reviewarticle the versatile effects of dihydromyricetin in ... · reviewarticle the versatile...

Review ArticleThe Versatile Effects of Dihydromyricetin in Health

Hongliang Li1 Qisheng Li2 Zhaowen Liu1 Kai Yang1 Zhixi Chen1

Qilai Cheng1 and LonghuoWu1

1College of Pharmacy Gannan Medical University Ganzhou 341000 China2Jiangxi Health Vocational College Nanchang 330052 China

Correspondence should be addressed to Qilai Cheng cql 57126com and Longhuo Wu longhwuhotmailcom

Received 24 May 2017 Accepted 27 July 2017 Published 30 August 2017

Academic Editor Siyaram Pandey

Copyright copy 2017 Hongliang Li et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Dihydromyricetin is a flavonoid isolated from Ampelopsis grossedentata which is traditionally used in China Dihydromyricetinexhibits health-benefiting activities withminimumadverse effects Dihydromyricetin has been demonstrated to show antioxidativeanti-inflammatory anticancer antimicrobial cell death-mediating and lipid and glucose metabolism-regulatory activitiesDihydromyricetin may scavenge ROS to protect against oxidative stress or potentiate ROS generation to counteract cancer cellsselectively without any effects on normal cells However the low bioavailability of dihydromyricetin limits its potential applicationsRecent research has gained positive and promising data This review will discuss the versatile effects and clinical prospective ofdihydromyricetin

1 Introduction

Dihydromyricetin also known as ampelopsin belonging toflavonoid family is isolated from Ampelopsis grossedentatawhich grows widely in the south of China TraditionallyAmpelopsis grossedentata is used as tea in Yao people inChina to treat pyretic fever and cough pain in phar-ynx and larynx and jaundice hepatitis It is also usedin nephritis hepatitis halitosis and polyorexia preventionand treatment [1] Dihydromyricetin is the richest compo-nent found in Ampelopsis grossedentata Biologically recentstudies have demonstrated that dihydromyricetin showsmultiple health-benefiting activities including antioxida-tive anti-inflammatory anticancer antimicrobial cell death-mediating and lipid and glucose-metabolism-regulatoryactivities In this review article these biological activities willbe discussed comprehensively

2 Chemical Characteristicsof Dihydromyricetin

Structurally due to the highly hydrophilic character dihy-dromyricetin shows poor bioavailability and significantly

limits its potential medicinal applications The solubil-ity of dihydromyricetin may be enhanced with tempera-ture increasing from 02mgml at 25∘C to 09mgml at37∘C The diagrams of phase-solubility show that dihy-dromyricetin solubility is positively correlated with the con-centration of hydroxypropyl-120573-cyclodextrin PVP K30 andPEG6000 Thus the solubility of dihydromyricetin increasesto 28mgml at 25∘C and 96mgml at 37∘C respectively [2]In addition enzyme-acylated product of dihydromyricetinimproves its lipid-solubility and also exhibits a good antiox-idative activity [3] The poor bioavailability is further sup-ported by the pharmacokinetic characteristics which show119862max (2163plusmn 362 ngmL) and t12 (370plusmn 099 h) after oraladministration [4] Similar results are obtained but show dif-ferent pharmacokinetic characteristics of dextroisomer andracemate in dihydromyricetin 119862max (813 and 107 ngmL)AUC0minusinfin (428 and 320mg times minL) and t12 (288 and367min) respectively [5]

However the low bioavailability of dihydromyricetinmay be also partially attributed to its poor structural stabilityDihydromyricetin decomposes when exposing to lightpH buffer pepsin and pancreatin enzymes Generallythe metabolites of flavonoids are produced by hydrolysisring fission and reduction [6] Dihydromyricetin can be

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2017 Article ID 1053617 10 pageshttpsdoiorg10115520171053617

2 Evidence-Based Complementary and Alternative Medicine

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Figure 1 The structure of dihydromyricetin (1) and its metabolites (2ndash8)

transformed into seven metabolites in rats [7] (Figure 1)They are 573101584051015840-tetrahydroxyflavanonol (2) 574101584051015840-tetra-hydroxy-31015840-methoxyflavone (3) 573101584051015840-tetrahydroxy-41015840-methoxyflavone (4) 57310158404101584051015840-pentahydroxyflavanone (5)3457310158404101584051015840-hepthydroxyflavan (6) (2R3S)-57310158404101584051015840-pentahydroxyflavanonol (7) and dihydromyricetin-O-5-120573-D-glucuronide (8)

3 Oxidative Stress-Mediating Activity

Oxidative stress is a state of cellular homeostasis imbalancecharacterized as reactive oxygen species (ROS) productionoverweighting the antioxidant enzyme system ExcessiveROS contributes to mitochondria-dependent apoptosis Themechanistic chemistry in radical scavenging ability of dihy-dromyricetin has been approved in protection against mes-enchymal stem cells damage [8] The antioxidative activ-ity of dihydromyricetin is also confirmed by two modelsystems including cooked ground beef and soybean oil[9] Excessive ROS may acts as a dominant factor con-tributing to myocardial fibrosis Cardiac fibroblast may beactivated by angiotensin II through induction of ROS pro-duction promoting proliferation and collagen synthesisDihydromyricetin restores these adverse effects induced byangiotensin II as indicating by decreased levels of ROSand MDA attenuated expression of p22phox (a subunit ofNADPH oxidase) and increased total antioxidant capacity[10] Similar results are showed in the antioxidative effectof dihydromyricetin on attenuating angiotensin II-inducedcardiomyocyte hypertrophy [11]

Excessive ROS is also correlated with neurogenerativediseases 3-Nitropropionic acid may induce motor dys-function and learning and memory impairments throughhyperactivation of ROS production Dihydromyricetinsignificantly restores metabolic abnormality in striatumimproves the expression of antioxidant system and inhibitsmitochondria-dependent apoptosis [12] Memory impair-ments are also subject to hypobaric hypoxia which ofteninduces oxidative stress in the brain Dihydromyricetin hasbeen showed to suppress ROS production and attenuate lipidperoxidation in the hippocampus promoting mitochondrialbiogenesis and improving mitochondrial functions (Table 1)In addition dihydromyricetin protects neurons fromhypobaric hypoxia through amelioration of Sirt3-FOXO3asignaling-induced oxidative stress [13]

Oxidative stress has been considered as the criticalfactor correlating with nephrotoxicity induced by cisplatinIn HK-2 cells dihydromyricetin may protect against suchnephrotoxicity through attenuation of oxidative stress andinflammatory stress leading to inhibition of apoptosis [14]ROS in osteocytes contributes to osteoporosis formation InMG63 cells dihydromyricetin effectively exhibits antioxida-tive activity to scavenge ROS and leads to attenuation ofcaspase-3 and caspase-9 and inhibition of cell apoptosis [15]In HUVECs dihydromyricetin ameliorates H2O2-inducedoxidative stress against apoptosis mitochondria dependently[16] In addition dihydromyricetin may increase the totalantioxidant capacity and attenuate ROS generation andNOX2 expression Thus dihydromyricetin ameliorates the

Evidence-Based Complementary and Alternative Medicine 3

Table 1 The biological activities of dihydromyricetin

Cell typesanimals Biological activities RefMesenchymal stem cells Radical scavenginguarr [8]

