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Hndw Pshn CopotonEvdnc-Bsd Compmnty nd Atntv MdcnVom 2013, Atc ID 625906, 9 pshttp://dx.do.o/10.1155/2013/625906

Research ArticleMetabonomics Study ofEssential Hypertension and Its Chinese Medicine Subtypes byUsing Gas Chromatography-Mass Spectrometry and NuclearMagnetic Resonance Spectroscopy

Yunlun Li,1 Lei Nie,2 Haiqiang Jiang,3 Jiamao Lin,3 Honglei Zhou,3 Jun Xie,3 Zhengjun Qu,3

Dongmei Qi,3 and Yunhui Zhang1

1 Department o Cardiology, Afliated Hospital o Shandong University o raditional Chinese Medicine, Jinan 250011, China2 School o Pharmaceutical Sciences, Shandong University, Jinan 250012, China3 Experimental Centre, Shandong University o raditional Chinese Medicine, Jinan 250355, China

Cospondnc shod ddssd to Ynn L; [email protected]

Rcvd 8 Ast 2012; Rvsd 25 Novm 2012; Accptd 30 Dcm 2012

Acdmc Edto: Apn L

Copyht 2013 Ynn L t .Ts s n opnccss tc dsttd ndth CtvCommons AtttonLcns, whchpmts nstctd s, dstton, nd podcton n ny mdm, povdd th on wok s popy ctd.

A mtonomc stdy ws pomd to nvstt th mtoc mchnsm o ssnt hyptnson nd ts Chns mdcnstyps, ncdn Yn-dfcncy nd Yn-hypctvty syndom (YDYHS) nd Yn-Yn dfcncy syndom (YYDS).Psm smps om 22 hthy vonts, 31 hyptnsv ptnts wth YDYHS, nd 29 hyptnsv ptnts wth YYDS wnyzd y1H-NMR spctoscopy nd s chomtophy copd wth mss spctomty (GC-MS). T th ops wdstncty cssfd y pncp componnts nyss (PCA) nd pt st sqs dscmnnt nyss (PLS-DA). Accodnto dntfd omks nd th td pthwys, nom cos mtosm mht th mn common pthwy omYDYHS to YYDS, nd sympthtc nvos systm ctvton wod py n mpotnt o n th pthonss o YDYHS, wh ow mtoc t sy occd n YYDS.

1. Introduction

Essnthyptnson (EH), knd o ntc, htonoscompx dss, s vy pvntwodwd. Yt, th dfnt

pthonss o EH s not c. Hh ood psss my pt o dss chn n mtoc dsod. Mny mtocctos nvovd n th pocss o EH, whch cn ncsth sk o dm o vsc ndoth c nd kdny[1]. T pthooc pocss nd chctstcs o EH hvn stdd y modn mdcn nd tdton Chnsmdcn (CM) om dnt vwponts o mny ys.In ddton to modn mdcn ny sn chmcds o EH ttmnt, CM s wdy mpoyd s qtmpotnt thptc stty y sn cpnct o CMh om n cnt Chns mdcn cnc pc-tc. Yt, ths two mdc systms n nsht nto EH om

vy dnt pspctvs. T ttmnt o o Wstn

mdcn ms t chns n ood pss nd hs tspoty n th oc chctzton o EH, whs CMcs mo ot th pthooc chns o EH ptntsnd mny ocss on physooc chns om hostc

pspctv[2]. T ov nomton ot ptnts symp-toms ndsnsjdd y thEstn pcttons s th mnss o Chns mdcn dnoss. And ccodn to CMthoy, th td symptoms nd sns n ctn dssphs nzd to syndom (Zhn n Chnsmdcn), whch s th sc nt nd ky concpt o CM[3]. Ts, ptnts wth th sm dss cn dvdd ntodnt syndoms (.., dnt Zhns). Accodn to ththoy o Zhn n CM, th sc nto Yn nd Yn stht Yn nd Yn smny two conty ocs nd cn ncd nd tnsomd nto ch oth [4]. In th d-noss o EH, th Yn-dfcncy nd Yn-hypctvty syn-dom (YDYHS) nd th Yn-Yn dfcncy syndom

