Review Article Systems Biology of Meridians, Acupoints, and Chinese Herbs in Disease

14 Pages·2014·1.81 MB·English

HindawiPublishingCorporation
Evidence-BasedComplementaryandAlternativeMedicine
Volume2012,ArticleID372670,13pages
doi:10.1155/2012/372670
Review Article
Systems Biology of Meridians, Acupoints, and
Chinese Herbs in Disease
Li-LingLin,1Ya-HuiWang,2Chi-YuLai,2Chan-LaoChau,3Guan-ChinSu,4
Chun-YiYang,4Shu-YingLou,1Szu-KaiChen,5Kuan-HaoHsu,5Yen-LingLai,1
Wei-MingWu,6Jian-LongHuang,7Chih-HsinLiao,1andHsueh-FenJuan1,5,7
1DepartmentofLifeScience,NationalTaiwanUniversity,No.1,Section4,RooseveltRoad,Taipei106,Taiwan
2GraduateInstituteofEpidemiologyandPreventiveMedicine,NationalTaiwanUniversity,Taipei100,Taiwan
3DepartmentofBioenvironmentalSystemsEngineering,NationalTaiwanUniversity,Taipei106,Taiwan
4InstituteofBiochemicalSciences,NationalTaiwanUniversity,Taipei106,Taiwan
5InstituteofMolecularandCellularBiology,NationalTaiwanUniversity,No.1,Section4,RooseveltRoad,
Taipei106,Taiwan
6DepartmentofBiochemicalScienceandTechnology,NationalTaiwanUniversity,Taipei106,Taiwan
7GraduateInstituteofBiomedicalElectronicandBioinformatics,NationalTaiwanUniversity,No.1,Section4,
RooseveltRoad,Taipei106,Taiwan
CorrespondenceshouldbeaddressedtoHsueh-FenJuan,[email protected]
Received2August2012;Accepted26September2012
AcademicEditor:WolfgangSchwarz
Copyright©2012Li-LingLinetal.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,
whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Meridians,acupoints,andChineseherbsareimportantcomponentsoftraditionalChinesemedicine(TCM).Theyhavebeenused
fordiseasetreatmentandpreventionandasalternativeandcomplementarytherapies.Systemsbiologyintegratesomicsdata,such
astranscriptional,proteomic,andmetabolomicsdata,inordertoobtainamoreglobalandcompletepictureofbiologicalactivity.
Tofurtherunderstandtheexistenceandfunctionsofthethreecomponentsabove,wereviewedrelevantresearchinthesystems
biologyliteratureandfoundmanyrecentstudiesthatindicatethevalueofacupunctureandChineseherbs.Acupunctureisuseful
inpainmoderationandrelievesvarioussymptomsarisingfromacutespinalcordinjuryandacuteischemicstroke.Moreover,
Chineseherbalextractshavebeenlinkedtowoundrepair,thealleviationofpostmenopausalosteoporosisseverity,andanti-tumor
effects,amongothers.Differentacupoints,variationsintreatmentduration,andherbalextractscanbeusedtoalleviatevarious
symptomsandconditionsandtoregulatebiologicalpathwaysbyalteringgeneandproteinexpression.Ourpaperdemonstrates
howsystemsbiologyhashelpedtoestablishaplatformforinvestigatingtheefficacyofTCMintreatingdifferentdiseasesand
improvingtreatmentstrategies.
1.Introduction visceraandmeridiansinfusesandeffuses.Thisphenomenon
is thought to be similar to how signals are passed through
According to traditional Chinese medicine (TCM), acu- neural networks. Acupoints are also considered reflection
pointsarelinkedinanetworkofmeridiansrunningalongthe points (i.e., points on the body whose reflexes provide
surfaceofthebody.Themeridiansystemisaspecialchannel diagnostic information) for certain diseases and are the
network that consists of skin with a high concentration of targetsforclinicalacupuncture[3].
nerves,variousnociceptivereceptors,anddeeperconnective Acupuncture is an alternative medicine methodology
tissues inside the body [1]. Moreover, “qi” (vital energy) thatoriginatedinancientChina.Itusesthinmetalneedlesto
in TCM is transferred by meridians, and its flow around piercethroughskinintoacupointstoregulatetheflowofqi
the body can reflect the health status of individuals [2]. around the whole body [4]. Needling at appropriate points
Acupointsarespeciallocationsinthebodywherethe“qi”of can induce effects in locations remote from the insertion
2 Evidence-BasedComplementaryandAlternativeMedicine
MS6 EX-HN3
BL10
LI20
GB20
CV17
CV12
CV6
CV4 PC6
LI4
ST32
SP10
BL40
EX32
GB34 ST36
ST40
SP6
GB39
LR3
Figure1:Theapproximatelocationsofacupointsonthehumanbodyreviewedinthispaper.ImagesarecreatedbyAcu3DVer.1.0.2011.0218.
site[5].Manyrecentbrainimagingstudieshaveshownthat systems, focuses on understanding functional activities
acupuncturehasaspecificcorrelationwiththehumanner- from a systems-wide perspective [22]. With the advent of
vous system. Using functional magnetic resonance imaging high-throughput global gene expression, proteomics, and
(fMRI) to scan the brains of subjects undergoing needling, metabolomic technologies, systems biology has become a
researchers found that different acupoints corresponded to viableapproachforimprovingourknowledgeofhealthand
different cerebral areas and conditioned reactions [3, 6]. disease [23, 24]. In this paper, we review recent research
Therefore, it has the potential to provide therapy for many articles on acupuncture and Chinese herbal therapy per-
diseases.Recentstudieshavefoundthatelectroacupuncture formed in conjunction with omics technologies to analyze
(EA) improved the pathology of motor disorders in a andinvestigatetheregulatorymechanismsofthetreatments
Parkinsonianratmodelbyrestoringhomeostasisinthebasal andtheirtherapeuticapplications.