Cardiac fibroblast ROSdarr MDAdarr p22phox darr SODuarr thioredoxinuarr total anti-oxidant capacityuarrproliferationdarr collagen synthesisdarr [10]

Cardiomyocyte ROSdarr MDAdarr NOdarr p22phox darr SODuarr total anti-oxidant capacityuarr cGMPuarrhypertrophydarr [11]

Rats motor dysfunctiondarr learning and memory impairmentsdarr MDAdarr glucosemetabolismuarr SODuarr Bcl-2uarr Baxdarr Cleaved Caspase-3darr [12]

Rats and HT-22 cells PGC-1120572 uarr TFAMuarr SIRT3uarr FOXO3 deacetylationuarr ROSdarr synaptic plasticityuarroxidative stressdarr mitochondrial functionuarr [13]

HK-2 cells MDAdarr CATuarr SODuarr Bcl-2uarr IL-1120573 darr IL-6darr TNF-120572 darr MCP-1darr [14]MG63 cells ROSdarr caspase-3darr caspase-9darr [15]

HUVECs ROSdarr p53darr Bcl-2uarr Baxdarr caspase-3darr caspase-9darr PARPdarr [16]ox-LDLdarr IL-6darr TNF-120572 darr PPAR120572 uarr LXR120572 uarr ABCA1uarr lipid accumulationdarrROSdarr NO2darr [17]

C57BL6 mice Nrf2HO-1uarr CYP2E1darr p62uarr Keap1darr LC3-IIuarr Beclin 1uarr [18]

RAW22647 IKK120573 darr p-IKK120572120573 darr p-p65darr COX-2darr iNOSdarr [19]p-NF-120581Bdarr p-p38darr p-JNKdarr [20]

HeLa cells p-I120581B120572 darr p-p65darr TRAF2darr RIP1darr c-IAP2darr Bcl-2darr TRAF1darr iNOSdarr cyclin D1darrCOX-2darr ICAM-1darr MMP-9darr VEGFdarr [21]

Mouse IL-4darr IL-5darr IL-13darr IgEdarr IgG1darr [22]

HepG2 cells

ROSdarr GSHdarr ATPdarr caspase-9uarr caspase-8uarr caspase-3uarr HO-1uarr BAKuarr Bcl-2darr [23]p-Akt-Ser473darr p-Bad-Ser112Ser136darr Baxuarr Baduarr [24]TGF120573 darr p53uarr Bcl-2darr [25]AMPKuarr p-ERK12darr p-Aktdarr mTORdarr autophagyuarr [26]

Hepal-6 cells TGF120573Smad3darr NOX4ROSdarr [27]SK-Hep-1 cells MMP-9darr p-p38darr p-ERK12darr p-JNKdarr PKC-120575 uarr [28]A2780 SKOV3 p53uarr survivindarr [29]HCT116L-OHP MRP2darr erythroid 2 p45 related factor 2darr [30]Osteosarcoma p21uarr AMPK120572-GSK-3120573-Sox2uarr [31]SK-MEL-28 cells p21uarr p53uarr cdc2darr p-cdc-2darr cdc25Adarr Baxuarr IKK120572 darr p65darr p-p38darr [32]HepG2 Hep3B Chk1Chk2cdc25Cuarr [33]Gastric cancer cell p53darr Bcl-2uarr [34]NSCLC ROSuarr ERK12uarr JNK12uarr [35]SK-MEL-28 ROSuarr p-NF-120581Buarr [36]Diabetic mice Beclin1uarr Atg7uarr Bcl-2uarr LC3 IILC3 Iuarr p62darr caspase-3-9darr p-AMPKuarr p-ULK1uarr [37]Liver IR injury BECN1uarr LC3uarr Atg5uarr Atg12uarr FOXO3auarr [38]HNSCC ROSuarr STAT3uarr Beclin1uarr LC3uarr p62uarr [39]Diabetic fatty rats p-PPAR120574-Ser273darr ERKCDK5darr insulin resistancedarr [40]

C2C12 myotubes p-IRS-1uarr p-AKTuarr AMPK-PGC-1120572-Sirt3uarr autophagosomesuarr [41 42]AMPKuarr PGC-1120572 uarr FNIP1darr [43]

LDLrminusminus mice ox-LDLdarr IL-6darr TNF-120572 darr PPAR120572 uarr LXR120572 uarr ABCA1uarr hyperlipidemiadarr foamcelldarr cholesterol effluxdarr [17]

Rats humans irisinuarr FNDC5uarr PGC-1120572 uarr [44]AD rats miR-34adarr p53p21darr Sirt1uarr p-mTOR-Ser2448uarr autophagyuarr [45]PD rats ROSdarr GSK-3120573 darr [46]LPS-induced rat kidney blood urea nitrogendarr molecule-1darr MDAdarr apoptosisdarr [47]Rat liver JNKuarr inflammationdarr apoptosisdarr proliferationuarr [48]B16F10 MAPKdarr cAMPPKAdarr PKCdarr CREBdarr MITFdarr [49]


Table 1 Continued

Cell typesanimals Biological activities Ref

Ratsglucose uptakeuarr GLU1uarr Krebsuarr insulin resistancedarr CSuarr SDHAuarr DLSTuarr serinedarrleucinedarr asparaginedarr SSAdarr 5-L-glutamyl-alaninedarr L-methylhistidinedarrp-IRS-Ser612darr Aktuarr AMPKuarr GSK-3120573 darr G6Pasedarr PEPCKdarr

[50]

L02 HepG2 cells TGdarr TCdarr ROSdarr AMPKuarr AKTuarr PPAR120574 uarr [51]

Humans glucosedarr LDL-Cdarr GGTdarr alaninedarr ASTdarr Apo Bdarr TNF-120572 darr CK-18 fragmentdarrFGF21darr [52]

Rats H9c2 PI3KAktuarr HIF1120572 uarr Bcl-2uarr Bcl-XLuarr Baxdarr Bnip3darr cleaved caspase-3-9darrcytochrome cdarr [53]

PC12 cells oxidative stressdarr calcium overloaddarr p-AMPK120572 uarr [54]

cytotoxicity induced by oxLDL as indicated by monocytesadhesion and oxidative stress [17]

P62 has been demonstrated to competitively bind toKeap1 which plays a negative role in modulating Nrf2 activ-ity The complex p62-Keap1-LC3II promotes Keap1 degrada-tion which further activates Nrf2 in a positive feedback loopDihydromyricetin significantly induces p62 expression andsubsequent Nrf2 and HO-1 activation leading to attenuationof oxidative stress and hepatoprotection against toxicityinduced by ethanol [18]