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2 Evdnc-Bsd Compmnty nd Atntv Mdcn

(YYDS) th two mn styps dnosd om thvwpont o CM nd ot 10 cnc pctc dns[5]. Whn Yn s nscnt, Yn oss ts stnt stmmdom Yn nd coms tvy pdomnnt, nd thnYDYHS w ccodny hppn. T ptnts wth YDYHSon show som symptoms sch s hdch, dzznss, tn-

nts, tty, hot c, nd wk wst. I YDYHS sts o on tm, th cpty o mt tnsomton twnYn nd Yn w dcd, nd Yn w com sodfcnt. Ssqnty, th Yn-Yn dfcncy syndom(YYDS) w occ. Pop sn om YYDS st mnstth syndoms sch s hdch, dzznss, t, syctchn cod, spontnos pspton, nd pptton [6].Howv, th dscpton o dnttn th two typs osyndom n CM s th stct, so t s vy ssnt todvop nw mthod to v mo ojctv psntton.

Mtonomcs, nw omcs tchnq concnn tho nomton o mtots n vn systms nd thdynmc sponss to th ndonos chns, xonos

stm, o ntc mnpton [7], hs wdy dmonsttdts potnts to xpo th oocmchnsmso Zhnn CM. T spcfc mtosm pttns n dntphysooc nd pthooc sts, nd th tton omtosm s cosy cotd wth th v o physooynd pthooy n nts [8]. To, th connotton oZhn n CM cod tt vd sd on mto-nomcs, nd th dynmc t o Zhn cod xps-sd s w [9]. In th psnt pp, mtonomcs mthodwsmpoyd to nvstt th ssnc o YDYHSnd YYDS

n EH. Sv nytc tchnqs, ncdn 1H-NMR ndmss spctomty (MS), hv n wdy sd n th fdo mtonomcs. NMR s n y tchnq sd n mt-

onomcs. Whs,

1

H-NMR nyss s stctd to m-td nm o hh-concntton mtots. An tn-tv ppoch s qd chomtophy (LC) o s chom-tophy (GC) comnd wth mss spctomty (MS),

whch cn o hh snstvty compd to 1H-NMR.Ts, GC-MS o LC-MS not ony cn sd to dtct ow-concntton mtots t so cn mpoyd to dn-ty th stct o omks. Nvthss, t shod

ncssy to conz tht 1H-NMR spctoscopy nd mssspctomty compmnty toos, nd th comntonw povd mo dtd nomton n mtonomcsstds [1012].

Rcnty, mtonomc ppoch hs n ppd to th

sch o Zhn typs o hyptnson n modn CM.GC/MS-sd mtonomcs mthod ws sd to nvsttpsm mtoomc mchnsm o hthy vonts ndhyptnsv ptnts who w dvdd nto th typs oZhn, ncdn v-f mn syndom, phmoshn syndom, nd YDYHS. T sts showd thtnom psm smps cod dstnshd om thoso th th CM Zhn typs, nd th mtonomc po-fs o psm twn Lv-f Fmn Syndom ndYDYHS w mkdy dnt [13].

Mtonomcs od sh nsht nto tons nddncs mon dnt typs o Zhn. In ths pp,psm mtonomcs stdy o EH nd ts two Chns

mdcn styps ws cd ot y sn 1HNMR ndGC-MS. Fsty, th psm mtoc chctstcs o EHnd ts two styps w stdd to n dp ndstnd-n o th mtoc pttons ssoctd wth dssnd to xpo th mtot vdnc n CM thoy.Scondy, th td mtosm ntwok ws constctd

ccodn to ochmc ctons ssoctd wth dntfdomks. Fny, th mtoc tndncy o omksn dnt ops ws so nyzd to xpo th possmtoc mchnsm o YDYHS nd YYDS.

