the activation of PPAR120572 PPAR120574 andadipocyte differentiation in vitrordquo Journal of Nutrition vol 136no 4 pp 899ndash905 2006

[19] WHO Radix Astragali vol 1 WHO Monographs on SelectedMedicinal Plants Geneva Switzerland 1999

[20] Thorne Research Incoporated ldquoAstragulus membranaceusmonograph alternative medicine reviewrdquoThorne Research Inco-porated vol 8 no 1 pp 72ndash77 2003

[21] X Liu M Wang H Wu X Zhao and H Li ldquoIsolation ofastragalan and its immunological activitiesrdquo Tianran ChanwuYanjiu Yu Kaifa vol 6 pp 23ndash31 1994

[22] S D Fang Y Chen C Q Ye S K Zhai and M L ShenldquoStudies of the active principles of Astragalus MongholicusBunge I isolation characterization and biological effect of its


polysaccharidesrdquo Chinese Journal of Organic Chemistry vol 1pp 26ndash31 1982

[23] Y Y Zou XQGu andQChen ldquoInvestigation of the polyphaseliposomal bipolysaccharides-Part 1 Selection and analysis ofthe effective ingredients in the two polysaccharidesrdquo Journal ofShenyang Pharmaceutical University vol 4 no 3 pp 170ndash1741987

[24] M Tomoda N Shimizu N Ohara R Gonda S Ishii and HOtsuki ldquoA reticuloendothelial system-activating glycan fromthe roots of Astragalus membranaceusrdquo Phytochemistry vol 31no 1 pp 63ndash66 1991

[25] L XMu L Zhu A H ZhaoMM Zhou andW Jia ldquoStudy onextraction and purification of polysaccharides from Astragalusmembranaceusrdquo Zhong Yao Cai vol 32 no 11 pp 1741ndash17452009

[26] S C Wang J J Shan Z T Wang and Z B Hu ldquoIsolation andstructural analysis of an acidic polysaccharide from Astragalusmembranaceus (Fisch) Bungerdquo Journal of Integrative PlantBiology vol 48 no 11 pp 1379ndash1384 2006

[27] L Jing Z Z Zhen and C H Biao ldquoReview of Astragali radixrdquoChinese Herbal Medicines vol 3 no 2 pp 90ndash105 2011

[28] K Kajimura Y Takagi N Ueba et al ldquoProtective effect ofAstragali Radix by intraperitoneal injection against Japaneseencephalitis virus infection inmicerdquo Biological and Pharmaceu-tical Bulletin vol 19 no 6 pp 855ndash859 1996

[29] E Bombardelli and R Pozzi ldquoPolysaccharides withimmunomodulating properties from Astragalus membranaceusand pharmaceutical compositions containing themrdquo 1994httpbrevets-patentsicgccaopic-cipocpdengpatent20359-48summaryhtml

[30] I Kitagawa H KWang andM Saito ldquoSaponin and SapogenolXXXV Chemical constituents of Astragali Radix the rootof Astragalus membranaceus Bunge (2) Astragalosides I IIand IV acetylastragaloside I and isoastragalosides I and IIrdquoChemical and Pharmaceutical Bulletin vol 31 no 2 pp 698ndash708 1983

[31] I Kitagawa H K Wang M Saito andM Yoshikawa ldquoSaponinand Sapogenol XXXVI Chemical constituents of AstragaliRadix the root of Astragalus membranaceus Bunge (3) Astra-galosides III V and VIrdquo Chemical and Pharmaceutical Bulletinvol 31 no 2 pp 709ndash715 1983

[32] I Kitagawa H K Wang and M Yoshikawa ldquoSaponin andSapogenol XXXVII Chemical constituents of Astragali Radixthe root of Astragalus membranaceus Bunge (4) AstragalosidesVII andVIIIrdquoChemical and Pharmaceutical Bulletin vol 31 no2 pp 716ndash722 1983