4 Anti-Inflammatory Activity

NF-120581B signaling has been demonstrated to play a criticalrole in regulating the expression of target genes relating toinflammationThe subunit I120581B120572 as a negative controller canbe degraded after phosphorylation modification leading toactivation and nuclear translocation of p65 and subsequentpromotion of NF-120581B target genes expression The computa-tional docking assays show that dihydromyricetin binds to anovel binding site IKK120573-Cys46 which plays a pivotal role inthe pathogenesis of inflammation The delayed-type hyper-sensitivity and an IKK120573C46A transgenicmousemodel confirmthat Cys46 is the binding site for dihydromyricetin to beresponsible for suppression of NF-120581B signaling [55] In LPS-induced RAW22647 microphages dihydromyricetin atten-uates IKK120573 activity and IKK120572120573 phosphorylation leadingto inhibiting p65 phosphorylation and nuclear translocationand suppressing target genes expression including COX-2and iNOS [19] Similar results showed that dihydromyricetininhibits the phosphorylation of NF-120581B p38 and JNK but notERK12 in LPS-induced RAW22647 microphages [20]

Dihydromyricetin has been reported to inhibit TNF-120572-induced inflammation through inactivation of NF-120581B sig-naling in HeLa cells Specifically dihydromyricetin dephos-phorylates and inhibits the degradation of I120581B120572 inactivatesp65 nuclear translocation and downregulates the TNF-120572-induced expression of TRAF2 and RIP1 In addition dihy-dromyricetin also downregulates the expression of NF-120581Btarget genes including c-IAP2 Bcl-2 TRAF1 iNOS cyclinD1 COX-2 ICAM-1 MMP-9 and VEGF [21] (Table 1) Inasthmatic mouse model ovalbumin promotes the secretionof proinflammatory cytokines IgE and IgG1 and the infiltra-tion of inflammatory cells into the bronchoalveolar lavage

Dihydromyricetin has been demonstrated to significantlyreduce ovalbumin-induced inflammatory activities [22]

5 Anticancer Activity

ROS may act as a messenger to balance redox signaling todetermine cell fates Higher ROS production and oxidativestress are positively correlating with carcinogenesis Interest-ingly dihydromyricetin may regulate cell death potentiallythrough mediating ROS generation Dihydromyricetin ina dose-dependent manner promotes ROS generation andactivation of mitochondria-dependent apoptosis in humanhepatocarcinoma HepG2 cells [23] Mechanistically dihy-dromyricetin triggers mitochondria-dependent apoptoticpathway through downregulating AktBad signaling Morespecific dihydromyricetin inhibits the phosphorylation ofAkt-Ser473 and Bad-Ser112Ser136 and enhances Bax andBad proteins expression leading to formation of Bcl-2Bcl-xL heterodimers and activation of Bax-stimulated mito-chondrial apoptosis in HepG2 cells [24] In mouse hepa-tocellular carcinoma Hepal-6 cells dihydromyricetin dose-dependently induces cell apoptosis through downregulationof TGF120573Smad3 pathway and NOX4ROS pathway [27] Inaddition dihydromyricetin significantly inhibits the expres-sion of MMP-9 but not MMP-2 which is the key factorresponsible for the migration and invasion of SK-Hep-1cells This underlying mechanism of dihydromyricetin inantimetastasis is related to the decreased phosphorylationlevels of p38 ERK12 and JNK and the increased expressionof PKC-120575 [28] (Table 1)

In A2780 and SKOV3 cell lines dihydromyricetin dose-and time-dependently inhibits cellular proliferation andcauses cell cycle arrest in G0G1 and S phases The activationof p53 signaling and the suppression of survivin expressionare involved in dihydromyricetin-induced ovarian cancercell apoptosis Survivin an inhibitors of apoptosis proteins(IAPs) family is a key factor in cellular chemotherapy-related resistance Thus dihydromyricetin may promote theresistant ovarian cancer cells to resensitize to paclitaxel anddoxorubicin through suppression of survivin expression [29]On molecular mechanism of drug resistance in colorectalcancer HCT116L-OHP cells dihydromyricetin significantlyinhibits the promoter activity and the expression ofmultidrugresistance protein 2 (MRP2) leading to chemosensitivityof cells to oxaliplatin In addition dihydromyricetin also


attenuates the nuclear translocation of erythroid 2 p45 relatedfactor 2 a MRP2 regulator [30]

In osteosarcoma dihydromyricetin may upregulate theexpression of p21 and cause cell cycle arrest in G2-M phageleading to cell apoptosisThemolecular mechanism is associ-ated with dihydromyricetin-induced activation of AMPK120572-GSK-3120573-Sox2 signaling pathway [31] (Table 1) In humanmelanoma SK-MEL-28 cells dihydromyricetin promotes theexpression of p21 and p53 and attenuates the expression ofcdc2 p-cdc-2 and cdc25A causing cell cycle arrest in G1Sphase In addition dihydromyricetin activates cell apoptosisthrough upregulation of the proapoptotic factor Bax anddownregulation of NF-120581B pathway and p38 pathway [32]In HepG2 and Hep3B cell lines dihydromyricetin maycause cell cycle arrest in G2M phase through activation ofChk1Chk2cdc25C However deficiency of p53 and Chk1does not cause dihydromyricetin-induced G2M arrest [33]

6 Cell Death-Mediating Activity

Apoptosis is a process of programmed cell death whichexhibits a critical role in cellular physiopathology of varioustissues and organs Dihydromyricetin in a dose-dependentmanner downregulates the expression of p53 and upregu-lation Bcl-2 expression leading to activation of apoptosisin gastric cancer cell [34] Interestingly dihydromyricetinpromotes cell apoptosis through reduction of TGF120573 and acti-vation of p53 signaling pathways in HepG2 cells [25] Consis-tently dihydromyricetin downregulates Bcl-2 expression andincreases BaxBcl-2 ratio through upregulation of p53 signal-ing pathway in HepG2 cells [56] Dihydromyricetin exhibitsa selective cytotoxicity against non-small-cell lung cancer(NSCLC) cells (A549 andH1975) but not against normal cells(WI-38)Thismight be related to dihydromyricetin-triggeredROS generation which causes a mitochondria-dependentapoptosis In addition dihydromyricetin promotes ROS-induced ERK12 and JNK12 signaling pathways which canbe reversed by N-acetylcysteine [35]

Dihydromyricetin can induce not only apoptosis butalso autophagy in human melanoma (SK-MEL-28) cellsDihydromyricetin potentiates ROS generation which canbe counteracted by N-acetyl-L-cysteine (NAC) The mech-anism of dihydromyricetin-induced autophagy is related toupregulation of NF-120581B phosphorylation induced by ROS[36] Similarly dihydromyricetin induces cardiac autophagyand protects against apoptosis in STZ-induced diabetic miceas indicated by upregulation of Beclin1 Atg7 and Bcl-2expression and LC3 IILC3 I ratio and downregulation of p62caspase-3-9 levels Further dihydromyricetin may promoteAMPK and ULK1 phosphorylation improve mitochondrialfunctions and subsequently prevent diabetic cardiomyopa-thy [37] mTOR a master regulator belonging to PI3Krelated kinase family regulates the activation of autophagymTOR can be phosphorylated and regulated by PI3KAktERK12 and AMPK through regulating TSC2 and TSC12phosphorylation Dihydromyricetin has been reported toactivate AMPK and attenuate the expression of p-ERK12

and p-Akt leading to inhibition of mTOR and activation ofautophagy in HepG2 cell lines [26] (Table 1)