2. Materials and Methods

2.1. Chemicals and Reagents. Dtm oxd 99.9%(D

2O) contnn 0.05% tmthysy-2,2,3,3-d

4po-

ponc cd sodm st (SP), pydn 99.8%, mthoxy-mn hydochod 98%, nd N-mthy-N-(tmthy-sy)tooctmd (MSFA) w pchsd omSm-Adch Ltd. (Okv, ON, Cnd). Mthno(99.9%) ws pchsd om Fsh Scntfc Compny(Ottw, ON, Cnd).

2.2. Sample Collection and Preparation. Ts stdy wsvwd ndppovd y th Ethcs Commtt o ShndonUnvsty o dton Chns Mdcn. T nstttonvw od ppovd th potoco, nd ptnts povdd wttn nomd consnt. Ptnts ( n: 1860 yso ) w thy mt th dnostc cto YDYHS nd YYDS, nd th dstoc ood pssws twn 90 mmH nd 109 mmH two-wkwshot pod. Ptnts wth dtc mts, ncontodhyptnson, ht , n dysncton, o v dssw xcdd. Smps coctd om ptnts mtchn

th ncson ct ndhthy vonts w nyzd y1H-NMR o GC-MS.

Bood smps w coctd om vn n th monnwth ntcoton nd stod n 80C to oth nyss. Po to nyss, psm smps wthwd t 4C. wo hndd ndfy mcots o mthnows ddd nto 100 L o psm o potn pcptton(kpt on c o 15 mn) nd mmdty cntd t11,200 o 10 mn. Awds, th spntnt ws ppttdot nd yophzd.

2.3. NMR Analysis. T yophzd smps w dssovdy 600 L D

2O mxd wth SP (0.05% (w/v) n D

2O) s

n ntn chmc sh nc (0). T smp sp-ntnts w thn tnsd nto 5-mm NMR ts.

A Bk spcondctn NMR spctomt wstzd to dtct th smps wth th ps sqnccpmp1d to mnt th ntnc o mcomoccompond n ood. A tot o 64 tnsnts nd 32000 dtponts w coctd. T oown pmts w st oNMR dtcton: spct wdth: 7288.63 Hz; cyc dy(RD): 2 s; nd cqston tm: 2.6 s. Wt sppsson wsdoptd y sn ow-pow pstton dn RD ndmxn pod (

= 0.15 s). Bo Fo tnsomton

(F), th ndcton dcy (FID) sns w zofd y cto o 2 nd mtpd y n xponnt

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Evdnc-Bsd Compmnty nd Atntv Mdcn 3

able 1: Bsc dmophc chctstcs o ptcpnts n NMR nyss.

Chctstcs Contos% () YDYHS op% () YYDS op% () v

Sx 1.000

Fm 45.45 (5) 42.86 (6) 40 (4)

M 54.56 (6) 57.14 (8) 60 (6)

A 1.0003040 9.09 (1) 14.29 (2) 10 (1)

4050 36.36 (4) 35.71 (5) 40 (4)

5060 54.55 (6) 50 (7) 50 (5)

n-odnn ncton o 0.5 Hz. T phs cocton,sn cocton, nd chmc sh nc to SP (0)w cd ot mny o ppocssn th vspct.

2.4. GC-MS Analysis. Fy mcots o mthoxymnhydochod (20 m/mL pydn) ws sd to dssov

dd sd, whch styd t 20

C o 24 h. Tn 75L oMSFA (wth 1% MCS) ws ddd to ntchn th cdcpotons t 37C o 1 h. In th nd, on hndd nd fymcots o n-hptn ws mpoyd to stop th cton.

