Review ArticleSalivary Markers for Periodontal and General Diseases

Stepan Podzimek Lucie Vondrackova Jana DuskovaTatjana Janatova and Zdenek Broukal

School of Dental Medicine First Faculty of Medicine and General University Hospital Charles UniversityKarlovo Namesti 32 and Katerinska 32 121 11 Prague Czech Republic

Correspondence should be addressed to Stepan Podzimek podzimekvuscz

Received 4 December 2015 Revised 7 March 2016 Accepted 15 March 2016

Academic Editor Shih-Ping Hsu

Copyright copy 2016 Stepan Podzimek et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

The determination of biomarkers in saliva is becoming an important part of laboratory diagnostics and the prediction of not onlyperiodontal but also other tissue and organ diseases Biomarkers in saliva (eg enzymes protein markers or oxidative stressmarkers) can be used for activity determination and for periodontal disease prognosis Saliva also contains many markers whichcan predict the risk of certain diseases (eg diabetes mellitus cardiovascular oncology endocrinology and psychiatric diseases)The study of salivary components proteomics clearly shows the relationship of periodontal diseases and diseases of distant systemsorgans or tissues

1 Introduction

Saliva is an accessible biofluid that contains components de-rived from the mucosal surfaces gingival crevices and toothsurfaces of the mouth Saliva also contains microorganismsthat colonize the mouth and other exogenous substances andso can potentially provide an insight into the relationship ofthe host with the environment [1]

Research on the composition of the saliva and the pres-ence of periodontal and other disease markers became inten-sive again thanks to the development of laboratory nanotech-nologies that pushed detection limits of various metabolitessignal molecules hormones and other substances by severalorders of magnitude In addition to molecular methodsanalytical chips are also available that may by merely chang-ing the detection plates detect a series of various chemicalsubstances

Most metabolites cytokines signal molecules or hor-mones move in a certain amount by passive filtration intosaliva and their levels in saliva reflect their levels in plasmaTherefore detection of these molecules in saliva is only amatter of the detection limits of new analytical methods Thepotential of saliva as a biomarker fluid has been transformedby the development of highly sensitive proteomic analysis

which has identified the presence of over 2000 proteinsapproximately 25ndash30 of which are shared with blood [2]

It is also important to mention that an advantage of usingsaliva as a diagnostic material is that it can be obtained forlaboratory tests noninvasively and repeatedly [3]

Saliva is a very complex system which includes not onlyboth its own components and sulcular fluid componentsmicroorganisms and products of inflammation ongoing inperiodontium but also metabolites and signal moleculesaccompanying remote processes Some components of salivacan come frommultiple sources such as proteolytic enzymesThese can come not only from polymorphonuclear leuko-cytes and periodontal microorganisms but also from thebloodstream It is similar to the products of inflammationwhich may also have both local and systemic origin

Enzymes specific and nonspecific proteins antibod-ies and other substances are among the potential salivarybiomarkers of periodontal and certain distant tissue diseasesAnd so saliva became the topic of interest among experts inproteomics research of sequential composition of individualproteins

A potential limitation in the use of saliva as a diag-nostic fluid is oral dryness caused by the failure to pro-duce saliva Dry mouth is most frequently the side effect

Hindawi Publishing CorporationDisease MarkersVolume 2016 Article ID 9179632 8 pageshttpdxdoiorg10115520169179632

2 Disease Markers

of the consumption of many prescribed medications andis more prevalent in older age groups A high degree ofmedication-induced dryness resulting from salivary hypo-function is associatedwith anticholinergicmuscarinic recep-tor blockers used to treat for example irritable bladdersAntidepressants can also cause salivary hypofunction as aresult of the activation of alpha-2-adrenergic receptors inthe central nervous system The most severe forms of long-lasting irreversible dry mouth are seen in patients withsquamous cell carcinoma given external irradiation of thehead and neck and in patients with Sjogrenrsquos syndrome [1]

In this review we will onlymention some of the biomark-ers of periodontal diseases and some distant diseases in salivato illustrate the direction of this researchThis reviewdoes notfocus on biomarkers in gingival crevicular fluid such reviewhas been recently published in Periodontology 2000 journal[4 5]

Three limitations prevent the full benefits of clinical diag-nostics from being realized definitive biomarkers associatedwith disease simple and inexpensive methods that are min-imally invasive and an accurate portable and easy-to-usediagnostic platform [6]

It is certain that more research effort is necessary todetermine the sensitivity and specificity of salivary biomarkerdetection and to increase the availability of routine detectionmethods [7 8]

2 Saliva as a Source of Markers forPeriodontal Diseases

21 Enzymatic Activity in Saliva

211 Aspartate Aminotransferase (AST) One of the longeststudied markers of inflammation is aspartate aminotrans-ferase It belongs among transaminases which have beeninvestigated for many years in clinical biochemistry Theenzyme catalyzes the transamination of glutamic acid tooxaloacetic and aspartic acids During inflammation ASTtissue level rises it gets into the blood plasma and alsoby diffusion through salivary glands into saliva Duringperiodontal inflammation it also passes into sulcular fluidand then into saliva AST levels are significantly and posi-tively correlated with the intensity and extent of periodontalinflammation [9]

Periodontal disease progression as defined by pocketdepth gingival bleeding and suppuration is linked withincreased levels of salivary aspartate aminotransferase [10]Periodontal scaling treatment causes a marked decrease inaspartate aminotransferase levels [11]

In periodontology chairside detection kits are alreadyavailable known under the names PerioGard Hawe Peri-monitor or Pocketwatch For the detection of AST in plasmaor saliva Reflotron multifunction system is now available

212 Proteinases Neutrophils and other phagocytic cells re-lease specific proteinases dipeptidyl peptidases and amino-peptidases Their levels in saliva correlate with the intensityand extent of inflammation in periodontal tissues [12 13]

213 Lactoferrin In addition to the increased levels of pro-teinases the level of lactoferrin in saliva during periodontalinflammation also increases It is known that during peri-odontitis lactoferrin saturationwith iron decreases thereforelactoferrin degrades into products that can damage tissue[14 15]

214 Metalloproteinases Many scientific articles focus onmetalloproteinases and their relationship to periodontalinflammation because collagen diseases may induce peri-odontal inflammation Today more than twenty metallopro-teinases isoenzymes and their tissue inhibitor systems areknown In patients with periodontitis it has been proven thatincreasing metalloproteinases simultaneously decreases theirtissue inhibitors in saliva [16]

Matrix metalloproteinases 8 and 9 are the major matrixmetalloproteinases in saliva in smaller amounts saliva alsocontains matrix metalloproteinases 1 2 3 7 12 13 14 25 and26 and tissue inhibitors of matrix metalloproteinases 1 and 2[17]

Increased bleeding upon probing clinical attachmentlevel and pocket depth have repeatedly demonstrated sig-nificant positive correlations with elevated levels of salivarymatrix metalloproteinase 8 [18 19]

After periodontal scaling and root planning significantreductions in salivary matrix metalloproteinase 8 levels havebeen found suggesting matrix metalloproteinase 8 potentialmarker for monitoring periodontal disease activity [20]

Matrix metalloproteinase 9 mediates many functions ofthe periodontal disease process including tissue destructionand immune responses Elevated salivary levels of matrixmetalloproteinase 9 were found in clinically diseased con-ditions and reduced salivary levels were found in clinicallystable conditions [21] Higher levels of matrix metallopro-teinase 9 have been detected in the saliva of subjects withperiodontitis than in the saliva of controls [22] and afterperiodontal therapy the amount of matrix metalloproteinase9 decreases [23]

Matrix metalloproteinase 9 appears to be associated withcardiovascular disease cancer multiple sclerosis and neu-ropsychiatric disorders such as schizophrenia and bipolarmood disorder [21]

Reviews on matrix metalloproteinases especially MMP-8 in saliva and other oral cavity fluids for monitoringperiodontal diseases have been recently published in Peri-odontology 2000 journal [24]

215 Chitinase and Hexosaminidase Chitinase and hexo-saminidase are antibacterial active enzymes derived fromphagocytic cells Their activity in saliva replicates that ofperiodontal inflammation [25]

22 Nitric Oxide Radical (NO) Nitric oxide radical is impor-tant for the proper function of neutrophils andmacrophagesIts production is controlled by reciprocal countercurrentinteraction of NO synthase and arginase with the participa-tion of neopterin In patients with periodontitis the arginase

Disease Markers 3

level in saliva decreases It is assumed that this can be aconsequence of a decrease in phagocytic activity [26]

23 Other Markers in Periodontal Diseases Upregulatedexpression of a variety of B-cell lymphoma-2-related tran-scripts in neutrophils from oral rinse samples of patientswith chronic periodontitis compared with healthy controlshas been demonstrated using the Illumina Human 12WGExpression BeadChip (Illumina San Diego CA USA) [27]

Korte and Kinney [28] have recently published an updat-ed review of salivary biomarkers for periodontal diseases

3 Specific and Nonspecific ProteinsPresent in Saliva

In saliva the numbers of proteins which also reflect thestate of inflammation in the periodontium and occasionallyeven the state of inflammation in distant organs systems aredetectable

The number of salivary biomarkers is increasing rapidlyand many of these markers appear to be unique to salivaFrom a list of 1939 salivary proteins that has been recentlypublished [29 30] around two-thirds have not been found inblood This may lead to the discovery of protein ldquosignaturesrdquoindicative of oral and systemic diseases [31ndash33]

31 C-Reactive Protein (CRP) C-reactive protein is a longknown indicator of inflammatory or rheumatic activity CRPlevels in plasma and saliva correlate During periodontitissalivary CRP levels increase and its decrease indicates asuccessful anti-inflammatory treatment

High CRP levels in saliva during diffuse periodontitis areamarker of local process risk for the formation or progressionof cardiovascular disease with risk coefficient OR 56 [34ndash36]

CRP levels increase subsequently with the severity of theperiodontal disease [37]

32 Fibronectin During periodontitis a decreased level offibronectin in saliva is evident Fibronectin blocks adhesins ofmany periodontal microorganisms reducing their adherenceto periodontal tissues [38]

33 Cystatins The levels of cystatins natural inhibitors ofphagocytic proteases decrease in sulcular fluid and salivaduring periodontitis ultimately leading to tissue damage bycathepsins [39]

34 Neopterin Neopterin is a cytokine produced by ma-crophages that participates in the formation of nitric oxideradical which is important for phagocytosis Its level in salivaincreases during periodontal inflammation [26]

35 Cytokines and Other Protein Markers Further proteinmarkers of inflammation whose levels correlate with theintensity of periodontal inflammation are detectable in salivaExamples of these include platelet-activating factor vascular

endothelial growth factor and hepatocyte growth factor [40ndash42]

Salivary interleukin-1 beta is elevated in periodontaldiseases and its levels are strongly correlatedwith periodontaldisease progression and considered to be a good biomarkerfor discriminating between active and inactive periodontalsites Salivary interleukin-1 beta has also been associated withadvanced periodontitis [43]

According to recent review interleukin-1 beta and hepa-tocyte growth factor are the most robust salivary biomarkersfor periodontal disease [44]

Increased salivary levels of interleukin-6 are presentin individuals with periodontitis compared with healthysubjects [45] Salivary interleukin-6 has also been shown tostimulate osteoclast differentiation and bone resorption andis associated with tissue destruction in peri-implant disease[46]

Salivary levels of tumor necrosis factor-alpha indicatethe presence of generalized chronic periodontitis and havealso demonstrated significant changes after nonsurgical peri-odontal therapy [20]

A great deal of work has been dedicated to catalogingthe salivary proteome and annotating identified saliva pro-teins [47] This large database is known as the SalivaProteome Knowledge Base and is available to the public(httpwwwskbuclaedu) This central database is crucialin the identification of combinations of biomarker panelsthat may provide distinct diagnostic information and thusserves as a valuable resource for identifying deviations withinproteins or peptides that align with oral and systemic diseaseand will aid in the development of saliva-based diagnostictests [48]

4 Oxidative Stress

One of the important molecular pathological processesaccompanying inflammation or tumor cell proliferation isthe so-called oxidative stress In the pathologically alteredtissue a number of substances with the character of reactiveoxygen species release and their compensation by the presentantioxidants are sustained The equilibrium is disturbedeither by increased production of reactive oxygen species bythe lack of antioxidants or by both mechanisms This resultsin damage to the cellular DNA certain signal proteins andtissue components inactivation of enzymes and stimulationof proinflammatory cytokines and lipid peroxidation It hasbeen proven that oxidative stress significantly succeeded inthe destruction of periodontal tissues [49]

One of the markers of oxidative stress is 8-hydroxy-21015840-deoxyguanosine (8-OHdG)which is formed by the oxidationof guanine from damaged DNA Deoxyguanosine levelsincrease in saliva during periodontitis and decrease withsuccessful anti-inflammatory treatment [50]

During chronic inflammation not only reactive oxygenspecies increase in affected tissues but also a decrease inantioxidants can be demonstrated This is true even forperiodontal tissues [51] This relationship is supported byresults from the study by Takane et al (2005) which showedsignificant differences between the levels of 8-OHdG in saliva

4 Disease Markers

in patients with aggressive and advanced periodontitis and inindividuals with clinically healthy periodontal tissues [52]

Ascorbate and albumin belong to the main tissue antiox-idants together with melatonin Melatonin has nonspecificanti-inflammatory and osteogenic effects which affects Tlymphocytes and its level in saliva positively correlates withthe intensity and extent of periodontal inflammation [53]

Reduced production of interleukin-2 known in patientswith type 1 diabetes together with a reduced level of mela-tonin may be one of the molecular pathological risks for theprogression of periodontal disease in diabetic patients [54]

Reactive oxygen species also play a role in anothermolecular pathological process known as lipid peroxidationReactive oxygen species attack the unsaturated fatty acidsof phospholipid and phosphoprotein membranes therebydisrupting their integrity The end products of lipid peroxi-dation are malondialdehyde and hydroxyalkenals If the lipidperoxidation is in equilibrium with tissue glutathione and itsperoxidase damage to the membranes does not occur Dur-ing periodontitis elevated levels of the end products of lipidperoxidation and decreased levels of natural antioxidants arefound in saliva indicating failure of equilibriumwith the riskof tissue destruction [55]

Reactive oxygen species are implicated in the patho-genesis of many diseases and have been suggested to playa role in the pathogenesis of various oral diseases Forexample the salivary levels of antioxidant enzymes includingsuperoxide dismutase catalase and glutathione peroxidasewere significantly higher in patients with recurrent aphthousstomatitis than in healthy controls [56]

5 Saliva as a Source of Biomarkers forOther Fields of Medicine

Studies investigating the use of saliva as a diagnostic fluidhave a long history This noninvasive approach is not limitedonly to the diagnosis of oral diseases because many systemicdiseases such as different types of cancers cardiovascular dis-eases immunologic syndromes and hereditary deficienciescan also be studied with the aid of salivary diagnostics [57]Even gynecology and psychiatry are interested in salivarybiomarkers monitoring

Reviews on salivary markers in dental caries [58] andoral mucosal diseases [59] have been recently published inPeriodontology 2000 journal

51 Diabetes Mellitus Nonenzymatic glycation of a numberof substances occurs during elevated or fluctuating bloodglucose levels The glycated hemoglobin level in blood haslong been used as amarker ofmetabolically poorly controlleddiabetes More recently it was shown that even in saliva someglycated proteins and fats can be detected and their levelscorrelate with the glycated hemoglobin level in plasma [60]

According to somepublished studies it appears that levelsof sorbitol and fructosamine in saliva correlate with levels ofglucose in capillary blood [61]

Increased plasma glycohemoglobin is also accompaniedby elevated levels of epidermal growth factor nitric oxide andtotal antioxidant activity of saliva [62]

In patients with type 1 diabetes increased levels of ureaand 120572-amylase have been shown in saliva According to thestudy of Lopez et al (2003) the increase of these markers insaliva precedes the clinical signs of diabetes These markersmay be used in the future for screening incipient diabetes[63]

52 Cardiovascular Diseases Wolfram et al (2005) demon-strated increased levels of isoprostane and oxidized low-density lipoproteins in saliva of individuals with coronaryheart disease [64]

Increased attention turns also to endothelin in salivaEndothelin is a peptide that plays a critical role in cardio-vascular regulation Endothelin receptors mediate vasocon-striction as a response to endothelin-1 the primary isoformof this peptide in the cardiovascular system It is assumed thatendothelin A receptors induce the proliferation of vascularsmooth muscle and myocardial hypertrophy whereas theactivations of endothelin B receptors lead to vasodilationvia nitric oxide or prostacyclin and have antithrombotic andantiproliferative effects Pulmonary receptors of endothelinB in addition help to scavenge endothelin-1 Endothelin-1stimulates the production of other neurohumoral factors andpromotes the activity of other neuroendocrine cascades Inpeople with coronary heart disease or chronic obstructivepulmonary disease elevated levels of endothelin and itsinhibitor are found in saliva [65]

In terms of cardiovascular biomarker research the feasi-bility and utility of a programmable bionanochip to identifybiomarkers of acute myocardial infarction in saliva wereinvestigated Interestingly this nanotechnology was able toidentify saliva-based biomarker panels that had significantdiagnostic capability when used in conjunction with anelectrocardiogram and far exceeded the screening capacity ofan electrocardiogram alone [66]

53 Oncological Screening In oncological screening thedetection of soluble factor CD44 or telomerase is beingconsidered as their levels in saliva increase with squamouscell carcinoma of the head and neck [67 68] High attentionis still paid to the possibilities of detecting markers foroncological diseases of the oral cavity [69 70]

In proteomics research of plasma and saliva proteincomposition it was found that in patients with breast orovarian cancer the fractions with molecular weight of 117228 and 287 kDa significantly increased in plasma and salivaIt seems that the biomarker of these malignancies could beprotein provisionally named as HER2neu [71]

CA 125 antigen is present in the plasma of ovarian cancerpatients and its detection is used as a marker for recurrenceafter oncologic treatment This marker is also detectable insaliva and a possible use of CA 125 determination in saliva isconsidered in the screening of this cancer [72]

Using Affymetrix HG-U133-Plus-20 array (AffymetrixSanta Clara CA USA) four salivary mRNA biomarkers(v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologmethyl-CpG binding domain protein 3-like 2 acrosomalvesicle protein 1 and dolichylphosphate mannosyltransferasepolypeptide 1) that can differentiate patients with early-stage

Disease Markers 5

resectable pancreatic cancer from noncancer subjects wereidentified [73] This is a breakthrough proof-of-conceptinvestigation for noninvasive detection of a systemic cancer

Gene panels of 4 to 10 genes for oral squamous cellcarcinoma were constructed based on significant differencesin DNA-methylation patterns between the preoperative andpostoperative saliva of patients with oral squamous cellcarcinoma and between preoperative saliva from patientswith oral squamous cell carcinoma and saliva from healthycontrols [74]

Three salivary metabolites (phenylalanine valine andlactic acid) could distinguish patients with oral squamous cellcarcinoma from healthy controls and could also distinguishpatients with oral leukoplakia from healthy controls [75]

A combination of three microbiotas (Capnocytophagagingivalis Prevotella melaninogenica and Streptococcus mitis)in saliva could be used as diagnostic biomarkers of patientswith oral squamous cell carcinoma [76]

Three proteins (zinc-a-2-glycoprotein haptoglobin andhuman calprotectin) that had good discriminatory powerin lung cancer patients and healthy control subjects werereported by Xiao et al [77]

54 Gynecology Increased levels of estriol in saliva predictthe risk of premature birth There is a range of detection setsfor self-diagnostics of premature birth risk on sale in theUSAAn example is the Salivary Estriol Immunoassay Kit fromSalimetrics LLC

Dynamics of estradiol levels in saliva is used in assistedreproduction to accurately determine the ovulation [78 79]

55 Endocrinology Salivary cortisol has long been usedin endocrinological examination methods as a biomarkerfor determining hypothalamus-pituitary-adrenal axis activity[80]

Another salivary marker used by endocrinologists issalivary 120572-amylase (sAA) that helps determine sympathetic-adrenal medulla axis activity The amount of salivary 120572-amylase significantly increases with adrenergic activationespecially with stress [81]

When hyperandrogenemia occurs for example in poly-cystic ovary syndrome increased levels of dehydroepiandros-terone sulfate (DHEA-S) and androstenedione can bedetected in saliva [82]

56 Psychiatry Research in psychiatry also has its markersthat can be measured in saliva It is for example the ratioof cortisol and dehydroepiandrosterone which increases indepressive conditions and varies with changes in affectivityThe good predictive value of this assay is used for theindividual dosing of antidepressants in adolescents [83]

It has been found that 3-methoxy-4-hydroxyphenylglycol(one of the noradrenalinemetabolites) level in saliva decreas-es in depression or in reduced mental activity Nowadays itsdetermination is used for research purposes only [84]

Two salivary metabolites (arginine and tyrosine) differedsignificantly between patients with dementia and healthysubjects [85]

57 Drug Addiction During drug addiction control thesaliva along with urine becomes an important material fordetecting amphetamine opiates phencyclidine marijuanaand cocaine and their metabolites There are already a num-ber of special detection kits ToxCup (Clia Laboratories)Saliva MultiDrug Screen test kit (Medimpex Inc) iScreen(BioCheck) QuickScreen (CraigMedical Inc) and so forth

58 Virus Diseases Saliva HIV tests have demonstratedcomparable accuracy to the traditional blood test Oral HIVtests can be a powerful tool for high-risk populations [86]

For HIV viral-load analysis a frequently used commer-cial assay is the COBASAmplicorHIV-1Monitor Test (RocheDiagnostics Indianapolis USA) and an example of a com-mercial assay based on signal amplification is the VERSANTHIV-1 RNA Assay (Siemens AG Munich Germany) [87]

Hepatitis C virus RNA can be consistently detectedin saliva from hepatitis C virus-infected individuals usingquantitative PCR [88]

Dengue virus specific IgA in salivawas detected soon afterinfection in dengue-endemic regions [89]

For the detection of human antibodies against measlesandmumps in oral fluid several simple platforms for antibodydetection in saliva have been published [90]

Currently only two oral-based commercial tests forinfectious disease are FDA approved for use in the USA theOraQuick oral HIV test and the OraRisk human papillo-mavirus salivary diagnostic test [87]

6 Conclusion

The determination of biomarkers in saliva is becoming animportant part of laboratory diagnostics and the prediction ofperiodontal and other diseases Biomarkers in salivamay alsoserve to determine the context of periodontal disease with analtered state of the body or with chronic diseases Saliva alsocontains a series of markers which may predict the risk ofsome systemic disease development

It is certain that a lotmore research efforts are necessary todetermine the sensitivity and specificity of salivary biomarkerdetection and to increase the availability of routine detectionmethods

The UK Biobank holds the worldrsquos largest bank of around85000 well-characterized saliva samples each accompaniedby blood and urine samples the results of a battery ofphysiological tests a full medical history and a detaileddescription of the subjectrsquos lifestyle [91] The evaluationof these samples can be compared with clinical status ofproject participants in future and may bring a lot of recentlyunavailable pieces of information about salivary biomarkers

Competing Interests

The authors declare that they have no competing interests

Acknowledgments

The study was supported by PRVOUK-P28LF16 (CharlesUniversity of Prague Czech Republic) by Project 14-37368G

6 Disease Markers

(Grant Agency Czech Republic) by Project NT 14164-3(Ministry of Health Czech Republic) and by Project 15-28142A (Czech Health Research Council Czech Republic)

References

[1] G B Proctor ldquoThe physiology of salivary secretionrdquo Periodon-tology 2000 vol 70 no 1 pp 11ndash25 2016

[2] J A Loo W Yan P Ramachandran and D TWong ldquoCompar-ative human salivary and plasma proteomesrdquo Journal of DentalResearch vol 89 no 10 pp 1016ndash1023 2010

[3] L A S Nunes S Mussavira and O S Bindhu ldquoClinical anddiagnostic utility of saliva as a non-invasive diagnostic fluid asystematic reviewrdquo BiochemiaMedica vol 25 no 2 pp 177ndash1922015

[4] S P Barros RWilliams S Offenbacher and TMorelli ldquoGingi-val crevicular fluid as a source of biomarkers for periodontitisrdquoPeriodontology 2000 vol 70 no 1 pp 53ndash64 2016

[5] R R Wassall and P M Preshaw ldquoClinical and technicalconsiderations in the analysis of gingival crevicular fluidrdquoPeriodontology 2000 vol 70 no 1 pp 65ndash79 2016

[6] Y Zhang J Sun C-C Lin E Abemayor M B Wang and DT W Wong ldquoThe emerging landscape of salivary diagnosticsrdquoPeriodontology 2000 vol 70 no 1 pp 38ndash52 2016

[7] A Segal and D T Wong ldquoSalivary diagnostics enhancing dis-ease detection and making medicine betterrdquo European Journalof Dental Education vol 12 no 1 pp 22ndash29 2008

[8] JMYoshizawaCA Schafer J J Schafer J J Farrell B J Pasterand D TWWong ldquoSalivary biomarkers toward future clinicaland diagnostic utilitiesrdquo Clinical Microbiology Reviews vol 26no 4 pp 781ndash791 2013

[9] D A Chambers P B Imrey R L Cohen J M Crawford M EAlves and T A McSwiggin ldquoA longitudinal study of aspartateaminotransferase in human gingival crevicular fluidrdquo Journal ofPeriodontal Research vol 26 no 2 pp 65ndash74 1991

[10] A Totan M Greabu C Totan and T Spinu ldquoSalivary aspartateaminotransferase alanine aminotransferase and alkaline phos-phatase possible markers in periodontal diseasesrdquo ClinicalChemistry and Laboratory Medicine vol 44 no 5 pp 612ndash6152006

[11] Y Nomura Y Shimada N Hanada et al ldquoSalivary biomark-ers for predicting the progression of chronic periodontitisrdquoArchives of Oral Biology vol 57 no 4 pp 413ndash420 2012

[12] I B Lamster E Kaufman J T Grbic L J Winston and RE Singer ldquo120573-glucuronidase activity in saliva relationship toclinical periodontal parametersrdquo Journal of Periodontology vol74 no 3 pp 353ndash359 2003

[13] S Elgun N Ozmeric and S Demirtas ldquoAlanine aminopepti-dase and dipeptidylpeptidase IV in Saliva the possible role inperiodontal diseaserdquo Clinica Chimica Acta vol 298 no 1-2 pp187ndash191 2000