[33] J S Kim M Yean E Lee et al ldquoTwo new cycloartane saponinsfrom the roots of Astragalus membranaceusrdquo Chemical andPharmaceutical Bulletin vol 56 no 1 pp 105ndash108 2008

[34] C Chu H Cai M Ren et al ldquoCharacterization of novelastragalosidemalonates fromRadixAstragali byHPLCwithESIquadrupole TOFMSrdquo Journal of Separation Science vol 33 no4-5 pp 570ndash581 2010

[35] Z Q He and J A Findlay ldquoConstituents of Astragalus mem-branaceusrdquo Journal of Natural Products vol 54 no 3 pp 810ndash815 1991

[36] Q Xu X Q Ma and X M Liang ldquoDetermination of astraga-losides in the roots of Astragalus spp using liquid chromatog-raphy tandem atmospheric pressure chemical ionization massspectrometryrdquo Phytochemical Analysis vol 18 no 5 pp 419ndash427 2007

[37] E J Lee M H Yean H S Jung J S Kim and S S KangldquoPhytochemical studies on Astragalus root (2)-flavonoids and alignanrdquoNatural Product Sciences vol 14 no 2 pp 131ndash137 2008

[38] L J Zhang H K Liu P C Hsiao et al ldquoNew isoflavonoid gly-cosides and related constituents from astragali radix (Astragalusmembranaceus) and their inhibitory activity on nitric oxideproductionrdquo Journal of Agricultural and Food Chemistry vol 59no 4 pp 1131ndash1137 2011

[39] L Z Lin X G He M Lindenmaier et al ldquoLiquidchromatography-electrospray ionization mass spectrometrystudy of the flavonoids of the roots of Astragalus mongholicusand A membranaceusrdquo Journal of Chromatography A vol 876no 1-2 pp 87ndash95 2000

[40] X Y Wu W Chen and M H Yu ldquoEffect of astragaluspolysaccharides on expression of IL-4 and IFN-120574 in non-obesediabetic micerdquo Chinese Journal of Rehabilitation Theory andPractice vol 14 no 2 pp 147ndash149 2008

[41] W Chen F Liu M Yu Q Zhu and X Zhu ldquoAstragaluspolysaccharide prevent type 1 diabetes in nonobese diabeticmicerdquo Fudan University Journal of Medical Sciences vol 28 no1 pp 57ndash60 2001

[42] W Chen Y-M Li and M-H Yu ldquoAstragalus polysaccharidesan effective treatment for diabetes prevention in NOD micerdquoExperimental and Clinical Endocrinology and Diabetes vol 116no 8 pp 468ndash474 2008

[43] W Chen Y P Xia M H Yu and X M Shi ldquoAstragaluspolysaccharides effect on pancreatic histopathologyrdquo ChinaJournal of Modern Medicine vol 17 no 2 pp 146ndash148 2007

[44] R J Li S D Qiu H X Chen H Tian and H X Wang ldquoTheimmunotherapeutic effects of Astragalus polysaccharide in type1 diabetic micerdquo Biological and Pharmaceutical Bulletin vol 30no 3 pp 470ndash476 2007

[45] R J Li S D Qiu H X Chen H Tian and G Liu ldquoEffectof Astragalus polysaccharide on pancreatic cell mass in type 1diabetic micerdquo Zhongguo Zhongyao Zazhi vol 32 no 20 pp2169ndash2173 2007

[46] W Chen Y M Li M H Yu and X M Shi ldquoImmunoloreg-ulation effects of Astragalus Polysaccharides on T helper lym-phocyte subgroups in nonobese diabetic Micerdquo China Journalof Modern Medicine vol 17 no 1 pp 28ndash35 2007

[47] F S Wong L K Siew G Scott et al ldquoActivation of insulin-reactive cd8 t-cells for development of autoimmune diabetesrdquoDiabetes vol 58 no 5 pp 1156ndash1164 2009

[48] J T Harty A R Tvinnereim and D W White ldquoCd8+ T celleffector mechanisms in resistance to infectionrdquo Annual Reviewof Immunology vol 18 pp 275ndash308 2000