ganglia circuit [7, 8]. In other reports, the effects of EA
treatmentonneuropathicpain[9],acutespinalcordinjury
[10],acuteischemicstroke[11],andreducinginflammation 2.SystemsBiologyandOmicsData
[12,13]werealsorigorouslystudied.Wereviewtherelevant
literature below and have depicted the human acupoints Systems biology is the computational integration of huge
describedinthispaperinFigure1. datasets to explore biomolecular functional networks [22,
Another important aspect of TCM is Chinese herbal 25]. The field offers many approaches and models for
medicine (CHM), which has been used for thousands of searchingforbiologicalpathwaysandpredictingtheireffects
yearsasamajorpreventiveandtherapeuticstrategyagainst andimplications[26,27].Morerecently,academicresearch
disease[14].Currently,morethan3,200speciesofmedicinal has focused on developing basic informatics tools that can
plants are used in CHM treatments. A fundamental feature integrate large quantities of global gene expression, pro-
of TCM is TCM compound formulas, which are composed teomic,andmetabolomicdatatomimicregulatorynetworks
of many kinds of herbs and sometimes minerals or animal andcellfunction[26,28].Theprincipleofsystemsbiology
components, similar to a cocktail therapy [15]. Each TCM is to understand and compare physiology and disease,
compound formula is usually designed to combat specific first from the level of molecular pathways and regulatory
symptoms and combined with other herbs or prescriptions networks,thenmovingupthroughthecell,tissue,andorgan,
totailortoindividualneeds.Herbalextractshavebeeninves- andfinallywholeorganismlevels[29,30].Ithasthepotential
tigatedforuseintreatingvariousdiseasesandhavebeenused toprovidenewconceptstorevealunknownfunctionsatall
as a complementary or alternative form of medical therapy levelsoftheorganismbeingstudied.
for cancer patients [16–18]. In other studies that focus on Omicsdatahelpstoexplorethedifferentlevelsinsystems
chronickidneydisease[19],neurodegenerativedisease[20], biology from a holistic perspective. The suffix “-omics”
anddiabetesmellitus[21],Chineseherbshavebeenreported is added to the object of study or the level of biological
toalleviatesymptomsandmediatesignaltransduction. process to form new terms to describe that information—
Systems biology, which combines computational and for example, genomics from gene data, proteomics from
experimental approaches to analyze complex biological proteindata,metabolomicsfrommetabolicdata[31].With
Evidence-BasedComplementaryandAlternativeMedicine 3
rapid progress in sequencing and computational methods, Table1:Listoftheacupuncturepoints(acupoints)reviewedinthis
omicstechniqueshavebecomepowerfultoolsforresearching paper.
biologicalmechanismsanddiseasesandforinterdisciplinary
Acupoint Acupoint
applications,forexample,biologics,mathematics,andinfor- Function/target References
Chinesename name
matics[32–34].
Weizhong BL40 Acuteischemicstroke [11]
Tianzhu BL10 Acuteischemicstroke [11]
3.GenomicStudiesofAcupunctureinDiseases
Guanyuan CV4 Kneeosteoarthritis [45]
Many individual transcriptional profiles of animals or Antiaging,
Qihai CV6 [41,45]
patients have been mined to search for target molecules of kneeosteoarthritis
acupuncturetreatments.Candidategenesorpathwaysasso- Zhongwan CV12 Antiaging [41]
ciated with the protective effect of acupuncture treatments
Danzhong CV17 Antiaging [41]
have been revealed through genomic analysis for several
Yintang EX-HN3 Allergicrhinitis [56]
diseases and symptoms. We list the acupoints and related
symptomsinTable1. Xiyan EX32 Kneeosteoarthritis [45]
Fengchi GB20 Acuteischemicstroke [11]
3.1. Analgesia. Acupuncture was reported to reduce pain Kneeosteoarthritis, [45,49–
during surgery in the 1950s [35] and can treat different Yanglingquan GB34 Parkinson’sdisease 52,63,64]
types of pain in many cases [36, 37]. Particularly, previous
Spinalcordinjury,
reportshaveindicatedamajorroleforacupointST36,whose Xuanzhong GB39 Parkinson’sdisease, [46,64]
therapeutic properties include analgesia [38]. Gao et al.
Allergicrhinitis,
compared the hypothalamus transcriptional profiles of rats [11,40,
Hegu LI4 analgesia,andacute
thatrespondedordidnotrespondtoEAanalgesiatreatment 56]
ischemicstroke
at ST36 [39]. They found that genes for glutamatergic
receptors, ghrelin precursor peptides, the melanocortin 4 Yingxiang LI20 Allergicrhinitis [46,56]
receptor, and neuroligin 1 may all be new targets for pain Taichong LR3 Parkinson’sdisease [49,50]
management.Moreover,Chaeetal.found375genesshowing
MotorArea MS6 Acuteischemicstroke [11]
significant variation in response to the analgesic effect of
Neiguan PC6 Acuteischemicstroke [11]
acupuncture (on LI4) [40]. Among these genes, cold shock
domain protein A and kruppel-like factor 5 were identified Spinalcordinjury,
Sanyinjiao SP6 [11,46]
acuteischemicstroke
aspotentialtargetsforinvestigatingthemechanismsbehind
acupuncture-inducedanalgesia. Xuehai SP10 Anti-aging [41]
Futu ST32 Spinalcordinjury [46]
3.2. Antiaging. In an anti-aging study, Ding et al. analyzed
Neuropathicpain,
the hippocampus gene expression profiles in senescence-
spinalcordinjury,
accelerated mice given acupuncture treatment [41]. Fol-
immunemodulation,
lowing applied acupuncture at the CV17, CV12, CV6, allergicrhinitis, [9,11,38–
ST36, and SP10 acupoints, the researchers observed eight Zusanli ST36 analgesia, 41,45–
genes affected by age. They found that acupuncture could anti-aging, 47,53–56]
completely or partially alter the gene expression of heat- kneeosteoarthritis,
shockproteins(Hsp84andHsp86)andY-boxbindingpro- andacuteischemic
tein 1—genes related to oxidative damage—in senescence- stroke
accelerated mice, indicating that acupuncture may show
Fenglong ST40 Hypercholesterolemia [42]
promiseinretardingaginginmammals.