AMPK increases the transcriptional activity of FOXO3athrough the phosphorylation at Ser588 In liver IR injurydihydromyricetin also increases the mRNA expression ofautophagy-related genes such as BECN1 LC3 Atg5 andAtg12 protecting liver cell against apoptosis This might beassociated with upregulation of FOXO3a protein expres-sion nuclear translocation and phosphorylation at Ser588induced by dihydromyricetin [38] FOXO3a activity is alsomediated by its acetylation induced by p300CBP or SirtHowever the acetylation levels of FOXO3a are not changedin the cytosol indicating that FOXO3a acetylation doesnot play an important role in dihydromyricetin-inducedautophagy [38] In head and neck squamous cell carci-noma (HNSCC) dihydromyricetin promotes the phospho-rylation and activation of STAT3 and subsequent inductionof autophagy through producing ROS Specifically dihy-dromyricetin induces the upregulation of autophagicmarkerssuch as Beclin1 LC3 and p62 In addition dihydromyricetinalso promote HNSCC cells apoptosis [39] (Table 1)

7 Metabolism-Mediating Activity

Flavonoids are also partial agonists of PPAR120574 which exhibitsan inhibitory effect on diabetes Upregulation of diabetogenicadipokines expression and downregulation of adiponectinexpression are mediated by PPAR120574-Ser273 phosphorylationwhich is regulated by ERKCDK5 signaling pathway InZucker diabetic fatty rats dihydromyricetin may inhibitthe phosphorylation of PPAR120574-Ser273 through attenuationof ERKCDK5 signaling pathway leading to retardation ofhyperglycemia onset and amelioration of insulin resistancewithout weight gain [40] Management of insulin resistancein skeletal muscle becomes a strategy for type II diabetes(T2D) treatment Dihydromyricetin increases skeletalmuscleinsulin sensitivity as indicated by upregulation of p-IRS-1and p-AKT expression by inducing formation of autophago-somes partially through activation of AMPK-PGC-1120572-Sirt3pathway in C2C12 myotubes [41 42] (Table 1)

In LDL receptor knockout (LDLrminusminus) mice dihydro-myricetin decreases high-fat diet-induced serum levels ofox-LDL IL-6 and TNF-120572 and increases PPAR120572 LXR120572and ABCA1 expression leading to amelioration of hyper-lipidemia suppression of hepatic lipid accumulation andinhibition of foam cell formation and cholesterol efflux [17]This is supported by the ApoEminusminus mouse model which showsthat dihydromyricetin can significantly prevent the devel-opment of weight gain hyperlipidemia and atherosclerosisinduced by a Western diet (high cholesterol high sucroseand high-fat) [57] Dyslipidemia constitutes a major healthproblem in inducing atherosclerosisMany flavonoids includ-ing naringenin quercetin and dihydromyricetin are involvedin glucose and lipid profiles improvement Synergized withbenzo[a]pyrene (BaP) 120573-naphthoflavone (BNF) activatesCYP1A1 expression and CYP1A1-mediated 7-ethoxyresorufin


O-deethylation (EROD)Dihydromyricetin has been demon-strated to promote tumorigenesis induced by BaP in smallintestine [58] However dihydromyricetin alone does notshowany significant effects onmetabolic activity ofCYP1A12and CYP2B1 enzymes [59]

Irisin is a newmyokine derived from the fibronectin typeIII domain-containing protein 5 (FNDC5) PGC-1120572 regulatesthe expression of FNDC5 mRNA and the metabolism ofirisin which is correlated with bodymass index (BMI) Dihy-dromyricetin has been demonstrated to increase irisin levelsin serum and upregulate the FNDC5 expression throughpartially activating PGC-1120572 pathway leading to ameliorationof metabolic diseases [44] Palmitate has been identified as amajor inducer of insulin resistance in obesity Also palmitatecan downregulate the expression of slow-twitch fiber pro-portion AMPK and PGC-1120572 and upregulate the expressionof folliculin-interacting protein 1 (FNIP1) and folliculin inC2C12myotubesThese effects induced by palmitate could beabrogated by dihydromyricetin administration [43]

8 Neuroprotective Activity

MicroRNAs (miRs) have been demonstrated to be involvedin the development of Alzheimerrsquos disease (AD) Sirt adirect substrate of miR-34a can promote cell tolerance toaging through induction of autophagy In aging modelsdihydromyricetin downregulates the D-gal-induced expres-sion of miR-34a and p53p21 pathways and upregulates Sirt1expression mTOR negatively modulates autophagy activa-tion Dihydromyricetin may increase the phosphorylationof mTOR at Ser2448 and inactivate it in D-gal-inducedmodels leading to activation of autophagy [45] In Parkin-sonrsquos disease (PD) dihydromyricetin also exhibits neuro-protective activity in behavioral tests through attenuationof MPTP-induced cytotoxicity ROS generation and GSK-3120573 activation dose- and time-dependently [46] (Table 1) L-Dopa has been implicated in PD management Catechol O-methyltransferase (COMT) may decrease the bioavailabilityof L-dopa Dihydromyricetin has been demonstrated to ben-efit PD management through inhibition of COMT activitydose-dependently [60]

Dihydromyricetin is also the main component of Hov-enia which is traditionally used for treatment of alcoholhangovers It has been demonstrated that dihydromyricetinmay exhibit the protective effects against alcohol intoxicationand alcohol tolerance The molecular mechanism might beassociated with competitively binding of dihydromyricetinto BZ sites on GABAARs [61] Fetal alcohol exposure (FAE)promotes long-lasting alternations in behavior and physiol-ogy which might be related to dysfunction of GABAARsin hippocampi In rat models dihydromyricetin effectivelyprevents FAE disorders through regulation of GABAARs[62] Dysfunction of GABAARs in neurotransmission alsocontributes to AD development In transgenic (TG2576) andSwedish transgenic (TG-SwDI) mice dihydromyricetin mayreduce A120573 peptide production and restore gephyrin levelsGABAergic transmission and functional synapses leading toimprovement of clinical symptoms [63]

9 Miscellaneous Section

Dihydromyricetin also exhibits anti-bacterial activity againstStaphylococcus aureus The possible mechanism is that dihy-dromyricetin may disrupt the integrity and the fluidityof membrane In addition dihydromyricetin also binds tointracellular DNA through the groove-binding mode in Saureus [64] This is inconsistent with reports from Huanget al (2015) that dihydromyricetin does not significantlyinhibit S aureus PriA which is an important helicase forDNA replication restart [65] Dihydropyrimidinase a keymember in the chain of pyrimidine catabolism plays animportant role in metabolism of DNA base in Pseudomonasaeruginosa PAO1 Abrogation of dihydropyrimidinase maylead to inhibition of bacterial growth and promotion ofdeath Dihydromyricetin substrate-dependently docks intothe active site of dihydropyrimidinase and inhibits its activitywith IC50 value of 80 120583M [66]