[49] C Dong and R A Flavell ldquoCell fate decision T-helper 1 andsubsets in immune responsesrdquo Arthritis Research vol 2 no 3pp 179ndash188 2000

[50] I J Crane and J V Forrester ldquoTh1 and Th2 lymphocytes inautoimmune diseaserdquo Critical Reviews in Immunology vol 25no 2 pp 75ndash102 2005

[51] W Chen andMH Yu ldquoEffects of Astragalus polysaccharide ongene expression profiles in islets of NOD mice with microar-ray technique Chineserdquo Chinese Journal of Endocrinology andMetabolism vol 20 no 6 pp 545ndash548 2004

[52] W Chen Y M Li and M H Yu ldquoAstragalus polysaccharidesinfluence ultrastructure of islets and Th1Th2 cvtokine geneexpression of pancrease in NOD micerdquo Chinese Journal ofEndocrinology andMetabolism vol 23 no 3 pp 269ndash271 2007


[53] R J Li S D Qiu H X Chen and L R Wang ldquoImmunomod-ulatory effects of Astragalus polysaccharide in diabetic micerdquoZhong Xi Yi Jie He Xue Bao vol 6 no 2 pp 166ndash170 2008

[54] S T Azar H Tamim H N Beyhum M Zouhair Habbaland W Y Almawi ldquoType I (insulin-dependent) diabetes isa Th1- and Th2-mediated autoimmune diseaserdquo Clinical andDiagnostic Laboratory Immunology vol 6 no 3 pp 306ndash3101999

[55] W Chen M H Yu and Y M Li ldquoEffects of astragaluspolysaccharides on ultrastructure and oxidation apoptosisrelated cytokinesrsquo gene expression of non-obese diabetic micersquosisletsrdquo Fudan University Journal of Medical Sciences vol 34 no2 pp 269ndash272 2007

[56] A J Guri S K Mohapatra W T Horne II R Hontecillasand J Bassaganya-Riera ldquoThe Role of T cell PPAR 120574 inmice with experimental inflammatory bowel diseaserdquo BMCGastroenterology vol 10 no 10 p 60 2010

[57] L W Soromou N Chen L Jiang et al ldquoAstragalin attenuateslipopolysaccharide-induced inflammatory responses by down-regulating NF-120581B signaling pathwayrdquo Biochemical and Biophys-ical Research Communications vol 419 no 2 pp 256ndash261 2012

[58] M S Kim and S H Kim ldquoInhibitory effect of astragalin onexpression of lipopolysaccharideinduced inflammatory medi-ators through NF-120581B in macrophagesrdquo Archives of PharmacalResearch vol 34 no 12 pp 2101ndash2107 2011

[59] S M Mao C D Li L Wang J Wang G Dai and BKang ldquoEffect and mechanism of astragalus polysaccharides onapoptosis of the islet beta cell in diabetes mellitus ratsrdquo ChinesePharmacological Bulletin vol 25 no 9 pp 1227ndash1229 2009

[60] X J Zhou Y C Xu G M Yang and F Li ldquoIncreased galectin-1expression inmuscle of Astragalus polysaccharide-treated Type1 diabetic micerdquo Journal of Natural Medicines vol 65 no 3-4pp 500ndash507 2011

[61] C D Li J J Li L Wang et al ldquoInhibitory effect of astragaluspolysaccharides on apoptosis of pancreatic beta-cells mediatedby Fas in diabetes mellitus ratsrdquo Zhong Yao Cai vol 34 no 10pp 1579ndash1582 2011

[62] SMMao C D Li LWang et al ldquoEffects of astragalus polysac-charides on the ultrastructure and Fas expression of pancreaticbeta-cells in diabetes mellitus ratsrdquo Chinese PharmacologicalBulletin vol 26 no 6 pp 791ndash793 2010

[63] Y Wang Y Zhu L Gao et al ldquoFormononetin attenuates IL-1120573-induced apoptosis and NF-120581B activation in INS-1 cellsrdquoMolecules vol 17 no 9 pp 10052ndash10064 2012