3.3.Hypercholesterolemia. LiandZhang stimulatedC57BL/ treatments. Among differentially expressed genes involved
6j mice, which are used in diabetes and obesity research, at inthepathways,oxidativephosphorylation(ATPsynthesis)
theST40acupointandfoundthatcholesterol7αhydroxylase was found in all patients. Analysis of profiles with respect
was upregulated following EA, while sodium taurocholate the Kyoto Encyclopedia of Genes and Genomes (KEGG)
cotransportingpolypeptidewasdownregulated[42].Eachof pathway database showed that the majority of differen-
thesevariationsingeneexpressionmightalterthebalanceof tially expressed genes were associated with seven types of
cholesterolmetabolismandreducecholesterolbyregulating metabolic pathways, particularly the primary, cellular, and
bilesaltbiosynthesisandflux,respectively[43,44]. energy metabolism pathways. These results showed that
acupuncture treatment may regulate gene expression to
3.4. Knee Osteoarthritis. Tan et al. compared the transcrip- balanceenergymetabolismofkneeosteoarthritispatients.
tional profiles of four patients stimulated at the CV4, CV6,
ST36,EX32,andGB34acupoints[45].Theycollectedsam- 3.5. Neuronal Diseases. In a spinal cord injury (SCI) study,
plesfromtheperipheralbloodofpatientsafteracupuncture EAtreatmentonratsatfouracupoints—ST36,GB39,ST32,
4 Evidence-BasedComplementaryandAlternativeMedicine
andSP6—wasseentorestoresensoryfunctionbymicroarray presumably through immune modulation [56, 57]. Allergic
analysis [46]. In this study, they found that extending rhinitis occurs when an allergen is inhaled and generates
the EA treatment time for SCI rats could result in more an immune response in an individual. Its symptoms can
changes in gene expression. After EA stimulation, the gene be reduced by acupuncture treatment at the EX-HN3, LI4,
expression of calcitonin gene-related polypeptide (CGRP) LI20, and ST36 acupoints [56]. The effectiveness of the
and neuropeptide Y (NPY) were up-regulated and func- treatment could be accounted for by modulation of pro-
tionally annotated with the recovery of sensory functions. and anti-inflammatory genes observed through microarray
Acupuncture treatment at ST36 has also been reported to analyses of blood samples. Immune responses to allergic
reduce neuropathic pain. Using microarray analysis, opioid rhinitis may vary depending on types of allergen. Shiue
receptorsigmawasoneofdifferentiallyexpressedgenesand et al. have used the Phadiatop (Ph) assay, an effective
involved in opioid signaling which has been implicated in screening tool that detects a diverse range of allergens, to
neuropathic pain and the analgesic effectsof EA at ST36 in demonstrate that patients with Ph-positive (+) and Ph-
neuropathicpainmodelrats[47]. negative(−)allergicrhinitisdisplaydifferentgeneexpression
Parkinson’sdiseaseisaneurodegenerativediseasecaused profiles after acupuncture treatment [57]. A hierarchical
by the death of dopaminergic neurons [48]. Several studies clustering analysis revealed that three gene groups—those
have performed acupuncture treatments on different acu- for active immune response, regulatory T cell differential,
points in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine- and apoptosis—were differentially expressed in the Ph (+)
(MPTP-) induced Parkinson’s models. These models were and Ph (−) patients aftertreatment[57]. These resultsalso
used to evaluate the effects of acupuncture treatment at indicatetheimportanceofpersonalizedmedicineforfuture
the GB34 and LR3 acupoints by analyzing the transcrip- investigations.
tional profiles from cervical spinal cord or brain bilateral
striatal tissues [49, 50]. Among the genes downregulated
4.ProteomicStudiesofAcupunctureinDiseases
by acupuncture treatment, proplatelet basic protein (Ppbp)
wasfunctionallyannotatedwithcytokine-cytokinereceptor
Proteomic technologies, such as two-dimensional elec-
interactionpathways,andcytotoxicTlymphocyte-associated trophoresis (2-DE), can screen for proteins differentially
protein 2 alpha (Ctla2a) was associated with a pathway
expressedbetweenindividualsresponsiveandnonresponsive
relevant to Parkinson’s disease according to KEGG analysis
to acupuncture treatments. These proteins were identified
[49]. Similar results were observed from substantia nigra
by various mass spectrometry (MS) techniques, and their
tissue of MPTP mice following treatment at the GB34
relatedpathwayswereexploredtodeterminethemechanism
acupoint [51]. In previous studies, myelin basic protein, a
of the acupuncture treatments. The results clarify the
major constituent of the axonal myelin sheath, has been relationships between different acupoints and functions
reportedtobeup-regulatedinMPTPmiceandParkinson’s
(Table1).
patientsstimulatedattheGB34acupoint[52].Inthebilateral
striatal tissue of mice brain following acupuncture at the
4.1. Acute Ischemic Stroke. EA efficacy has been studied by
GB34 and LR3 acupoints, the gene expression levels of
comparing levels of serum proteins in response to EA or
gap junction alpha 4 protein (Gja4) and tubulin alpha
drug treatments in acute ischemic stroke patients [11].