[14] K Suomalainen L Saxen P Vilja and J Tenovuo ldquoPeroxidaseslactoferrin and lysozyme in peripheral blood neutrophils gin-gival crevicular fluid and whole saliva of patients with localizedjuvenile periodontitisrdquo Oral Diseases vol 2 no 2 pp 129ndash1341996

[15] B E Britigan and B L Edeker ldquoPseudomonas and neutrophilproductsmodify transferrin and lactoferrin to create conditionsthat favor hydroxyl radical formationrdquo The Journal of ClinicalInvestigation vol 88 no 4 pp 1092ndash1102 1991

[16] T Ingman T Tervahartiala Y Ding et al ldquoMatrix metallo-proteinases and their inhibitors in gingival crevicular fluid andsaliva of periodontitis patientsrdquo Journal of Clinical Periodontol-ogy vol 23 no 12 pp 1127ndash1132 1996

[17] T Sorsa L Tjaderhane Y T Konttinen et al ldquoMatrix met-alloproteinases contribution to pathogenesis diagnosis andtreatment of periodontal inflammationrdquo Annals of Medicinevol 38 no 5 pp 306ndash321 2006

[18] J L Ebersole J L Schuster J Stevens et al ldquoPatterns ofsalivary analytes provide diagnostic capacity for distinguishingchronic adult periodontitis from healthrdquo Journal of ClinicalImmunology vol 33 no 1 pp 271ndash279 2013

[19] N Rathnayake S Akerman B Klinge et al ldquoSalivary biomark-ers of oral healthmdasha cross-sectional studyrdquo Journal of ClinicalPeriodontology vol 40 no 2 pp 140ndash147 2013

[20] W M Sexton Y Lin R J Kryscio D R Dawson III J LEbersole and C S Miller ldquoSalivary biomarkers of periodontaldisease in response to treatmentrdquo Journal of Clinical Periodon-tology vol 38 no 5 pp 434ndash441 2011

[21] J S Kinney T Morelli T Braun et al ldquoSalivapathogenbiomarker signatures and periodontal disease progressionrdquoJournal of Dental Research vol 90 no 6 pp 752ndash758 2011

[22] U K Gursoy E Kononen S Huumonen et al ldquoSalivary type Icollagen degradation end-products and related matrix metallo-proteinases in periodontitisrdquo Journal of Clinical Periodontologyvol 40 no 1 pp 18ndash25 2013

[23] C A Meschiari A M Marcaccini B C Santos Moura L RZuardi J E Tanus-Santos and R F Gerlach ldquoSalivary MMPsTIMPs and MPO levels in periodontal disease patients andcontrolsrdquo Clinica Chimica Acta vol 421 pp 140ndash146 2013

[24] T SorsaU KGursoy SNwhator et al ldquoAnalysis ofmatrixmet-alloproteinases especially MMP-8 in gingival crevicular fluidmouthrinse and saliva for monitoring periodontal diseasesrdquoPeriodontology 2000 vol 70 no 1 pp 142ndash163 2016

[25] G J Van Steijn A V Nieuw Amerongen E C I Veerman SKasanmoentalib and B Overdijk ldquoEffect of periodontal treat-ment on the activity of chitinase in whole saliva of periodontitispatientsrdquo Journal of Periodontal Research vol 37 no 4 pp 245ndash249 2002

[26] N Ozmeric T Baydar A Bodur et al ldquoLevel of neopterin amarker of immune cell activation in gingival crevicular fluidsaliva and urine in patients with aggressive periodontitisrdquoJournal of Periodontology vol 73 no 7 pp 720ndash725 2002

[27] F S Lakschevitz G M Aboodi and M Glogauer ldquoOralneutrophil transcriptome changes result in a pro-survival phe-notype in periodontal diseasesrdquo PLoS ONE vol 8 no 7 ArticleID e68983 2013

[28] D L Korte and J Kinney ldquoPersonalized medicine an updateof salivary biomarkers for periodontal diseasesrdquo Periodontology2000 vol 70 no 1 pp 26ndash37 2016

[29] M Desvarieux R T Demmer T Rundek et al ldquoRelationshipbetween periodontal disease tooth loss and carotid arteryplaque the oral infections and vascular disease epidemiologystudy (INVEST)rdquo Stroke vol 34 no 9 pp 2120ndash2125 2003

[30] N J Park Y Li T Yu B M N Brinkman and D T WongldquoCharacterization of RNA in salivardquo Clinical Chemistry vol 52no 6 pp 988ndash994 2006

[31] Z Chen M G Mauk J Wang et al ldquoA microfluidic system forsaliva-based detection of infectious diseasesrdquoAnnals of the NewYork Academy of Sciences vol 1098 pp 429ndash436 2007

Disease Markers 7

[32] W R Abrams C A Barber K McCann et al ldquoDevelopment ofa microfluidic device for detection of pathogens in oral samplesusing upconverting phosphor technology (UPT)rdquo Annals of theNew York Academy of Sciences vol 1098 pp 375ndash388 2007

[33] P L AM Corstjens Z ChenM Zuiderwijk et al ldquoRapid assayformat formultiplex detection of humoral immune responses toinfectious disease pathogens (HIVHCV andTB)rdquoAnnals of theNew York Academy of Sciences vol 1098 pp 437ndash445 2007

[34] F DrsquoAiuto M Parkar G Andreou et al ldquoPeriodontitis and sys-temic inflammation control of the local infection is associatedwith a reduction in serum inflammatory markersrdquo Journal ofDental Research vol 83 no 2 pp 156ndash160 2004

[35] I Ouellet-Morin A Danese B Williams and L ArseneaultldquoValidation of a high-sensitivity assay for C-reactive protein inhuman salivardquo Brain Behavior and Immunity vol 25 no 4 pp640ndash646 2011

[36] E Megson T Fitzsimmons K Dharmapatni and P MarkBartold ldquoC-reactive protein in gingival crevicular fluid maybe indicative of systemic inflammationrdquo Journal of ClinicalPeriodontology vol 37 no 9 pp 797ndash804 2010

[37] S Podzimek J Mysak T Janatova and J Duskova ldquoC-reactive protein in peripheral blood of patients with chronicand aggressive periodontitis gingivitis and gingival recessionsrdquoMediators of Inflammation vol 2015 Article ID 564858 7 pages2015

[38] Y Murakami S Hanazawa S Tanaka H Iwahashi S Kitanoand S Fujisawa ldquoFibronectin in saliva inhibits Porphy-romonas gingivalis fimbria-induced expression of inflamma-tory cytokine gene in mouse macrophagesrdquo FEMS Immunologyand Medical Microbiology vol 22 no 3 pp 257ndash262 1998

[39] M A Lie B G Loos YM C Henskens et al ldquoSalivary cystatinactivity and cystatin C in natural and experimental gingivitis insmokers and non-smokersrdquo Journal of Clinical Periodontologyvol 28 no 10 pp 979ndash984 2001

[40] M S Rasch B LMealey T J PrihodaD SWoodard and LMMcManus ldquoThe effect of initial periodontal therapy on salivaryplatelet-activating factor levels in chronic adult periodontitisrdquoJournal of Periodontology vol 66 no 7 pp 613ndash623 1995

[41] V Booth S Young A Cruchley N S Taichman and E Pale-olog ldquoVascular endothelial growth factor in human periodontaldiseaserdquo Journal of Periodontal Research vol 33 no 8 pp 491ndash499 1998

[42] M Ohshima K Fujikawa H Akutagawa T Kato K Ito and KOtsuka ldquoHepatocyte growth factor in saliva a possible markerfor periodontal disease statusrdquo Journal of oral science vol 44no 1 pp 35ndash39 2002

[43] U K Gursoy E Kononen P J Pussinen et al ldquoUse of host- andbacteria-derived salivary markers in detection of periodontitisa cumulative approachrdquoDiseaseMarkers vol 30 no 6 pp 299ndash305 2011

[44] K M Jaedicke P M Preshaw and J J Taylor ldquoSalivarycytokines as biomarkers of periodontal diseasesrdquo Periodontol-ogy 2000 vol 70 no 1 pp 164ndash183 2016

[45] P P Costa G L Trevisan G O Macedo et al ldquoSalivaryinterleukin-6 matrix metalloproteinase-8 and osteoprotegerinin patients with periodontitis and diabetesrdquo Journal of Periodon-tology vol 81 no 3 pp 384ndash391 2010

[46] S Liskmann T Vihalemm O Salum K Zilmer K Fischerand M Zilmer ldquoCorrelations between clinical parameters andinterleukin-6 and interleukin-10 levels in saliva from totally

edentulous patients with peri-implant diseaserdquo The Interna-tional Journal of Oral and Maxillofacial Implants vol 21 no 4pp 543ndash550 2006

[47] N Spielmann andDWong ldquoSaliva diagnostics and therapeuticperspectivesrdquo Oral Diseases vol 17 no 4 pp 345ndash354 2011

[48] P Denny F KHagenMHardt et al ldquoThe proteomes of humanparotid and submandibularsublingual gland salivas collectedas the ductal secretionsrdquo Journal of Proteome Research vol 7no 5 pp 1994ndash2006 2008

[49] D V Sculley and S C Langley-Evans ldquoPeriodontal disease isassociated with lower antioxidant capacity in whole saliva andevidence of increased protein oxidationrdquo Clinical Science vol105 no 2 pp 167ndash172 2003

[50] M Takane N Sugano H Iwasaki Y Iwano N Shimizu andK Ito ldquoNew biomarker evidence of oxidative DNA damage inwhole saliva from clinically healthy and periodontally diseasedindividualsrdquo Journal of Periodontology vol 73 no 5 pp 551ndash554 2002

[51] R Diab-Ladki B Pellat and R Chahine ldquoDecrease in thetotal antioxidant activity of saliva in patients with periodontaldiseasesrdquo Clinical Oral Investigations vol 7 no 2 pp 103ndash1072003

[52] M Takane N Sugano T Ezawa T Uchiyama and K ItoldquoA marker of oxidative stress in saliva association withperiodontally-involved teeth of a hopeless prognosisrdquo Journalof Oral Science vol 47 no 1 pp 53ndash57 2005

[53] D-X Tan L C Manchester R J Reiter W-B Qi M Kar-bownik and J R Calvo ldquoSignificance ofmelatonin in antioxida-tive defense system reactions and productsrdquo Biological Signalsand Receptors vol 9 no 3-4 pp 137ndash159 2000

[54] A Cutando G Gomez-Moreno J Villalba M J Ferrera GEscames and D Acuna-Castroviejo ldquoRelationship betweensalivary melatonin levels and periodontal status in diabeticpatientsrdquo Journal of Pineal Research vol 35 no 4 pp 239ndash2442003

[55] C C Tsai H S Chen S L Chen et al ldquoLipid peroxidationa possible role in the induction and progression of chronicperiodontitisrdquo Journal of Periodontal Research vol 40 no 5 pp378ndash386 2005

[56] Y Karincaoglu K Batcioglu T Erdem M Esrefoglu and MGene ldquoThe levels of plasma and salivary antioxidants in thepatient with recurrent aphthous stomatitisrdquo Journal of OralPathology and Medicine vol 34 no 1 pp 7ndash12 2005

[57] C SMiller J D Foley A L Bailey et al ldquoCurrent developmentsin salivary diagnosticsrdquo Biomarkers inMedicine vol 4 no 1 pp171ndash189 2010

[58] X Gao S Jiang D Koh and C S Hsu ldquoSalivary biomarkersfor dental cariesrdquo Periodontology 2000 vol 70 no 1 pp 128ndash141 2016

[59] Y Hassona and C Scully ldquoSalivary changes in oral mucosaldiseasesrdquo Periodontology 2000 vol 70 no 1 pp 111ndash127 2016

[60] A M Schmidt E Weidman E Lalla et al ldquoAdvanced glycationendproducts (AGEs) induce oxidant stress in the gingiva apotential mechanism underlying accelerated periodontal dis-ease associated with diabetesrdquo Journal of Periodontal Researchvol 31 no 7 pp 508ndash515 1996

[61] S AMorenkova ldquoComparative analysis of dependence of salivasorbitol and fructoseamine levels on blood glucose level inpatients with diabetesrdquo Biomeditsinskaya Khimiya vol 50 no6 pp 612ndash614 2004 (Russian)

8 Disease Markers

[62] F Astaneie M Afshari A Mojtahedi et al ldquoTotal antioxidantcapacity and levels of epidermal growth factor and nitric oxidein blood and saliva of insulin-dependent diabetic patientsrdquoArchives of Medical Research vol 36 no 4 pp 376ndash381 2005

[63] M E Lopez M E Colloca R G Paez J N Schallmach M AKoss andA Chervonagura ldquoSalivary characteristics of diabeticchildrenrdquoBrazilianDental Journal vol 14 no 1 pp 26ndash31 2003

[64] R Wolfram A Oguogho B Palumbo and H SinzingerldquoEnhanced oxidative stress in coronary heart disease andchronic heart failure as indicated by an increased 8-epi-PGF2120572rdquoEuropean Journal of Heart Failure vol 7 no 2 pp 167ndash172 2005

[65] S Xiang R Denver M Bailey and H Krum ldquoPhysiologicdeterminants of endothelin concentrations in human salivardquoClinical Chemistry vol 49 no 12 pp 2012ndash2019 2003

[66] N Christodoulides F N Pierre X Sanchez et al ldquoPro-grammable bio-nanochip technology for the diagnosis of car-diovascular disease at the point-of-carerdquo Methodist DeBakeyCardiovascular Journal vol 8 no 1 pp 6ndash12 2012

[67] E J Franzmann E P Reategui K L Carraway K L HamiltonD T Weed and W J Goodwin ldquoSalivary soluble CD44 apotential molecular marker for head and neck cancerrdquo CancerEpidemiology Biomarkers and Prevention vol 14 no 3 pp 735ndash739 2005

[68] L-P Zhong G-F Chen Z-F Xu X Zhang F-Y Ping and S-F Zhao ldquoDetection of telomerase activity in saliva from oralsquamous cell carcinoma patientsrdquo International Journal of Oraland Maxillofacial Surgery vol 34 no 5 pp 566ndash570 2005

[69] A K Markopoulos E Z Michailidou and G TzimagiorgisldquoSalivary markers for oral cancer detectionrdquo Open DentistryJournal no 4 pp 172ndash178 2010

[70] F D Shah R Begum B N Vajaria et al ldquoA review on salivarygenomics and proteomics biomarkers in oral cancerrdquo IndianJournal of Clinical Biochemistry vol 26 no 4 pp 326ndash334 2011

[71] C F Streckfus L Bigler T Dellinger M Kuhn N Chouinardand X Dai ldquoThe expression of the c-erbB-2 receptor proteinin glandular salivary secretionsrdquo Journal of Oral Pathology andMedicine vol 33 no 10 pp 595ndash600 2004

[72] M Markman ldquoNormal CA-125 and the risk of progression inovarian cancerrdquo Journal of Clinical Oncology vol 24 no 20 p3310 2006

[73] L Zhang J J Farrell H Zhou et al ldquoSalivary transcriptomicbiomarkers for detection of resectable pancreatic cancerrdquo Gas-troenterology vol 138 no 3 pp 949ndash957 2010

[74] C T Viet and B L Schmidt ldquoMethylation array analysisof preoperative and postoperative saliva DNA in oral cancerpatientsrdquo Cancer Epidemiology Biomarkers and Prevention vol17 no 12 pp 3603ndash3611 2008

[75] J Wei G Xie Z Zhou et al ldquoSalivary metabolite signatures oforal cancer and leukoplakiardquo International Journal of Cancervol 129 no 9 pp 2207ndash2217 2011

[76] D L Mager A D Haffajee P M Delvin C M Norris M RPosner and J M Goodson ldquoThe salivary microbiota as a diag-nostic indicator of oral cancer a descriptive non-randomizedstudy of cancer-free and oral squamous cell carcinoma subjectsrdquoJournal of Translational Medicine vol 3 article 27 2005

[77] H Xiao L Zhang H Zhou J M Lee E B Garon and D T WWong ldquoProteomic analysis of human saliva from lung cancerpatients using two-dimensional difference gel electrophoresisand mass spectrometryrdquo Molecular amp Cellular Proteomics vol11 no 2 2012

[78] P S Ramsey and W W Andrews ldquoBiochemical predictors ofpreterm labor fetal fibronectin and salivary estriolrdquo Clinics inPerinatology vol 30 no 4 pp 701ndash733 2003

[79] L D Belkien J Bordt P Moller R Hano and E NieschlagldquoEstradiol in saliva for monitoring follicular stimulation in anin vitro fertilization programrdquo Fertility and Sterility vol 44 no3 pp 322ndash327 1985

[80] K Simunkova R Hampl M Hill J Doucha L Starka and KVondra ldquoSalivary cortisol in low dose (1 microg) ACTH test inhealthy women comparison with serum cortisolrdquo PhysiologicalResearch vol 56 no 4 pp 449ndash453 2007

[81] A van Stegeren N Rohleder W Everaerd and O T WolfldquoSalivary alpha amylase asmarker for adrenergic activity duringstress effect of betablockaderdquo Psychoneuroendocrinology vol31 no 1 pp 137ndash141 2006

[82] R S Rittmaster and D L Thompson ldquoEffect of leuprolide anddexamethasone on hair growth and hormone levels in hirsutewomen the relative importance of the ovary and the adrenal inthe pathogenesis of hirsutismrdquo Journal of Clinical Endocrinologyand Metabolism vol 70 no 4 pp 1096ndash1102 1990

[83] I M Goodyer J Herbert and A Tamplin ldquoPsychoendocrineantecedents of persistent first-episode major depression inadolescents a community-based longitudinal enquiryrdquo Psycho-logical Medicine vol 33 no 4 pp 601ndash610 2003

[84] S Yamada ldquoAssessment of mental condition by saliva level of 3-methoxy-4-hydroxyphenylglycolrdquo Seishin Shinkeigaku Zasshivol 107 no 7 pp 712ndash717 2005 (Japanese)

[85] M Tsuruoka J Hara A Hirayama et al ldquoCapillaryelectrophoresis-mass spectrometry-based metabolomeanalysis of serum and saliva from neurodegenerative dementiapatientsrdquo Electrophoresis vol 34 no 19 pp 2865ndash2872 2013

[86] N Pant Pai B Balram S Shivkumar et al ldquoHead-to-headcomparison of accuracy of a rapid point-of-care HIV test withoral versus whole-blood specimens a systematic review andmeta-analysisrdquoThe Lancet Infectious Diseases vol 12 no 5 pp373ndash380 2012

[87] P L CorstjensW RAbrams andDMalamud ldquoSaliva and viralinfectionsrdquo Periodontology 2000 vol 70 no 1 pp 93ndash110 2016

[88] G B L Menezes F A Pereira C A B Duarte et al ldquoHepatitisC virus quantification in serum and saliva of HCV-infectedpatientsrdquo Memorias do Instituto Oswaldo Cruz vol 107 no 5pp 680ndash683 2012

[89] G Yap B K Sil and L-C Ng ldquoUse of saliva for early denguediagnosisrdquo PLoSNeglected Tropical Diseases vol 5 no 5 ArticleID e1046 2011

[90] P L A M Corstjens and D Malamud ldquoPoint-of-care diagnos-tics for infectious diseasesrdquo in Salivary Diagnostics D T WongEd chapter 13 pp 136ndash149Wiley-Blackwell Ames Iowa USA2008

[91] J W Galloway B J F Keijser and D M Williams ldquoSaliva instudies of epidemiology of human disease the UK Biobankprojectrdquo Periodontology 2000 vol 70 no 1 pp 184ndash195 2016

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

2 Disease Markers

of the consumption of many prescribed medications andis more prevalent in older age groups A high degree ofmedication-induced dryness resulting from salivary hypo-function is associatedwith anticholinergicmuscarinic recep-tor blockers used to treat for example irritable bladdersAntidepressants can also cause salivary hypofunction as aresult of the activation of alpha-2-adrenergic receptors inthe central nervous system The most severe forms of long-lasting irreversible dry mouth are seen in patients withsquamous cell carcinoma given external irradiation of thehead and neck and in patients with Sjogrenrsquos syndrome [1]

In this review we will onlymention some of the biomark-ers of periodontal diseases and some distant diseases in salivato illustrate the direction of this researchThis reviewdoes notfocus on biomarkers in gingival crevicular fluid such reviewhas been recently published in Periodontology 2000 journal[4 5]

Three limitations prevent the full benefits of clinical diag-nostics from being realized definitive biomarkers associatedwith disease simple and inexpensive methods that are min-imally invasive and an accurate portable and easy-to-usediagnostic platform [6]

It is certain that more research effort is necessary todetermine the sensitivity and specificity of salivary biomarkerdetection and to increase the availability of routine detectionmethods [7 8]

2 Saliva as a Source of Markers forPeriodontal Diseases

21 Enzymatic Activity in Saliva

211 Aspartate Aminotransferase (AST) One of the longeststudied markers of inflammation is aspartate aminotrans-ferase It belongs among transaminases which have beeninvestigated for many years in clinical biochemistry Theenzyme catalyzes the transamination of glutamic acid tooxaloacetic and aspartic acids During inflammation ASTtissue level rises it gets into the blood plasma and alsoby diffusion through salivary glands into saliva Duringperiodontal inflammation it also passes into sulcular fluidand then into saliva AST levels are significantly and posi-tively correlated with the intensity and extent of periodontalinflammation [9]

Periodontal disease progression as defined by pocketdepth gingival bleeding and suppuration is linked withincreased levels of salivary aspartate aminotransferase [10]Periodontal scaling treatment causes a marked decrease inaspartate aminotransferase levels [11]

In periodontology chairside detection kits are alreadyavailable known under the names PerioGard Hawe Peri-monitor or Pocketwatch For the detection of AST in plasmaor saliva Reflotron multifunction system is now available

212 Proteinases Neutrophils and other phagocytic cells re-lease specific proteinases dipeptidyl peptidases and amino-peptidases Their levels in saliva correlate with the intensityand extent of inflammation in periodontal tissues [12 13]

213 Lactoferrin In addition to the increased levels of pro-teinases the level of lactoferrin in saliva during periodontalinflammation also increases It is known that during peri-odontitis lactoferrin saturationwith iron decreases thereforelactoferrin degrades into products that can damage tissue[14 15]

214 Metalloproteinases Many scientific articles focus onmetalloproteinases and their relationship to periodontalinflammation because collagen diseases may induce peri-odontal inflammation Today more than twenty metallopro-teinases isoenzymes and their tissue inhibitor systems areknown In patients with periodontitis it has been proven thatincreasing metalloproteinases simultaneously decreases theirtissue inhibitors in saliva [16]

Matrix metalloproteinases 8 and 9 are the major matrixmetalloproteinases in saliva in smaller amounts saliva alsocontains matrix metalloproteinases 1 2 3 7 12 13 14 25 and26 and tissue inhibitors of matrix metalloproteinases 1 and 2[17]

Increased bleeding upon probing clinical attachmentlevel and pocket depth have repeatedly demonstrated sig-nificant positive correlations with elevated levels of salivarymatrix metalloproteinase 8 [18 19]

After periodontal scaling and root planning significantreductions in salivary matrix metalloproteinase 8 levels havebeen found suggesting matrix metalloproteinase 8 potentialmarker for monitoring periodontal disease activity [20]

Matrix metalloproteinase 9 mediates many functions ofthe periodontal disease process including tissue destructionand immune responses Elevated salivary levels of matrixmetalloproteinase 9 were found in clinically diseased con-ditions and reduced salivary levels were found in clinicallystable conditions [21] Higher levels of matrix metallopro-teinase 9 have been detected in the saliva of subjects withperiodontitis than in the saliva of controls [22] and afterperiodontal therapy the amount of matrix metalloproteinase9 decreases [23]

Matrix metalloproteinase 9 appears to be associated withcardiovascular disease cancer multiple sclerosis and neu-ropsychiatric disorders such as schizophrenia and bipolarmood disorder [21]

Reviews on matrix metalloproteinases especially MMP-8 in saliva and other oral cavity fluids for monitoringperiodontal diseases have been recently published in Peri-odontology 2000 journal [24]

215 Chitinase and Hexosaminidase Chitinase and hexo-saminidase are antibacterial active enzymes derived fromphagocytic cells Their activity in saliva replicates that ofperiodontal inflammation [25]

22 Nitric Oxide Radical (NO) Nitric oxide radical is impor-tant for the proper function of neutrophils andmacrophagesIts production is controlled by reciprocal countercurrentinteraction of NO synthase and arginase with the participa-tion of neopterin In patients with periodontitis the arginase

Disease Markers 3

level in saliva decreases It is assumed that this can be aconsequence of a decrease in phagocytic activity [26]

23 Other Markers in Periodontal Diseases Upregulatedexpression of a variety of B-cell lymphoma-2-related tran-scripts in neutrophils from oral rinse samples of patientswith chronic periodontitis compared with healthy controlshas been demonstrated using the Illumina Human 12WGExpression BeadChip (Illumina San Diego CA USA) [27]

Korte and Kinney [28] have recently published an updat-ed review of salivary biomarkers for periodontal diseases

3 Specific and Nonspecific ProteinsPresent in Saliva

In saliva the numbers of proteins which also reflect thestate of inflammation in the periodontium and occasionallyeven the state of inflammation in distant organs systems aredetectable

The number of salivary biomarkers is increasing rapidlyand many of these markers appear to be unique to salivaFrom a list of 1939 salivary proteins that has been recentlypublished [29 30] around two-thirds have not been found inblood This may lead to the discovery of protein ldquosignaturesrdquoindicative of oral and systemic diseases [31ndash33]

31 C-Reactive Protein (CRP) C-reactive protein is a longknown indicator of inflammatory or rheumatic activity CRPlevels in plasma and saliva correlate During periodontitissalivary CRP levels increase and its decrease indicates asuccessful anti-inflammatory treatment

High CRP levels in saliva during diffuse periodontitis areamarker of local process risk for the formation or progressionof cardiovascular disease with risk coefficient OR 56 [34ndash36]

CRP levels increase subsequently with the severity of theperiodontal disease [37]

32 Fibronectin During periodontitis a decreased level offibronectin in saliva is evident Fibronectin blocks adhesins ofmany periodontal microorganisms reducing their adherenceto periodontal tissues [38]

33 Cystatins The levels of cystatins natural inhibitors ofphagocytic proteases decrease in sulcular fluid and salivaduring periodontitis ultimately leading to tissue damage bycathepsins [39]

34 Neopterin Neopterin is a cytokine produced by ma-crophages that participates in the formation of nitric oxideradical which is important for phagocytosis Its level in salivaincreases during periodontal inflammation [26]