Ant 6890N s chomtophy nd qdpmssspctomt qppd wth HP-5 MS cpy comn(30m 0.25 mm .d. 0.32m thcknss) w sd to nyzth spntnt n v. T njcto tmpt ws 270C.A constnt ow t o 1 mL/mn o hm c s wsst. T nt tmpt o GC ovn ws hd t 85C o5 mn nd thn mpd to fn tmpt o 300C t t o 10C/mn wth 5 mn hod tm. T tmpts otns n, on soc, nd qdpos w st t 270C,230C, nd 150C, spctvy. Ionzton ws chvd y 70 V cton m t cnt o 2.0 mA. T sovntdy tm ws st t 2 mn. Mss spct w otnd wth mss-to-ch to (/) o 50550 [14].

2.5. Data Analysis. wo hndd nd twnty fv ntons o q wdth (0.04 ppm) w otnd om thNMR spct dt o psm smps n n o 100sn MstR-C (vson 4.9.9.9, http://www.mstc.com/).T on wthn 4.55.0 ws dtd to mnt thchmc sh o wt. A GC-MS nyss, svnty-fvcommon pks nd th pk s w cqd om thtot on chomtoms (ICs) ccodn to th tntontm. T common chctstc pks w svd s xc

fs o th dt nyss.Pncp componnt nyss (PCA) nd pt st-

sqs dscmnnt nyss (PLS-DA) w mpmntdy SIMCA-P (vson 11.5, Umtcs, Um, Swdn) oNMR nd GC-MS dt nyss. Bo PCA nd PLS-DA, vs w ppocssd y nomzton to cth nnc o ncotd ctos sch s nconstncyn th pocss o smp ppton. T (th mtpcoton cocnt) nd th (th coss-vdtd co-ton cocnt), whch vd th cton o th tot

vton pdctd y componnts, w sd to ms thostnss o pttn conton mod [15].Ttwovso nd cod sd to vt mod ft nd pdctv

ty, spctvy. V nnc on pojcton (VIP)povddy SIMCA-P pom wsmpoydto comp thtv nnc o vs ccodn to th conttonto th mod.

2.6. Structure Identication o Potential Biomarkers. Tpotnt omks w sctd ccodn to th VIP v-

s t thn 1, whch ws ny sd s cton ov scton [16]. Fo th dt o NMR spctoscopy, thchmc sh o compond ws nqd o dntfctonn th dts ncdn MELIN, HMDB, nd KEGG.Fo GC-MS dt, th / v ws schd n NIS2008dts.

3. Results and Discussions

3.1. Sample Characteristics. A tot o 11 hthy vonts,14 hyptnsv ptnts wth YDYHS, nd 10 hyptnsvptnts wth YYDS w octd to NMR nyss, wh11 hthy vonts, 17 hyptnsv ptnts wth YDYHS,nd 19 hyptnsv ptnts wth YYDS w octd toGC-MS nyss. Dmophc chctstcs w shown ns 1 nd 2. Sn om s 1 nd 2, o oth NMR ndGC-MS nyss, th w no snfcnt dncs month th ops n nd sx.

3.2. Analysis o PlasmaSamples by NMR Spectroscopyand GC-MS. NMR spctoscopy nd GC-MS w sd to cqth mtoc pof o psm smps om hyptnsonptnts wth YDYHS, hyptnson ptnts wth YYDS, ndhthy vonts.

T psnttv NMR spct om dnt opsw shown n F 1. T mn componnts o psm cos, onc cds, mno cds, nd pd componds.

T typc tot on chomtoms o GC-MS o psmsmps w dspyd n F 2. Svnty-fv commonpks w sctd om ICs o GC-MS s th ndonosmtots, ncdn mno cds, tty cds, ss, ndonc cds.

3.3. Data Analysis. T PCA sco sctt pots w cc-td sd on th sscton nt vs o NMR spctnd th pk s o GC-MS ICs (shown n Fs 3nd 5), spctvy. T s no ovp twn YDYHSnd YYDS smps, sstn th two ops ovosydnt n mtosm mod. Snc YDYHS ptnts ndhthy vonts mxd toth (s Fs 3 nd 5),

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able 2: Bsc dmophc chctstcs o ptcpnts n GC-MS nyss.