8 (Tuba8) were down-regulated and annotated with the
PatientsweretreatedwithEAateightacupoints(MS6,BL10,
cellcommunicationandgapjunctionpathway,respectively.
GB20, LI4, PC6, B40, SP6, and ST36) once daily for ten
Furthermore,anup-regulatedgene,neurotrophin-3(Ntf3),
consecutivedays.Theproteinprofileswereanalyzedusing2-
was annotated with the mitogen-activated protein kinases
DE;SerpinG1wasup-regulated,whilegelsolin,complement
(MAPK)signalingpathway[50].
component1(C1),C3,C4B,andbeta-2-glycoproteinIwere
alldown-regulated.Otherstudieshaveindicatedthatplatelet
C4 expression is associated with acute ischemic stroke by
3.6. Immune Modulation and Allergic Rhinitis. Evidence
comparing serum proteins from healthy individuals and
frommousemodelshasdemonstratedthatEAoracupunc-
ischemicstrokepatients[58].
turestimulationatST36canmodulatetheimmuneresponse
[53–55]. Two studies using a 2,4-dinitrophenylated keyhole
limpet protein (DNP-KLH) immunized mouse model have 4.2. Neuronal Diseases. Using matrix-assisted laser desorp-
shown that gene expression patterns can change in the tion/ionization time-of-flight mass spectroscopy (MALDI
spleen[55]andhypothalamus[54]afterEAtreatment.Using TOF-MS)andsubsequentproteindatabasemining,Lietal.
Sprague Dawley (SD) rats, Kim et al. found that the genes identifiedfifteencandidateproteinswhoseexpressionlevels
altered following EA at ST36 play crucial roles in natural varied with acupuncture treatment for SCI [59]. Among
killercellactivationinspleentissue[53].However,theeffects them, annexin A5 (ANXA5) and collapsin response mod-
ofEAtreatmentsremaindiverse,partlybecauseofvariation ifier protein 2 (CRMP2) were determined to be beneficial
in immune responses when triggered in different types of for neuronal survival and axonal regeneration. ANXA5 is
tissues or models (e.g., DNP-KLH immunized mice versus a member of the annexin superfamily of calcium- and
SDrats). phospholipid-binding proteins, which are related to apop-
Acupuncture treatment has also demonstrated some tosis and inflammation [60]. CRMP2 is a member of the
effectiveness against allergic rhinitis in clinical settings, collapsinresponsemediatorproteinfamilyandisexpressed
Evidence-BasedComplementaryandAlternativeMedicine 5
exclusively in the nervous system, especially during devel- CCL20,CCL5,andCCL19;interleukins(IL)IL-27,IL-23A,
opment [61]. Additionally, among up-regulated proteins, IL-12A,andIL-12B;costimulatorymoleculesCD40,CD54,
heat shock protein beta-1 (HSPB1) has a reported role in CD80, and CD86 [67]. Additionally, altered expression
cellstress/neuroprotectionaswellasinaxonalregeneration levels of CD209, CCL20, CCL5, IL-27, CD54, CD80, and
[62]. These results reveal the potential for proteomics CD86 in cells after treatment with F3 (a polysaccharide
researchtosupplementandguidethetreatmentofSCIwith fraction extracted from lingzhi) have been observed by Lai
acupunctureinfutureresearch. et al., with CD209 expression down-regulated proportional
Moreover, Sung et al. applied EA at ST36 in a SD to treatment time [66]. Another study investigated the
rat model, and subsequent 2-DE was used to identify treatmentofhumanCD14+monocyteswithpolysaccharide
signalingpathwaysinvolvedinneuropathicpain[9].Thirty- fractions extracted from North American ginseng [68].
six differentially expressed proteins were identified in the The MAPK (extracellular regulated protein kinases-1/2),
neuropathic pain model, and the normal expression levels phosphoinositide-3-kinase, p38, and nuclear factor-kappaB
oftheircorrespondinggenescouldberestoredfollowingEA (NF-κB)cascadesarekeysignalingpathwaysthatmaytrigger
treatment. Furthermore, Jeon et al. performed EA at GB34 immunomodulatory functions, as determined by Ingenuity
inanMPTPmousemodelofParkinson’sdisease[63].They PathwayAnalysis[68].Withregardtootherextracts,Cheng
observedrestorationofbehavioralimpairmentandrescued et al. reported that the NF-κB pathway was up-regulated
tyrosinehydroxylase-positivedopaminergicneurodegenera- in THP-1 by treatment with ethanol extracts of G. sinense,
tionafterthetreatment.Inpreviousstudies,theexpression but not by G. lucidum [69]. Moreover, protosappanin A
of myelin basic protein can also be restored to normal treatment (an ethanol extract of Caesalpinia sappan) has
levelsafterEAtreatment[63].Kimetal.performedsimilar beenreportedtoinduceanimmunosuppressiveeffectviathe
studies at GB34 and GB39 [64]. They identified thirteen NF-κBpathwayinahearttransplantationratmodel[70].