35 Cytokines and Other Protein Markers Further proteinmarkers of inflammation whose levels correlate with theintensity of periodontal inflammation are detectable in salivaExamples of these include platelet-activating factor vascular

endothelial growth factor and hepatocyte growth factor [40ndash42]

Salivary interleukin-1 beta is elevated in periodontaldiseases and its levels are strongly correlatedwith periodontaldisease progression and considered to be a good biomarkerfor discriminating between active and inactive periodontalsites Salivary interleukin-1 beta has also been associated withadvanced periodontitis [43]

According to recent review interleukin-1 beta and hepa-tocyte growth factor are the most robust salivary biomarkersfor periodontal disease [44]

Increased salivary levels of interleukin-6 are presentin individuals with periodontitis compared with healthysubjects [45] Salivary interleukin-6 has also been shown tostimulate osteoclast differentiation and bone resorption andis associated with tissue destruction in peri-implant disease[46]

Salivary levels of tumor necrosis factor-alpha indicatethe presence of generalized chronic periodontitis and havealso demonstrated significant changes after nonsurgical peri-odontal therapy [20]

A great deal of work has been dedicated to catalogingthe salivary proteome and annotating identified saliva pro-teins [47] This large database is known as the SalivaProteome Knowledge Base and is available to the public(httpwwwskbuclaedu) This central database is crucialin the identification of combinations of biomarker panelsthat may provide distinct diagnostic information and thusserves as a valuable resource for identifying deviations withinproteins or peptides that align with oral and systemic diseaseand will aid in the development of saliva-based diagnostictests [48]

4 Oxidative Stress

One of the important molecular pathological processesaccompanying inflammation or tumor cell proliferation isthe so-called oxidative stress In the pathologically alteredtissue a number of substances with the character of reactiveoxygen species release and their compensation by the presentantioxidants are sustained The equilibrium is disturbedeither by increased production of reactive oxygen species bythe lack of antioxidants or by both mechanisms This resultsin damage to the cellular DNA certain signal proteins andtissue components inactivation of enzymes and stimulationof proinflammatory cytokines and lipid peroxidation It hasbeen proven that oxidative stress significantly succeeded inthe destruction of periodontal tissues [49]

One of the markers of oxidative stress is 8-hydroxy-21015840-deoxyguanosine (8-OHdG)which is formed by the oxidationof guanine from damaged DNA Deoxyguanosine levelsincrease in saliva during periodontitis and decrease withsuccessful anti-inflammatory treatment [50]

During chronic inflammation not only reactive oxygenspecies increase in affected tissues but also a decrease inantioxidants can be demonstrated This is true even forperiodontal tissues [51] This relationship is supported byresults from the study by Takane et al (2005) which showedsignificant differences between the levels of 8-OHdG in saliva

4 Disease Markers

in patients with aggressive and advanced periodontitis and inindividuals with clinically healthy periodontal tissues [52]

Ascorbate and albumin belong to the main tissue antiox-idants together with melatonin Melatonin has nonspecificanti-inflammatory and osteogenic effects which affects Tlymphocytes and its level in saliva positively correlates withthe intensity and extent of periodontal inflammation [53]

Reduced production of interleukin-2 known in patientswith type 1 diabetes together with a reduced level of mela-tonin may be one of the molecular pathological risks for theprogression of periodontal disease in diabetic patients [54]

Reactive oxygen species also play a role in anothermolecular pathological process known as lipid peroxidationReactive oxygen species attack the unsaturated fatty acidsof phospholipid and phosphoprotein membranes therebydisrupting their integrity The end products of lipid peroxi-dation are malondialdehyde and hydroxyalkenals If the lipidperoxidation is in equilibrium with tissue glutathione and itsperoxidase damage to the membranes does not occur Dur-ing periodontitis elevated levels of the end products of lipidperoxidation and decreased levels of natural antioxidants arefound in saliva indicating failure of equilibriumwith the riskof tissue destruction [55]

Reactive oxygen species are implicated in the patho-genesis of many diseases and have been suggested to playa role in the pathogenesis of various oral diseases Forexample the salivary levels of antioxidant enzymes includingsuperoxide dismutase catalase and glutathione peroxidasewere significantly higher in patients with recurrent aphthousstomatitis than in healthy controls [56]

5 Saliva as a Source of Biomarkers forOther Fields of Medicine

Studies investigating the use of saliva as a diagnostic fluidhave a long history This noninvasive approach is not limitedonly to the diagnosis of oral diseases because many systemicdiseases such as different types of cancers cardiovascular dis-eases immunologic syndromes and hereditary deficienciescan also be studied with the aid of salivary diagnostics [57]Even gynecology and psychiatry are interested in salivarybiomarkers monitoring

Reviews on salivary markers in dental caries [58] andoral mucosal diseases [59] have been recently published inPeriodontology 2000 journal

51 Diabetes Mellitus Nonenzymatic glycation of a numberof substances occurs during elevated or fluctuating bloodglucose levels The glycated hemoglobin level in blood haslong been used as amarker ofmetabolically poorly controlleddiabetes More recently it was shown that even in saliva someglycated proteins and fats can be detected and their levelscorrelate with the glycated hemoglobin level in plasma [60]

According to somepublished studies it appears that levelsof sorbitol and fructosamine in saliva correlate with levels ofglucose in capillary blood [61]

Increased plasma glycohemoglobin is also accompaniedby elevated levels of epidermal growth factor nitric oxide andtotal antioxidant activity of saliva [62]

In patients with type 1 diabetes increased levels of ureaand 120572-amylase have been shown in saliva According to thestudy of Lopez et al (2003) the increase of these markers insaliva precedes the clinical signs of diabetes These markersmay be used in the future for screening incipient diabetes[63]

52 Cardiovascular Diseases Wolfram et al (2005) demon-strated increased levels of isoprostane and oxidized low-density lipoproteins in saliva of individuals with coronaryheart disease [64]

Increased attention turns also to endothelin in salivaEndothelin is a peptide that plays a critical role in cardio-vascular regulation Endothelin receptors mediate vasocon-striction as a response to endothelin-1 the primary isoformof this peptide in the cardiovascular system It is assumed thatendothelin A receptors induce the proliferation of vascularsmooth muscle and myocardial hypertrophy whereas theactivations of endothelin B receptors lead to vasodilationvia nitric oxide or prostacyclin and have antithrombotic andantiproliferative effects Pulmonary receptors of endothelinB in addition help to scavenge endothelin-1 Endothelin-1stimulates the production of other neurohumoral factors andpromotes the activity of other neuroendocrine cascades Inpeople with coronary heart disease or chronic obstructivepulmonary disease elevated levels of endothelin and itsinhibitor are found in saliva [65]

In terms of cardiovascular biomarker research the feasi-bility and utility of a programmable bionanochip to identifybiomarkers of acute myocardial infarction in saliva wereinvestigated Interestingly this nanotechnology was able toidentify saliva-based biomarker panels that had significantdiagnostic capability when used in conjunction with anelectrocardiogram and far exceeded the screening capacity ofan electrocardiogram alone [66]

53 Oncological Screening In oncological screening thedetection of soluble factor CD44 or telomerase is beingconsidered as their levels in saliva increase with squamouscell carcinoma of the head and neck [67 68] High attentionis still paid to the possibilities of detecting markers foroncological diseases of the oral cavity [69 70]

In proteomics research of plasma and saliva proteincomposition it was found that in patients with breast orovarian cancer the fractions with molecular weight of 117228 and 287 kDa significantly increased in plasma and salivaIt seems that the biomarker of these malignancies could beprotein provisionally named as HER2neu [71]

CA 125 antigen is present in the plasma of ovarian cancerpatients and its detection is used as a marker for recurrenceafter oncologic treatment This marker is also detectable insaliva and a possible use of CA 125 determination in saliva isconsidered in the screening of this cancer [72]

Using Affymetrix HG-U133-Plus-20 array (AffymetrixSanta Clara CA USA) four salivary mRNA biomarkers(v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologmethyl-CpG binding domain protein 3-like 2 acrosomalvesicle protein 1 and dolichylphosphate mannosyltransferasepolypeptide 1) that can differentiate patients with early-stage

Disease Markers 5

resectable pancreatic cancer from noncancer subjects wereidentified [73] This is a breakthrough proof-of-conceptinvestigation for noninvasive detection of a systemic cancer

Gene panels of 4 to 10 genes for oral squamous cellcarcinoma were constructed based on significant differencesin DNA-methylation patterns between the preoperative andpostoperative saliva of patients with oral squamous cellcarcinoma and between preoperative saliva from patientswith oral squamous cell carcinoma and saliva from healthycontrols [74]

Three salivary metabolites (phenylalanine valine andlactic acid) could distinguish patients with oral squamous cellcarcinoma from healthy controls and could also distinguishpatients with oral leukoplakia from healthy controls [75]

A combination of three microbiotas (Capnocytophagagingivalis Prevotella melaninogenica and Streptococcus mitis)in saliva could be used as diagnostic biomarkers of patientswith oral squamous cell carcinoma [76]

Three proteins (zinc-a-2-glycoprotein haptoglobin andhuman calprotectin) that had good discriminatory powerin lung cancer patients and healthy control subjects werereported by Xiao et al [77]

54 Gynecology Increased levels of estriol in saliva predictthe risk of premature birth There is a range of detection setsfor self-diagnostics of premature birth risk on sale in theUSAAn example is the Salivary Estriol Immunoassay Kit fromSalimetrics LLC

Dynamics of estradiol levels in saliva is used in assistedreproduction to accurately determine the ovulation [78 79]

55 Endocrinology Salivary cortisol has long been usedin endocrinological examination methods as a biomarkerfor determining hypothalamus-pituitary-adrenal axis activity[80]

Another salivary marker used by endocrinologists issalivary 120572-amylase (sAA) that helps determine sympathetic-adrenal medulla axis activity The amount of salivary 120572-amylase significantly increases with adrenergic activationespecially with stress [81]

When hyperandrogenemia occurs for example in poly-cystic ovary syndrome increased levels of dehydroepiandros-terone sulfate (DHEA-S) and androstenedione can bedetected in saliva [82]

56 Psychiatry Research in psychiatry also has its markersthat can be measured in saliva It is for example the ratioof cortisol and dehydroepiandrosterone which increases indepressive conditions and varies with changes in affectivityThe good predictive value of this assay is used for theindividual dosing of antidepressants in adolescents [83]

It has been found that 3-methoxy-4-hydroxyphenylglycol(one of the noradrenalinemetabolites) level in saliva decreas-es in depression or in reduced mental activity Nowadays itsdetermination is used for research purposes only [84]

Two salivary metabolites (arginine and tyrosine) differedsignificantly between patients with dementia and healthysubjects [85]

57 Drug Addiction During drug addiction control thesaliva along with urine becomes an important material fordetecting amphetamine opiates phencyclidine marijuanaand cocaine and their metabolites There are already a num-ber of special detection kits ToxCup (Clia Laboratories)Saliva MultiDrug Screen test kit (Medimpex Inc) iScreen(BioCheck) QuickScreen (CraigMedical Inc) and so forth

58 Virus Diseases Saliva HIV tests have demonstratedcomparable accuracy to the traditional blood test Oral HIVtests can be a powerful tool for high-risk populations [86]

For HIV viral-load analysis a frequently used commer-cial assay is the COBASAmplicorHIV-1Monitor Test (RocheDiagnostics Indianapolis USA) and an example of a com-mercial assay based on signal amplification is the VERSANTHIV-1 RNA Assay (Siemens AG Munich Germany) [87]

Hepatitis C virus RNA can be consistently detectedin saliva from hepatitis C virus-infected individuals usingquantitative PCR [88]

Dengue virus specific IgA in salivawas detected soon afterinfection in dengue-endemic regions [89]

For the detection of human antibodies against measlesandmumps in oral fluid several simple platforms for antibodydetection in saliva have been published [90]

Currently only two oral-based commercial tests forinfectious disease are FDA approved for use in the USA theOraQuick oral HIV test and the OraRisk human papillo-mavirus salivary diagnostic test [87]

6 Conclusion

The determination of biomarkers in saliva is becoming animportant part of laboratory diagnostics and the prediction ofperiodontal and other diseases Biomarkers in salivamay alsoserve to determine the context of periodontal disease with analtered state of the body or with chronic diseases Saliva alsocontains a series of markers which may predict the risk ofsome systemic disease development

It is certain that a lotmore research efforts are necessary todetermine the sensitivity and specificity of salivary biomarkerdetection and to increase the availability of routine detectionmethods

The UK Biobank holds the worldrsquos largest bank of around85000 well-characterized saliva samples each accompaniedby blood and urine samples the results of a battery ofphysiological tests a full medical history and a detaileddescription of the subjectrsquos lifestyle [91] The evaluationof these samples can be compared with clinical status ofproject participants in future and may bring a lot of recentlyunavailable pieces of information about salivary biomarkers

Competing Interests

The authors declare that they have no competing interests

Acknowledgments

The study was supported by PRVOUK-P28LF16 (CharlesUniversity of Prague Czech Republic) by Project 14-37368G

6 Disease Markers

(Grant Agency Czech Republic) by Project NT 14164-3(Ministry of Health Czech Republic) and by Project 15-28142A (Czech Health Research Council Czech Republic)

References

[1] G B Proctor ldquoThe physiology of salivary secretionrdquo Periodon-tology 2000 vol 70 no 1 pp 11ndash25 2016

[2] J A Loo W Yan P Ramachandran and D TWong ldquoCompar-ative human salivary and plasma proteomesrdquo Journal of DentalResearch vol 89 no 10 pp 1016ndash1023 2010

[3] L A S Nunes S Mussavira and O S Bindhu ldquoClinical anddiagnostic utility of saliva as a non-invasive diagnostic fluid asystematic reviewrdquo BiochemiaMedica vol 25 no 2 pp 177ndash1922015

[4] S P Barros RWilliams S Offenbacher and TMorelli ldquoGingi-val crevicular fluid as a source of biomarkers for periodontitisrdquoPeriodontology 2000 vol 70 no 1 pp 53ndash64 2016

[5] R R Wassall and P M Preshaw ldquoClinical and technicalconsiderations in the analysis of gingival crevicular fluidrdquoPeriodontology 2000 vol 70 no 1 pp 65ndash79 2016

[6] Y Zhang J Sun C-C Lin E Abemayor M B Wang and DT W Wong ldquoThe emerging landscape of salivary diagnosticsrdquoPeriodontology 2000 vol 70 no 1 pp 38ndash52 2016

[7] A Segal and D T Wong ldquoSalivary diagnostics enhancing dis-ease detection and making medicine betterrdquo European Journalof Dental Education vol 12 no 1 pp 22ndash29 2008

[8] JMYoshizawaCA Schafer J J Schafer J J Farrell B J Pasterand D TWWong ldquoSalivary biomarkers toward future clinicaland diagnostic utilitiesrdquo Clinical Microbiology Reviews vol 26no 4 pp 781ndash791 2013

[9] D A Chambers P B Imrey R L Cohen J M Crawford M EAlves and T A McSwiggin ldquoA longitudinal study of aspartateaminotransferase in human gingival crevicular fluidrdquo Journal ofPeriodontal Research vol 26 no 2 pp 65ndash74 1991

[10] A Totan M Greabu C Totan and T Spinu ldquoSalivary aspartateaminotransferase alanine aminotransferase and alkaline phos-phatase possible markers in periodontal diseasesrdquo ClinicalChemistry and Laboratory Medicine vol 44 no 5 pp 612ndash6152006

[11] Y Nomura Y Shimada N Hanada et al ldquoSalivary biomark-ers for predicting the progression of chronic periodontitisrdquoArchives of Oral Biology vol 57 no 4 pp 413ndash420 2012

[12] I B Lamster E Kaufman J T Grbic L J Winston and RE Singer ldquo120573-glucuronidase activity in saliva relationship toclinical periodontal parametersrdquo Journal of Periodontology vol74 no 3 pp 353ndash359 2003

[13] S Elgun N Ozmeric and S Demirtas ldquoAlanine aminopepti-dase and dipeptidylpeptidase IV in Saliva the possible role inperiodontal diseaserdquo Clinica Chimica Acta vol 298 no 1-2 pp187ndash191 2000

[14] K Suomalainen L Saxen P Vilja and J Tenovuo ldquoPeroxidaseslactoferrin and lysozyme in peripheral blood neutrophils gin-gival crevicular fluid and whole saliva of patients with localizedjuvenile periodontitisrdquo Oral Diseases vol 2 no 2 pp 129ndash1341996

[15] B E Britigan and B L Edeker ldquoPseudomonas and neutrophilproductsmodify transferrin and lactoferrin to create conditionsthat favor hydroxyl radical formationrdquo The Journal of ClinicalInvestigation vol 88 no 4 pp 1092ndash1102 1991

[16] T Ingman T Tervahartiala Y Ding et al ldquoMatrix metallo-proteinases and their inhibitors in gingival crevicular fluid andsaliva of periodontitis patientsrdquo Journal of Clinical Periodontol-ogy vol 23 no 12 pp 1127ndash1132 1996

[17] T Sorsa L Tjaderhane Y T Konttinen et al ldquoMatrix met-alloproteinases contribution to pathogenesis diagnosis andtreatment of periodontal inflammationrdquo Annals of Medicinevol 38 no 5 pp 306ndash321 2006

[18] J L Ebersole J L Schuster J Stevens et al ldquoPatterns ofsalivary analytes provide diagnostic capacity for distinguishingchronic adult periodontitis from healthrdquo Journal of ClinicalImmunology vol 33 no 1 pp 271ndash279 2013

[19] N Rathnayake S Akerman B Klinge et al ldquoSalivary biomark-ers of oral healthmdasha cross-sectional studyrdquo Journal of ClinicalPeriodontology vol 40 no 2 pp 140ndash147 2013

[20] W M Sexton Y Lin R J Kryscio D R Dawson III J LEbersole and C S Miller ldquoSalivary biomarkers of periodontaldisease in response to treatmentrdquo Journal of Clinical Periodon-tology vol 38 no 5 pp 434ndash441 2011

[21] J S Kinney T Morelli T Braun et al ldquoSalivapathogenbiomarker signatures and periodontal disease progressionrdquoJournal of Dental Research vol 90 no 6 pp 752ndash758 2011

[22] U K Gursoy E Kononen S Huumonen et al ldquoSalivary type Icollagen degradation end-products and related matrix metallo-proteinases in periodontitisrdquo Journal of Clinical Periodontologyvol 40 no 1 pp 18ndash25 2013

[23] C A Meschiari A M Marcaccini B C Santos Moura L RZuardi J E Tanus-Santos and R F Gerlach ldquoSalivary MMPsTIMPs and MPO levels in periodontal disease patients andcontrolsrdquo Clinica Chimica Acta vol 421 pp 140ndash146 2013

[24] T SorsaU KGursoy SNwhator et al ldquoAnalysis ofmatrixmet-alloproteinases especially MMP-8 in gingival crevicular fluidmouthrinse and saliva for monitoring periodontal diseasesrdquoPeriodontology 2000 vol 70 no 1 pp 142ndash163 2016

[25] G J Van Steijn A V Nieuw Amerongen E C I Veerman SKasanmoentalib and B Overdijk ldquoEffect of periodontal treat-ment on the activity of chitinase in whole saliva of periodontitispatientsrdquo Journal of Periodontal Research vol 37 no 4 pp 245ndash249 2002

[26] N Ozmeric T Baydar A Bodur et al ldquoLevel of neopterin amarker of immune cell activation in gingival crevicular fluidsaliva and urine in patients with aggressive periodontitisrdquoJournal of Periodontology vol 73 no 7 pp 720ndash725 2002

[27] F S Lakschevitz G M Aboodi and M Glogauer ldquoOralneutrophil transcriptome changes result in a pro-survival phe-notype in periodontal diseasesrdquo PLoS ONE vol 8 no 7 ArticleID e68983 2013

[28] D L Korte and J Kinney ldquoPersonalized medicine an updateof salivary biomarkers for periodontal diseasesrdquo Periodontology2000 vol 70 no 1 pp 26ndash37 2016

[29] M Desvarieux R T Demmer T Rundek et al ldquoRelationshipbetween periodontal disease tooth loss and carotid arteryplaque the oral infections and vascular disease epidemiologystudy (INVEST)rdquo Stroke vol 34 no 9 pp 2120ndash2125 2003

[30] N J Park Y Li T Yu B M N Brinkman and D T WongldquoCharacterization of RNA in salivardquo Clinical Chemistry vol 52no 6 pp 988ndash994 2006

[31] Z Chen M G Mauk J Wang et al ldquoA microfluidic system forsaliva-based detection of infectious diseasesrdquoAnnals of the NewYork Academy of Sciences vol 1098 pp 429ndash436 2007

Disease Markers 7

[32] W R Abrams C A Barber K McCann et al ldquoDevelopment ofa microfluidic device for detection of pathogens in oral samplesusing upconverting phosphor technology (UPT)rdquo Annals of theNew York Academy of Sciences vol 1098 pp 375ndash388 2007

[33] P L AM Corstjens Z ChenM Zuiderwijk et al ldquoRapid assayformat formultiplex detection of humoral immune responses toinfectious disease pathogens (HIVHCV andTB)rdquoAnnals of theNew York Academy of Sciences vol 1098 pp 437ndash445 2007

[34] F DrsquoAiuto M Parkar G Andreou et al ldquoPeriodontitis and sys-temic inflammation control of the local infection is associatedwith a reduction in serum inflammatory markersrdquo Journal ofDental Research vol 83 no 2 pp 156ndash160 2004

[35] I Ouellet-Morin A Danese B Williams and L ArseneaultldquoValidation of a high-sensitivity assay for C-reactive protein inhuman salivardquo Brain Behavior and Immunity vol 25 no 4 pp640ndash646 2011

[36] E Megson T Fitzsimmons K Dharmapatni and P MarkBartold ldquoC-reactive protein in gingival crevicular fluid maybe indicative of systemic inflammationrdquo Journal of ClinicalPeriodontology vol 37 no 9 pp 797ndash804 2010

[37] S Podzimek J Mysak T Janatova and J Duskova ldquoC-reactive protein in peripheral blood of patients with chronicand aggressive periodontitis gingivitis and gingival recessionsrdquoMediators of Inflammation vol 2015 Article ID 564858 7 pages2015

[38] Y Murakami S Hanazawa S Tanaka H Iwahashi S Kitanoand S Fujisawa ldquoFibronectin in saliva inhibits Porphy-romonas gingivalis fimbria-induced expression of inflamma-tory cytokine gene in mouse macrophagesrdquo FEMS Immunologyand Medical Microbiology vol 22 no 3 pp 257ndash262 1998

[39] M A Lie B G Loos YM C Henskens et al ldquoSalivary cystatinactivity and cystatin C in natural and experimental gingivitis insmokers and non-smokersrdquo Journal of Clinical Periodontologyvol 28 no 10 pp 979ndash984 2001

[40] M S Rasch B LMealey T J PrihodaD SWoodard and LMMcManus ldquoThe effect of initial periodontal therapy on salivaryplatelet-activating factor levels in chronic adult periodontitisrdquoJournal of Periodontology vol 66 no 7 pp 613ndash623 1995

[41] V Booth S Young A Cruchley N S Taichman and E Pale-olog ldquoVascular endothelial growth factor in human periodontaldiseaserdquo Journal of Periodontal Research vol 33 no 8 pp 491ndash499 1998

[42] M Ohshima K Fujikawa H Akutagawa T Kato K Ito and KOtsuka ldquoHepatocyte growth factor in saliva a possible markerfor periodontal disease statusrdquo Journal of oral science vol 44no 1 pp 35ndash39 2002

[43] U K Gursoy E Kononen P J Pussinen et al ldquoUse of host- andbacteria-derived salivary markers in detection of periodontitisa cumulative approachrdquoDiseaseMarkers vol 30 no 6 pp 299ndash305 2011

[44] K M Jaedicke P M Preshaw and J J Taylor ldquoSalivarycytokines as biomarkers of periodontal diseasesrdquo Periodontol-ogy 2000 vol 70 no 1 pp 164ndash183 2016

[45] P P Costa G L Trevisan G O Macedo et al ldquoSalivaryinterleukin-6 matrix metalloproteinase-8 and osteoprotegerinin patients with periodontitis and diabetesrdquo Journal of Periodon-tology vol 81 no 3 pp 384ndash391 2010

[46] S Liskmann T Vihalemm O Salum K Zilmer K Fischerand M Zilmer ldquoCorrelations between clinical parameters andinterleukin-6 and interleukin-10 levels in saliva from totally

edentulous patients with peri-implant diseaserdquo The Interna-tional Journal of Oral and Maxillofacial Implants vol 21 no 4pp 543ndash550 2006

[47] N Spielmann andDWong ldquoSaliva diagnostics and therapeuticperspectivesrdquo Oral Diseases vol 17 no 4 pp 345ndash354 2011

[48] P Denny F KHagenMHardt et al ldquoThe proteomes of humanparotid and submandibularsublingual gland salivas collectedas the ductal secretionsrdquo Journal of Proteome Research vol 7no 5 pp 1994ndash2006 2008

[49] D V Sculley and S C Langley-Evans ldquoPeriodontal disease isassociated with lower antioxidant capacity in whole saliva andevidence of increased protein oxidationrdquo Clinical Science vol105 no 2 pp 167ndash172 2003

[50] M Takane N Sugano H Iwasaki Y Iwano N Shimizu andK Ito ldquoNew biomarker evidence of oxidative DNA damage inwhole saliva from clinically healthy and periodontally diseasedindividualsrdquo Journal of Periodontology vol 73 no 5 pp 551ndash554 2002

[51] R Diab-Ladki B Pellat and R Chahine ldquoDecrease in thetotal antioxidant activity of saliva in patients with periodontaldiseasesrdquo Clinical Oral Investigations vol 7 no 2 pp 103ndash1072003

[52] M Takane N Sugano T Ezawa T Uchiyama and K ItoldquoA marker of oxidative stress in saliva association withperiodontally-involved teeth of a hopeless prognosisrdquo Journalof Oral Science vol 47 no 1 pp 53ndash57 2005

[53] D-X Tan L C Manchester R J Reiter W-B Qi M Kar-bownik and J R Calvo ldquoSignificance ofmelatonin in antioxida-tive defense system reactions and productsrdquo Biological Signalsand Receptors vol 9 no 3-4 pp 137ndash159 2000

[54] A Cutando G Gomez-Moreno J Villalba M J Ferrera GEscames and D Acuna-Castroviejo ldquoRelationship betweensalivary melatonin levels and periodontal status in diabeticpatientsrdquo Journal of Pineal Research vol 35 no 4 pp 239ndash2442003