Chctstcs Contos% () YDYHS op% () YYDS op% () v

Sx 0.913

Fm 54.55 (6) 47.06 (8) 47.37 (9)

M 45.55 (5) 52.94 (9) 52.63 (10)

A 0.941

3040 9.09 (1) 5.88 (1) 10.53 (2)

4050 36.36 (4) 52.94 (9) 42.11 (8)

5060 54.55 (6) 41.18 (7) 47.37 (9)

3.5

10

5

0

10 5 0

-g

lucose

-g

lucose

Lacticacid

Lipid

Aceticacid

Tyrosine

,

-g

lucose

()

10 5 0

10

5

0

()

10 5 0

10

5

0

(c)

Figure 1: Rpsnttv1

H-NMR spct o psm smps om () hyptnson ptnts wth YDYHS, () hyptnson ptnts wthYYDS (c), nd hthy vonts.

5 10 15 20 25

5

4

3

2

1

106

()

106

5

4

3

2

1

5 10 15 20 25

()

5 10 15 20 25

87654321

106

(c)

Figure 2: Rpsnttv GC-MS ICs o psm smps om () hyptnson ptnts wth YDYHS, () hyptnson ptnts wth YYDS(c), nd hthy vonts.

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10

5

0

5

10

30 20 10 0 10 20 30

Figure 3: PCA sco sctt pot o psm smps om NMR dto hyptnson ptnts wth YDYHS (Nm 1225), hyptn-son ptnts wth YYDS (Nm 2635), nd hthy vonts(Nm 111).

43210

1234

30 20 10 0 10 20 30

Figure 4: PLS-DA sco sctt pot o psm smps omNMR dt o hyptnson ptnts wth YDYHS (Nm 1225),hyptnson ptnts wth YYDS (Nm 2635), nd hthyvonts (Nm 111).

PLS-DA ws sd o th dt nyss. T cssfctonty o PLS-DA s mkdy mpovd compd wth PCA

o NMR nd GC-MS dt (shown n Fs 4 nd 6). FoNMR dt, th v o2 s 0.878, whch ndctd tht thfst fv PLS componnts cn xpn 87.8% o tot vnco (.., ctoy nomton). T pdcton ty o

th mod chs 71.4% (2 = 0.714). Fo GC-MS dt,th v o 2 s 0.770, whch dnots tht th fst thPLS componnts cn xpn 77.0% o tot vnc. Tpdcton ty o th mod s 65.1% dnotd y2 (0.651).

T vs o 2 nd 2 sst tht th mods sd onNMR nd GC-MS dt oth hv ston fttn ty ndpdctv ty. T vs o VIP vs (s Fs 7nd 8) t thn 1 vn y PLS-DA w sctd csthy w consdd to nnt o cssfcton [16].

T componds cospondn to ths snfcnt vsw dd s th potnt omks.

Toh PCA nd PLS-DA mthods, th ops wsccssy cssfd. T sts sd on NMR nd GC-MS dt sm. Accodn to th sts, YDYHS ops pty mxd wth hthy vonts, t YYDS opdos not ovp wth th oth two ops, ndctn thtYDYHS nd YYDS mht on to two dnt mtocctos o hyptnson. T mtoc mod o YDYHSptnts compd wth tht o YYDS ptnts s cos tohthy vonts. To, th st shown n PCA scopot s consstnt wth CM thoy, whch s tht YDYHShppns n y EH wh YYDS pps n thst[17].

6

4

2

0

2

4

6

8

14 12 10 8 6 4 2 0 2 4 6 8 10 12 14

Figure 5: PCA sco sctt pot o psm smps om GC-MS dt o hyptnson ptnts wth YDYHS (Nm 1228),hyptnson ptnts wth YYDS (Nm 2947), nd hthyvonts (Nm 111).