Dihydromyricetin decreases the expression of MDAblood urea nitrogen and kidney tissue molecule-1 andinhibits cell apoptosis protecting against kidney injuryinduced by LPS [47] On protection against acute liverinjury dihydromyricetin exhibits anti-inflammatory anti-apoptotic and proliferation-accelerating activities in carbontetrachloride- (CCl4-) induced hepatocytes through upreg-ulation of JNK expression [48] Melanogenesis is positivelyregulated by MAPK pathway cAMPPKA pathway and PKCpathway through upregulating of CREBMITF axis Dihy-dromyricetin has been demonstrated to attenuate the activi-ties of these three signaling pathways and inhibits the expres-sion of CREB and MITF leading to blockage of melano-genesis in B16F10 melanoma cells [49] (Table 1) Wnt120573-catenin signaling pathway plays a pivotal role in mediatingosteogenic differentiation in bone mesenchymal stem cells(BMSCs) Evidences show that dihydromyricetin decreasesthe expression of kickkopf-1 and sclerostin and increase120573-catenin transcriptional activity resulting in enhancingosteogenic differentiation in vitro [67]

10 Clinical Prospective

It is well proved that high-fat diet may severely causehyperlipidemia hepatic steatosis and type II diabetes Inhigh-fat diet rats dihydromyricetin improves glucose uptakepromotes glucose transporter 1 (GLU1) translocation andenhances Krebs cycle activity leading to amelioration ofinsulin resistance Specifically dihydromyricetin reversesthe decreased levels of CS SDHA and DLST inducedby high-fat diet Similarly the increased levels of ser-ine leucine asparagine SSA 5-L-glutamyl-alanine and L-methylhistidine are also restored by dihydromyricetinTheseare associated with downregulation of phosphorylation ofIRS-Ser612 and upregulation of Akt and AMPK resultingin inhibitory phosphorylation of GSK-3120573 and reduction ofG6Pase and PEPCK expression [50] (Table 1) Nonalcoholicfatty liver disease is characterized by accumulation of TGand TC in the cytoplasm of hepatocytes Dihydromyricetin


exhibits inhibitory effects on this accumulation and ROSgeneration which are related to regulation of AMPK AKTand PPAR120574 pathways in oleic acid-induced L02 and HepG2cells [51] In a double-blind clinical trial either two dihy-dromyricetin or two placebo capsules are applied for twicedaily and three months Dihydromyricetin supplementa-tion may significantly ameliorate the serum levels of glu-cose LDL-C GGT alanine AST and Apo B resultingin dihydromyricetin-enhanced metabolism of glucose andlipid In addition dihydromyricetin also downregulates theexpression of TNF-120572 CK-18 fragment and FGF21 [52]

Oxidative stressmay exaggerate ischemia and reperfusion(IR) injury leading to cell apoptosis In rats in vivo andH9c2 cardiomyocytes in vitro dihydromyricetin provideseffective protection against IR-induced injury through acti-vation of PI3KAkt and HIF1120572 signaling pathways leadingto augment of cellular antioxidant capacity and inhibitionof apoptosis These are characterized by upregulation ofantiapoptotic factors Bcl-2 and Bcl-XL and downregulationof proapoptotic factors Bax Bnip3 cleaved caspase-3-9 andcytochrome c [53]Methylglyoxal (MG) an endogenous toxiccompound from the glycolytic pathway may accumulate andimpair cognitive dysfunction in metabolic diseases MGmaypotentiate oxidative stress and calcium overload leading toactivation of mitochondrial apoptosis in PC12 cells Thismight be associated with impairing of BLUT4 translocationand downregulating the expression of glyoxalase 1 and p-AMPK120572 Dihydromyricetin exhibits a protective role intreating diabetic encephalopathy through ameliorating MGtoxicity [54]

Combined with nedaplatin dihydromyricetin synergis-tically induces apoptosis in p53Bcl-2 signaling-dependentmanner in hepatocellular carcinoma (SMMC7721 andQGY7701) cells In addition dihydromyricetin selectivelyprotects normal hepatocytes (HL7702) against damageinduced by nedaplatin [68] Similarly dihydromyricetinhas been reported to show no cytotoxicity to normalhepatocytes but significant inhibition of cellular proliferationand activation of apoptosis in a p53-dependent mannerin HCC cells [69] Dihydromyricetin selectively inducestumor cells mitochondrial apoptosis and synergisticallypotentiates the cytotoxicity of cisplatin in HepG2 andSMMC-7721 This is possibly related to dihydromyricetin-induced enhancement of p53 phosphorylation at Ser15 [70]Adriamycin causes serious cardiotoxicity as indicated byincreased levels of ALT LDH and CKMB in the serumleading to activation of apoptosis Dihydromyricetin exhibitsthe cardioprotective activity that it ameliorates adriamycin-induced cardiotoxicity and synergistically potentiatesanticancer activity of adriamycin p53-dependently [71]

11 Concluding Marks

In this review we focus on dihydromyricetin biological activ-ities including antioxidative anti-inflammatory anticancerand lipid and glucose metabolism-regulatory activities ROSacts as a dual role in redox signaling to control cell fatesDihydromyricetin may scavenge ROS to ameliorate oxidative

stress for protection or potentiate ROS generation to kill can-cer cells Intriguingly dihydromyricetin improves metabolicdiseases through mediating lipid and glucose metabolismThese make dihydromyricetin to be a possible candidatefor clinical potentials However the low bioavailability ofdihydromyricetin limits its applications Thus more effortsshould be needed for its underlying mechanism in biology

Conflicts of Interest

The authors declare no conflicts of interest

Authorsrsquo Contributions

LonghuoWu andQilai Cheng provided the idea of this paperHongliang Li and Qisheng Li contributed equally to thisstudy Zhaowen Liu Kai Yang and Zhixi Chen revised andfinalized the paper All authors approved the final paper

Acknowledgments

This study was financially supported by the NationalScience Foundation of China (81660371 and 81360627)and the National Science Foundation of Jiangxi Province(20161BAB205227)

References

[1] T Murakami M Miyakoshi D Araho et al ldquoHepatoprotectiveactivity of tocha the stems and leaves of Ampelopsis grosseden-tata and ampelopsinrdquo BioFactors vol 21 no 1-4 pp 175ndash1782004

[2] L-P Ruan B-Y Yu G-M Fu and D-N Zhu ldquoImprovingthe solubility of ampelopsin by solid dispersions and inclusioncomplexesrdquo Journal of Pharmaceutical and Biomedical Analysisvol 38 no 3 pp 457ndash464 2005

[3] S-L Cao X Deng P Xu et al ldquoHighly Efficient EnzymaticAcylation of Dihydromyricetin by the Immobilized Lipase withDeep Eutectic Solvents as Cosolventrdquo Journal of Agriculturaland Food Chemistry vol 65 no 10 pp 2084ndash2088 2017

[4] L Liu X Yin X Wang and X Li ldquoDetermination of dihy-dromyricetin in rat plasma by LC-MSMS and its application toa pharmacokinetic studyrdquo Pharmaceutical biology vol 55 no 1pp 657ndash662 2017

[5] Q Tong X Hou J Fang et al ldquoDetermination of dihy-dromyricetin in rat plasma by LC-MSMS and its applicationto a pharmacokinetic studyrdquo Journal of Pharmaceutical andBiomedical Analysis vol 114 pp 455ndash461 2015

[6] D Xiang C-G Wang W-Q Wang et al ldquoGastrointestinalstability of dihydromyricetin myricetin and myricitrin an invitro investigationrdquo International Journal of Food Sciences andNutrition pp 1ndash11 2017

[7] Y Zhang S Que X Yang BWang L Qiao and Y Zhao ldquoIsola-tion and identification of metabolites from dihydromyricetinrdquoMagnetic Resonance in Chemistry vol 45 no 11 pp 909ndash9162007