differentially expressed proteins using MS, and four of
theseproteins—cytosolicmalatedehydrogenase,munc18-1,
5.2. Wound Repair. Herbal formulas containing extracts of
hydroxyacylglutathionehydrolase,andcytochromecoxidase
Astragaliradix,Rehmanniaeradix,andAngelicasinensisshow
subunit Vb—were restored to normal expression levels
potential therapeutic benefits for wound repair [72]. For
following EA treatment. These proteins are involved in cell
example, the formula NF3, which consists of a 2:1 ratio
metabolism, and may reduce MPTP-induced dopaminergic of A. radix and R. radix, has been found to affect cell
neuronal destruction by decreasing oxidative stress. Taken
proliferation, angiogenesis, extracellular matrix formation,
together,theseresultssuggestthatacupuncturetreatmentis
and inflammation in the Hs27 skin fibroblast cell line
likely to have a neuroprotective effect on neuronal diseases
through microarray analysis [72]. Another study in human
through cell metabolic and nervous tissue developmental
skin substitutes revealed that SBD.4 extracts of A. sinensis
pathways,amongothers.
possessesskin-andwound-healingactivity[73].AfterSBD.4
stimulation, the gene expression of collagen XVI and XVII,
5.GenomicStudiesofChineseHerbsinDiseases laminin γ-2 and 5, claudin 1 and 4, hyaluronan synthase 3,
superoxide dismutase 2, and heparin-binding EGF was up-
Many studies have investigated genes impacted by Chinese regulatedand ADAM9 wasdown-regulated in EpiDermFT
herb extracts from transcriptional profiles after treatment skin substitute tissues. The elevation of collagen XVI and
andanalyzedtheirfunctionsusingpathwaydatabases.These XVII can enhance collagen fibril organization and the
resultswereusedtoevaluatewhetherChineseherbextracts reductionofADAM9maystimulatecollagendeposition[89,
could be used as a complementary drug to treat specific 90].Theseresultssuggestthattheseskin-andwound-healing
symptoms.Here,wereviewChineseherbaltreatment-related relatedgenesfunctionincell-substratejunctionassembly.
studiesthatincorporatedgenomicanalysisandinterpretthe
efficacyof Chinese herb extractsforvarious symptoms and 5.3.PostmenopausalOsteoporosis. TraditionalChineseherb-
conditions(Table2). alistshavebeentreatingpatientswithchronickidneydisease
forthousandsofyears[19].Theeffectofanherbalmixture
consisting of Herba Epimedii, Fructus Ligustri Lucidi, and
5.1.ImmunomodulatoryFunction. Itisgenerallyagreedthat
FructusPsoraleaewasinvestigatedinagedovariectomyand
the fungus Ganoderma lucidum contains an abundance of
calcium deficiency-induced osteoporotic rats [74]. A com-
polysaccharides with immunostimulatory properties [65],
parison of the transcriptional profiles between nontreated
and these have been investigated using human CD14 (+)
(clusterofdifferentiation14)deriveddendriticcells[66,67]. and herbal formula-treated ovariectomized rats found that
somegenesspecificallyactivatedbytheherbalmixture,such
Dendriticcellsareantigen-presentingcellsthatplayacritical
as prostaglandin EP3 receptor and osteoprotegerin, were
role in the regulation of the adaptive immune response.
involvedinboneremodelingandboneprotection.Moreover,
A comparison of transcriptional profiles from the polysac-
they identified the involvement of estrogen-related proteins
charide of G. lucidum-treated dendritic cells and untreated
andsuggestedthattheherbalformulamayactlikeestrogens.
dendritic cells showed a decrease in the expression of some
phagocytosis-relatedgenes,forexample,CD36,CD206,and
CD209.Theexpressionofproinflammatorychemokineswas 5.4. Diabetes Mellitus. Type 2 diabetes mellitus (T2DM) is
increased, that is, chemokine (C-C motif) ligands (CCL) characterized by insufficient insulin secretion and insulin
6 Evidence-BasedComplementaryandAlternativeMedicine
Table2:ListofChineseherbalstudiesthathaveincorporatedgenomicandproteomicanalysis.
Authors Herbname Extracts Commonfunctions
Sliva[65],
Laietal.[66], Immunomodulatory,
G.lucidum(lingzhi) Polysaccharidefraction/F3
Linetal.[67], antitumoractivity
Chengetal.[71]
Chengetal.[69] G.sinense(lingzhi) Ethanolextracts Immunomodulatory
Wuetal.[70] C.sappan ProtosappaninA Immunomodulatory
NF3(A.RadixandR.Radix
Zhangetal.[72] A.RadixandR.Radix Woundrepair
intheratioof2:1)
Zhaoetal.[73] A.Sinensis SBD.4 Woundrepair
HerbaEpimedii,
Sunetal.[74] FructusLigustriLucidi,and Postmenopausalosteoporosis
FructusPsoraleae
Hanetal.[21] C.A.Meyer CK Diabetesmellitus
Luoetal.[75],
Americanginseng
KingandMurphy GinsenosideRg3/ginsengextracts Antitumoractivity
(P.quinquefoliusL.)