1412 10 8 6 4 2 0 2 4 6 8 10 12 14

3

2

1

1

2

3

0

Figure 6: PLS-DA sco sctt pot o psm smps om GC-MS dt o hyptnson ptnts wth YDYHS (Nm 1228),hyptnson ptnts wth YYDS (Nm 2947), nd hthyvonts (Nm 111).

4

3

2

1

0

Figure 7: VIP pot o PLS-DA sd on NMR dt.

3.4. Biomarkers and Metabolic Perturbations. Accodn toth VIP pots o PLS-DA (shown n Fs 7 nd 8), thcospondn chmc shs nd / vs o snf-cnt vs conttd to cssfcton w ond. Tdtss ncdn HMDB, KEGG, MELIN, LIPID MAPS,nd PUBCHEM [18] w sd to tv th stcts ocomponds ccodn to th chmc shs. A NIS2008dts ws mpoyd to dnty th stcts o com-ponds sd on /vs. T td mtoc pthwysw schd n KEGG dts. T chnd mtocpttns ndcd y hyptnson std n th chndmtoc tnds. T dntfd omks ndth tvchns w shown n 3.

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2

1

0

397 5 9 62

1437

27

10

1831

117

38

29

26

16

19

34

32

25

35

12

40

42

14

13

2813

13324

123

15

36

22

43

2083

044

24

Figure 8: VIP pot o PLS-DA sd on GC-MS dt.

MVA Corticosterone

Tyrosine

Leucine

Glycine

Betaine

Homocysteine

Epinephrine

Norepinephrine

THF

MTHF

Dimethylglycine

S-adenosyl-L-HCY

S-adenosyl-L-methionine

L-methionine

Figure 9: Mtoc ntwok o Yn hypctvty n hyptnson. T componds n y ctn to th dntfd omks.

CM consds tht Yn dfcncy s th commonpthooc chn o YDYHS nd YYDS. To, ny mtot showd th sm mtoc tndncy n twoZhns, t cod dd s th omk o Yndfcncy o hyptnson. In 3, compd to contoop, cos showd n ncsn tndncy n oth oth YDYHS nd YYDS ops. To, t ssts thtcos my mtoc omk o Yn dfcncyn hyptnson, nd nom mtosm o cos my mtoc pthwy o Yn dfcncy n hyptn-

son.In hyptnson, dsods o cos sy csd

y nsn sstnc [19]. T cnt xpmnts showdtht nsn sstnc pyd n mpotnt o n ncsnth sk o EH [20, 21]. Both sympthtc nv systm ct-

vty [22, 23] nd ctvtn nn-notnsn-dostonsystm csd y nsn sstnc py ctc os n thpthooc mchnsm o EH [24, 25]. Fthmo, thpvos xpmnts v sts tht hyptnsv ptntswth YDYHS nd YYDS hd th sm symptom o nsnsstnc compd to hthy pop, nd YYDS ws mosos n nsn sstnc thn YDYHS [26, 27].

3.5. Metabolic Pathway Analysis. T omks nd thmtoc pthwys my show th sotd chn o EH.Howv, ccodn to ochmc cton, th mtocntwok t y comnn th omks wth th co-spondn mtoc pthwys cn dspy th hostc chnsn hmn ody (s F 9).

T vyn vs o omks (s 3) n YDYHSsm to son consqnc o th sympthtcnvos systm ctvton, whch th ky ctos n thtooy o EH [28]. As shown n F 9, tyosn s p-

cso o th synthss o nopnphn nd pnphn,wh tn nd L-mthonn cn sppy mthy o no-pnphn nd pnphn. Mvonc cd, n mpotntsmfnshd podct n th pocss o chosto synthss,s ntd y cty-CoA wth th ctyss o HMG-CoA,whch cn ctvtd y pnphn. Chosto cn tnsomd to dnocotc homon, sch s cotcos-ton [29]. Consqnty, tyosn, tn, L-mthonn,nd mvonc cd (MVA) qd n mo qnttsdn th pocss o sympthtc nvos systm ctvton,whch mht n mpotnt mchnsm o pthonss oYDYHS n EH.