[8] X Li J Liu J Lin et al ldquoProtective effects of dihydromyricetinagainst ∙OH-induced mesenchymal stem cells damage andmechanistic chemistryrdquoMolecules vol 21 no 5 article no 6042016


[9] L Ye H Wang S E Duncan W N Eigel and S F OrsquoKeefeldquoAntioxidant activities of Vine Tea (Ampelopsis grossedentata)extract and its major component dihydromyricetin in soybeanoil and cooked ground beefrdquo Food Chemistry vol 172 pp 416ndash422 2015

[10] Q Song L Liu J Yu et al ldquoDihydromyricetin attenuated AngII induced cardiac fibroblasts proliferation related to inhibitoryof oxidative stressrdquo European Journal of Pharmacology vol 807pp 159ndash167 2017

[11] G Meng S Yang Y Chen W Yao H Zhu and W ZhangldquoAttenuating effects of dihydromyricetin on angiotensin II-induced rat cardiomyocyte hypertrophy related to antioxidativeactivity in a NO-dependent mannerrdquo Pharmaceutical Biologyvol 53 no 6 pp 904ndash912 2015

[12] S Mu Y Li B Liu et al ldquoDihydromyricetin Ameliorates 3NP-induced Behavioral Deficits and Striatal Injury in Ratsrdquo Journalof Molecular Neuroscience vol 60 no 2 pp 267ndash275 2016

[13] P Liu D Zou K Chen et al ldquoDihydromyricetin ImprovesHypobaric Hypoxia-Induced Memory Impairment via Modu-lation of SIRT3 Signalingrdquo Molecular Neurobiology vol 53 no10 pp 7200ndash7212 2016

[14] F Wu Y Li H Song et al ldquoPreventive effect of dihy-dromyricetin against cisplatin-induced nephrotoxicity in vitroand in vivordquo Evidence-based Complementary and AlternativeMedicine vol 2016 Article ID 7937385 9 pages 2016

[15] Y Wang W Wang and E Qiu ldquoProtection of oxidativestress induced apoptosis in osteosarcoma cells by dihy-dromyricetin through down-regulation of caspase activationand up-regulation of BcL-2rdquo Saudi Journal of Biological Sciences2016

[16] X Hou Q Tong W Wang W Xiong C Shi and J FangldquoDihydromyricetin protects endothelial cells from hydrogenperoxide-induced oxidative stress damage by regulating mito-chondrial pathwaysrdquo Life Sciences vol 130 Article ID 14330 pp38ndash46 2015

[17] T T Liu Y Zeng K Tang X Chen W Zhang and X L XuldquoDihydromyricetin ameliorates atherosclerosis in LDL receptordeficient micerdquo Atherosclerosis vol 262 pp 39ndash50 2017

[18] P Qiu Y Dong B Li et al ldquoDihydromyricetin modulatesp62 and autophagy crosstalk with the Keap-1Nrf2 pathway toalleviate ethanol-induced hepatic injuryrdquoToxicology Letters vol274 pp 31ndash41 2017

[19] R Wang J Pi X Su et al ldquoDihydromyricetin suppressesinflammatory responses in vitro and in vivo through inhibitionof IKK120573 activity in macrophagesrdquo Scanning vol 38 no 6 pp901ndash912 2016

[20] X L Hou Q Tong W Q Wang et al ldquoSuppression ofinflammatory responses by dihydromyricetin a flavonoid fromampelopsis grossedentata via inhibiting the activation of NF-120581B andMAPK signaling pathwaysrdquo Journal of Natural Productsvol 78 no 7 pp 1689ndash1696 2015

[21] N Tang J Ma K S Wang et al ldquoDihydromyricetin suppressesTNF-120572-induced NF-120581B activation and target gene expressionrdquoMolecular and Cellular Biochemistry vol 422 no 1-2 pp 11ndash202016

[22] B Xu S Huang C Wang H Zhang S Fang and Y ZhangldquoAntiinflammatory effects of dihydromyricetin in a mousemodel of asthmardquoMolecular Medicine Reports vol 15 no 6 pp3674ndash3680 2017

[23] B Lin X Tan J Liang et al ldquoA reduction in reactive oxygenspecies contributes to dihydromyricetin-induced apoptosis in

human hepatocellular carcinoma cellsrdquo Scientific Reports vol4 p 7041 2014

[24] Z Zhang H Zhang S Chen et al ldquoDihydromyricetin inducesmitochondria-mediated apoptosis in HepG2 cells throughdown-regulation of the AktBad pathwayrdquo Nutrition Researchvol 38 pp 27ndash33 2017

[25] X Huang T Lian X Guan et al ldquoDihydromyricetin ReducesTGF-120573 Via P53 Activation-dependent Mechanism in Hepato-cellular CarcinomaHepG2 Cellsrdquo Protein amp Peptide Letters vol24 no 5 pp 419ndash424 2017

[26] J Xia S Guo T Fang et al ldquoDihydromyricetin inducesautophagy in HepG2 cells involved in inhibition of mTORand regulating its upstream pathwaysrdquo Food and ChemicalToxicology vol 66 pp 7ndash13 2014

[27] B Liu W Zhou X Chen et al ldquoDihydromyricetin inducesmouse hepatoma Hepal-6 cell apoptosis via the transforminggrowth factor-120573 pathwayrdquo Molecular Medicine Reports vol 11no 3 pp 1609ndash1614 2015

[28] Q-Y Zhang R Li G-F Zeng et al ldquoDihydromyricetin inhibitsmigration and invasion of hepatoma cells through regulation ofMMP-9 expressionrdquo World Journal of Gastroenterology no 29pp 10082ndash10093 2014

[29] Y Xu S Wang H F Chan et al ldquoDihydromyricetin InducesApoptosis and Reverses Drug Resistance in Ovarian CancerCells by p53-mediated Downregulation of Survivinrdquo ScientificReports vol 7 p 46060 2017

[30] Z Wang X Sun Y Feng et al ldquoDihydromyricetin reversesMRP2-mediated MDR and enhances anticancer activityinduced by oxaliplatin in colorectal cancer cellsrdquo Anti-CancerDrugs vol 28 no 3 pp 281ndash288 2016

[31] Z Zhao J-Q Yin M-S Wu et al ldquoDihydromyricetin activatesAMP-activated protein kinase and P38119872119860119875119870exerting antitumorpotential in osteosarcomardquo Cancer Prevention Research vol 7no 9 pp 927ndash938 2014

[32] G Zeng J Liu H Chen et al ldquoDihydromyricetin inducescell cycle arrest and apoptosis in melanoma SK-MEL-28 cellsrdquoOncology Reports vol 31 no 6 pp 2713ndash2719 2014

[33] H Huang M Hu R Zhao P Li and M Li ldquoDihydromyricetinsuppresses the proliferation of hepatocellular carcinoma cellsby inducing G2M arrest through the Chk1Chk2Cdc25Cpathwayrdquo Oncology Reports vol 30 no 5 pp 2467ndash2475 2013

[34] F J Ji X F Tian X W Liu et al ldquoDihydromyricetin inducescell apoptosis via a p53-related pathway in AGS human gastriccancer cellsrdquo Genetics and Molecular Research vol 14 no 4 pp15564ndash15571 2015