[76]
Haraetal.[77],
C.rhizome Benzodixoloquinolizinealkaloids/berberine Anti-tumoractivity
Iizukaetal.[78]
Wangetal.[79] L.rubescens Oridonin Anti-tumoractivity
Xuetal.[80] Franquet TBMS1 Anti-tumoractivity
Chengetal.[81] R.paridis RPTS Anti-tumoractivity
Yueetal.[82] P.ginseng Rg1 Angiogenesis
Konkimallaetal.[83] Artemisinin Nitricoxidebiosynthesis
Suetal.[20,84] P.suffruticosa Paeonol Neurodegenerativedisease
Wangetal.[85] S.miltiorrhiza SALorTAN Acutemyocardialinfarction
Loetal.[86] U.rhynchophylla Convulsivedisorders
Hungetal.[87,88] S.miltiorrhiza SMAE Cardiovasculardisorder
resistance, such that the liver lacks the ability to regulate humanstudies[92].Furthermore,Fuetal.havefoundthat
glycolysis and gluconeogenesis [91]. Han et al. compared adiponectinincreasestotalglucosetransporter4expression,
gene expression profiles of C57BL/KsJ-db/db mice (insulin- which can aid in the response to insulin at the plasma
resistant model of insulin-dependent diabetes and obesity) membrane [93]. These results suggest that CK might be a
followingtreatmentwithcompoundK(CK),afinalmetabo- potentialtargetforantidiabeticdrugs.
lite of Panax ginseng C.A. Meyer [21]. They found that
somedifferentiallyexpressedgenesinlivertissuewereassoci-
atedwithglycolysis/gluconeogenesisandpentosephosphate 5.5. Antitumor Activity. Chinese herbs have been known to
pathways,forexample,upregulationofaldolase2,Bisoform possess anti-tumor activity, and some studies have investi-
and phosphogluconate dehydrogenase for glycolysis and gatedthisfunctionalityanditsmechanismsincancertreat-
pentosephosphatepathways,anddownregulationoffructose ments. F3-treated human leukemia THP-1 cells have been
bisphosphatase 1 for gluconeogenesis pathways after CK foundtoundergoapoptosisthroughdeathreceptorpathways
treatment.Inadiposetissue,ontheotherhand,theyfound as determined through microarray analysis [71]. Further-
differentially expressed genes there was linked to adipocy- more,F3inducesmacrophage-likedifferentiationbycaspase
tokine signaling and fatty acid synthesis/metabolism path- cleavage and p53 activation in THP-1 cells [94]. Another
ways,forexample,upregulationofperoxisomeproliferator- studyusingamicroarrayapproachdeterminedthat25%of
activated receptor gamma for adipocytokine signaling and genes regulated by two lingzhi (G. lucidum and G. sinense)
fattyacidsynthaseforfattyacidsynthesispathwaysafterCK was determined to be similar [69]. G. sinense was observed
treatment. to regulate inflammation and immune response pathways,
Plasmaadiponectin,ahormoneresponsibleforincreas- while G. lucidum appeared to increase the expression levels
ing neoglucogenesis, is secreted from adipocytes and might ofNF-κBpathwaygenes.Therefore,lingzhiappearstohave
play a key role in linking obesity, insulin resistance, and efficacyasananti-tumoragentagainstTHP-1cells.
the T2DM syndrome. A higher adiponectin expression has Other Chinese herbs have also been associated with
beenobservedinconjunctionwithloweredobesitylevelsin anti-tumor effects [95–101]. Two studies have shown that
Evidence-BasedComplementaryandAlternativeMedicine 7
American ginseng (Panax quinquefolius L.) extracts can in Wistar rats [85]. SAL decreases the gene expression of
inhibittumorgrowthinHCT-116[75]andMCF-7cells[76]. apoptosis-related genes at in a later period after ischemia,
A-kinase (PRKA) and anchor protein 8-like (AKAPA8L) for example, BCL2 modifying factor (Bmf). TAN decreases
gene expression were up-regulated, and phosphatidylinos- thegeneexpressionofintracellularcalciumpathways-related
itol transfer protein alpha (PITPNA) gene expression was genes at an early stage after ischemic injury, for example,
down-regulated after ginsenoside Rg3 treatment in HCT- voltage-dependent calcium channel alpha 1 (CACNA1).
116 cells [75]. The inhibition of the MAPK pathway and Intracellular calcium and apoptosis pathways have been
the up-regulation of Raf-1 kinase inhibitor protein (RKIP) reported to be associated with ischemic cardiac injury and
expression were determined in the ginseng extract of hot repair [105, 106]. These results suggest that SAL and TAN
water-extractedAmericanginseng-treatedMCF-7cells[76]. couldbeusedtopreventinjuryandinvolvedinafterinjury
Thesegeneshaveanticancerpotentialandareconsideredto repairofacutemyocardialinfarction.
be involved in anti-tumor mechanism of America ginseng.
A comparison of transcriptional profiles between mouse
5.8. Neuronal Diseases. Su et al. compared gene expression
macrophage RAW 264.7 cells before and after artemisinin
treatments[83]foundthatthedifferentiallyexpressedgenes profiles of H2O2-exposed human neuroblastoma SH-SY5Y
cells following treatment with paeonol, which is extracted
were most associated with the nitric oxide, cAMP, and
from Paeonia suffruticosa [20, 84]. They identified that the
Wnt/beta-catenin pathways. They suggested that the tumor
regulationfunctionofartemisininmightarisefromitseffect extract up-regulated the mature T-cell gene set and found
thatpaeonolwasabletoreduceH O -inducedNF-κBactiv-
on nitric oxide biosynthesis. Nitric oxide has been proved 2 2
ity.Thesedataindicatethatpaeonolmighthaveantioxidative
thatitcansuppresstumorigenesis[102].
relatedpropertiesandcouldbeusedtotreatneurodegenera-
Inanotherstudy,Haraetal.examinedeightbenzodixolo-
tivediseases,forexample,Alzheimer’sdisease[107].