[55] C C Tsai H S Chen S L Chen et al ldquoLipid peroxidationa possible role in the induction and progression of chronicperiodontitisrdquo Journal of Periodontal Research vol 40 no 5 pp378ndash386 2005

[56] Y Karincaoglu K Batcioglu T Erdem M Esrefoglu and MGene ldquoThe levels of plasma and salivary antioxidants in thepatient with recurrent aphthous stomatitisrdquo Journal of OralPathology and Medicine vol 34 no 1 pp 7ndash12 2005

[57] C SMiller J D Foley A L Bailey et al ldquoCurrent developmentsin salivary diagnosticsrdquo Biomarkers inMedicine vol 4 no 1 pp171ndash189 2010

[58] X Gao S Jiang D Koh and C S Hsu ldquoSalivary biomarkersfor dental cariesrdquo Periodontology 2000 vol 70 no 1 pp 128ndash141 2016

[59] Y Hassona and C Scully ldquoSalivary changes in oral mucosaldiseasesrdquo Periodontology 2000 vol 70 no 1 pp 111ndash127 2016

[60] A M Schmidt E Weidman E Lalla et al ldquoAdvanced glycationendproducts (AGEs) induce oxidant stress in the gingiva apotential mechanism underlying accelerated periodontal dis-ease associated with diabetesrdquo Journal of Periodontal Researchvol 31 no 7 pp 508ndash515 1996

[61] S AMorenkova ldquoComparative analysis of dependence of salivasorbitol and fructoseamine levels on blood glucose level inpatients with diabetesrdquo Biomeditsinskaya Khimiya vol 50 no6 pp 612ndash614 2004 (Russian)

8 Disease Markers

[62] F Astaneie M Afshari A Mojtahedi et al ldquoTotal antioxidantcapacity and levels of epidermal growth factor and nitric oxidein blood and saliva of insulin-dependent diabetic patientsrdquoArchives of Medical Research vol 36 no 4 pp 376ndash381 2005

[63] M E Lopez M E Colloca R G Paez J N Schallmach M AKoss andA Chervonagura ldquoSalivary characteristics of diabeticchildrenrdquoBrazilianDental Journal vol 14 no 1 pp 26ndash31 2003

[64] R Wolfram A Oguogho B Palumbo and H SinzingerldquoEnhanced oxidative stress in coronary heart disease andchronic heart failure as indicated by an increased 8-epi-PGF2120572rdquoEuropean Journal of Heart Failure vol 7 no 2 pp 167ndash172 2005

[65] S Xiang R Denver M Bailey and H Krum ldquoPhysiologicdeterminants of endothelin concentrations in human salivardquoClinical Chemistry vol 49 no 12 pp 2012ndash2019 2003

[66] N Christodoulides F N Pierre X Sanchez et al ldquoPro-grammable bio-nanochip technology for the diagnosis of car-diovascular disease at the point-of-carerdquo Methodist DeBakeyCardiovascular Journal vol 8 no 1 pp 6ndash12 2012

[67] E J Franzmann E P Reategui K L Carraway K L HamiltonD T Weed and W J Goodwin ldquoSalivary soluble CD44 apotential molecular marker for head and neck cancerrdquo CancerEpidemiology Biomarkers and Prevention vol 14 no 3 pp 735ndash739 2005

[68] L-P Zhong G-F Chen Z-F Xu X Zhang F-Y Ping and S-F Zhao ldquoDetection of telomerase activity in saliva from oralsquamous cell carcinoma patientsrdquo International Journal of Oraland Maxillofacial Surgery vol 34 no 5 pp 566ndash570 2005

[69] A K Markopoulos E Z Michailidou and G TzimagiorgisldquoSalivary markers for oral cancer detectionrdquo Open DentistryJournal no 4 pp 172ndash178 2010

[70] F D Shah R Begum B N Vajaria et al ldquoA review on salivarygenomics and proteomics biomarkers in oral cancerrdquo IndianJournal of Clinical Biochemistry vol 26 no 4 pp 326ndash334 2011

[71] C F Streckfus L Bigler T Dellinger M Kuhn N Chouinardand X Dai ldquoThe expression of the c-erbB-2 receptor proteinin glandular salivary secretionsrdquo Journal of Oral Pathology andMedicine vol 33 no 10 pp 595ndash600 2004

[72] M Markman ldquoNormal CA-125 and the risk of progression inovarian cancerrdquo Journal of Clinical Oncology vol 24 no 20 p3310 2006

[73] L Zhang J J Farrell H Zhou et al ldquoSalivary transcriptomicbiomarkers for detection of resectable pancreatic cancerrdquo Gas-troenterology vol 138 no 3 pp 949ndash957 2010

[74] C T Viet and B L Schmidt ldquoMethylation array analysisof preoperative and postoperative saliva DNA in oral cancerpatientsrdquo Cancer Epidemiology Biomarkers and Prevention vol17 no 12 pp 3603ndash3611 2008

[75] J Wei G Xie Z Zhou et al ldquoSalivary metabolite signatures oforal cancer and leukoplakiardquo International Journal of Cancervol 129 no 9 pp 2207ndash2217 2011

[76] D L Mager A D Haffajee P M Delvin C M Norris M RPosner and J M Goodson ldquoThe salivary microbiota as a diag-nostic indicator of oral cancer a descriptive non-randomizedstudy of cancer-free and oral squamous cell carcinoma subjectsrdquoJournal of Translational Medicine vol 3 article 27 2005

[77] H Xiao L Zhang H Zhou J M Lee E B Garon and D T WWong ldquoProteomic analysis of human saliva from lung cancerpatients using two-dimensional difference gel electrophoresisand mass spectrometryrdquo Molecular amp Cellular Proteomics vol11 no 2 2012

[78] P S Ramsey and W W Andrews ldquoBiochemical predictors ofpreterm labor fetal fibronectin and salivary estriolrdquo Clinics inPerinatology vol 30 no 4 pp 701ndash733 2003

[79] L D Belkien J Bordt P Moller R Hano and E NieschlagldquoEstradiol in saliva for monitoring follicular stimulation in anin vitro fertilization programrdquo Fertility and Sterility vol 44 no3 pp 322ndash327 1985

[80] K Simunkova R Hampl M Hill J Doucha L Starka and KVondra ldquoSalivary cortisol in low dose (1 microg) ACTH test inhealthy women comparison with serum cortisolrdquo PhysiologicalResearch vol 56 no 4 pp 449ndash453 2007

[81] A van Stegeren N Rohleder W Everaerd and O T WolfldquoSalivary alpha amylase asmarker for adrenergic activity duringstress effect of betablockaderdquo Psychoneuroendocrinology vol31 no 1 pp 137ndash141 2006

[82] R S Rittmaster and D L Thompson ldquoEffect of leuprolide anddexamethasone on hair growth and hormone levels in hirsutewomen the relative importance of the ovary and the adrenal inthe pathogenesis of hirsutismrdquo Journal of Clinical Endocrinologyand Metabolism vol 70 no 4 pp 1096ndash1102 1990

[83] I M Goodyer J Herbert and A Tamplin ldquoPsychoendocrineantecedents of persistent first-episode major depression inadolescents a community-based longitudinal enquiryrdquo Psycho-logical Medicine vol 33 no 4 pp 601ndash610 2003

[84] S Yamada ldquoAssessment of mental condition by saliva level of 3-methoxy-4-hydroxyphenylglycolrdquo Seishin Shinkeigaku Zasshivol 107 no 7 pp 712ndash717 2005 (Japanese)

[85] M Tsuruoka J Hara A Hirayama et al ldquoCapillaryelectrophoresis-mass spectrometry-based metabolomeanalysis of serum and saliva from neurodegenerative dementiapatientsrdquo Electrophoresis vol 34 no 19 pp 2865ndash2872 2013

[86] N Pant Pai B Balram S Shivkumar et al ldquoHead-to-headcomparison of accuracy of a rapid point-of-care HIV test withoral versus whole-blood specimens a systematic review andmeta-analysisrdquoThe Lancet Infectious Diseases vol 12 no 5 pp373ndash380 2012

[87] P L CorstjensW RAbrams andDMalamud ldquoSaliva and viralinfectionsrdquo Periodontology 2000 vol 70 no 1 pp 93ndash110 2016

[88] G B L Menezes F A Pereira C A B Duarte et al ldquoHepatitisC virus quantification in serum and saliva of HCV-infectedpatientsrdquo Memorias do Instituto Oswaldo Cruz vol 107 no 5pp 680ndash683 2012

[89] G Yap B K Sil and L-C Ng ldquoUse of saliva for early denguediagnosisrdquo PLoSNeglected Tropical Diseases vol 5 no 5 ArticleID e1046 2011

[90] P L A M Corstjens and D Malamud ldquoPoint-of-care diagnos-tics for infectious diseasesrdquo in Salivary Diagnostics D T WongEd chapter 13 pp 136ndash149Wiley-Blackwell Ames Iowa USA2008

[91] J W Galloway B J F Keijser and D M Williams ldquoSaliva instudies of epidemiology of human disease the UK Biobankprojectrdquo Periodontology 2000 vol 70 no 1 pp 184ndash195 2016

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Disease Markers 3

level in saliva decreases It is assumed that this can be aconsequence of a decrease in phagocytic activity [26]

23 Other Markers in Periodontal Diseases Upregulatedexpression of a variety of B-cell lymphoma-2-related tran-scripts in neutrophils from oral rinse samples of patientswith chronic periodontitis compared with healthy controlshas been demonstrated using the Illumina Human 12WGExpression BeadChip (Illumina San Diego CA USA) [27]

Korte and Kinney [28] have recently published an updat-ed review of salivary biomarkers for periodontal diseases

3 Specific and Nonspecific ProteinsPresent in Saliva

In saliva the numbers of proteins which also reflect thestate of inflammation in the periodontium and occasionallyeven the state of inflammation in distant organs systems aredetectable

The number of salivary biomarkers is increasing rapidlyand many of these markers appear to be unique to salivaFrom a list of 1939 salivary proteins that has been recentlypublished [29 30] around two-thirds have not been found inblood This may lead to the discovery of protein ldquosignaturesrdquoindicative of oral and systemic diseases [31ndash33]

31 C-Reactive Protein (CRP) C-reactive protein is a longknown indicator of inflammatory or rheumatic activity CRPlevels in plasma and saliva correlate During periodontitissalivary CRP levels increase and its decrease indicates asuccessful anti-inflammatory treatment

High CRP levels in saliva during diffuse periodontitis areamarker of local process risk for the formation or progressionof cardiovascular disease with risk coefficient OR 56 [34ndash36]

CRP levels increase subsequently with the severity of theperiodontal disease [37]

32 Fibronectin During periodontitis a decreased level offibronectin in saliva is evident Fibronectin blocks adhesins ofmany periodontal microorganisms reducing their adherenceto periodontal tissues [38]

33 Cystatins The levels of cystatins natural inhibitors ofphagocytic proteases decrease in sulcular fluid and salivaduring periodontitis ultimately leading to tissue damage bycathepsins [39]

34 Neopterin Neopterin is a cytokine produced by ma-crophages that participates in the formation of nitric oxideradical which is important for phagocytosis Its level in salivaincreases during periodontal inflammation [26]

35 Cytokines and Other Protein Markers Further proteinmarkers of inflammation whose levels correlate with theintensity of periodontal inflammation are detectable in salivaExamples of these include platelet-activating factor vascular

endothelial growth factor and hepatocyte growth factor [40ndash42]

Salivary interleukin-1 beta is elevated in periodontaldiseases and its levels are strongly correlatedwith periodontaldisease progression and considered to be a good biomarkerfor discriminating between active and inactive periodontalsites Salivary interleukin-1 beta has also been associated withadvanced periodontitis [43]

According to recent review interleukin-1 beta and hepa-tocyte growth factor are the most robust salivary biomarkersfor periodontal disease [44]

Increased salivary levels of interleukin-6 are presentin individuals with periodontitis compared with healthysubjects [45] Salivary interleukin-6 has also been shown tostimulate osteoclast differentiation and bone resorption andis associated with tissue destruction in peri-implant disease[46]

Salivary levels of tumor necrosis factor-alpha indicatethe presence of generalized chronic periodontitis and havealso demonstrated significant changes after nonsurgical peri-odontal therapy [20]

A great deal of work has been dedicated to catalogingthe salivary proteome and annotating identified saliva pro-teins [47] This large database is known as the SalivaProteome Knowledge Base and is available to the public(httpwwwskbuclaedu) This central database is crucialin the identification of combinations of biomarker panelsthat may provide distinct diagnostic information and thusserves as a valuable resource for identifying deviations withinproteins or peptides that align with oral and systemic diseaseand will aid in the development of saliva-based diagnostictests [48]

4 Oxidative Stress

One of the important molecular pathological processesaccompanying inflammation or tumor cell proliferation isthe so-called oxidative stress In the pathologically alteredtissue a number of substances with the character of reactiveoxygen species release and their compensation by the presentantioxidants are sustained The equilibrium is disturbedeither by increased production of reactive oxygen species bythe lack of antioxidants or by both mechanisms This resultsin damage to the cellular DNA certain signal proteins andtissue components inactivation of enzymes and stimulationof proinflammatory cytokines and lipid peroxidation It hasbeen proven that oxidative stress significantly succeeded inthe destruction of periodontal tissues [49]

One of the markers of oxidative stress is 8-hydroxy-21015840-deoxyguanosine (8-OHdG)which is formed by the oxidationof guanine from damaged DNA Deoxyguanosine levelsincrease in saliva during periodontitis and decrease withsuccessful anti-inflammatory treatment [50]

During chronic inflammation not only reactive oxygenspecies increase in affected tissues but also a decrease inantioxidants can be demonstrated This is true even forperiodontal tissues [51] This relationship is supported byresults from the study by Takane et al (2005) which showedsignificant differences between the levels of 8-OHdG in saliva

4 Disease Markers

in patients with aggressive and advanced periodontitis and inindividuals with clinically healthy periodontal tissues [52]

Ascorbate and albumin belong to the main tissue antiox-idants together with melatonin Melatonin has nonspecificanti-inflammatory and osteogenic effects which affects Tlymphocytes and its level in saliva positively correlates withthe intensity and extent of periodontal inflammation [53]

Reduced production of interleukin-2 known in patientswith type 1 diabetes together with a reduced level of mela-tonin may be one of the molecular pathological risks for theprogression of periodontal disease in diabetic patients [54]

Reactive oxygen species also play a role in anothermolecular pathological process known as lipid peroxidationReactive oxygen species attack the unsaturated fatty acidsof phospholipid and phosphoprotein membranes therebydisrupting their integrity The end products of lipid peroxi-dation are malondialdehyde and hydroxyalkenals If the lipidperoxidation is in equilibrium with tissue glutathione and itsperoxidase damage to the membranes does not occur Dur-ing periodontitis elevated levels of the end products of lipidperoxidation and decreased levels of natural antioxidants arefound in saliva indicating failure of equilibriumwith the riskof tissue destruction [55]

Reactive oxygen species are implicated in the patho-genesis of many diseases and have been suggested to playa role in the pathogenesis of various oral diseases Forexample the salivary levels of antioxidant enzymes includingsuperoxide dismutase catalase and glutathione peroxidasewere significantly higher in patients with recurrent aphthousstomatitis than in healthy controls [56]

5 Saliva as a Source of Biomarkers forOther Fields of Medicine

Studies investigating the use of saliva as a diagnostic fluidhave a long history This noninvasive approach is not limitedonly to the diagnosis of oral diseases because many systemicdiseases such as different types of cancers cardiovascular dis-eases immunologic syndromes and hereditary deficienciescan also be studied with the aid of salivary diagnostics [57]Even gynecology and psychiatry are interested in salivarybiomarkers monitoring

Reviews on salivary markers in dental caries [58] andoral mucosal diseases [59] have been recently published inPeriodontology 2000 journal

51 Diabetes Mellitus Nonenzymatic glycation of a numberof substances occurs during elevated or fluctuating bloodglucose levels The glycated hemoglobin level in blood haslong been used as amarker ofmetabolically poorly controlleddiabetes More recently it was shown that even in saliva someglycated proteins and fats can be detected and their levelscorrelate with the glycated hemoglobin level in plasma [60]

According to somepublished studies it appears that levelsof sorbitol and fructosamine in saliva correlate with levels ofglucose in capillary blood [61]

Increased plasma glycohemoglobin is also accompaniedby elevated levels of epidermal growth factor nitric oxide andtotal antioxidant activity of saliva [62]

In patients with type 1 diabetes increased levels of ureaand 120572-amylase have been shown in saliva According to thestudy of Lopez et al (2003) the increase of these markers insaliva precedes the clinical signs of diabetes These markersmay be used in the future for screening incipient diabetes[63]

52 Cardiovascular Diseases Wolfram et al (2005) demon-strated increased levels of isoprostane and oxidized low-density lipoproteins in saliva of individuals with coronaryheart disease [64]

Increased attention turns also to endothelin in salivaEndothelin is a peptide that plays a critical role in cardio-vascular regulation Endothelin receptors mediate vasocon-striction as a response to endothelin-1 the primary isoformof this peptide in the cardiovascular system It is assumed thatendothelin A receptors induce the proliferation of vascularsmooth muscle and myocardial hypertrophy whereas theactivations of endothelin B receptors lead to vasodilationvia nitric oxide or prostacyclin and have antithrombotic andantiproliferative effects Pulmonary receptors of endothelinB in addition help to scavenge endothelin-1 Endothelin-1stimulates the production of other neurohumoral factors andpromotes the activity of other neuroendocrine cascades Inpeople with coronary heart disease or chronic obstructivepulmonary disease elevated levels of endothelin and itsinhibitor are found in saliva [65]

In terms of cardiovascular biomarker research the feasi-bility and utility of a programmable bionanochip to identifybiomarkers of acute myocardial infarction in saliva wereinvestigated Interestingly this nanotechnology was able toidentify saliva-based biomarker panels that had significantdiagnostic capability when used in conjunction with anelectrocardiogram and far exceeded the screening capacity ofan electrocardiogram alone [66]

53 Oncological Screening In oncological screening thedetection of soluble factor CD44 or telomerase is beingconsidered as their levels in saliva increase with squamouscell carcinoma of the head and neck [67 68] High attentionis still paid to the possibilities of detecting markers foroncological diseases of the oral cavity [69 70]

In proteomics research of plasma and saliva proteincomposition it was found that in patients with breast orovarian cancer the fractions with molecular weight of 117228 and 287 kDa significantly increased in plasma and salivaIt seems that the biomarker of these malignancies could beprotein provisionally named as HER2neu [71]

CA 125 antigen is present in the plasma of ovarian cancerpatients and its detection is used as a marker for recurrenceafter oncologic treatment This marker is also detectable insaliva and a possible use of CA 125 determination in saliva isconsidered in the screening of this cancer [72]

Using Affymetrix HG-U133-Plus-20 array (AffymetrixSanta Clara CA USA) four salivary mRNA biomarkers(v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologmethyl-CpG binding domain protein 3-like 2 acrosomalvesicle protein 1 and dolichylphosphate mannosyltransferasepolypeptide 1) that can differentiate patients with early-stage

Disease Markers 5

resectable pancreatic cancer from noncancer subjects wereidentified [73] This is a breakthrough proof-of-conceptinvestigation for noninvasive detection of a systemic cancer

Gene panels of 4 to 10 genes for oral squamous cellcarcinoma were constructed based on significant differencesin DNA-methylation patterns between the preoperative andpostoperative saliva of patients with oral squamous cellcarcinoma and between preoperative saliva from patientswith oral squamous cell carcinoma and saliva from healthycontrols [74]

Three salivary metabolites (phenylalanine valine andlactic acid) could distinguish patients with oral squamous cellcarcinoma from healthy controls and could also distinguishpatients with oral leukoplakia from healthy controls [75]

A combination of three microbiotas (Capnocytophagagingivalis Prevotella melaninogenica and Streptococcus mitis)in saliva could be used as diagnostic biomarkers of patientswith oral squamous cell carcinoma [76]

Three proteins (zinc-a-2-glycoprotein haptoglobin andhuman calprotectin) that had good discriminatory powerin lung cancer patients and healthy control subjects werereported by Xiao et al [77]

54 Gynecology Increased levels of estriol in saliva predictthe risk of premature birth There is a range of detection setsfor self-diagnostics of premature birth risk on sale in theUSAAn example is the Salivary Estriol Immunoassay Kit fromSalimetrics LLC

Dynamics of estradiol levels in saliva is used in assistedreproduction to accurately determine the ovulation [78 79]

55 Endocrinology Salivary cortisol has long been usedin endocrinological examination methods as a biomarkerfor determining hypothalamus-pituitary-adrenal axis activity[80]

Another salivary marker used by endocrinologists issalivary 120572-amylase (sAA) that helps determine sympathetic-adrenal medulla axis activity The amount of salivary 120572-amylase significantly increases with adrenergic activationespecially with stress [81]

When hyperandrogenemia occurs for example in poly-cystic ovary syndrome increased levels of dehydroepiandros-terone sulfate (DHEA-S) and androstenedione can bedetected in saliva [82]

56 Psychiatry Research in psychiatry also has its markersthat can be measured in saliva It is for example the ratioof cortisol and dehydroepiandrosterone which increases indepressive conditions and varies with changes in affectivityThe good predictive value of this assay is used for theindividual dosing of antidepressants in adolescents [83]

It has been found that 3-methoxy-4-hydroxyphenylglycol(one of the noradrenalinemetabolites) level in saliva decreas-es in depression or in reduced mental activity Nowadays itsdetermination is used for research purposes only [84]

Two salivary metabolites (arginine and tyrosine) differedsignificantly between patients with dementia and healthysubjects [85]

57 Drug Addiction During drug addiction control thesaliva along with urine becomes an important material fordetecting amphetamine opiates phencyclidine marijuanaand cocaine and their metabolites There are already a num-ber of special detection kits ToxCup (Clia Laboratories)Saliva MultiDrug Screen test kit (Medimpex Inc) iScreen(BioCheck) QuickScreen (CraigMedical Inc) and so forth

58 Virus Diseases Saliva HIV tests have demonstratedcomparable accuracy to the traditional blood test Oral HIVtests can be a powerful tool for high-risk populations [86]

For HIV viral-load analysis a frequently used commer-cial assay is the COBASAmplicorHIV-1Monitor Test (RocheDiagnostics Indianapolis USA) and an example of a com-mercial assay based on signal amplification is the VERSANTHIV-1 RNA Assay (Siemens AG Munich Germany) [87]

Hepatitis C virus RNA can be consistently detectedin saliva from hepatitis C virus-infected individuals usingquantitative PCR [88]

Dengue virus specific IgA in salivawas detected soon afterinfection in dengue-endemic regions [89]

For the detection of human antibodies against measlesandmumps in oral fluid several simple platforms for antibodydetection in saliva have been published [90]

Currently only two oral-based commercial tests forinfectious disease are FDA approved for use in the USA theOraQuick oral HIV test and the OraRisk human papillo-mavirus salivary diagnostic test [87]

6 Conclusion

The determination of biomarkers in saliva is becoming animportant part of laboratory diagnostics and the prediction ofperiodontal and other diseases Biomarkers in salivamay alsoserve to determine the context of periodontal disease with analtered state of the body or with chronic diseases Saliva alsocontains a series of markers which may predict the risk ofsome systemic disease development

It is certain that a lotmore research efforts are necessary todetermine the sensitivity and specificity of salivary biomarkerdetection and to increase the availability of routine detectionmethods

The UK Biobank holds the worldrsquos largest bank of around85000 well-characterized saliva samples each accompaniedby blood and urine samples the results of a battery ofphysiological tests a full medical history and a detaileddescription of the subjectrsquos lifestyle [91] The evaluationof these samples can be compared with clinical status ofproject participants in future and may bring a lot of recentlyunavailable pieces of information about salivary biomarkers

Competing Interests

The authors declare that they have no competing interests

Acknowledgments

The study was supported by PRVOUK-P28LF16 (CharlesUniversity of Prague Czech Republic) by Project 14-37368G

6 Disease Markers

(Grant Agency Czech Republic) by Project NT 14164-3(Ministry of Health Czech Republic) and by Project 15-28142A (Czech Health Research Council Czech Republic)

References

[1] G B Proctor ldquoThe physiology of salivary secretionrdquo Periodon-tology 2000 vol 70 no 1 pp 11ndash25 2016

[2] J A Loo W Yan P Ramachandran and D TWong ldquoCompar-ative human salivary and plasma proteomesrdquo Journal of DentalResearch vol 89 no 10 pp 1016ndash1023 2010

[3] L A S Nunes S Mussavira and O S Bindhu ldquoClinical anddiagnostic utility of saliva as a non-invasive diagnostic fluid asystematic reviewrdquo BiochemiaMedica vol 25 no 2 pp 177ndash1922015

[4] S P Barros RWilliams S Offenbacher and TMorelli ldquoGingi-val crevicular fluid as a source of biomarkers for periodontitisrdquoPeriodontology 2000 vol 70 no 1 pp 53ndash64 2016

[5] R R Wassall and P M Preshaw ldquoClinical and technicalconsiderations in the analysis of gingival crevicular fluidrdquoPeriodontology 2000 vol 70 no 1 pp 65ndash79 2016

[6] Y Zhang J Sun C-C Lin E Abemayor M B Wang and DT W Wong ldquoThe emerging landscape of salivary diagnosticsrdquoPeriodontology 2000 vol 70 no 1 pp 38ndash52 2016

[7] A Segal and D T Wong ldquoSalivary diagnostics enhancing dis-ease detection and making medicine betterrdquo European Journalof Dental Education vol 12 no 1 pp 22ndash29 2008

[8] JMYoshizawaCA Schafer J J Schafer J J Farrell B J Pasterand D TWWong ldquoSalivary biomarkers toward future clinicaland diagnostic utilitiesrdquo Clinical Microbiology Reviews vol 26no 4 pp 781ndash791 2013

[9] D A Chambers P B Imrey R L Cohen J M Crawford M EAlves and T A McSwiggin ldquoA longitudinal study of aspartateaminotransferase in human gingival crevicular fluidrdquo Journal ofPeriodontal Research vol 26 no 2 pp 65ndash74 1991

[10] A Totan M Greabu C Totan and T Spinu ldquoSalivary aspartateaminotransferase alanine aminotransferase and alkaline phos-phatase possible markers in periodontal diseasesrdquo ClinicalChemistry and Laboratory Medicine vol 44 no 5 pp 612ndash6152006