[35] S-J Kao W-J Lee J-H Chang et al ldquoSuppression of reactiveoxygen species-mediated ERK and JNK activation sensitizesdihydromyricetin-induced mitochondrial apoptosis in humannon-small cell lung cancerrdquo Environmental Toxicology vol 32no 4 pp 1426ndash1438 2017

[36] D Zhou H Sun J Yue Y Peng Y Chen and Z Zhong ldquoDihy-dromyricetin induces apoptosis and cytoprotective autophagythrough ROS-NF-120581B signalling in humanmelanoma cellsrdquo FreeRadical Research vol 51 no 5 pp 517ndash528 2017

[37] B Wu J Lin J Luo et al ldquoDihydromyricetin protects againstdiabetic cardiomyopathy in streptozotocin-induced diabeticmicerdquo BioMed Research International vol 2017 Article ID3764370 2017

[38] Y Chen L Lv H Pi et al ldquoDihydromyricetin protects againstliver ischemiareperfusion induced apoptosis via activation ofFOXO3a-mediated autophagyrdquo Oncotarget vol 7 no 47 pp76508ndash76522 2016


[39] T-F Fan T-F Wu L-L Bu et al ldquoDihydromyricetin promotesautophagy and apoptosis through ROS-STAT3 signaling inhead and neck squamous cell carcinomardquoOncotarget vol 7 no37 pp 59691ndash59703 2016

[40] L Liu JWanH Lang et al ldquoDihydromyricetin delays the onsetof hyperglycemia and ameliorates insulin resistance withoutexcessive weight gain in Zucker diabetic fatty ratsrdquo Molecularand Cellular Endocrinology vol 439 pp 105ndash115 2017

[41] L Shi T Zhang Y Zhou et al ldquoDihydromyricetin improvesskeletalmuscle insulin sensitivity by inducing autophagy via theAMPK-PGC-1120572-Sirt3 signaling pathwayrdquoEndocrine vol 50 no2 pp 378ndash389 2015

[42] L Shi T Zhang X Liang et al ldquoDihydromyricetin improvesskeletal muscle insulin resistance by inducing autophagy via theAMPK signaling pathwayrdquo Molecular and Cellular Endocrinol-ogy vol 409 pp 92ndash102 2015

[43] Q Zhou Y Gu H Lang et al ldquoDihydromyricetin pre-vents obesity-induced slow-twitch-fiber reduction partially viaFLCNFNIP1AMPK pathwayrdquo Biochimica et Biophysica Acta(BBA) - Molecular Basis of Disease vol 1863 no 6 pp 1282ndash1291 2017

[44] Q Zhou K Chen P Liu et al ldquoDihydromyricetin stimulatesirisin secretion partially via the PGC-1120572 pathwayrdquo Molecularand Cellular Endocrinology vol 412 pp 349ndash357 2015

[45] X Kou X Liu X Chen et al ldquoAmpelopsin attenuatesbrain aging of D-gal-induced rats through miR-34a-mediatedSIRT1mTOR signal pathwayrdquo Oncotarget vol 7 no 46 pp74484ndash74495 2016

[46] Z-X Ren Y-F Zhao T Cao and X-C Zhen ldquoDihy-dromyricetin protects neurons in an MPTP-induced model ofParkinsonrsquos disease by suppressing glycogen synthase kinase-3beta activityrdquo Acta Pharmacologica Sinica vol 37 no 10 pp1315ndash1324 2016

[47] J-T Wang P Jiao Y Zhou and Q Liu ldquoProtective effectof dihydromyricetin against Lipopolysaccharide-Induced acutekidney injury in a rat modelrdquo Medical Science Monitor vol 22pp 454ndash459 2016

[48] J Xie J Liu T-M Chen et al ldquoDihydromyricetin allevi-ates carbon tetrachloride-induced acute liver injury via JNK-dependentmechanism inmicerdquoWorld Journal of Gastroenterol-ogy vol 21 no 18 pp 5473ndash5481 2015

[49] H-C Huang C-C Liao C-C Peng et al ldquoDihydromyricetinfrom Ampelopsis grossedentata inhibits melanogenesisthrough down-regulation of MAPK PKA and PKC signalingpathwaysrdquo Chemico-Biological Interactions vol 258 pp166ndash174 2016

[50] L Le B Jiang W Wan et al ldquoMetabolomics reveals theprotective of Dihydromyricetin on glucose homeostasis byenhancing insulin sensitivityrdquo Scientific Reports vol 6 ArticleID 36184 2016

[51] C Xie Z Chen C Zhang et al ldquoDihydromyricetin amelioratesoleic acid-induced lipid accumulation in L02 and HepG2 cellsby inhibiting lipogenesis and oxidative stressrdquo Life Sciences vol157 pp 131ndash139 2016

[52] S Chen X Zhao JWan et al ldquoDihydromyricetin improves glu-cose and lipid metabolism and exerts anti-inflammatory effectsin nonalcoholic fatty liver disease a randomized controlledtrialrdquo Pharmacological Research vol 99 pp 74ndash81 2015

[53] S Liu Q Ai K Feng Y Li and X Liu ldquoThe cardioprotec-tive effect of dihydromyricetin prevents ischemiandashreperfusion-induced apoptosis in vivo and in vitro via the PI3KAkt and

HIF-1120572 signaling pathwaysrdquo Apoptosis vol 21 no 12 pp 1366ndash1385 2016

[54] B Jiang L Le H Pan K Hu L Xu and P Xiao ldquoDihy-dromyricetin ameliorates the oxidative stress response inducedby methylglyoxal via the AMPKGLUT4 signaling pathway inPC12 cellsrdquo Brain Research Bulletin vol 109 pp 117ndash126 2014

[55] T Li V K W Wong Z H Jiang et al ldquoMutation of cysteine46 in IKK-beta increases inflammatory responsesrdquo Oncotargetvol 6 no 31 pp 31805ndash31819 2015

[56] S Wu B Liu Q Zhang et al ldquoDihydromyricetin reduced bcl-2 expression via p53 in human hepatoma HepG2 cellsrdquo PLoSONE vol 8 no 11 Article ID e76886 2013

[57] J Williams C Ensor S Gardner R Smith and R LodderldquoBSN723T Prevents Atherosclerosis and Weight Gain in ApoEKnockout Mice Fed aWestern DietrdquoWebmedcentral vol 6 no12 2015

[58] P Hodek P Fousova E Brabencova et al ldquoEffect of dihy-dromyricetin on benzo[a]pyrene activation in ratsrdquo Neuroen-docrinology Letters vol 35 pp 158ndash168 2014

[59] Z Bostikova M Moserova P Pavek M Stiborova andP Hodek ldquoRole of dihydromyricetin in cytochrome P450-mediated metabolism and carcinogen activationrdquo Neuroen-docrinology Letters vol 36 no 2015 pp 46ndash52 2015

[60] X Zhu and Y-H Jia ldquoInhibition of catechol-o-methyltransferase (COMT) by myricetin dihydromyricetinand myricitrinrdquo Pharmazie vol 69 no 3 pp 183ndash186 2014