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Metabolic

disorders of

glucose

Metabolic

disorders of

glucose

YYDSYDYHS

SNS

activation

Low

metabolic

rate

YDYHS YDSYHS

Refers to Yang

Refers to Yin

Controls

Controls

Figure 10: Mtoc mchnsm n EH sd on th tv chns o Yn nd Yn.

able 3: Potnt omks, mtoc pthwys, nd mtoc tndncs o omks om YDYHS to YYDS.

Nm Instmnt Mtots Mtoc pthwyMtoc tndncy

YDYHS vsscontos

YYDS vsscontos

YYDS vssYDYHS

1 NMR BtnEpnphnosynthss

2 NMR Mvonc cd Chosto osynthss

3 NMR CotcostonStod homonosynthss

4 NMR Bt-cnVn, cn, ndsocn ddton

5 NMR Poponc cdCystn nd mthonnmtosm

6 GC-MS MthonnCystn nd mthonnmtosm

7 GC-MS D-cos coxyc cd cyc

8 GC-MS GycnGycn, sn, ndthonn mtosm

9 GC-MS yosn yosn mtosm

10 GC-MS Mc cd Ftty cd osynthss

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Yn, s CM concpton, s to cst o mtsocs ncdn wmth, xctmnt, nd pomoton [4],nd th sympthtc nvos systm ctvton s n mpo-tnt pthooc poss o Yn hypctvty [30]. Tsts o pvos xpmnts w sm to th psntstdy tht th vs o nopnphn nd pnphn n

th ood o hyptnsv ptnts wth YDYHS w hhthn tht o hthy pop nd YYDS ptnts. To, thvso nopnphn ndpnphnmht thoht to th mpotnt dnostc ct o YDYHS o EH.

Fth, ccodn to CM thoy, Yn cn so kpmtoc t n nom v to stsy th nom physo-oc ctvts o th hmn ody [31]. Howv, o YYDSo EH, th nom physooc ncton s dpssd ndthody s sy n ow mtoc stts. T ptnts wthYYDS wys xht ss o Yn-hyponcton symp-toms sch s cod, wknss, poo pptt, nd stssnss.As sttd n 3, compn to YDYHS nd contoop, omks xcpt o cos showd dcsdmtoc tndncy n YYDS, nd thy mht dds th chctstc omks o Yn hyponcton. Asshown n F 10, mtoc dsods o cos my th shd pthwy o YDYHS nd YYDS. Howv, dntmtoc mods ntd s th st o tton nth two Zhns.

4. Conclusion

T ojctfcton o Zhn n CM thoy s vy d-ct ss n th modn mdc sch. T ncopotono CM pttn cssfcton nd omdc dss d-noss w d to nw wth th dvopmnt o mdc

scncs. Impovn ttmnt ctvnss nd mo mth-ods ppd to dnoss, cnc t, nd nw d dscov-y n CM w povdd [32, 33]. Mtonomcs wsdmonsttd s s too o ndstndn ths kndo ncopoton. Howv, dnt mtoc mods wntd d to tton n two dnt Zhns. Tsympthtc nvos systm ctvton my n mpotntpthonss n YDYHS chctzd y Yn hypctvty,wh owd mtoc t sy occd n YYDS.It ws so woth notcn tht th compmnty nto th dt otnd y GC-MS nd NMR ws sttdn th sts o th psnt stdy, so mo mtoc o-mks cod dntfd thn thos otnd y ny sntchnq [34]. Hnc, th comnton o dnt mt-onomcs tchnqs wod hp s to dscov ndv thmtoc mods n dnt Zhn o CM.

Authors Contributions

Y. L nd L. N conttd qy to ths wok nd shod dd s cofst thos.

Acknowledgment

T stdy ws sppotd y th ndn om Nton N-t Scnc Fondton o Chn (no. 30772865).

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