[11] Y Nomura Y Shimada N Hanada et al ldquoSalivary biomark-ers for predicting the progression of chronic periodontitisrdquoArchives of Oral Biology vol 57 no 4 pp 413ndash420 2012

[12] I B Lamster E Kaufman J T Grbic L J Winston and RE Singer ldquo120573-glucuronidase activity in saliva relationship toclinical periodontal parametersrdquo Journal of Periodontology vol74 no 3 pp 353ndash359 2003

[13] S Elgun N Ozmeric and S Demirtas ldquoAlanine aminopepti-dase and dipeptidylpeptidase IV in Saliva the possible role inperiodontal diseaserdquo Clinica Chimica Acta vol 298 no 1-2 pp187ndash191 2000

[14] K Suomalainen L Saxen P Vilja and J Tenovuo ldquoPeroxidaseslactoferrin and lysozyme in peripheral blood neutrophils gin-gival crevicular fluid and whole saliva of patients with localizedjuvenile periodontitisrdquo Oral Diseases vol 2 no 2 pp 129ndash1341996

[15] B E Britigan and B L Edeker ldquoPseudomonas and neutrophilproductsmodify transferrin and lactoferrin to create conditionsthat favor hydroxyl radical formationrdquo The Journal of ClinicalInvestigation vol 88 no 4 pp 1092ndash1102 1991

[16] T Ingman T Tervahartiala Y Ding et al ldquoMatrix metallo-proteinases and their inhibitors in gingival crevicular fluid andsaliva of periodontitis patientsrdquo Journal of Clinical Periodontol-ogy vol 23 no 12 pp 1127ndash1132 1996

[17] T Sorsa L Tjaderhane Y T Konttinen et al ldquoMatrix met-alloproteinases contribution to pathogenesis diagnosis andtreatment of periodontal inflammationrdquo Annals of Medicinevol 38 no 5 pp 306ndash321 2006

[18] J L Ebersole J L Schuster J Stevens et al ldquoPatterns ofsalivary analytes provide diagnostic capacity for distinguishingchronic adult periodontitis from healthrdquo Journal of ClinicalImmunology vol 33 no 1 pp 271ndash279 2013

[19] N Rathnayake S Akerman B Klinge et al ldquoSalivary biomark-ers of oral healthmdasha cross-sectional studyrdquo Journal of ClinicalPeriodontology vol 40 no 2 pp 140ndash147 2013

[20] W M Sexton Y Lin R J Kryscio D R Dawson III J LEbersole and C S Miller ldquoSalivary biomarkers of periodontaldisease in response to treatmentrdquo Journal of Clinical Periodon-tology vol 38 no 5 pp 434ndash441 2011

[21] J S Kinney T Morelli T Braun et al ldquoSalivapathogenbiomarker signatures and periodontal disease progressionrdquoJournal of Dental Research vol 90 no 6 pp 752ndash758 2011

[22] U K Gursoy E Kononen S Huumonen et al ldquoSalivary type Icollagen degradation end-products and related matrix metallo-proteinases in periodontitisrdquo Journal of Clinical Periodontologyvol 40 no 1 pp 18ndash25 2013

[23] C A Meschiari A M Marcaccini B C Santos Moura L RZuardi J E Tanus-Santos and R F Gerlach ldquoSalivary MMPsTIMPs and MPO levels in periodontal disease patients andcontrolsrdquo Clinica Chimica Acta vol 421 pp 140ndash146 2013

[24] T SorsaU KGursoy SNwhator et al ldquoAnalysis ofmatrixmet-alloproteinases especially MMP-8 in gingival crevicular fluidmouthrinse and saliva for monitoring periodontal diseasesrdquoPeriodontology 2000 vol 70 no 1 pp 142ndash163 2016

[25] G J Van Steijn A V Nieuw Amerongen E C I Veerman SKasanmoentalib and B Overdijk ldquoEffect of periodontal treat-ment on the activity of chitinase in whole saliva of periodontitispatientsrdquo Journal of Periodontal Research vol 37 no 4 pp 245ndash249 2002

[26] N Ozmeric T Baydar A Bodur et al ldquoLevel of neopterin amarker of immune cell activation in gingival crevicular fluidsaliva and urine in patients with aggressive periodontitisrdquoJournal of Periodontology vol 73 no 7 pp 720ndash725 2002

[27] F S Lakschevitz G M Aboodi and M Glogauer ldquoOralneutrophil transcriptome changes result in a pro-survival phe-notype in periodontal diseasesrdquo PLoS ONE vol 8 no 7 ArticleID e68983 2013

[28] D L Korte and J Kinney ldquoPersonalized medicine an updateof salivary biomarkers for periodontal diseasesrdquo Periodontology2000 vol 70 no 1 pp 26ndash37 2016

[29] M Desvarieux R T Demmer T Rundek et al ldquoRelationshipbetween periodontal disease tooth loss and carotid arteryplaque the oral infections and vascular disease epidemiologystudy (INVEST)rdquo Stroke vol 34 no 9 pp 2120ndash2125 2003

[30] N J Park Y Li T Yu B M N Brinkman and D T WongldquoCharacterization of RNA in salivardquo Clinical Chemistry vol 52no 6 pp 988ndash994 2006

[31] Z Chen M G Mauk J Wang et al ldquoA microfluidic system forsaliva-based detection of infectious diseasesrdquoAnnals of the NewYork Academy of Sciences vol 1098 pp 429ndash436 2007

Disease Markers 7

[32] W R Abrams C A Barber K McCann et al ldquoDevelopment ofa microfluidic device for detection of pathogens in oral samplesusing upconverting phosphor technology (UPT)rdquo Annals of theNew York Academy of Sciences vol 1098 pp 375ndash388 2007

[33] P L AM Corstjens Z ChenM Zuiderwijk et al ldquoRapid assayformat formultiplex detection of humoral immune responses toinfectious disease pathogens (HIVHCV andTB)rdquoAnnals of theNew York Academy of Sciences vol 1098 pp 437ndash445 2007

[34] F DrsquoAiuto M Parkar G Andreou et al ldquoPeriodontitis and sys-temic inflammation control of the local infection is associatedwith a reduction in serum inflammatory markersrdquo Journal ofDental Research vol 83 no 2 pp 156ndash160 2004

[35] I Ouellet-Morin A Danese B Williams and L ArseneaultldquoValidation of a high-sensitivity assay for C-reactive protein inhuman salivardquo Brain Behavior and Immunity vol 25 no 4 pp640ndash646 2011

[36] E Megson T Fitzsimmons K Dharmapatni and P MarkBartold ldquoC-reactive protein in gingival crevicular fluid maybe indicative of systemic inflammationrdquo Journal of ClinicalPeriodontology vol 37 no 9 pp 797ndash804 2010

[37] S Podzimek J Mysak T Janatova and J Duskova ldquoC-reactive protein in peripheral blood of patients with chronicand aggressive periodontitis gingivitis and gingival recessionsrdquoMediators of Inflammation vol 2015 Article ID 564858 7 pages2015

[38] Y Murakami S Hanazawa S Tanaka H Iwahashi S Kitanoand S Fujisawa ldquoFibronectin in saliva inhibits Porphy-romonas gingivalis fimbria-induced expression of inflamma-tory cytokine gene in mouse macrophagesrdquo FEMS Immunologyand Medical Microbiology vol 22 no 3 pp 257ndash262 1998

[39] M A Lie B G Loos YM C Henskens et al ldquoSalivary cystatinactivity and cystatin C in natural and experimental gingivitis insmokers and non-smokersrdquo Journal of Clinical Periodontologyvol 28 no 10 pp 979ndash984 2001

[40] M S Rasch B LMealey T J PrihodaD SWoodard and LMMcManus ldquoThe effect of initial periodontal therapy on salivaryplatelet-activating factor levels in chronic adult periodontitisrdquoJournal of Periodontology vol 66 no 7 pp 613ndash623 1995

[41] V Booth S Young A Cruchley N S Taichman and E Pale-olog ldquoVascular endothelial growth factor in human periodontaldiseaserdquo Journal of Periodontal Research vol 33 no 8 pp 491ndash499 1998

[42] M Ohshima K Fujikawa H Akutagawa T Kato K Ito and KOtsuka ldquoHepatocyte growth factor in saliva a possible markerfor periodontal disease statusrdquo Journal of oral science vol 44no 1 pp 35ndash39 2002

[43] U K Gursoy E Kononen P J Pussinen et al ldquoUse of host- andbacteria-derived salivary markers in detection of periodontitisa cumulative approachrdquoDiseaseMarkers vol 30 no 6 pp 299ndash305 2011

[44] K M Jaedicke P M Preshaw and J J Taylor ldquoSalivarycytokines as biomarkers of periodontal diseasesrdquo Periodontol-ogy 2000 vol 70 no 1 pp 164ndash183 2016

[45] P P Costa G L Trevisan G O Macedo et al ldquoSalivaryinterleukin-6 matrix metalloproteinase-8 and osteoprotegerinin patients with periodontitis and diabetesrdquo Journal of Periodon-tology vol 81 no 3 pp 384ndash391 2010

[46] S Liskmann T Vihalemm O Salum K Zilmer K Fischerand M Zilmer ldquoCorrelations between clinical parameters andinterleukin-6 and interleukin-10 levels in saliva from totally

edentulous patients with peri-implant diseaserdquo The Interna-tional Journal of Oral and Maxillofacial Implants vol 21 no 4pp 543ndash550 2006

[47] N Spielmann andDWong ldquoSaliva diagnostics and therapeuticperspectivesrdquo Oral Diseases vol 17 no 4 pp 345ndash354 2011

[48] P Denny F KHagenMHardt et al ldquoThe proteomes of humanparotid and submandibularsublingual gland salivas collectedas the ductal secretionsrdquo Journal of Proteome Research vol 7no 5 pp 1994ndash2006 2008

[49] D V Sculley and S C Langley-Evans ldquoPeriodontal disease isassociated with lower antioxidant capacity in whole saliva andevidence of increased protein oxidationrdquo Clinical Science vol105 no 2 pp 167ndash172 2003

[50] M Takane N Sugano H Iwasaki Y Iwano N Shimizu andK Ito ldquoNew biomarker evidence of oxidative DNA damage inwhole saliva from clinically healthy and periodontally diseasedindividualsrdquo Journal of Periodontology vol 73 no 5 pp 551ndash554 2002

[51] R Diab-Ladki B Pellat and R Chahine ldquoDecrease in thetotal antioxidant activity of saliva in patients with periodontaldiseasesrdquo Clinical Oral Investigations vol 7 no 2 pp 103ndash1072003

[52] M Takane N Sugano T Ezawa T Uchiyama and K ItoldquoA marker of oxidative stress in saliva association withperiodontally-involved teeth of a hopeless prognosisrdquo Journalof Oral Science vol 47 no 1 pp 53ndash57 2005

[53] D-X Tan L C Manchester R J Reiter W-B Qi M Kar-bownik and J R Calvo ldquoSignificance ofmelatonin in antioxida-tive defense system reactions and productsrdquo Biological Signalsand Receptors vol 9 no 3-4 pp 137ndash159 2000

[54] A Cutando G Gomez-Moreno J Villalba M J Ferrera GEscames and D Acuna-Castroviejo ldquoRelationship betweensalivary melatonin levels and periodontal status in diabeticpatientsrdquo Journal of Pineal Research vol 35 no 4 pp 239ndash2442003

[55] C C Tsai H S Chen S L Chen et al ldquoLipid peroxidationa possible role in the induction and progression of chronicperiodontitisrdquo Journal of Periodontal Research vol 40 no 5 pp378ndash386 2005

[56] Y Karincaoglu K Batcioglu T Erdem M Esrefoglu and MGene ldquoThe levels of plasma and salivary antioxidants in thepatient with recurrent aphthous stomatitisrdquo Journal of OralPathology and Medicine vol 34 no 1 pp 7ndash12 2005

[57] C SMiller J D Foley A L Bailey et al ldquoCurrent developmentsin salivary diagnosticsrdquo Biomarkers inMedicine vol 4 no 1 pp171ndash189 2010

[58] X Gao S Jiang D Koh and C S Hsu ldquoSalivary biomarkersfor dental cariesrdquo Periodontology 2000 vol 70 no 1 pp 128ndash141 2016

[59] Y Hassona and C Scully ldquoSalivary changes in oral mucosaldiseasesrdquo Periodontology 2000 vol 70 no 1 pp 111ndash127 2016

[60] A M Schmidt E Weidman E Lalla et al ldquoAdvanced glycationendproducts (AGEs) induce oxidant stress in the gingiva apotential mechanism underlying accelerated periodontal dis-ease associated with diabetesrdquo Journal of Periodontal Researchvol 31 no 7 pp 508ndash515 1996

[61] S AMorenkova ldquoComparative analysis of dependence of salivasorbitol and fructoseamine levels on blood glucose level inpatients with diabetesrdquo Biomeditsinskaya Khimiya vol 50 no6 pp 612ndash614 2004 (Russian)

8 Disease Markers

[62] F Astaneie M Afshari A Mojtahedi et al ldquoTotal antioxidantcapacity and levels of epidermal growth factor and nitric oxidein blood and saliva of insulin-dependent diabetic patientsrdquoArchives of Medical Research vol 36 no 4 pp 376ndash381 2005

[63] M E Lopez M E Colloca R G Paez J N Schallmach M AKoss andA Chervonagura ldquoSalivary characteristics of diabeticchildrenrdquoBrazilianDental Journal vol 14 no 1 pp 26ndash31 2003

[64] R Wolfram A Oguogho B Palumbo and H SinzingerldquoEnhanced oxidative stress in coronary heart disease andchronic heart failure as indicated by an increased 8-epi-PGF2120572rdquoEuropean Journal of Heart Failure vol 7 no 2 pp 167ndash172 2005

[65] S Xiang R Denver M Bailey and H Krum ldquoPhysiologicdeterminants of endothelin concentrations in human salivardquoClinical Chemistry vol 49 no 12 pp 2012ndash2019 2003

[66] N Christodoulides F N Pierre X Sanchez et al ldquoPro-grammable bio-nanochip technology for the diagnosis of car-diovascular disease at the point-of-carerdquo Methodist DeBakeyCardiovascular Journal vol 8 no 1 pp 6ndash12 2012

[67] E J Franzmann E P Reategui K L Carraway K L HamiltonD T Weed and W J Goodwin ldquoSalivary soluble CD44 apotential molecular marker for head and neck cancerrdquo CancerEpidemiology Biomarkers and Prevention vol 14 no 3 pp 735ndash739 2005

[68] L-P Zhong G-F Chen Z-F Xu X Zhang F-Y Ping and S-F Zhao ldquoDetection of telomerase activity in saliva from oralsquamous cell carcinoma patientsrdquo International Journal of Oraland Maxillofacial Surgery vol 34 no 5 pp 566ndash570 2005

[69] A K Markopoulos E Z Michailidou and G TzimagiorgisldquoSalivary markers for oral cancer detectionrdquo Open DentistryJournal no 4 pp 172ndash178 2010

[70] F D Shah R Begum B N Vajaria et al ldquoA review on salivarygenomics and proteomics biomarkers in oral cancerrdquo IndianJournal of Clinical Biochemistry vol 26 no 4 pp 326ndash334 2011

[71] C F Streckfus L Bigler T Dellinger M Kuhn N Chouinardand X Dai ldquoThe expression of the c-erbB-2 receptor proteinin glandular salivary secretionsrdquo Journal of Oral Pathology andMedicine vol 33 no 10 pp 595ndash600 2004

[72] M Markman ldquoNormal CA-125 and the risk of progression inovarian cancerrdquo Journal of Clinical Oncology vol 24 no 20 p3310 2006

[73] L Zhang J J Farrell H Zhou et al ldquoSalivary transcriptomicbiomarkers for detection of resectable pancreatic cancerrdquo Gas-troenterology vol 138 no 3 pp 949ndash957 2010

[74] C T Viet and B L Schmidt ldquoMethylation array analysisof preoperative and postoperative saliva DNA in oral cancerpatientsrdquo Cancer Epidemiology Biomarkers and Prevention vol17 no 12 pp 3603ndash3611 2008

[75] J Wei G Xie Z Zhou et al ldquoSalivary metabolite signatures oforal cancer and leukoplakiardquo International Journal of Cancervol 129 no 9 pp 2207ndash2217 2011

[76] D L Mager A D Haffajee P M Delvin C M Norris M RPosner and J M Goodson ldquoThe salivary microbiota as a diag-nostic indicator of oral cancer a descriptive non-randomizedstudy of cancer-free and oral squamous cell carcinoma subjectsrdquoJournal of Translational Medicine vol 3 article 27 2005

[77] H Xiao L Zhang H Zhou J M Lee E B Garon and D T WWong ldquoProteomic analysis of human saliva from lung cancerpatients using two-dimensional difference gel electrophoresisand mass spectrometryrdquo Molecular amp Cellular Proteomics vol11 no 2 2012

[78] P S Ramsey and W W Andrews ldquoBiochemical predictors ofpreterm labor fetal fibronectin and salivary estriolrdquo Clinics inPerinatology vol 30 no 4 pp 701ndash733 2003

[79] L D Belkien J Bordt P Moller R Hano and E NieschlagldquoEstradiol in saliva for monitoring follicular stimulation in anin vitro fertilization programrdquo Fertility and Sterility vol 44 no3 pp 322ndash327 1985

[80] K Simunkova R Hampl M Hill J Doucha L Starka and KVondra ldquoSalivary cortisol in low dose (1 microg) ACTH test inhealthy women comparison with serum cortisolrdquo PhysiologicalResearch vol 56 no 4 pp 449ndash453 2007

[81] A van Stegeren N Rohleder W Everaerd and O T WolfldquoSalivary alpha amylase asmarker for adrenergic activity duringstress effect of betablockaderdquo Psychoneuroendocrinology vol31 no 1 pp 137ndash141 2006

[82] R S Rittmaster and D L Thompson ldquoEffect of leuprolide anddexamethasone on hair growth and hormone levels in hirsutewomen the relative importance of the ovary and the adrenal inthe pathogenesis of hirsutismrdquo Journal of Clinical Endocrinologyand Metabolism vol 70 no 4 pp 1096ndash1102 1990

[83] I M Goodyer J Herbert and A Tamplin ldquoPsychoendocrineantecedents of persistent first-episode major depression inadolescents a community-based longitudinal enquiryrdquo Psycho-logical Medicine vol 33 no 4 pp 601ndash610 2003

[84] S Yamada ldquoAssessment of mental condition by saliva level of 3-methoxy-4-hydroxyphenylglycolrdquo Seishin Shinkeigaku Zasshivol 107 no 7 pp 712ndash717 2005 (Japanese)

[85] M Tsuruoka J Hara A Hirayama et al ldquoCapillaryelectrophoresis-mass spectrometry-based metabolomeanalysis of serum and saliva from neurodegenerative dementiapatientsrdquo Electrophoresis vol 34 no 19 pp 2865ndash2872 2013

[86] N Pant Pai B Balram S Shivkumar et al ldquoHead-to-headcomparison of accuracy of a rapid point-of-care HIV test withoral versus whole-blood specimens a systematic review andmeta-analysisrdquoThe Lancet Infectious Diseases vol 12 no 5 pp373ndash380 2012

[87] P L CorstjensW RAbrams andDMalamud ldquoSaliva and viralinfectionsrdquo Periodontology 2000 vol 70 no 1 pp 93ndash110 2016

[88] G B L Menezes F A Pereira C A B Duarte et al ldquoHepatitisC virus quantification in serum and saliva of HCV-infectedpatientsrdquo Memorias do Instituto Oswaldo Cruz vol 107 no 5pp 680ndash683 2012

[89] G Yap B K Sil and L-C Ng ldquoUse of saliva for early denguediagnosisrdquo PLoSNeglected Tropical Diseases vol 5 no 5 ArticleID e1046 2011

[90] P L A M Corstjens and D Malamud ldquoPoint-of-care diagnos-tics for infectious diseasesrdquo in Salivary Diagnostics D T WongEd chapter 13 pp 136ndash149Wiley-Blackwell Ames Iowa USA2008

[91] J W Galloway B J F Keijser and D M Williams ldquoSaliva instudies of epidemiology of human disease the UK Biobankprojectrdquo Periodontology 2000 vol 70 no 1 pp 184ndash195 2016

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

4 Disease Markers

in patients with aggressive and advanced periodontitis and inindividuals with clinically healthy periodontal tissues [52]

Ascorbate and albumin belong to the main tissue antiox-idants together with melatonin Melatonin has nonspecificanti-inflammatory and osteogenic effects which affects Tlymphocytes and its level in saliva positively correlates withthe intensity and extent of periodontal inflammation [53]

Reduced production of interleukin-2 known in patientswith type 1 diabetes together with a reduced level of mela-tonin may be one of the molecular pathological risks for theprogression of periodontal disease in diabetic patients [54]

Reactive oxygen species also play a role in anothermolecular pathological process known as lipid peroxidationReactive oxygen species attack the unsaturated fatty acidsof phospholipid and phosphoprotein membranes therebydisrupting their integrity The end products of lipid peroxi-dation are malondialdehyde and hydroxyalkenals If the lipidperoxidation is in equilibrium with tissue glutathione and itsperoxidase damage to the membranes does not occur Dur-ing periodontitis elevated levels of the end products of lipidperoxidation and decreased levels of natural antioxidants arefound in saliva indicating failure of equilibriumwith the riskof tissue destruction [55]

Reactive oxygen species are implicated in the patho-genesis of many diseases and have been suggested to playa role in the pathogenesis of various oral diseases Forexample the salivary levels of antioxidant enzymes includingsuperoxide dismutase catalase and glutathione peroxidasewere significantly higher in patients with recurrent aphthousstomatitis than in healthy controls [56]

5 Saliva as a Source of Biomarkers forOther Fields of Medicine

Studies investigating the use of saliva as a diagnostic fluidhave a long history This noninvasive approach is not limitedonly to the diagnosis of oral diseases because many systemicdiseases such as different types of cancers cardiovascular dis-eases immunologic syndromes and hereditary deficienciescan also be studied with the aid of salivary diagnostics [57]Even gynecology and psychiatry are interested in salivarybiomarkers monitoring

Reviews on salivary markers in dental caries [58] andoral mucosal diseases [59] have been recently published inPeriodontology 2000 journal

51 Diabetes Mellitus Nonenzymatic glycation of a numberof substances occurs during elevated or fluctuating bloodglucose levels The glycated hemoglobin level in blood haslong been used as amarker ofmetabolically poorly controlleddiabetes More recently it was shown that even in saliva someglycated proteins and fats can be detected and their levelscorrelate with the glycated hemoglobin level in plasma [60]

According to somepublished studies it appears that levelsof sorbitol and fructosamine in saliva correlate with levels ofglucose in capillary blood [61]

Increased plasma glycohemoglobin is also accompaniedby elevated levels of epidermal growth factor nitric oxide andtotal antioxidant activity of saliva [62]

In patients with type 1 diabetes increased levels of ureaand 120572-amylase have been shown in saliva According to thestudy of Lopez et al (2003) the increase of these markers insaliva precedes the clinical signs of diabetes These markersmay be used in the future for screening incipient diabetes[63]

52 Cardiovascular Diseases Wolfram et al (2005) demon-strated increased levels of isoprostane and oxidized low-density lipoproteins in saliva of individuals with coronaryheart disease [64]

Increased attention turns also to endothelin in salivaEndothelin is a peptide that plays a critical role in cardio-vascular regulation Endothelin receptors mediate vasocon-striction as a response to endothelin-1 the primary isoformof this peptide in the cardiovascular system It is assumed thatendothelin A receptors induce the proliferation of vascularsmooth muscle and myocardial hypertrophy whereas theactivations of endothelin B receptors lead to vasodilationvia nitric oxide or prostacyclin and have antithrombotic andantiproliferative effects Pulmonary receptors of endothelinB in addition help to scavenge endothelin-1 Endothelin-1stimulates the production of other neurohumoral factors andpromotes the activity of other neuroendocrine cascades Inpeople with coronary heart disease or chronic obstructivepulmonary disease elevated levels of endothelin and itsinhibitor are found in saliva [65]

In terms of cardiovascular biomarker research the feasi-bility and utility of a programmable bionanochip to identifybiomarkers of acute myocardial infarction in saliva wereinvestigated Interestingly this nanotechnology was able toidentify saliva-based biomarker panels that had significantdiagnostic capability when used in conjunction with anelectrocardiogram and far exceeded the screening capacity ofan electrocardiogram alone [66]

53 Oncological Screening In oncological screening thedetection of soluble factor CD44 or telomerase is beingconsidered as their levels in saliva increase with squamouscell carcinoma of the head and neck [67 68] High attentionis still paid to the possibilities of detecting markers foroncological diseases of the oral cavity [69 70]

In proteomics research of plasma and saliva proteincomposition it was found that in patients with breast orovarian cancer the fractions with molecular weight of 117228 and 287 kDa significantly increased in plasma and salivaIt seems that the biomarker of these malignancies could beprotein provisionally named as HER2neu [71]

CA 125 antigen is present in the plasma of ovarian cancerpatients and its detection is used as a marker for recurrenceafter oncologic treatment This marker is also detectable insaliva and a possible use of CA 125 determination in saliva isconsidered in the screening of this cancer [72]

Using Affymetrix HG-U133-Plus-20 array (AffymetrixSanta Clara CA USA) four salivary mRNA biomarkers(v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologmethyl-CpG binding domain protein 3-like 2 acrosomalvesicle protein 1 and dolichylphosphate mannosyltransferasepolypeptide 1) that can differentiate patients with early-stage

Disease Markers 5

resectable pancreatic cancer from noncancer subjects wereidentified [73] This is a breakthrough proof-of-conceptinvestigation for noninvasive detection of a systemic cancer

Gene panels of 4 to 10 genes for oral squamous cellcarcinoma were constructed based on significant differencesin DNA-methylation patterns between the preoperative andpostoperative saliva of patients with oral squamous cellcarcinoma and between preoperative saliva from patientswith oral squamous cell carcinoma and saliva from healthycontrols [74]

Three salivary metabolites (phenylalanine valine andlactic acid) could distinguish patients with oral squamous cellcarcinoma from healthy controls and could also distinguishpatients with oral leukoplakia from healthy controls [75]

A combination of three microbiotas (Capnocytophagagingivalis Prevotella melaninogenica and Streptococcus mitis)in saliva could be used as diagnostic biomarkers of patientswith oral squamous cell carcinoma [76]