[61] J Liang and R W Olsen ldquoAlcohol use disorders and currentpharmacological therapiesThe role of GABAA receptorsrdquoActaPharmacologica Sinica vol 35 no 8 pp 981ndash993 2014

[62] J Liang Y Shen X M Shao et al ldquoDihydromyricetin preventsfetal alcohol exposure-induced behavioral and physiologicaldeficits the roles of GABAA receptors in adolescencerdquo Neuro-chemical Research vol 39 no 6 pp 1147ndash1161 2014

[63] J Liang A K Lindemeyer Y Shen et al ldquoDihydromyricetinameliorates behavioral deficits and reverses neuropathology oftransgenic mouse models of Alzheimerrsquos diseaserdquo Neurochemi-cal Research vol 39 no 6 pp 1171ndash1181 2014

[64] Y Wu J Bai K Zhong Y Huang and H Gao ldquoA dualantibacterial mechanism involved in membrane disruption andDNA binding of 2R3R-dihydromyricetin from pine needles ofCedrus deodara against Staphylococcus aureusrdquo Food Chem-istry vol 218 pp 463ndash470 2017

[65] Y-H Huang C-C Huang C-C Chen K-J Yang and C-YHuang ldquoInhibition of Staphylococcus aureus PriA Helicase byFlavonol Kaempferolrdquo Protein Journal vol 34 no 3 pp 169ndash172 2015

[66] C-Y Huang ldquoInhibition of a putative dihydropyrimidinasefrom Pseudomonas aeruginosa PAO1 by flavonoids and sub-strates of cyclic amidohydrolasesrdquo PLoS ONE vol 10 no 5Article ID e0127634 2015

[67] W Zhang S Wang H Yin et al ldquoDihydromyricetin enhancesthe osteogenic differentiation of human bone marrow mes-enchymal stem cells in vitro partially via the activation ofWnt120573-catenin signaling pathwayrdquo Fundamental and ClinicalPharmacology vol 30 no 6 pp 596ndash606 2016

[68] L Jiang Q Zhang H Ren et al ldquoDihydromyricetin enhancesthe chemo-sensitivity of nedaplatin via regulation of thep53Bcl-2 pathway in hepatocellular carcinoma cellsrdquo PLoSONE vol 10 no 4 Article ID e0124994 2015

[69] J Liu Y Shu Q Zhang et al ldquoDihydromyricetin inducesapoptosis and inhibits proliferation in hepatocellular carcinomacellsrdquo Oncology Letters vol 8 no 4 pp 1645ndash1651 2014


[70] Q Zhang J Liu B Liu et al ldquoDihydromyricetin promotes hep-atocellular carcinoma regression via a p53 activation-dependentmechanismrdquo Scientific Reports vol 4 article no 4628 2014

[71] H Zhu P Luo Y Fu et al ldquoDihydromyricetin preventscardiotoxicity and enhances anticancer activity induced byadriamycinrdquo Oncotarget vol 6 no 5 pp 3254ndash3267 2015

Submit your manuscripts athttpswwwhindawicom

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


O

O

O

O

O

O

O

OHOH

OH

OHOH

OH

OH

HO HO

OH

O

O

O OOCOOH

O

O

RR

RS

O

OH

O

O

1

23 4

5

6

7

8

OC（3

OC（3

OH

OH

OH

OH

HO

OH

OH

OHOH

HO

OH

OHOH

OH

OHOH

OHOH

HO

OHOH

OH

OH OHOH

HO

OH

OH

OH

HO

OH

OH

OH

OH

OHHO

Figure 1 The structure of dihydromyricetin (1) and its metabolites (2ndash8)

transformed into seven metabolites in rats [7] (Figure 1)They are 573101584051015840-tetrahydroxyflavanonol (2) 574101584051015840-tetra-hydroxy-31015840-methoxyflavone (3) 573101584051015840-tetrahydroxy-41015840-methoxyflavone (4) 57310158404101584051015840-pentahydroxyflavanone (5)3457310158404101584051015840-hepthydroxyflavan (6) (2R3S)-57310158404101584051015840-pentahydroxyflavanonol (7) and dihydromyricetin-O-5-120573-D-glucuronide (8)

3 Oxidative Stress-Mediating Activity

Oxidative stress is a state of cellular homeostasis imbalancecharacterized as reactive oxygen species (ROS) productionoverweighting the antioxidant enzyme system ExcessiveROS contributes to mitochondria-dependent apoptosis Themechanistic chemistry in radical scavenging ability of dihy-dromyricetin has been approved in protection against mes-enchymal stem cells damage [8] The antioxidative activ-ity of dihydromyricetin is also confirmed by two modelsystems including cooked ground beef and soybean oil[9] Excessive ROS may acts as a dominant factor con-tributing to myocardial fibrosis Cardiac fibroblast may beactivated by angiotensin II through induction of ROS pro-duction promoting proliferation and collagen synthesisDihydromyricetin restores these adverse effects induced byangiotensin II as indicating by decreased levels of ROSand MDA attenuated expression of p22phox (a subunit ofNADPH oxidase) and increased total antioxidant capacity[10] Similar results are showed in the antioxidative effectof dihydromyricetin on attenuating angiotensin II-inducedcardiomyocyte hypertrophy [11]

Excessive ROS is also correlated with neurogenerativediseases 3-Nitropropionic acid may induce motor dys-function and learning and memory impairments throughhyperactivation of ROS production Dihydromyricetinsignificantly restores metabolic abnormality in striatumimproves the expression of antioxidant system and inhibitsmitochondria-dependent apoptosis [12] Memory impair-ments are also subject to hypobaric hypoxia which ofteninduces oxidative stress in the brain Dihydromyricetin hasbeen showed to suppress ROS production and attenuate lipidperoxidation in the hippocampus promoting mitochondrialbiogenesis and improving mitochondrial functions (Table 1)In addition dihydromyricetin protects neurons fromhypobaric hypoxia through amelioration of Sirt3-FOXO3asignaling-induced oxidative stress [13]

Oxidative stress has been considered as the criticalfactor correlating with nephrotoxicity induced by cisplatinIn HK-2 cells dihydromyricetin may protect against suchnephrotoxicity through attenuation of oxidative stress andinflammatory stress leading to inhibition of apoptosis [14]ROS in osteocytes contributes to osteoporosis formation InMG63 cells dihydromyricetin effectively exhibits antioxida-tive activity to scavenge ROS and leads to attenuation ofcaspase-3 and caspase-9 and inhibition of cell apoptosis [15]In HUVECs dihydromyricetin ameliorates H2O2-inducedoxidative stress against apoptosis mitochondria dependently[16] In addition dihydromyricetin may increase the totalantioxidant capacity and attenuate ROS generation andNOX2 expression Thus dihydromyricetin ameliorates the














HepG2 cells







Table 1 Continued



[50]








































11 Concluding Marks







Acknowledgments


References


















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























HepG2 cells







Table 1 Continued



[50]








































11 Concluding Marks







Acknowledgments


References


















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table 1 Continued



[50]








































11 Concluding Marks







Acknowledgments


References


















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of










































11 Concluding Marks







Acknowledgments


References


















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















reviewarticle the versatile effects of dihydromyricetin in ... · reviewarticle the versatile...

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