[64] M Liu K Wu X Mao Y Wu and J Ouyang ldquoAstragaluspolysaccharide improves insulin sensitivity in KKAy miceregulation of PKBGLUT4 signaling in skeletal musclerdquo Journalof Ethnopharmacology vol 127 no 1 pp 32ndash37 2010

[65] F Zou XQMaoNWang J Liu and J POu-Yang ldquoAstragaluspolysaccharides alleviates glucose toxicity and restores glucosehomeostasis in diabetic states via activation of AMPKrdquo ActaPharmacologica Sinica vol 30 no 12 pp 1607ndash1615 2009

[66] W P Liao and Y G Shi ldquoEffect of astragalus polysaccharidesand soy isoflavones on glucose metabolism in diabetic ratsrdquoActa Academiae Medicinae Militaris Tertiae vol 29 no 5 pp416ndash418 2007

[67] N Wang D Zhang X Mao F Zou H Jin and J OuyangldquoAstragalus polysaccharides decreased the expression of PTP1Bthrough relieving ER stress induced activation of ATF6 in a ratmodel of type 2 diabetesrdquoMolecular andCellular Endocrinologyvol 307 no 1-2 pp 89ndash98 2009

[68] H F Liu Y H Ren Z X Han et al ldquoEffect of astragalus polysaccharides on insulin resistance and gene expression ofGLUT4in type 2 diabetes mellitus ratsrdquo Chinese Journal of Gerontologyvol 31 no 20 pp 3988ndash3989 2011

[69] D E Kelley and B H Goodpaster ldquoSkeletal muscle triglyceridean aspect of regional adiposity and insulin resistancerdquo DiabetesCare vol 24 no 5 pp 933ndash941 2001

[70] N Li Y Fan X M Jia Z Ma and S R Lin ldquoEffect of astragaliradix active ingredients on serum insulin and adiponectinin diabetes ratsrdquo Chinese Journal of Experimental TraditionalMedical Formulae vol 17 no 5 pp 144ndash146 2011

[71] N Li Y Fan XM Jia S R Lin and ZMa ldquoEffect of Astragalusactive ingredients on AdipoR1 and AMPKmRNA expression indiabetic ratsrdquoChina Journal of Traditional ChineseMedicine andPharmacy vol 26 no 5 pp 1176ndash1181 2011

[72] D H Wu F J Wang J Deng et al ldquoEffect of APS on theexpression of phosphyorylation of AMPK in liver tissue of type2 diabetic ratrdquo Chinese Journal of Microcirculation vol 19 no 3pp 1ndash3 2009

[73] J Spranger A Kroke M Mohlig et al ldquoAdiponectin andprotection against type 2 diabetes mellitusrdquoThe Lancet vol 361no 9353 pp 226ndash228 2003

[74] R D Lele ldquoPro-insulin C peptide glucagon adiponectinTNF120572 AMPK neglected players in type 2 diabetes mellitusrdquoJournal of Association of Physicians of India vol 58 no 30 pp35ndash40 2010

[75] E H Koh M Kim J Park et al ldquoPeroxisome proliferator-activated receptor (PPAR)-120572 activation prevents diabetes inOLETF rats comparisonwith PPAR-120574 activationrdquoDiabetes vol52 no 9 pp 2331ndash2337 2003

[76] C Wei X Yanping Z Xuelan et al ldquoThe critical role ofAstragalus polysaccharides for the improvement of PPRA120572-mediated lipotoxicity in diabetic cardiomyopathyrdquo PLOS Onevol 7 no 10 Article ID e45541 pp 1ndash10 2012

[77] Y S Chen H Q Liu W Qin and X M Luo ldquoEffect ofAstragalus polysaccharides on neuropeptide Y and its receptorY2expression in streptozotocin-induced diabetic ratsrdquo Journal

of Liaoning University of Traditional Chinese Medicine vol 13no 1 pp 48ndash49 2011