Three proteins (zinc-a-2-glycoprotein haptoglobin andhuman calprotectin) that had good discriminatory powerin lung cancer patients and healthy control subjects werereported by Xiao et al [77]

54 Gynecology Increased levels of estriol in saliva predictthe risk of premature birth There is a range of detection setsfor self-diagnostics of premature birth risk on sale in theUSAAn example is the Salivary Estriol Immunoassay Kit fromSalimetrics LLC

Dynamics of estradiol levels in saliva is used in assistedreproduction to accurately determine the ovulation [78 79]

55 Endocrinology Salivary cortisol has long been usedin endocrinological examination methods as a biomarkerfor determining hypothalamus-pituitary-adrenal axis activity[80]

Another salivary marker used by endocrinologists issalivary 120572-amylase (sAA) that helps determine sympathetic-adrenal medulla axis activity The amount of salivary 120572-amylase significantly increases with adrenergic activationespecially with stress [81]

When hyperandrogenemia occurs for example in poly-cystic ovary syndrome increased levels of dehydroepiandros-terone sulfate (DHEA-S) and androstenedione can bedetected in saliva [82]

56 Psychiatry Research in psychiatry also has its markersthat can be measured in saliva It is for example the ratioof cortisol and dehydroepiandrosterone which increases indepressive conditions and varies with changes in affectivityThe good predictive value of this assay is used for theindividual dosing of antidepressants in adolescents [83]

It has been found that 3-methoxy-4-hydroxyphenylglycol(one of the noradrenalinemetabolites) level in saliva decreas-es in depression or in reduced mental activity Nowadays itsdetermination is used for research purposes only [84]

Two salivary metabolites (arginine and tyrosine) differedsignificantly between patients with dementia and healthysubjects [85]

57 Drug Addiction During drug addiction control thesaliva along with urine becomes an important material fordetecting amphetamine opiates phencyclidine marijuanaand cocaine and their metabolites There are already a num-ber of special detection kits ToxCup (Clia Laboratories)Saliva MultiDrug Screen test kit (Medimpex Inc) iScreen(BioCheck) QuickScreen (CraigMedical Inc) and so forth

58 Virus Diseases Saliva HIV tests have demonstratedcomparable accuracy to the traditional blood test Oral HIVtests can be a powerful tool for high-risk populations [86]

For HIV viral-load analysis a frequently used commer-cial assay is the COBASAmplicorHIV-1Monitor Test (RocheDiagnostics Indianapolis USA) and an example of a com-mercial assay based on signal amplification is the VERSANTHIV-1 RNA Assay (Siemens AG Munich Germany) [87]

Hepatitis C virus RNA can be consistently detectedin saliva from hepatitis C virus-infected individuals usingquantitative PCR [88]

Dengue virus specific IgA in salivawas detected soon afterinfection in dengue-endemic regions [89]

For the detection of human antibodies against measlesandmumps in oral fluid several simple platforms for antibodydetection in saliva have been published [90]

Currently only two oral-based commercial tests forinfectious disease are FDA approved for use in the USA theOraQuick oral HIV test and the OraRisk human papillo-mavirus salivary diagnostic test [87]

6 Conclusion

The determination of biomarkers in saliva is becoming animportant part of laboratory diagnostics and the prediction ofperiodontal and other diseases Biomarkers in salivamay alsoserve to determine the context of periodontal disease with analtered state of the body or with chronic diseases Saliva alsocontains a series of markers which may predict the risk ofsome systemic disease development

It is certain that a lotmore research efforts are necessary todetermine the sensitivity and specificity of salivary biomarkerdetection and to increase the availability of routine detectionmethods

The UK Biobank holds the worldrsquos largest bank of around85000 well-characterized saliva samples each accompaniedby blood and urine samples the results of a battery ofphysiological tests a full medical history and a detaileddescription of the subjectrsquos lifestyle [91] The evaluationof these samples can be compared with clinical status ofproject participants in future and may bring a lot of recentlyunavailable pieces of information about salivary biomarkers

Competing Interests

The authors declare that they have no competing interests

Acknowledgments

The study was supported by PRVOUK-P28LF16 (CharlesUniversity of Prague Czech Republic) by Project 14-37368G

6 Disease Markers

(Grant Agency Czech Republic) by Project NT 14164-3(Ministry of Health Czech Republic) and by Project 15-28142A (Czech Health Research Council Czech Republic)

References

[1] G B Proctor ldquoThe physiology of salivary secretionrdquo Periodon-tology 2000 vol 70 no 1 pp 11ndash25 2016

[2] J A Loo W Yan P Ramachandran and D TWong ldquoCompar-ative human salivary and plasma proteomesrdquo Journal of DentalResearch vol 89 no 10 pp 1016ndash1023 2010

[3] L A S Nunes S Mussavira and O S Bindhu ldquoClinical anddiagnostic utility of saliva as a non-invasive diagnostic fluid asystematic reviewrdquo BiochemiaMedica vol 25 no 2 pp 177ndash1922015

[4] S P Barros RWilliams S Offenbacher and TMorelli ldquoGingi-val crevicular fluid as a source of biomarkers for periodontitisrdquoPeriodontology 2000 vol 70 no 1 pp 53ndash64 2016

[5] R R Wassall and P M Preshaw ldquoClinical and technicalconsiderations in the analysis of gingival crevicular fluidrdquoPeriodontology 2000 vol 70 no 1 pp 65ndash79 2016

[6] Y Zhang J Sun C-C Lin E Abemayor M B Wang and DT W Wong ldquoThe emerging landscape of salivary diagnosticsrdquoPeriodontology 2000 vol 70 no 1 pp 38ndash52 2016

[7] A Segal and D T Wong ldquoSalivary diagnostics enhancing dis-ease detection and making medicine betterrdquo European Journalof Dental Education vol 12 no 1 pp 22ndash29 2008

[8] JMYoshizawaCA Schafer J J Schafer J J Farrell B J Pasterand D TWWong ldquoSalivary biomarkers toward future clinicaland diagnostic utilitiesrdquo Clinical Microbiology Reviews vol 26no 4 pp 781ndash791 2013

[9] D A Chambers P B Imrey R L Cohen J M Crawford M EAlves and T A McSwiggin ldquoA longitudinal study of aspartateaminotransferase in human gingival crevicular fluidrdquo Journal ofPeriodontal Research vol 26 no 2 pp 65ndash74 1991

[10] A Totan M Greabu C Totan and T Spinu ldquoSalivary aspartateaminotransferase alanine aminotransferase and alkaline phos-phatase possible markers in periodontal diseasesrdquo ClinicalChemistry and Laboratory Medicine vol 44 no 5 pp 612ndash6152006

[11] Y Nomura Y Shimada N Hanada et al ldquoSalivary biomark-ers for predicting the progression of chronic periodontitisrdquoArchives of Oral Biology vol 57 no 4 pp 413ndash420 2012

[12] I B Lamster E Kaufman J T Grbic L J Winston and RE Singer ldquo120573-glucuronidase activity in saliva relationship toclinical periodontal parametersrdquo Journal of Periodontology vol74 no 3 pp 353ndash359 2003

[13] S Elgun N Ozmeric and S Demirtas ldquoAlanine aminopepti-dase and dipeptidylpeptidase IV in Saliva the possible role inperiodontal diseaserdquo Clinica Chimica Acta vol 298 no 1-2 pp187ndash191 2000

[14] K Suomalainen L Saxen P Vilja and J Tenovuo ldquoPeroxidaseslactoferrin and lysozyme in peripheral blood neutrophils gin-gival crevicular fluid and whole saliva of patients with localizedjuvenile periodontitisrdquo Oral Diseases vol 2 no 2 pp 129ndash1341996

[15] B E Britigan and B L Edeker ldquoPseudomonas and neutrophilproductsmodify transferrin and lactoferrin to create conditionsthat favor hydroxyl radical formationrdquo The Journal of ClinicalInvestigation vol 88 no 4 pp 1092ndash1102 1991

[16] T Ingman T Tervahartiala Y Ding et al ldquoMatrix metallo-proteinases and their inhibitors in gingival crevicular fluid andsaliva of periodontitis patientsrdquo Journal of Clinical Periodontol-ogy vol 23 no 12 pp 1127ndash1132 1996

[17] T Sorsa L Tjaderhane Y T Konttinen et al ldquoMatrix met-alloproteinases contribution to pathogenesis diagnosis andtreatment of periodontal inflammationrdquo Annals of Medicinevol 38 no 5 pp 306ndash321 2006

[18] J L Ebersole J L Schuster J Stevens et al ldquoPatterns ofsalivary analytes provide diagnostic capacity for distinguishingchronic adult periodontitis from healthrdquo Journal of ClinicalImmunology vol 33 no 1 pp 271ndash279 2013

[19] N Rathnayake S Akerman B Klinge et al ldquoSalivary biomark-ers of oral healthmdasha cross-sectional studyrdquo Journal of ClinicalPeriodontology vol 40 no 2 pp 140ndash147 2013

[20] W M Sexton Y Lin R J Kryscio D R Dawson III J LEbersole and C S Miller ldquoSalivary biomarkers of periodontaldisease in response to treatmentrdquo Journal of Clinical Periodon-tology vol 38 no 5 pp 434ndash441 2011

[21] J S Kinney T Morelli T Braun et al ldquoSalivapathogenbiomarker signatures and periodontal disease progressionrdquoJournal of Dental Research vol 90 no 6 pp 752ndash758 2011

[22] U K Gursoy E Kononen S Huumonen et al ldquoSalivary type Icollagen degradation end-products and related matrix metallo-proteinases in periodontitisrdquo Journal of Clinical Periodontologyvol 40 no 1 pp 18ndash25 2013

[23] C A Meschiari A M Marcaccini B C Santos Moura L RZuardi J E Tanus-Santos and R F Gerlach ldquoSalivary MMPsTIMPs and MPO levels in periodontal disease patients andcontrolsrdquo Clinica Chimica Acta vol 421 pp 140ndash146 2013

[24] T SorsaU KGursoy SNwhator et al ldquoAnalysis ofmatrixmet-alloproteinases especially MMP-8 in gingival crevicular fluidmouthrinse and saliva for monitoring periodontal diseasesrdquoPeriodontology 2000 vol 70 no 1 pp 142ndash163 2016

[25] G J Van Steijn A V Nieuw Amerongen E C I Veerman SKasanmoentalib and B Overdijk ldquoEffect of periodontal treat-ment on the activity of chitinase in whole saliva of periodontitispatientsrdquo Journal of Periodontal Research vol 37 no 4 pp 245ndash249 2002

[26] N Ozmeric T Baydar A Bodur et al ldquoLevel of neopterin amarker of immune cell activation in gingival crevicular fluidsaliva and urine in patients with aggressive periodontitisrdquoJournal of Periodontology vol 73 no 7 pp 720ndash725 2002

[27] F S Lakschevitz G M Aboodi and M Glogauer ldquoOralneutrophil transcriptome changes result in a pro-survival phe-notype in periodontal diseasesrdquo PLoS ONE vol 8 no 7 ArticleID e68983 2013

[28] D L Korte and J Kinney ldquoPersonalized medicine an updateof salivary biomarkers for periodontal diseasesrdquo Periodontology2000 vol 70 no 1 pp 26ndash37 2016

[29] M Desvarieux R T Demmer T Rundek et al ldquoRelationshipbetween periodontal disease tooth loss and carotid arteryplaque the oral infections and vascular disease epidemiologystudy (INVEST)rdquo Stroke vol 34 no 9 pp 2120ndash2125 2003

[30] N J Park Y Li T Yu B M N Brinkman and D T WongldquoCharacterization of RNA in salivardquo Clinical Chemistry vol 52no 6 pp 988ndash994 2006

[31] Z Chen M G Mauk J Wang et al ldquoA microfluidic system forsaliva-based detection of infectious diseasesrdquoAnnals of the NewYork Academy of Sciences vol 1098 pp 429ndash436 2007

Disease Markers 7

[32] W R Abrams C A Barber K McCann et al ldquoDevelopment ofa microfluidic device for detection of pathogens in oral samplesusing upconverting phosphor technology (UPT)rdquo Annals of theNew York Academy of Sciences vol 1098 pp 375ndash388 2007

[33] P L AM Corstjens Z ChenM Zuiderwijk et al ldquoRapid assayformat formultiplex detection of humoral immune responses toinfectious disease pathogens (HIVHCV andTB)rdquoAnnals of theNew York Academy of Sciences vol 1098 pp 437ndash445 2007

[34] F DrsquoAiuto M Parkar G Andreou et al ldquoPeriodontitis and sys-temic inflammation control of the local infection is associatedwith a reduction in serum inflammatory markersrdquo Journal ofDental Research vol 83 no 2 pp 156ndash160 2004

[35] I Ouellet-Morin A Danese B Williams and L ArseneaultldquoValidation of a high-sensitivity assay for C-reactive protein inhuman salivardquo Brain Behavior and Immunity vol 25 no 4 pp640ndash646 2011

[36] E Megson T Fitzsimmons K Dharmapatni and P MarkBartold ldquoC-reactive protein in gingival crevicular fluid maybe indicative of systemic inflammationrdquo Journal of ClinicalPeriodontology vol 37 no 9 pp 797ndash804 2010

[37] S Podzimek J Mysak T Janatova and J Duskova ldquoC-reactive protein in peripheral blood of patients with chronicand aggressive periodontitis gingivitis and gingival recessionsrdquoMediators of Inflammation vol 2015 Article ID 564858 7 pages2015

[38] Y Murakami S Hanazawa S Tanaka H Iwahashi S Kitanoand S Fujisawa ldquoFibronectin in saliva inhibits Porphy-romonas gingivalis fimbria-induced expression of inflamma-tory cytokine gene in mouse macrophagesrdquo FEMS Immunologyand Medical Microbiology vol 22 no 3 pp 257ndash262 1998

[39] M A Lie B G Loos YM C Henskens et al ldquoSalivary cystatinactivity and cystatin C in natural and experimental gingivitis insmokers and non-smokersrdquo Journal of Clinical Periodontologyvol 28 no 10 pp 979ndash984 2001

[40] M S Rasch B LMealey T J PrihodaD SWoodard and LMMcManus ldquoThe effect of initial periodontal therapy on salivaryplatelet-activating factor levels in chronic adult periodontitisrdquoJournal of Periodontology vol 66 no 7 pp 613ndash623 1995

[41] V Booth S Young A Cruchley N S Taichman and E Pale-olog ldquoVascular endothelial growth factor in human periodontaldiseaserdquo Journal of Periodontal Research vol 33 no 8 pp 491ndash499 1998

[42] M Ohshima K Fujikawa H Akutagawa T Kato K Ito and KOtsuka ldquoHepatocyte growth factor in saliva a possible markerfor periodontal disease statusrdquo Journal of oral science vol 44no 1 pp 35ndash39 2002

[43] U K Gursoy E Kononen P J Pussinen et al ldquoUse of host- andbacteria-derived salivary markers in detection of periodontitisa cumulative approachrdquoDiseaseMarkers vol 30 no 6 pp 299ndash305 2011

[44] K M Jaedicke P M Preshaw and J J Taylor ldquoSalivarycytokines as biomarkers of periodontal diseasesrdquo Periodontol-ogy 2000 vol 70 no 1 pp 164ndash183 2016

[45] P P Costa G L Trevisan G O Macedo et al ldquoSalivaryinterleukin-6 matrix metalloproteinase-8 and osteoprotegerinin patients with periodontitis and diabetesrdquo Journal of Periodon-tology vol 81 no 3 pp 384ndash391 2010

[46] S Liskmann T Vihalemm O Salum K Zilmer K Fischerand M Zilmer ldquoCorrelations between clinical parameters andinterleukin-6 and interleukin-10 levels in saliva from totally

edentulous patients with peri-implant diseaserdquo The Interna-tional Journal of Oral and Maxillofacial Implants vol 21 no 4pp 543ndash550 2006

[47] N Spielmann andDWong ldquoSaliva diagnostics and therapeuticperspectivesrdquo Oral Diseases vol 17 no 4 pp 345ndash354 2011

[48] P Denny F KHagenMHardt et al ldquoThe proteomes of humanparotid and submandibularsublingual gland salivas collectedas the ductal secretionsrdquo Journal of Proteome Research vol 7no 5 pp 1994ndash2006 2008

[49] D V Sculley and S C Langley-Evans ldquoPeriodontal disease isassociated with lower antioxidant capacity in whole saliva andevidence of increased protein oxidationrdquo Clinical Science vol105 no 2 pp 167ndash172 2003

[50] M Takane N Sugano H Iwasaki Y Iwano N Shimizu andK Ito ldquoNew biomarker evidence of oxidative DNA damage inwhole saliva from clinically healthy and periodontally diseasedindividualsrdquo Journal of Periodontology vol 73 no 5 pp 551ndash554 2002

[51] R Diab-Ladki B Pellat and R Chahine ldquoDecrease in thetotal antioxidant activity of saliva in patients with periodontaldiseasesrdquo Clinical Oral Investigations vol 7 no 2 pp 103ndash1072003

[52] M Takane N Sugano T Ezawa T Uchiyama and K ItoldquoA marker of oxidative stress in saliva association withperiodontally-involved teeth of a hopeless prognosisrdquo Journalof Oral Science vol 47 no 1 pp 53ndash57 2005

[53] D-X Tan L C Manchester R J Reiter W-B Qi M Kar-bownik and J R Calvo ldquoSignificance ofmelatonin in antioxida-tive defense system reactions and productsrdquo Biological Signalsand Receptors vol 9 no 3-4 pp 137ndash159 2000

[54] A Cutando G Gomez-Moreno J Villalba M J Ferrera GEscames and D Acuna-Castroviejo ldquoRelationship betweensalivary melatonin levels and periodontal status in diabeticpatientsrdquo Journal of Pineal Research vol 35 no 4 pp 239ndash2442003

[55] C C Tsai H S Chen S L Chen et al ldquoLipid peroxidationa possible role in the induction and progression of chronicperiodontitisrdquo Journal of Periodontal Research vol 40 no 5 pp378ndash386 2005

[56] Y Karincaoglu K Batcioglu T Erdem M Esrefoglu and MGene ldquoThe levels of plasma and salivary antioxidants in thepatient with recurrent aphthous stomatitisrdquo Journal of OralPathology and Medicine vol 34 no 1 pp 7ndash12 2005

[57] C SMiller J D Foley A L Bailey et al ldquoCurrent developmentsin salivary diagnosticsrdquo Biomarkers inMedicine vol 4 no 1 pp171ndash189 2010

[58] X Gao S Jiang D Koh and C S Hsu ldquoSalivary biomarkersfor dental cariesrdquo Periodontology 2000 vol 70 no 1 pp 128ndash141 2016

[59] Y Hassona and C Scully ldquoSalivary changes in oral mucosaldiseasesrdquo Periodontology 2000 vol 70 no 1 pp 111ndash127 2016

[60] A M Schmidt E Weidman E Lalla et al ldquoAdvanced glycationendproducts (AGEs) induce oxidant stress in the gingiva apotential mechanism underlying accelerated periodontal dis-ease associated with diabetesrdquo Journal of Periodontal Researchvol 31 no 7 pp 508ndash515 1996

[61] S AMorenkova ldquoComparative analysis of dependence of salivasorbitol and fructoseamine levels on blood glucose level inpatients with diabetesrdquo Biomeditsinskaya Khimiya vol 50 no6 pp 612ndash614 2004 (Russian)

8 Disease Markers

[62] F Astaneie M Afshari A Mojtahedi et al ldquoTotal antioxidantcapacity and levels of epidermal growth factor and nitric oxidein blood and saliva of insulin-dependent diabetic patientsrdquoArchives of Medical Research vol 36 no 4 pp 376ndash381 2005

[63] M E Lopez M E Colloca R G Paez J N Schallmach M AKoss andA Chervonagura ldquoSalivary characteristics of diabeticchildrenrdquoBrazilianDental Journal vol 14 no 1 pp 26ndash31 2003

[64] R Wolfram A Oguogho B Palumbo and H SinzingerldquoEnhanced oxidative stress in coronary heart disease andchronic heart failure as indicated by an increased 8-epi-PGF2120572rdquoEuropean Journal of Heart Failure vol 7 no 2 pp 167ndash172 2005

[65] S Xiang R Denver M Bailey and H Krum ldquoPhysiologicdeterminants of endothelin concentrations in human salivardquoClinical Chemistry vol 49 no 12 pp 2012ndash2019 2003

[66] N Christodoulides F N Pierre X Sanchez et al ldquoPro-grammable bio-nanochip technology for the diagnosis of car-diovascular disease at the point-of-carerdquo Methodist DeBakeyCardiovascular Journal vol 8 no 1 pp 6ndash12 2012

[67] E J Franzmann E P Reategui K L Carraway K L HamiltonD T Weed and W J Goodwin ldquoSalivary soluble CD44 apotential molecular marker for head and neck cancerrdquo CancerEpidemiology Biomarkers and Prevention vol 14 no 3 pp 735ndash739 2005

[68] L-P Zhong G-F Chen Z-F Xu X Zhang F-Y Ping and S-F Zhao ldquoDetection of telomerase activity in saliva from oralsquamous cell carcinoma patientsrdquo International Journal of Oraland Maxillofacial Surgery vol 34 no 5 pp 566ndash570 2005

[69] A K Markopoulos E Z Michailidou and G TzimagiorgisldquoSalivary markers for oral cancer detectionrdquo Open DentistryJournal no 4 pp 172ndash178 2010

[70] F D Shah R Begum B N Vajaria et al ldquoA review on salivarygenomics and proteomics biomarkers in oral cancerrdquo IndianJournal of Clinical Biochemistry vol 26 no 4 pp 326ndash334 2011

[71] C F Streckfus L Bigler T Dellinger M Kuhn N Chouinardand X Dai ldquoThe expression of the c-erbB-2 receptor proteinin glandular salivary secretionsrdquo Journal of Oral Pathology andMedicine vol 33 no 10 pp 595ndash600 2004

[72] M Markman ldquoNormal CA-125 and the risk of progression inovarian cancerrdquo Journal of Clinical Oncology vol 24 no 20 p3310 2006

[73] L Zhang J J Farrell H Zhou et al ldquoSalivary transcriptomicbiomarkers for detection of resectable pancreatic cancerrdquo Gas-troenterology vol 138 no 3 pp 949ndash957 2010

[74] C T Viet and B L Schmidt ldquoMethylation array analysisof preoperative and postoperative saliva DNA in oral cancerpatientsrdquo Cancer Epidemiology Biomarkers and Prevention vol17 no 12 pp 3603ndash3611 2008

[75] J Wei G Xie Z Zhou et al ldquoSalivary metabolite signatures oforal cancer and leukoplakiardquo International Journal of Cancervol 129 no 9 pp 2207ndash2217 2011

[76] D L Mager A D Haffajee P M Delvin C M Norris M RPosner and J M Goodson ldquoThe salivary microbiota as a diag-nostic indicator of oral cancer a descriptive non-randomizedstudy of cancer-free and oral squamous cell carcinoma subjectsrdquoJournal of Translational Medicine vol 3 article 27 2005

[77] H Xiao L Zhang H Zhou J M Lee E B Garon and D T WWong ldquoProteomic analysis of human saliva from lung cancerpatients using two-dimensional difference gel electrophoresisand mass spectrometryrdquo Molecular amp Cellular Proteomics vol11 no 2 2012

[78] P S Ramsey and W W Andrews ldquoBiochemical predictors ofpreterm labor fetal fibronectin and salivary estriolrdquo Clinics inPerinatology vol 30 no 4 pp 701ndash733 2003

[79] L D Belkien J Bordt P Moller R Hano and E NieschlagldquoEstradiol in saliva for monitoring follicular stimulation in anin vitro fertilization programrdquo Fertility and Sterility vol 44 no3 pp 322ndash327 1985

[80] K Simunkova R Hampl M Hill J Doucha L Starka and KVondra ldquoSalivary cortisol in low dose (1 microg) ACTH test inhealthy women comparison with serum cortisolrdquo PhysiologicalResearch vol 56 no 4 pp 449ndash453 2007

[81] A van Stegeren N Rohleder W Everaerd and O T WolfldquoSalivary alpha amylase asmarker for adrenergic activity duringstress effect of betablockaderdquo Psychoneuroendocrinology vol31 no 1 pp 137ndash141 2006

[82] R S Rittmaster and D L Thompson ldquoEffect of leuprolide anddexamethasone on hair growth and hormone levels in hirsutewomen the relative importance of the ovary and the adrenal inthe pathogenesis of hirsutismrdquo Journal of Clinical Endocrinologyand Metabolism vol 70 no 4 pp 1096ndash1102 1990

[83] I M Goodyer J Herbert and A Tamplin ldquoPsychoendocrineantecedents of persistent first-episode major depression inadolescents a community-based longitudinal enquiryrdquo Psycho-logical Medicine vol 33 no 4 pp 601ndash610 2003

[84] S Yamada ldquoAssessment of mental condition by saliva level of 3-methoxy-4-hydroxyphenylglycolrdquo Seishin Shinkeigaku Zasshivol 107 no 7 pp 712ndash717 2005 (Japanese)

[85] M Tsuruoka J Hara A Hirayama et al ldquoCapillaryelectrophoresis-mass spectrometry-based metabolomeanalysis of serum and saliva from neurodegenerative dementiapatientsrdquo Electrophoresis vol 34 no 19 pp 2865ndash2872 2013

[86] N Pant Pai B Balram S Shivkumar et al ldquoHead-to-headcomparison of accuracy of a rapid point-of-care HIV test withoral versus whole-blood specimens a systematic review andmeta-analysisrdquoThe Lancet Infectious Diseases vol 12 no 5 pp373ndash380 2012

[87] P L CorstjensW RAbrams andDMalamud ldquoSaliva and viralinfectionsrdquo Periodontology 2000 vol 70 no 1 pp 93ndash110 2016

[88] G B L Menezes F A Pereira C A B Duarte et al ldquoHepatitisC virus quantification in serum and saliva of HCV-infectedpatientsrdquo Memorias do Instituto Oswaldo Cruz vol 107 no 5pp 680ndash683 2012

[89] G Yap B K Sil and L-C Ng ldquoUse of saliva for early denguediagnosisrdquo PLoSNeglected Tropical Diseases vol 5 no 5 ArticleID e1046 2011

[90] P L A M Corstjens and D Malamud ldquoPoint-of-care diagnos-tics for infectious diseasesrdquo in Salivary Diagnostics D T WongEd chapter 13 pp 136ndash149Wiley-Blackwell Ames Iowa USA2008