quinolizine alkaloids extracted from Coptidis rhizome and
assessed the strength of their antiproliferative activity in
eight human pancreatic cancer cell lines [77]. These results
6.ProteomicStudiesof
indicated that berberine is the major compound behind
ChineseHerbsinDiseases
boosting the anti-proliferative response. However, the anti-
tumor effect of berberine isolated from C. rhizome was
Compared with studies investigating Chinese herbs using
poorer than that of whole C. rhizome, suggesting other
genomicanalysis,proteomicanalyticstudieshavebeenper-
components of the fungus are to some degree responsible
formed far less and on fewerherbs. Tumors and convulsive
as well [78]. MCF-7 cells treated with Coptidisextracts also
disorders are the major subjects of analysis by proteomic
displayedincreasedactivationofanti-tumorpathways.Two
technologies to date. The Chinese herbs used for these
critical anti-tumor cytokines were identified—interferon-β
conditionsandrelatedreferencesaredocumentedinTable2.
andtumornecrosisfactor-α—andCoptidisextractswerealso
foundtoinducecellgrowtharrestandapoptosis[103].These
studiessuggestthatC.rhizomeorCoptidisextractsareableto 6.1.AntitumorActivity. HepG2livercancercellsweretreated
inhibitcellproliferationbyreducingtumorcellgrowthand withoridoninextractedfromIsodonrubescensandanalyzed
promotingapoptosis. by2-DEandMALDI-TOF-MS[79].Proteomicdatashowed
thatexpressionlevelsofheatshock70kDaprotein1,Sti1h,
and hnRNP-E1 were altered after treatment; these proteins
5.6. Angiogenesis. Some Chinese herbs have been reported
are associated with apoptosis pathways. An extract from
to promote angiogenesis. Ginseng refers to both Panax
Franquet(Cucurbitaceae),tubeimoside-1(TBMS1),hasalso
ginseng C.A.MeyerandPanaxquinquefoliusL.(Araliaceae),
beenusedasananticancertreatment[108].Xuetal.found
whichcontainsimilarcomponents.Rg1,aP.ginsengextract,
15 proteins differentially expressed between TBMS-treated
canpromoteangiogenesisbymodulatingcytoskeletal-related
or-untreatedHeLacellsthroughMALDI-TOF-MSanalysis
genesandenhancingendothelialnitricoxidesynthaseactiv-
[80]. These proteins were associated with mitochondrial
ities in human umbilical vein endothelial cells (HUVEC)
dysfunction and ER stress-induced cell death pathways and
[82]. Chan et al. also illustrated that Rg1-induced down-
participatedinTBMS1-inducedcytotoxicity[80].
regulation of miR-214 led to an increase in the expression
The major component of Rhizoma paridis, Rhizoma
of eNOS in HUVEC through miRNA microarray analysis
paridistotalsaponin(RPTS),isresponsiblefortheantitumor
[104]. Taken together, the findings suggest that Rg1, the
effects of this herb. Using MALDI-TOF-MS, Cheng et al.
majorcomponentginosenosidefromP.ginseng,canpromote
identified 15 proteins altered in HepG2 cells differentially
angiogenesisinHUVEC.
expressed between RPTS-treated or untreated HepG2 cells,
with most of them implicated in tumor initiation, pro-
5.7. Cardiovascular Disease. Salvia miltiorrhiza is widely motion, and progression [81]. These results suggest that
used for human cardiovascular disorders in Asia, but the proteomic approaches could be useful tools to elucidate
cellular mechanism by which it attenuates the growth of pharmacological mechanisms responsible for anti-cancer
aorticsmoothmuscleunderoxidativestressremainsunclear. drugactivities.
Salvianolic acid (SAL) or tanshinone (TAN) purified from Moreover,Hungetal.foundthatS.miltiorrhizaaqueous
S.miltiorrhizawasusedtotreatacutemyocardialinfarction extract (SMAE) inhibited the proliferation of rat aortic
8 Evidence-BasedComplementaryandAlternativeMedicine
smooth muscle cell line A10 under homocysteine (Hcy)- They found 10 metabolites and 24 parent components and
induced oxidative stress [87, 88]. Furthermore, the intra- suggested that metabolomic approaches may prove useful
cellular reactive oxygen species concentration significantly in exploring the efficacy of CHM. Moreover, Yan et al.
decreasedinA10cellsafterSMAEtreatment.UsingMALDI- investigated the antiaging effect of flavones contained in
TOF-MS,theresearcherssuggestedthattheSMAE-induced Epimedium extract in rats through LC-MS [116]. They
inhibition of growth in Hcy-stimulated A10 cells occurred were able to identify differences in multiple changed age-
viathePKC/MAPK-dependentpathway[87,88]. related metabolites in serum, including carnosine, ergoth-
ioneine, unsaturated fatty acids, saturated fatty acids, and
6.2. Convulsive Disorders. Uncaria rhynchophylla (UR) and nucleotides. The expression levels of these age-related pro-
its major component, rhynchophylline, have demonstrated teins were restored to levels found in younger rats after
effectiveness in treating convulsive disorders [109]. Lo et Epimediumtreatment.