[78] S Narayanan ldquoAldose reductase and its inhibition in the controlof diabetic complicationsrdquo Annals of Clinical and LaboratoryScience vol 23 no 2 pp 148ndash158 1993

[79] H Z Yang M M Zhou A H Zhao S N Xing Z QFan and W Jia ldquoStudy on effects of baicalin berberine andAstragalus polysaccharides and their combinative effects onaldose reductase in vitrordquoZhongYaoCai vol 32 no 8 pp 1259ndash1261 2009

[80] A Xu H Wang R L C Hoo et al ldquoSelective elevation ofadiponectin production by the natural compounds derivedfrom a medicinal herb alleviates insulin resistance and glucoseintolerance in obese micerdquo Endocrinology vol 150 no 2 pp625ndash633 2009

[81] J Yu Y Zhang S Sun et al ldquoInhibitory effects of astragalosideIV on diabetic peripheral neuropathy in ratsrdquoCanadian Journalof Physiology and Pharmacology vol 84 no 6 pp 579ndash5872006

[82] N Wang X Q Mao S Wang C Zhang F Zou and J POuyang ldquoEffects of APS on reducing ER stress and increasinginsulin sensitivity in a rat model of type 2 diabetesrdquo Journal ofPublic Health and Preventive Medicine vol 18 no 4 pp 13ndash162007


[83] X Q Mao Y Wu K Wu et al ldquoAstragalus polysaccharidereduces hepatic endoplasmic reticulum stress and restoresglucose homeostasis in a diabetic KKAy mouse modelrdquo ActaPharmacologica Sinica vol 28 no 12 pp 1947ndash1956 2007

[84] Y Wu J P Ou-Yang K Wu Y Wang Y Zhou and C WenldquoHypoglycemic effect of Astragalus polysaccharide and its effecton PTP1Brdquo Acta Pharmacologica Sinica vol 26 no 3 pp 345ndash352 2005

[85] X Mao F Yu N Wang et al ldquoHypoglycemic effect ofpolysaccharide enriched extract ofAstragalus membranaceus indiet induced insulin resistant C57BL6J mice and its potentialmechanismrdquo Phytomedicine vol 16 no 5 pp 416ndash425 2009

[86] P Kovacs R L Hanson Y Lee et al ldquoThe role of insulinreceptor substrate-1 gene (IRS1) in type 2 diabetes in PimaIndiansrdquo Diabetes vol 52 no 12 pp 3005ndash3009 2003

[87] E Zeggini J Parkinson S Halford et al ldquoAssociation studiesof insulin receptor substrate 1 gene (IRS1) variants in type 2diabetes samples enriched for family history and early age ofonsetrdquo Diabetes vol 53 no 12 pp 3319ndash3322 2004

[88] H F Liu Y Zhang ZHu et al ldquoEffect ofAstragalus polysaccha-rides on gene expression of resistin in type 2 diabetes mellitusratsrdquo Journal of Mudanjiang Medical University vol 32 no 4pp 9ndash10 2011

[89] H F LiuH J Chen G YWang Z XHan and J Zhang ldquoEffectof astragalus polysaccharides on insulin resistance and proteinpxpression of resistin in type 2 diabetes mellitus ratsrdquo Food andNutrition in China vol 18 no 1 pp 69ndash71 2012

[90] M A Lawlor and D R Alessi ldquoPKBAkt a key mediator of cellproliferation survival and insulin responsesrdquo Journal of CellScience vol 114 no 16 pp 2903ndash2910 2001

[91] H K R Karlsson J R Zierath S Kane A Krook G ELienhard and H Wallberg-Henriksson ldquoInsulin-stimulatedphosphorylation of the Akt substrate AS160 is impaired inskeletal muscle of type 2 diabetic subjectsrdquoDiabetes vol 54 no6 pp 1692ndash1697 2005

[92] U Ozcan Q Cao E Yilmaz et al ldquoEndoplasmic reticulumstress links obesity insulin action and type 2 diabetesrdquo Sciencevol 306 no 5695 pp 457ndash461 2004