[91] J W Galloway B J F Keijser and D M Williams ldquoSaliva instudies of epidemiology of human disease the UK Biobankprojectrdquo Periodontology 2000 vol 70 no 1 pp 184ndash195 2016

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Disease Markers 5

resectable pancreatic cancer from noncancer subjects wereidentified [73] This is a breakthrough proof-of-conceptinvestigation for noninvasive detection of a systemic cancer

Gene panels of 4 to 10 genes for oral squamous cellcarcinoma were constructed based on significant differencesin DNA-methylation patterns between the preoperative andpostoperative saliva of patients with oral squamous cellcarcinoma and between preoperative saliva from patientswith oral squamous cell carcinoma and saliva from healthycontrols [74]

Three salivary metabolites (phenylalanine valine andlactic acid) could distinguish patients with oral squamous cellcarcinoma from healthy controls and could also distinguishpatients with oral leukoplakia from healthy controls [75]

A combination of three microbiotas (Capnocytophagagingivalis Prevotella melaninogenica and Streptococcus mitis)in saliva could be used as diagnostic biomarkers of patientswith oral squamous cell carcinoma [76]

Three proteins (zinc-a-2-glycoprotein haptoglobin andhuman calprotectin) that had good discriminatory powerin lung cancer patients and healthy control subjects werereported by Xiao et al [77]

54 Gynecology Increased levels of estriol in saliva predictthe risk of premature birth There is a range of detection setsfor self-diagnostics of premature birth risk on sale in theUSAAn example is the Salivary Estriol Immunoassay Kit fromSalimetrics LLC

Dynamics of estradiol levels in saliva is used in assistedreproduction to accurately determine the ovulation [78 79]

55 Endocrinology Salivary cortisol has long been usedin endocrinological examination methods as a biomarkerfor determining hypothalamus-pituitary-adrenal axis activity[80]

Another salivary marker used by endocrinologists issalivary 120572-amylase (sAA) that helps determine sympathetic-adrenal medulla axis activity The amount of salivary 120572-amylase significantly increases with adrenergic activationespecially with stress [81]

When hyperandrogenemia occurs for example in poly-cystic ovary syndrome increased levels of dehydroepiandros-terone sulfate (DHEA-S) and androstenedione can bedetected in saliva [82]

56 Psychiatry Research in psychiatry also has its markersthat can be measured in saliva It is for example the ratioof cortisol and dehydroepiandrosterone which increases indepressive conditions and varies with changes in affectivityThe good predictive value of this assay is used for theindividual dosing of antidepressants in adolescents [83]

It has been found that 3-methoxy-4-hydroxyphenylglycol(one of the noradrenalinemetabolites) level in saliva decreas-es in depression or in reduced mental activity Nowadays itsdetermination is used for research purposes only [84]

Two salivary metabolites (arginine and tyrosine) differedsignificantly between patients with dementia and healthysubjects [85]

57 Drug Addiction During drug addiction control thesaliva along with urine becomes an important material fordetecting amphetamine opiates phencyclidine marijuanaand cocaine and their metabolites There are already a num-ber of special detection kits ToxCup (Clia Laboratories)Saliva MultiDrug Screen test kit (Medimpex Inc) iScreen(BioCheck) QuickScreen (CraigMedical Inc) and so forth

58 Virus Diseases Saliva HIV tests have demonstratedcomparable accuracy to the traditional blood test Oral HIVtests can be a powerful tool for high-risk populations [86]

For HIV viral-load analysis a frequently used commer-cial assay is the COBASAmplicorHIV-1Monitor Test (RocheDiagnostics Indianapolis USA) and an example of a com-mercial assay based on signal amplification is the VERSANTHIV-1 RNA Assay (Siemens AG Munich Germany) [87]

Hepatitis C virus RNA can be consistently detectedin saliva from hepatitis C virus-infected individuals usingquantitative PCR [88]

Dengue virus specific IgA in salivawas detected soon afterinfection in dengue-endemic regions [89]

For the detection of human antibodies against measlesandmumps in oral fluid several simple platforms for antibodydetection in saliva have been published [90]

Currently only two oral-based commercial tests forinfectious disease are FDA approved for use in the USA theOraQuick oral HIV test and the OraRisk human papillo-mavirus salivary diagnostic test [87]

6 Conclusion

The determination of biomarkers in saliva is becoming animportant part of laboratory diagnostics and the prediction ofperiodontal and other diseases Biomarkers in salivamay alsoserve to determine the context of periodontal disease with analtered state of the body or with chronic diseases Saliva alsocontains a series of markers which may predict the risk ofsome systemic disease development

It is certain that a lotmore research efforts are necessary todetermine the sensitivity and specificity of salivary biomarkerdetection and to increase the availability of routine detectionmethods

The UK Biobank holds the worldrsquos largest bank of around85000 well-characterized saliva samples each accompaniedby blood and urine samples the results of a battery ofphysiological tests a full medical history and a detaileddescription of the subjectrsquos lifestyle [91] The evaluationof these samples can be compared with clinical status ofproject participants in future and may bring a lot of recentlyunavailable pieces of information about salivary biomarkers

Competing Interests

The authors declare that they have no competing interests

Acknowledgments

The study was supported by PRVOUK-P28LF16 (CharlesUniversity of Prague Czech Republic) by Project 14-37368G

6 Disease Markers

(Grant Agency Czech Republic) by Project NT 14164-3(Ministry of Health Czech Republic) and by Project 15-28142A (Czech Health Research Council Czech Republic)

References

[1] G B Proctor ldquoThe physiology of salivary secretionrdquo Periodon-tology 2000 vol 70 no 1 pp 11ndash25 2016

[2] J A Loo W Yan P Ramachandran and D TWong ldquoCompar-ative human salivary and plasma proteomesrdquo Journal of DentalResearch vol 89 no 10 pp 1016ndash1023 2010

[3] L A S Nunes S Mussavira and O S Bindhu ldquoClinical anddiagnostic utility of saliva as a non-invasive diagnostic fluid asystematic reviewrdquo BiochemiaMedica vol 25 no 2 pp 177ndash1922015

[4] S P Barros RWilliams S Offenbacher and TMorelli ldquoGingi-val crevicular fluid as a source of biomarkers for periodontitisrdquoPeriodontology 2000 vol 70 no 1 pp 53ndash64 2016

[5] R R Wassall and P M Preshaw ldquoClinical and technicalconsiderations in the analysis of gingival crevicular fluidrdquoPeriodontology 2000 vol 70 no 1 pp 65ndash79 2016

[6] Y Zhang J Sun C-C Lin E Abemayor M B Wang and DT W Wong ldquoThe emerging landscape of salivary diagnosticsrdquoPeriodontology 2000 vol 70 no 1 pp 38ndash52 2016

[7] A Segal and D T Wong ldquoSalivary diagnostics enhancing dis-ease detection and making medicine betterrdquo European Journalof Dental Education vol 12 no 1 pp 22ndash29 2008

[8] JMYoshizawaCA Schafer J J Schafer J J Farrell B J Pasterand D TWWong ldquoSalivary biomarkers toward future clinicaland diagnostic utilitiesrdquo Clinical Microbiology Reviews vol 26no 4 pp 781ndash791 2013

[9] D A Chambers P B Imrey R L Cohen J M Crawford M EAlves and T A McSwiggin ldquoA longitudinal study of aspartateaminotransferase in human gingival crevicular fluidrdquo Journal ofPeriodontal Research vol 26 no 2 pp 65ndash74 1991

[10] A Totan M Greabu C Totan and T Spinu ldquoSalivary aspartateaminotransferase alanine aminotransferase and alkaline phos-phatase possible markers in periodontal diseasesrdquo ClinicalChemistry and Laboratory Medicine vol 44 no 5 pp 612ndash6152006

[11] Y Nomura Y Shimada N Hanada et al ldquoSalivary biomark-ers for predicting the progression of chronic periodontitisrdquoArchives of Oral Biology vol 57 no 4 pp 413ndash420 2012

[12] I B Lamster E Kaufman J T Grbic L J Winston and RE Singer ldquo120573-glucuronidase activity in saliva relationship toclinical periodontal parametersrdquo Journal of Periodontology vol74 no 3 pp 353ndash359 2003

[13] S Elgun N Ozmeric and S Demirtas ldquoAlanine aminopepti-dase and dipeptidylpeptidase IV in Saliva the possible role inperiodontal diseaserdquo Clinica Chimica Acta vol 298 no 1-2 pp187ndash191 2000

[14] K Suomalainen L Saxen P Vilja and J Tenovuo ldquoPeroxidaseslactoferrin and lysozyme in peripheral blood neutrophils gin-gival crevicular fluid and whole saliva of patients with localizedjuvenile periodontitisrdquo Oral Diseases vol 2 no 2 pp 129ndash1341996

[15] B E Britigan and B L Edeker ldquoPseudomonas and neutrophilproductsmodify transferrin and lactoferrin to create conditionsthat favor hydroxyl radical formationrdquo The Journal of ClinicalInvestigation vol 88 no 4 pp 1092ndash1102 1991

[16] T Ingman T Tervahartiala Y Ding et al ldquoMatrix metallo-proteinases and their inhibitors in gingival crevicular fluid andsaliva of periodontitis patientsrdquo Journal of Clinical Periodontol-ogy vol 23 no 12 pp 1127ndash1132 1996

[17] T Sorsa L Tjaderhane Y T Konttinen et al ldquoMatrix met-alloproteinases contribution to pathogenesis diagnosis andtreatment of periodontal inflammationrdquo Annals of Medicinevol 38 no 5 pp 306ndash321 2006

[18] J L Ebersole J L Schuster J Stevens et al ldquoPatterns ofsalivary analytes provide diagnostic capacity for distinguishingchronic adult periodontitis from healthrdquo Journal of ClinicalImmunology vol 33 no 1 pp 271ndash279 2013

[19] N Rathnayake S Akerman B Klinge et al ldquoSalivary biomark-ers of oral healthmdasha cross-sectional studyrdquo Journal of ClinicalPeriodontology vol 40 no 2 pp 140ndash147 2013

[20] W M Sexton Y Lin R J Kryscio D R Dawson III J LEbersole and C S Miller ldquoSalivary biomarkers of periodontaldisease in response to treatmentrdquo Journal of Clinical Periodon-tology vol 38 no 5 pp 434ndash441 2011

[21] J S Kinney T Morelli T Braun et al ldquoSalivapathogenbiomarker signatures and periodontal disease progressionrdquoJournal of Dental Research vol 90 no 6 pp 752ndash758 2011

[22] U K Gursoy E Kononen S Huumonen et al ldquoSalivary type Icollagen degradation end-products and related matrix metallo-proteinases in periodontitisrdquo Journal of Clinical Periodontologyvol 40 no 1 pp 18ndash25 2013

[23] C A Meschiari A M Marcaccini B C Santos Moura L RZuardi J E Tanus-Santos and R F Gerlach ldquoSalivary MMPsTIMPs and MPO levels in periodontal disease patients andcontrolsrdquo Clinica Chimica Acta vol 421 pp 140ndash146 2013

[24] T SorsaU KGursoy SNwhator et al ldquoAnalysis ofmatrixmet-alloproteinases especially MMP-8 in gingival crevicular fluidmouthrinse and saliva for monitoring periodontal diseasesrdquoPeriodontology 2000 vol 70 no 1 pp 142ndash163 2016

[25] G J Van Steijn A V Nieuw Amerongen E C I Veerman SKasanmoentalib and B Overdijk ldquoEffect of periodontal treat-ment on the activity of chitinase in whole saliva of periodontitispatientsrdquo Journal of Periodontal Research vol 37 no 4 pp 245ndash249 2002

[26] N Ozmeric T Baydar A Bodur et al ldquoLevel of neopterin amarker of immune cell activation in gingival crevicular fluidsaliva and urine in patients with aggressive periodontitisrdquoJournal of Periodontology vol 73 no 7 pp 720ndash725 2002

[27] F S Lakschevitz G M Aboodi and M Glogauer ldquoOralneutrophil transcriptome changes result in a pro-survival phe-notype in periodontal diseasesrdquo PLoS ONE vol 8 no 7 ArticleID e68983 2013

[28] D L Korte and J Kinney ldquoPersonalized medicine an updateof salivary biomarkers for periodontal diseasesrdquo Periodontology2000 vol 70 no 1 pp 26ndash37 2016

[29] M Desvarieux R T Demmer T Rundek et al ldquoRelationshipbetween periodontal disease tooth loss and carotid arteryplaque the oral infections and vascular disease epidemiologystudy (INVEST)rdquo Stroke vol 34 no 9 pp 2120ndash2125 2003

[30] N J Park Y Li T Yu B M N Brinkman and D T WongldquoCharacterization of RNA in salivardquo Clinical Chemistry vol 52no 6 pp 988ndash994 2006

[31] Z Chen M G Mauk J Wang et al ldquoA microfluidic system forsaliva-based detection of infectious diseasesrdquoAnnals of the NewYork Academy of Sciences vol 1098 pp 429ndash436 2007

Disease Markers 7

[32] W R Abrams C A Barber K McCann et al ldquoDevelopment ofa microfluidic device for detection of pathogens in oral samplesusing upconverting phosphor technology (UPT)rdquo Annals of theNew York Academy of Sciences vol 1098 pp 375ndash388 2007

[33] P L AM Corstjens Z ChenM Zuiderwijk et al ldquoRapid assayformat formultiplex detection of humoral immune responses toinfectious disease pathogens (HIVHCV andTB)rdquoAnnals of theNew York Academy of Sciences vol 1098 pp 437ndash445 2007

[34] F DrsquoAiuto M Parkar G Andreou et al ldquoPeriodontitis and sys-temic inflammation control of the local infection is associatedwith a reduction in serum inflammatory markersrdquo Journal ofDental Research vol 83 no 2 pp 156ndash160 2004

[35] I Ouellet-Morin A Danese B Williams and L ArseneaultldquoValidation of a high-sensitivity assay for C-reactive protein inhuman salivardquo Brain Behavior and Immunity vol 25 no 4 pp640ndash646 2011

[36] E Megson T Fitzsimmons K Dharmapatni and P MarkBartold ldquoC-reactive protein in gingival crevicular fluid maybe indicative of systemic inflammationrdquo Journal of ClinicalPeriodontology vol 37 no 9 pp 797ndash804 2010

[37] S Podzimek J Mysak T Janatova and J Duskova ldquoC-reactive protein in peripheral blood of patients with chronicand aggressive periodontitis gingivitis and gingival recessionsrdquoMediators of Inflammation vol 2015 Article ID 564858 7 pages2015

[38] Y Murakami S Hanazawa S Tanaka H Iwahashi S Kitanoand S Fujisawa ldquoFibronectin in saliva inhibits Porphy-romonas gingivalis fimbria-induced expression of inflamma-tory cytokine gene in mouse macrophagesrdquo FEMS Immunologyand Medical Microbiology vol 22 no 3 pp 257ndash262 1998

[39] M A Lie B G Loos YM C Henskens et al ldquoSalivary cystatinactivity and cystatin C in natural and experimental gingivitis insmokers and non-smokersrdquo Journal of Clinical Periodontologyvol 28 no 10 pp 979ndash984 2001

[40] M S Rasch B LMealey T J PrihodaD SWoodard and LMMcManus ldquoThe effect of initial periodontal therapy on salivaryplatelet-activating factor levels in chronic adult periodontitisrdquoJournal of Periodontology vol 66 no 7 pp 613ndash623 1995

[41] V Booth S Young A Cruchley N S Taichman and E Pale-olog ldquoVascular endothelial growth factor in human periodontaldiseaserdquo Journal of Periodontal Research vol 33 no 8 pp 491ndash499 1998

[42] M Ohshima K Fujikawa H Akutagawa T Kato K Ito and KOtsuka ldquoHepatocyte growth factor in saliva a possible markerfor periodontal disease statusrdquo Journal of oral science vol 44no 1 pp 35ndash39 2002

[43] U K Gursoy E Kononen P J Pussinen et al ldquoUse of host- andbacteria-derived salivary markers in detection of periodontitisa cumulative approachrdquoDiseaseMarkers vol 30 no 6 pp 299ndash305 2011

[44] K M Jaedicke P M Preshaw and J J Taylor ldquoSalivarycytokines as biomarkers of periodontal diseasesrdquo Periodontol-ogy 2000 vol 70 no 1 pp 164ndash183 2016

[45] P P Costa G L Trevisan G O Macedo et al ldquoSalivaryinterleukin-6 matrix metalloproteinase-8 and osteoprotegerinin patients with periodontitis and diabetesrdquo Journal of Periodon-tology vol 81 no 3 pp 384ndash391 2010

[46] S Liskmann T Vihalemm O Salum K Zilmer K Fischerand M Zilmer ldquoCorrelations between clinical parameters andinterleukin-6 and interleukin-10 levels in saliva from totally

edentulous patients with peri-implant diseaserdquo The Interna-tional Journal of Oral and Maxillofacial Implants vol 21 no 4pp 543ndash550 2006

[47] N Spielmann andDWong ldquoSaliva diagnostics and therapeuticperspectivesrdquo Oral Diseases vol 17 no 4 pp 345ndash354 2011

[48] P Denny F KHagenMHardt et al ldquoThe proteomes of humanparotid and submandibularsublingual gland salivas collectedas the ductal secretionsrdquo Journal of Proteome Research vol 7no 5 pp 1994ndash2006 2008

[49] D V Sculley and S C Langley-Evans ldquoPeriodontal disease isassociated with lower antioxidant capacity in whole saliva andevidence of increased protein oxidationrdquo Clinical Science vol105 no 2 pp 167ndash172 2003

[50] M Takane N Sugano H Iwasaki Y Iwano N Shimizu andK Ito ldquoNew biomarker evidence of oxidative DNA damage inwhole saliva from clinically healthy and periodontally diseasedindividualsrdquo Journal of Periodontology vol 73 no 5 pp 551ndash554 2002

[51] R Diab-Ladki B Pellat and R Chahine ldquoDecrease in thetotal antioxidant activity of saliva in patients with periodontaldiseasesrdquo Clinical Oral Investigations vol 7 no 2 pp 103ndash1072003

[52] M Takane N Sugano T Ezawa T Uchiyama and K ItoldquoA marker of oxidative stress in saliva association withperiodontally-involved teeth of a hopeless prognosisrdquo Journalof Oral Science vol 47 no 1 pp 53ndash57 2005

[53] D-X Tan L C Manchester R J Reiter W-B Qi M Kar-bownik and J R Calvo ldquoSignificance ofmelatonin in antioxida-tive defense system reactions and productsrdquo Biological Signalsand Receptors vol 9 no 3-4 pp 137ndash159 2000

[54] A Cutando G Gomez-Moreno J Villalba M J Ferrera GEscames and D Acuna-Castroviejo ldquoRelationship betweensalivary melatonin levels and periodontal status in diabeticpatientsrdquo Journal of Pineal Research vol 35 no 4 pp 239ndash2442003

[55] C C Tsai H S Chen S L Chen et al ldquoLipid peroxidationa possible role in the induction and progression of chronicperiodontitisrdquo Journal of Periodontal Research vol 40 no 5 pp378ndash386 2005

[56] Y Karincaoglu K Batcioglu T Erdem M Esrefoglu and MGene ldquoThe levels of plasma and salivary antioxidants in thepatient with recurrent aphthous stomatitisrdquo Journal of OralPathology and Medicine vol 34 no 1 pp 7ndash12 2005

[57] C SMiller J D Foley A L Bailey et al ldquoCurrent developmentsin salivary diagnosticsrdquo Biomarkers inMedicine vol 4 no 1 pp171ndash189 2010

[58] X Gao S Jiang D Koh and C S Hsu ldquoSalivary biomarkersfor dental cariesrdquo Periodontology 2000 vol 70 no 1 pp 128ndash141 2016

[59] Y Hassona and C Scully ldquoSalivary changes in oral mucosaldiseasesrdquo Periodontology 2000 vol 70 no 1 pp 111ndash127 2016

[60] A M Schmidt E Weidman E Lalla et al ldquoAdvanced glycationendproducts (AGEs) induce oxidant stress in the gingiva apotential mechanism underlying accelerated periodontal dis-ease associated with diabetesrdquo Journal of Periodontal Researchvol 31 no 7 pp 508ndash515 1996

[61] S AMorenkova ldquoComparative analysis of dependence of salivasorbitol and fructoseamine levels on blood glucose level inpatients with diabetesrdquo Biomeditsinskaya Khimiya vol 50 no6 pp 612ndash614 2004 (Russian)

8 Disease Markers

[62] F Astaneie M Afshari A Mojtahedi et al ldquoTotal antioxidantcapacity and levels of epidermal growth factor and nitric oxidein blood and saliva of insulin-dependent diabetic patientsrdquoArchives of Medical Research vol 36 no 4 pp 376ndash381 2005

[63] M E Lopez M E Colloca R G Paez J N Schallmach M AKoss andA Chervonagura ldquoSalivary characteristics of diabeticchildrenrdquoBrazilianDental Journal vol 14 no 1 pp 26ndash31 2003

[64] R Wolfram A Oguogho B Palumbo and H SinzingerldquoEnhanced oxidative stress in coronary heart disease andchronic heart failure as indicated by an increased 8-epi-PGF2120572rdquoEuropean Journal of Heart Failure vol 7 no 2 pp 167ndash172 2005

[65] S Xiang R Denver M Bailey and H Krum ldquoPhysiologicdeterminants of endothelin concentrations in human salivardquoClinical Chemistry vol 49 no 12 pp 2012ndash2019 2003

[66] N Christodoulides F N Pierre X Sanchez et al ldquoPro-grammable bio-nanochip technology for the diagnosis of car-diovascular disease at the point-of-carerdquo Methodist DeBakeyCardiovascular Journal vol 8 no 1 pp 6ndash12 2012

[67] E J Franzmann E P Reategui K L Carraway K L HamiltonD T Weed and W J Goodwin ldquoSalivary soluble CD44 apotential molecular marker for head and neck cancerrdquo CancerEpidemiology Biomarkers and Prevention vol 14 no 3 pp 735ndash739 2005

[68] L-P Zhong G-F Chen Z-F Xu X Zhang F-Y Ping and S-F Zhao ldquoDetection of telomerase activity in saliva from oralsquamous cell carcinoma patientsrdquo International Journal of Oraland Maxillofacial Surgery vol 34 no 5 pp 566ndash570 2005

[69] A K Markopoulos E Z Michailidou and G TzimagiorgisldquoSalivary markers for oral cancer detectionrdquo Open DentistryJournal no 4 pp 172ndash178 2010

[70] F D Shah R Begum B N Vajaria et al ldquoA review on salivarygenomics and proteomics biomarkers in oral cancerrdquo IndianJournal of Clinical Biochemistry vol 26 no 4 pp 326ndash334 2011

[71] C F Streckfus L Bigler T Dellinger M Kuhn N Chouinardand X Dai ldquoThe expression of the c-erbB-2 receptor proteinin glandular salivary secretionsrdquo Journal of Oral Pathology andMedicine vol 33 no 10 pp 595ndash600 2004

[72] M Markman ldquoNormal CA-125 and the risk of progression inovarian cancerrdquo Journal of Clinical Oncology vol 24 no 20 p3310 2006

[73] L Zhang J J Farrell H Zhou et al ldquoSalivary transcriptomicbiomarkers for detection of resectable pancreatic cancerrdquo Gas-troenterology vol 138 no 3 pp 949ndash957 2010

[74] C T Viet and B L Schmidt ldquoMethylation array analysisof preoperative and postoperative saliva DNA in oral cancerpatientsrdquo Cancer Epidemiology Biomarkers and Prevention vol17 no 12 pp 3603ndash3611 2008

[75] J Wei G Xie Z Zhou et al ldquoSalivary metabolite signatures oforal cancer and leukoplakiardquo International Journal of Cancervol 129 no 9 pp 2207ndash2217 2011

[76] D L Mager A D Haffajee P M Delvin C M Norris M RPosner and J M Goodson ldquoThe salivary microbiota as a diag-nostic indicator of oral cancer a descriptive non-randomizedstudy of cancer-free and oral squamous cell carcinoma subjectsrdquoJournal of Translational Medicine vol 3 article 27 2005

[77] H Xiao L Zhang H Zhou J M Lee E B Garon and D T WWong ldquoProteomic analysis of human saliva from lung cancerpatients using two-dimensional difference gel electrophoresisand mass spectrometryrdquo Molecular amp Cellular Proteomics vol11 no 2 2012

[78] P S Ramsey and W W Andrews ldquoBiochemical predictors ofpreterm labor fetal fibronectin and salivary estriolrdquo Clinics inPerinatology vol 30 no 4 pp 701ndash733 2003

[79] L D Belkien J Bordt P Moller R Hano and E NieschlagldquoEstradiol in saliva for monitoring follicular stimulation in anin vitro fertilization programrdquo Fertility and Sterility vol 44 no3 pp 322ndash327 1985

[80] K Simunkova R Hampl M Hill J Doucha L Starka and KVondra ldquoSalivary cortisol in low dose (1 microg) ACTH test inhealthy women comparison with serum cortisolrdquo PhysiologicalResearch vol 56 no 4 pp 449ndash453 2007

[81] A van Stegeren N Rohleder W Everaerd and O T WolfldquoSalivary alpha amylase asmarker for adrenergic activity duringstress effect of betablockaderdquo Psychoneuroendocrinology vol31 no 1 pp 137ndash141 2006

[82] R S Rittmaster and D L Thompson ldquoEffect of leuprolide anddexamethasone on hair growth and hormone levels in hirsutewomen the relative importance of the ovary and the adrenal inthe pathogenesis of hirsutismrdquo Journal of Clinical Endocrinologyand Metabolism vol 70 no 4 pp 1096ndash1102 1990

[83] I M Goodyer J Herbert and A Tamplin ldquoPsychoendocrineantecedents of persistent first-episode major depression inadolescents a community-based longitudinal enquiryrdquo Psycho-logical Medicine vol 33 no 4 pp 601ndash610 2003

[84] S Yamada ldquoAssessment of mental condition by saliva level of 3-methoxy-4-hydroxyphenylglycolrdquo Seishin Shinkeigaku Zasshivol 107 no 7 pp 712ndash717 2005 (Japanese)

[85] M Tsuruoka J Hara A Hirayama et al ldquoCapillaryelectrophoresis-mass spectrometry-based metabolomeanalysis of serum and saliva from neurodegenerative dementiapatientsrdquo Electrophoresis vol 34 no 19 pp 2865ndash2872 2013