al. used SD rats with kainic acid (KA)-induced epileptic Terpenoids,agroupofimportantsecondarymetabolites
seizuresandtreatedthemwithUR[86].Theythenanalyzed in plants, are found in Ganoderma sp., which have high
proteomicprofilesfromthefrontalcortexandhippocampus cytotoxicandanti-tumoractivity.GanoderiolF,atetracyclic
of rat brain tissues and identified proteins differentially triterpene, has been analyzed by LC/MS/MS and adminis-
expressedbetweentreatedanduntreatedtissue.Macrophage teredtoratsformetabolomicsandpharmacokineticsexper-
migration inhibitory factor (MIF) and cyclophilin A were iments[117].AnalysisofthemetabolitesofganoderiolFby
down-regulated and restored to normal levels in epileptic HPLC/MS/MS from orally or i.v.-treated rats showed good
seizureratsafterURtreatment.MIFhasbeenconsideredas viability and low acute toxicity. According to these reports,
acounterregulatorofnormalneuronalactionsandincreases ganoderiolFmayshowpotentialasananti-cancerdrug.
its expression level to reduce the chronotropic actions in
SDrats[110].CyclophilinAisaphylogenetically-conserved
protein and regulates immunosuppression [111]. These 8.SummaryandFuturePerspectives
results showed that MIF and cyclophilin A involved in the
mechanismofanticonvulsiveeffectofUR. In this paper, we described and discussed omics research
to date combined with acupuncture or CHM, performed
at the systems biology level. We found that the ST36
7.MetabolomicsStudiesof
acupoint is the most widely used acupoints, and that it
ChineseHerbsinDiseases
has multiple therapeutic functions and targets, including
spinalcordinjury[46],allergicrhinitis[56],analgesia[38],
Another platform for systems biology research is meta-
neuropathicpain[9,47],antiaging[41],kneeosteoarthritis
bolomics, involving the study of targeted small molecule [45], and acute ischemic stroke [11]. Different from other
metabolites (<1500Da). In 1998, the metabolome was first
therapies, acupuncture treatments show variation in the
introduced in the elucidation of yeast gene function [112]. transcriptionalprofilesandperceivedeffectoftheirsubjects,
However, the application of this concept can be traced
whether rats [39] or humans [40]. Gao et al. reported that
back to the development of traditional medicine; while approximately30%ofratsdemonstratednoanalgesiceffects
metabonomicschemicallytracksmetabolitesinurine,feces,
during EA [39]. Similarly, Chae et al. reported that 40%
and so forth, traditional medicine used color, smell, and of their participants felt only low analgesic effects during
tastetofacilitatediagnoses.Overgenomicsandproteomics,
acupuncture, an observation that is more likely caused by
metabolomicscanprovideamoresolidlinkbetweengeno- geneticvariationratherthandifferencesinpsychology[40].
typeandphenotype.
Individual variance in treatment response is becoming an
important issue when deciding whether it is suitable or
7.1. NMR-Based Metabolomics Analysis. NMR-based meta- nottoadministeracupuncturetherapy.Basedonthispaper
bolomicsisanattractivemethodforthestudyofmedicinal results, we suggest that system biology approaches can be
herb efficacy on disease symptoms. Using this method, performed to construct exhaustive clinical data of patients
nonselectiveandcomprehensiveanalysiswasperformedon with acupuncture or CHM treatments, for example, up-
ginkgo extracts [113]. Moreover, Zhang et al. found that regulated or down-regulated genes of Ph (+) or Ph (−)
ginkgo extracts have multidirectional lipid-lowering effects allergic rhinitis patients with acupuncture treatments, and
on the rat metabonome [114]. They suggested that ginkgo provideusefulinformationforimprovingfuturetherapeutic
extractspossessmetabolomicfunctions,includinglimitation strategies. In term of acupuncture treatment, one acupoint
of cholesterol absorption, inactivation of HMGCoA, and commonly used for different symptoms, for example, LI4
favorable regulation of essential polyunsaturated fatty acid acupointcouldbeperformedforallergicrhinitis,analgesia,
profiles[114]. and acute ischemic stroke. Compared with acupuncture
treatments,Chineseherbaltreatmentsaremoreofteninves-
7.2. Liquid Chromatography (LC)-TOF MS-Based Metabo- tigatedfortheireffectivenessonspecificdiseases,andstudies
lomics. LC-MS-based metabolomics have been explored in focusonthepharmacologicalmechanismsofdifferentherbal
many studies to date. Tan et al. performed LC-TOF MS extracts, for example, benzodixoloquinolizine alkaloids has
to investigate the metabolites of aconitum alkaloids in rat anti-tumoractivity[77]orCKhasanti-diabeticefficacy[21].
urineafteroraladministrationofaconiterootextracts[115]. In summary, we suggest appropriate therapies—whether
Evidence-BasedComplementaryandAlternativeMedicine 9
Proteomic Genomic
analysis analysis
Metabolomic Personalized
Meridians
analysis medicine
Chinese Acupoints
herbs
Figure2:Thecompositionof“personalizedmedicineinTCM.”Combininggenomic,proteomic,andmetabolomicinformationcanprovide
morecomprehensivestrategiesforTCMtherapies.
acupuncture,TCM,oracombination—canbepersonalized gangliaoutputpathwaytoamelioratemotorimpairmentin
to individuals through analyzing their transcriptional or parkinsonianmodelrats,”BehavioralNeuroscience,vol.124,
proteomic profiles (Figure2). “Personalized medicine in no.2,pp.305–310,2010.
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ThisworkwassupportedbytheNationalTaiwanUniversity [10] X.C.Yuan,J.L.Song,G.H.Tian,S.H.Shi,andZ.G.Li,
Cutting-Edge Steering Research Project (101R7602C3) and “Proteomeanalysisonthemechanismofelectroacupuncture
the National Science Council of Taiwan (NSC99-2621-B- inrelievingacutespinalcordinjuryatdifferenttimecourses
inrats,”ChineseAcupuncture&Moxibustion,vol.34,no.2,
010-001-MY3,andNSC99-2621-B-002-005-MY3).
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