[93] Z Fu E R Gilbert and D M Liu ldquoRegulation of insulinsynthesis and secretion and pancreatic beta-cell dysfunction indiabetesrdquoCurrent Diabetes Reviews vol 9 no 1 pp 25ndash53 2013

[94] M J Reginato and M A Lazar ldquoMechanisms by which thiazo-lidinediones enhance insulin actionrdquo Trends in Endocrinologyand Metabolism vol 10 no 1 pp 9ndash13 1999

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


2 Ethnopharmacology Effects ofAM on Diabetes Mellitus

The roots of AM have a long history for the treatment ofdiabetes-related symptoms in China In traditional Chinesemedicine it is used to reinforce Qi in order to induceurination consolidate the exterior express toxins outwardand make new tissues grow [7 12] A number of studieshave emphasized its pharmacological relation to diabetesmellitus Earlier ethnopharmacological studies analyzed var-ious crude extracts for their anti-diabetic activities and theirpossible pharmacological processes They were studied asa single extract or as part of a compound formula andwere reported to have demonstrated potentials of attenuatingDM and their associated complications They were generallyobserved to have lowered increasing blood glucose andlipid levels improved insulin sensitivity and also correctedseveral pathological indicators of DM and its complications[6 13ndash16] In a clinical study of the effect of AM on insulinsensitivity AM decoction reduced fasting blood glucose andhomeostatic model assessment (HOMA) levels in type 2DM patients [14] Anti-diabetic studies onQilan Tangzhiningcapsule a Chinese herbal anti-diabetic formula containingAM showed its potential to reduce blood glucose levels andimprove lipid profiles in streptotozocin-induced diabetic rats[16] A number of pharmacological processes for inducingthese anti-diabetic effects have been suggested Some ofwhich include the suppression of macrophage- and cytokine-induced inflammatory responses stimulation of insulin sig-nal transduction and lowering of the hyperglycemic effects ofglucagon in experimental animals Its mechanism of actionhas been associated with several enzymes proteins andmolecularmarkers such as peroxisome-proliferator-activatedreceptor gamma (PPAR120574) phosphatidylinositide-3-kinase(PI-3-K) and Na+ K+-ATPase among others [10 14 16ndash18]Further studies have sought to elucidate the phytochemicalconstituents inducing these anti-diabetic effects

3 Phytochemical Constituents

Several classes of organic compounds namely Astragaluspolysaccharides saponins flavonoids isoflavonoids sterolsamino acids and volatile oils have been isolated from AMThe polysaccharides saponins and flavonoids are the majorchemical constituents demonstrating biological activity toDM [19 20]

31 Polysaccharides The polysaccharides of AM are byextractionmethods water-soluble and -insoluble glucans andheteropolysaccharides Astragalans I II and III are polysac-charides extracted by hot water Astragalan Ι was elucidatedas a neutral heteropolysaccharide containing D-glucose D-galactose and L-arabinose in the ratio of 175 163 1 It hasa molecular weight of 36 kD Astragalans ΙΙ and ΙΙΙ were120572-(14)-glucans with molecular weights of 12 kD and 34 kDrespectively [21 22] APS I and APS II were isolated by waterextraction and alcohol precipitation technique Structural

and content analyses showed that APS I consisted of arabi-nose and glucose in the ratio of 1 345 ASP II consisted ofrhamnose arabinose and glucose in the ratio of 1 625 1786[22 23] Acidic polysaccharides such as AMem-P AH-1and APSID3 have also been isolated [24ndash27] AMem-P is acomplex acidic polysaccharide with a molecular weight of60 kD It consists mainly of hexuronic acid and has terminaland 120572-15-linked-arabinofuranose terminal and120573-13-120573-14- 120573-16-linked 36-branched-D-galactose and 24-branched-L-rhamnose residue groups attached [24] Other Astragaluspolysaccharides include AH-2 AE AEF-1 and AEF-2 andastroglucans A B and C [27ndash29]

32 Saponins The saponin content of AM consists mainly oftriterpene saponins Structurally they are cycloartane triter-pene glycosides with one-to-three sugars attached at the 3-6- and 25-positions Kitagawa (1983) reported the isolation ofseveral cycloartane triterpenoids such as astragaloside IndashVIII[30ndash32] and isoastragalosides I and II [30] AstragalosidesVIIand VIII were elucidated as saponins with oleanane skeleton[32] Azukisaponin V methyl ester has been isolated andidentified as an oleanane-type triterpene saponin [33] Anastragaloside malonate has also been identified as malonylas-tragaloside [34] Several other astragalus saponins includingisoastragalosides III and IV astramembrannin II cyclogalegi-noside B cycloaraloside A brachyoside B cyclocanthoside Ecyclounifolioside B [27 35 36] and astramembranosides Aand B [33] have also been isolated

33 Flavonoids Flavonoids of varying structures have beenisolated from AM They are mainly in structural groupsof flavones isoflavones isoflavanones and pterocarpansKaempferol isorhamnetin rhamnocitrin kumatakeninand rhamnocitrin-3-glucoside and quercetin-3-glucosidehave been isolated as flavones [27] Formononetin ononincalycosin calycosin-7-O-120573-D-glucoside-610158401015840-O-malonate 31015840-methoxy-51015840-hydroxy-isoflavone-7-O-120573-D-glucoside and(3R)-2101584031015840-dihydroxy-410158407-dimethoxyisoflavone have beenisolated as isoflavones [27 37 38] The isoflavanones include21015840-hydroxy-3101584041015840-dimethoxyisoflavone-7-O-120573-D-glucopyra-noside 21015840-hydroxy-31015840410158407-trimethoxyisoflavone 210158407-dihy-droxy-31015840410158407-trimethoxyisoflavone 3101584041015840-dimethoxyisofla-vone-7-O-120573-D-glucoside 821015840-dihydroxy-410158407-dimethoxyis-oflavone and 21015840310158407-trihydroxy-41015840-methoxyisoflavone[27] The reported pterocarpans include 3910-trimethox-ypterocarpan (6aR11aR)-10-hydroxy-39-dimethoxyptero-carpan and 910-dimethoxypterocarpan-7-O-120573-D-glucopy-ranoside [27 38 39]

4 Pharmacological Effects of AstragalusChemical Constituents on Diabetes Mellitus

The polysaccharides (APS) saponins (ASS) and flavonoids(ASF) fractions of AM have been the most studied fortheir anti-diabetic effects on types 1 and 2 DM Several sin-gle isolated compounds including astragalin formononetinastragalosides I II and IV and isoastragaloside I (Figure 1)have also been analyzed Their pharmacological processes


OHO

HO

OH OH

OH

O

HO

O

O

OH

Astragalin

(a)

O

OHO

OFormononetin

(b)

O O

HO

OH

OH

OH

O

O

OHO

OH

O

HO

HO

O

O

Astragaloside II

(c)

O

HO

OH

OH

OHO

O

OH

O

OH

OHO

HO

OH

Astragaloside IV

(d)

O

HO

OH

OH

OHOO

OH

O

OH

OO

O

HO O

O

Isoastragaloside I

(e)






























Acknowledgments


References










































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















OHO

HO

OH OH

OH

O

HO

O

O

OH

Astragalin

(a)

O

OHO

OFormononetin

(b)

O O

HO

OH

OH

OH

O

O

OHO

OH

O

HO

HO

O

O

Astragaloside II

(c)

O

HO

OH

OH

OHO

O

OH

O

OH

OHO

HO

OH

Astragaloside IV

(d)

O

HO

OH

OH

OHOO

OH

O

OH

OO

O

HO O

O

Isoastragaloside I

(e)






























Acknowledgments


References










































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of








































Acknowledgments


References










































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Review Article Recent Advances in Astragalus membranaceus...

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Transcript of Review Article Recent Advances in Astragalus membranaceus...