[86] N Pant Pai B Balram S Shivkumar et al ldquoHead-to-headcomparison of accuracy of a rapid point-of-care HIV test withoral versus whole-blood specimens a systematic review andmeta-analysisrdquoThe Lancet Infectious Diseases vol 12 no 5 pp373ndash380 2012

[87] P L CorstjensW RAbrams andDMalamud ldquoSaliva and viralinfectionsrdquo Periodontology 2000 vol 70 no 1 pp 93ndash110 2016

[88] G B L Menezes F A Pereira C A B Duarte et al ldquoHepatitisC virus quantification in serum and saliva of HCV-infectedpatientsrdquo Memorias do Instituto Oswaldo Cruz vol 107 no 5pp 680ndash683 2012

[89] G Yap B K Sil and L-C Ng ldquoUse of saliva for early denguediagnosisrdquo PLoSNeglected Tropical Diseases vol 5 no 5 ArticleID e1046 2011

[90] P L A M Corstjens and D Malamud ldquoPoint-of-care diagnos-tics for infectious diseasesrdquo in Salivary Diagnostics D T WongEd chapter 13 pp 136ndash149Wiley-Blackwell Ames Iowa USA2008

[91] J W Galloway B J F Keijser and D M Williams ldquoSaliva instudies of epidemiology of human disease the UK Biobankprojectrdquo Periodontology 2000 vol 70 no 1 pp 184ndash195 2016

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

6 Disease Markers

(Grant Agency Czech Republic) by Project NT 14164-3(Ministry of Health Czech Republic) and by Project 15-28142A (Czech Health Research Council Czech Republic)

References

[1] G B Proctor ldquoThe physiology of salivary secretionrdquo Periodon-tology 2000 vol 70 no 1 pp 11ndash25 2016

[2] J A Loo W Yan P Ramachandran and D TWong ldquoCompar-ative human salivary and plasma proteomesrdquo Journal of DentalResearch vol 89 no 10 pp 1016ndash1023 2010

[3] L A S Nunes S Mussavira and O S Bindhu ldquoClinical anddiagnostic utility of saliva as a non-invasive diagnostic fluid asystematic reviewrdquo BiochemiaMedica vol 25 no 2 pp 177ndash1922015

[4] S P Barros RWilliams S Offenbacher and TMorelli ldquoGingi-val crevicular fluid as a source of biomarkers for periodontitisrdquoPeriodontology 2000 vol 70 no 1 pp 53ndash64 2016

[5] R R Wassall and P M Preshaw ldquoClinical and technicalconsiderations in the analysis of gingival crevicular fluidrdquoPeriodontology 2000 vol 70 no 1 pp 65ndash79 2016

[6] Y Zhang J Sun C-C Lin E Abemayor M B Wang and DT W Wong ldquoThe emerging landscape of salivary diagnosticsrdquoPeriodontology 2000 vol 70 no 1 pp 38ndash52 2016

[7] A Segal and D T Wong ldquoSalivary diagnostics enhancing dis-ease detection and making medicine betterrdquo European Journalof Dental Education vol 12 no 1 pp 22ndash29 2008

[8] JMYoshizawaCA Schafer J J Schafer J J Farrell B J Pasterand D TWWong ldquoSalivary biomarkers toward future clinicaland diagnostic utilitiesrdquo Clinical Microbiology Reviews vol 26no 4 pp 781ndash791 2013

[9] D A Chambers P B Imrey R L Cohen J M Crawford M EAlves and T A McSwiggin ldquoA longitudinal study of aspartateaminotransferase in human gingival crevicular fluidrdquo Journal ofPeriodontal Research vol 26 no 2 pp 65ndash74 1991

[10] A Totan M Greabu C Totan and T Spinu ldquoSalivary aspartateaminotransferase alanine aminotransferase and alkaline phos-phatase possible markers in periodontal diseasesrdquo ClinicalChemistry and Laboratory Medicine vol 44 no 5 pp 612ndash6152006

[11] Y Nomura Y Shimada N Hanada et al ldquoSalivary biomark-ers for predicting the progression of chronic periodontitisrdquoArchives of Oral Biology vol 57 no 4 pp 413ndash420 2012

[12] I B Lamster E Kaufman J T Grbic L J Winston and RE Singer ldquo120573-glucuronidase activity in saliva relationship toclinical periodontal parametersrdquo Journal of Periodontology vol74 no 3 pp 353ndash359 2003

[13] S Elgun N Ozmeric and S Demirtas ldquoAlanine aminopepti-dase and dipeptidylpeptidase IV in Saliva the possible role inperiodontal diseaserdquo Clinica Chimica Acta vol 298 no 1-2 pp187ndash191 2000

[14] K Suomalainen L Saxen P Vilja and J Tenovuo ldquoPeroxidaseslactoferrin and lysozyme in peripheral blood neutrophils gin-gival crevicular fluid and whole saliva of patients with localizedjuvenile periodontitisrdquo Oral Diseases vol 2 no 2 pp 129ndash1341996

[15] B E Britigan and B L Edeker ldquoPseudomonas and neutrophilproductsmodify transferrin and lactoferrin to create conditionsthat favor hydroxyl radical formationrdquo The Journal of ClinicalInvestigation vol 88 no 4 pp 1092ndash1102 1991

[16] T Ingman T Tervahartiala Y Ding et al ldquoMatrix metallo-proteinases and their inhibitors in gingival crevicular fluid andsaliva of periodontitis patientsrdquo Journal of Clinical Periodontol-ogy vol 23 no 12 pp 1127ndash1132 1996

[17] T Sorsa L Tjaderhane Y T Konttinen et al ldquoMatrix met-alloproteinases contribution to pathogenesis diagnosis andtreatment of periodontal inflammationrdquo Annals of Medicinevol 38 no 5 pp 306ndash321 2006

[18] J L Ebersole J L Schuster J Stevens et al ldquoPatterns ofsalivary analytes provide diagnostic capacity for distinguishingchronic adult periodontitis from healthrdquo Journal of ClinicalImmunology vol 33 no 1 pp 271ndash279 2013

[19] N Rathnayake S Akerman B Klinge et al ldquoSalivary biomark-ers of oral healthmdasha cross-sectional studyrdquo Journal of ClinicalPeriodontology vol 40 no 2 pp 140ndash147 2013

[20] W M Sexton Y Lin R J Kryscio D R Dawson III J LEbersole and C S Miller ldquoSalivary biomarkers of periodontaldisease in response to treatmentrdquo Journal of Clinical Periodon-tology vol 38 no 5 pp 434ndash441 2011

[21] J S Kinney T Morelli T Braun et al ldquoSalivapathogenbiomarker signatures and periodontal disease progressionrdquoJournal of Dental Research vol 90 no 6 pp 752ndash758 2011

[22] U K Gursoy E Kononen S Huumonen et al ldquoSalivary type Icollagen degradation end-products and related matrix metallo-proteinases in periodontitisrdquo Journal of Clinical Periodontologyvol 40 no 1 pp 18ndash25 2013

[23] C A Meschiari A M Marcaccini B C Santos Moura L RZuardi J E Tanus-Santos and R F Gerlach ldquoSalivary MMPsTIMPs and MPO levels in periodontal disease patients andcontrolsrdquo Clinica Chimica Acta vol 421 pp 140ndash146 2013

[24] T SorsaU KGursoy SNwhator et al ldquoAnalysis ofmatrixmet-alloproteinases especially MMP-8 in gingival crevicular fluidmouthrinse and saliva for monitoring periodontal diseasesrdquoPeriodontology 2000 vol 70 no 1 pp 142ndash163 2016

[25] G J Van Steijn A V Nieuw Amerongen E C I Veerman SKasanmoentalib and B Overdijk ldquoEffect of periodontal treat-ment on the activity of chitinase in whole saliva of periodontitispatientsrdquo Journal of Periodontal Research vol 37 no 4 pp 245ndash249 2002

[26] N Ozmeric T Baydar A Bodur et al ldquoLevel of neopterin amarker of immune cell activation in gingival crevicular fluidsaliva and urine in patients with aggressive periodontitisrdquoJournal of Periodontology vol 73 no 7 pp 720ndash725 2002

[27] F S Lakschevitz G M Aboodi and M Glogauer ldquoOralneutrophil transcriptome changes result in a pro-survival phe-notype in periodontal diseasesrdquo PLoS ONE vol 8 no 7 ArticleID e68983 2013

[28] D L Korte and J Kinney ldquoPersonalized medicine an updateof salivary biomarkers for periodontal diseasesrdquo Periodontology2000 vol 70 no 1 pp 26ndash37 2016

[29] M Desvarieux R T Demmer T Rundek et al ldquoRelationshipbetween periodontal disease tooth loss and carotid arteryplaque the oral infections and vascular disease epidemiologystudy (INVEST)rdquo Stroke vol 34 no 9 pp 2120ndash2125 2003

[30] N J Park Y Li T Yu B M N Brinkman and D T WongldquoCharacterization of RNA in salivardquo Clinical Chemistry vol 52no 6 pp 988ndash994 2006

[31] Z Chen M G Mauk J Wang et al ldquoA microfluidic system forsaliva-based detection of infectious diseasesrdquoAnnals of the NewYork Academy of Sciences vol 1098 pp 429ndash436 2007

Disease Markers 7

[32] W R Abrams C A Barber K McCann et al ldquoDevelopment ofa microfluidic device for detection of pathogens in oral samplesusing upconverting phosphor technology (UPT)rdquo Annals of theNew York Academy of Sciences vol 1098 pp 375ndash388 2007

[33] P L AM Corstjens Z ChenM Zuiderwijk et al ldquoRapid assayformat formultiplex detection of humoral immune responses toinfectious disease pathogens (HIVHCV andTB)rdquoAnnals of theNew York Academy of Sciences vol 1098 pp 437ndash445 2007

[34] F DrsquoAiuto M Parkar G Andreou et al ldquoPeriodontitis and sys-temic inflammation control of the local infection is associatedwith a reduction in serum inflammatory markersrdquo Journal ofDental Research vol 83 no 2 pp 156ndash160 2004

[35] I Ouellet-Morin A Danese B Williams and L ArseneaultldquoValidation of a high-sensitivity assay for C-reactive protein inhuman salivardquo Brain Behavior and Immunity vol 25 no 4 pp640ndash646 2011

[36] E Megson T Fitzsimmons K Dharmapatni and P MarkBartold ldquoC-reactive protein in gingival crevicular fluid maybe indicative of systemic inflammationrdquo Journal of ClinicalPeriodontology vol 37 no 9 pp 797ndash804 2010

[37] S Podzimek J Mysak T Janatova and J Duskova ldquoC-reactive protein in peripheral blood of patients with chronicand aggressive periodontitis gingivitis and gingival recessionsrdquoMediators of Inflammation vol 2015 Article ID 564858 7 pages2015

[38] Y Murakami S Hanazawa S Tanaka H Iwahashi S Kitanoand S Fujisawa ldquoFibronectin in saliva inhibits Porphy-romonas gingivalis fimbria-induced expression of inflamma-tory cytokine gene in mouse macrophagesrdquo FEMS Immunologyand Medical Microbiology vol 22 no 3 pp 257ndash262 1998

[39] M A Lie B G Loos YM C Henskens et al ldquoSalivary cystatinactivity and cystatin C in natural and experimental gingivitis insmokers and non-smokersrdquo Journal of Clinical Periodontologyvol 28 no 10 pp 979ndash984 2001

[40] M S Rasch B LMealey T J PrihodaD SWoodard and LMMcManus ldquoThe effect of initial periodontal therapy on salivaryplatelet-activating factor levels in chronic adult periodontitisrdquoJournal of Periodontology vol 66 no 7 pp 613ndash623 1995

[41] V Booth S Young A Cruchley N S Taichman and E Pale-olog ldquoVascular endothelial growth factor in human periodontaldiseaserdquo Journal of Periodontal Research vol 33 no 8 pp 491ndash499 1998

[42] M Ohshima K Fujikawa H Akutagawa T Kato K Ito and KOtsuka ldquoHepatocyte growth factor in saliva a possible markerfor periodontal disease statusrdquo Journal of oral science vol 44no 1 pp 35ndash39 2002

[43] U K Gursoy E Kononen P J Pussinen et al ldquoUse of host- andbacteria-derived salivary markers in detection of periodontitisa cumulative approachrdquoDiseaseMarkers vol 30 no 6 pp 299ndash305 2011

[44] K M Jaedicke P M Preshaw and J J Taylor ldquoSalivarycytokines as biomarkers of periodontal diseasesrdquo Periodontol-ogy 2000 vol 70 no 1 pp 164ndash183 2016

[45] P P Costa G L Trevisan G O Macedo et al ldquoSalivaryinterleukin-6 matrix metalloproteinase-8 and osteoprotegerinin patients with periodontitis and diabetesrdquo Journal of Periodon-tology vol 81 no 3 pp 384ndash391 2010

[46] S Liskmann T Vihalemm O Salum K Zilmer K Fischerand M Zilmer ldquoCorrelations between clinical parameters andinterleukin-6 and interleukin-10 levels in saliva from totally

edentulous patients with peri-implant diseaserdquo The Interna-tional Journal of Oral and Maxillofacial Implants vol 21 no 4pp 543ndash550 2006

[47] N Spielmann andDWong ldquoSaliva diagnostics and therapeuticperspectivesrdquo Oral Diseases vol 17 no 4 pp 345ndash354 2011

[48] P Denny F KHagenMHardt et al ldquoThe proteomes of humanparotid and submandibularsublingual gland salivas collectedas the ductal secretionsrdquo Journal of Proteome Research vol 7no 5 pp 1994ndash2006 2008

[49] D V Sculley and S C Langley-Evans ldquoPeriodontal disease isassociated with lower antioxidant capacity in whole saliva andevidence of increased protein oxidationrdquo Clinical Science vol105 no 2 pp 167ndash172 2003

[50] M Takane N Sugano H Iwasaki Y Iwano N Shimizu andK Ito ldquoNew biomarker evidence of oxidative DNA damage inwhole saliva from clinically healthy and periodontally diseasedindividualsrdquo Journal of Periodontology vol 73 no 5 pp 551ndash554 2002

[51] R Diab-Ladki B Pellat and R Chahine ldquoDecrease in thetotal antioxidant activity of saliva in patients with periodontaldiseasesrdquo Clinical Oral Investigations vol 7 no 2 pp 103ndash1072003

[52] M Takane N Sugano T Ezawa T Uchiyama and K ItoldquoA marker of oxidative stress in saliva association withperiodontally-involved teeth of a hopeless prognosisrdquo Journalof Oral Science vol 47 no 1 pp 53ndash57 2005

[53] D-X Tan L C Manchester R J Reiter W-B Qi M Kar-bownik and J R Calvo ldquoSignificance ofmelatonin in antioxida-tive defense system reactions and productsrdquo Biological Signalsand Receptors vol 9 no 3-4 pp 137ndash159 2000

[54] A Cutando G Gomez-Moreno J Villalba M J Ferrera GEscames and D Acuna-Castroviejo ldquoRelationship betweensalivary melatonin levels and periodontal status in diabeticpatientsrdquo Journal of Pineal Research vol 35 no 4 pp 239ndash2442003

[55] C C Tsai H S Chen S L Chen et al ldquoLipid peroxidationa possible role in the induction and progression of chronicperiodontitisrdquo Journal of Periodontal Research vol 40 no 5 pp378ndash386 2005

[56] Y Karincaoglu K Batcioglu T Erdem M Esrefoglu and MGene ldquoThe levels of plasma and salivary antioxidants in thepatient with recurrent aphthous stomatitisrdquo Journal of OralPathology and Medicine vol 34 no 1 pp 7ndash12 2005

[57] C SMiller J D Foley A L Bailey et al ldquoCurrent developmentsin salivary diagnosticsrdquo Biomarkers inMedicine vol 4 no 1 pp171ndash189 2010

[58] X Gao S Jiang D Koh and C S Hsu ldquoSalivary biomarkersfor dental cariesrdquo Periodontology 2000 vol 70 no 1 pp 128ndash141 2016

[59] Y Hassona and C Scully ldquoSalivary changes in oral mucosaldiseasesrdquo Periodontology 2000 vol 70 no 1 pp 111ndash127 2016

[60] A M Schmidt E Weidman E Lalla et al ldquoAdvanced glycationendproducts (AGEs) induce oxidant stress in the gingiva apotential mechanism underlying accelerated periodontal dis-ease associated with diabetesrdquo Journal of Periodontal Researchvol 31 no 7 pp 508ndash515 1996

[61] S AMorenkova ldquoComparative analysis of dependence of salivasorbitol and fructoseamine levels on blood glucose level inpatients with diabetesrdquo Biomeditsinskaya Khimiya vol 50 no6 pp 612ndash614 2004 (Russian)

8 Disease Markers

[62] F Astaneie M Afshari A Mojtahedi et al ldquoTotal antioxidantcapacity and levels of epidermal growth factor and nitric oxidein blood and saliva of insulin-dependent diabetic patientsrdquoArchives of Medical Research vol 36 no 4 pp 376ndash381 2005

[63] M E Lopez M E Colloca R G Paez J N Schallmach M AKoss andA Chervonagura ldquoSalivary characteristics of diabeticchildrenrdquoBrazilianDental Journal vol 14 no 1 pp 26ndash31 2003

[64] R Wolfram A Oguogho B Palumbo and H SinzingerldquoEnhanced oxidative stress in coronary heart disease andchronic heart failure as indicated by an increased 8-epi-PGF2120572rdquoEuropean Journal of Heart Failure vol 7 no 2 pp 167ndash172 2005

[65] S Xiang R Denver M Bailey and H Krum ldquoPhysiologicdeterminants of endothelin concentrations in human salivardquoClinical Chemistry vol 49 no 12 pp 2012ndash2019 2003

[66] N Christodoulides F N Pierre X Sanchez et al ldquoPro-grammable bio-nanochip technology for the diagnosis of car-diovascular disease at the point-of-carerdquo Methodist DeBakeyCardiovascular Journal vol 8 no 1 pp 6ndash12 2012

[67] E J Franzmann E P Reategui K L Carraway K L HamiltonD T Weed and W J Goodwin ldquoSalivary soluble CD44 apotential molecular marker for head and neck cancerrdquo CancerEpidemiology Biomarkers and Prevention vol 14 no 3 pp 735ndash739 2005

[68] L-P Zhong G-F Chen Z-F Xu X Zhang F-Y Ping and S-F Zhao ldquoDetection of telomerase activity in saliva from oralsquamous cell carcinoma patientsrdquo International Journal of Oraland Maxillofacial Surgery vol 34 no 5 pp 566ndash570 2005

[69] A K Markopoulos E Z Michailidou and G TzimagiorgisldquoSalivary markers for oral cancer detectionrdquo Open DentistryJournal no 4 pp 172ndash178 2010

[70] F D Shah R Begum B N Vajaria et al ldquoA review on salivarygenomics and proteomics biomarkers in oral cancerrdquo IndianJournal of Clinical Biochemistry vol 26 no 4 pp 326ndash334 2011

[71] C F Streckfus L Bigler T Dellinger M Kuhn N Chouinardand X Dai ldquoThe expression of the c-erbB-2 receptor proteinin glandular salivary secretionsrdquo Journal of Oral Pathology andMedicine vol 33 no 10 pp 595ndash600 2004

[72] M Markman ldquoNormal CA-125 and the risk of progression inovarian cancerrdquo Journal of Clinical Oncology vol 24 no 20 p3310 2006

[73] L Zhang J J Farrell H Zhou et al ldquoSalivary transcriptomicbiomarkers for detection of resectable pancreatic cancerrdquo Gas-troenterology vol 138 no 3 pp 949ndash957 2010

[74] C T Viet and B L Schmidt ldquoMethylation array analysisof preoperative and postoperative saliva DNA in oral cancerpatientsrdquo Cancer Epidemiology Biomarkers and Prevention vol17 no 12 pp 3603ndash3611 2008

[75] J Wei G Xie Z Zhou et al ldquoSalivary metabolite signatures oforal cancer and leukoplakiardquo International Journal of Cancervol 129 no 9 pp 2207ndash2217 2011

[76] D L Mager A D Haffajee P M Delvin C M Norris M RPosner and J M Goodson ldquoThe salivary microbiota as a diag-nostic indicator of oral cancer a descriptive non-randomizedstudy of cancer-free and oral squamous cell carcinoma subjectsrdquoJournal of Translational Medicine vol 3 article 27 2005

[77] H Xiao L Zhang H Zhou J M Lee E B Garon and D T WWong ldquoProteomic analysis of human saliva from lung cancerpatients using two-dimensional difference gel electrophoresisand mass spectrometryrdquo Molecular amp Cellular Proteomics vol11 no 2 2012

[78] P S Ramsey and W W Andrews ldquoBiochemical predictors ofpreterm labor fetal fibronectin and salivary estriolrdquo Clinics inPerinatology vol 30 no 4 pp 701ndash733 2003

[79] L D Belkien J Bordt P Moller R Hano and E NieschlagldquoEstradiol in saliva for monitoring follicular stimulation in anin vitro fertilization programrdquo Fertility and Sterility vol 44 no3 pp 322ndash327 1985

[80] K Simunkova R Hampl M Hill J Doucha L Starka and KVondra ldquoSalivary cortisol in low dose (1 microg) ACTH test inhealthy women comparison with serum cortisolrdquo PhysiologicalResearch vol 56 no 4 pp 449ndash453 2007

[81] A van Stegeren N Rohleder W Everaerd and O T WolfldquoSalivary alpha amylase asmarker for adrenergic activity duringstress effect of betablockaderdquo Psychoneuroendocrinology vol31 no 1 pp 137ndash141 2006

[82] R S Rittmaster and D L Thompson ldquoEffect of leuprolide anddexamethasone on hair growth and hormone levels in hirsutewomen the relative importance of the ovary and the adrenal inthe pathogenesis of hirsutismrdquo Journal of Clinical Endocrinologyand Metabolism vol 70 no 4 pp 1096ndash1102 1990

[83] I M Goodyer J Herbert and A Tamplin ldquoPsychoendocrineantecedents of persistent first-episode major depression inadolescents a community-based longitudinal enquiryrdquo Psycho-logical Medicine vol 33 no 4 pp 601ndash610 2003

[84] S Yamada ldquoAssessment of mental condition by saliva level of 3-methoxy-4-hydroxyphenylglycolrdquo Seishin Shinkeigaku Zasshivol 107 no 7 pp 712ndash717 2005 (Japanese)

[85] M Tsuruoka J Hara A Hirayama et al ldquoCapillaryelectrophoresis-mass spectrometry-based metabolomeanalysis of serum and saliva from neurodegenerative dementiapatientsrdquo Electrophoresis vol 34 no 19 pp 2865ndash2872 2013

[86] N Pant Pai B Balram S Shivkumar et al ldquoHead-to-headcomparison of accuracy of a rapid point-of-care HIV test withoral versus whole-blood specimens a systematic review andmeta-analysisrdquoThe Lancet Infectious Diseases vol 12 no 5 pp373ndash380 2012

[87] P L CorstjensW RAbrams andDMalamud ldquoSaliva and viralinfectionsrdquo Periodontology 2000 vol 70 no 1 pp 93ndash110 2016

[88] G B L Menezes F A Pereira C A B Duarte et al ldquoHepatitisC virus quantification in serum and saliva of HCV-infectedpatientsrdquo Memorias do Instituto Oswaldo Cruz vol 107 no 5pp 680ndash683 2012

[89] G Yap B K Sil and L-C Ng ldquoUse of saliva for early denguediagnosisrdquo PLoSNeglected Tropical Diseases vol 5 no 5 ArticleID e1046 2011

[90] P L A M Corstjens and D Malamud ldquoPoint-of-care diagnos-tics for infectious diseasesrdquo in Salivary Diagnostics D T WongEd chapter 13 pp 136ndash149Wiley-Blackwell Ames Iowa USA2008

[91] J W Galloway B J F Keijser and D M Williams ldquoSaliva instudies of epidemiology of human disease the UK Biobankprojectrdquo Periodontology 2000 vol 70 no 1 pp 184ndash195 2016

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Disease Markers 7

[32] W R Abrams C A Barber K McCann et al ldquoDevelopment ofa microfluidic device for detection of pathogens in oral samplesusing upconverting phosphor technology (UPT)rdquo Annals of theNew York Academy of Sciences vol 1098 pp 375ndash388 2007

[33] P L AM Corstjens Z ChenM Zuiderwijk et al ldquoRapid assayformat formultiplex detection of humoral immune responses toinfectious disease pathogens (HIVHCV andTB)rdquoAnnals of theNew York Academy of Sciences vol 1098 pp 437ndash445 2007

[34] F DrsquoAiuto M Parkar G Andreou et al ldquoPeriodontitis and sys-temic inflammation control of the local infection is associatedwith a reduction in serum inflammatory markersrdquo Journal ofDental Research vol 83 no 2 pp 156ndash160 2004

[35] I Ouellet-Morin A Danese B Williams and L ArseneaultldquoValidation of a high-sensitivity assay for C-reactive protein inhuman salivardquo Brain Behavior and Immunity vol 25 no 4 pp640ndash646 2011

[36] E Megson T Fitzsimmons K Dharmapatni and P MarkBartold ldquoC-reactive protein in gingival crevicular fluid maybe indicative of systemic inflammationrdquo Journal of ClinicalPeriodontology vol 37 no 9 pp 797ndash804 2010

[37] S Podzimek J Mysak T Janatova and J Duskova ldquoC-reactive protein in peripheral blood of patients with chronicand aggressive periodontitis gingivitis and gingival recessionsrdquoMediators of Inflammation vol 2015 Article ID 564858 7 pages2015

[38] Y Murakami S Hanazawa S Tanaka H Iwahashi S Kitanoand S Fujisawa ldquoFibronectin in saliva inhibits Porphy-romonas gingivalis fimbria-induced expression of inflamma-tory cytokine gene in mouse macrophagesrdquo FEMS Immunologyand Medical Microbiology vol 22 no 3 pp 257ndash262 1998

[39] M A Lie B G Loos YM C Henskens et al ldquoSalivary cystatinactivity and cystatin C in natural and experimental gingivitis insmokers and non-smokersrdquo Journal of Clinical Periodontologyvol 28 no 10 pp 979ndash984 2001

[40] M S Rasch B LMealey T J PrihodaD SWoodard and LMMcManus ldquoThe effect of initial periodontal therapy on salivaryplatelet-activating factor levels in chronic adult periodontitisrdquoJournal of Periodontology vol 66 no 7 pp 613ndash623 1995

[41] V Booth S Young A Cruchley N S Taichman and E Pale-olog ldquoVascular endothelial growth factor in human periodontaldiseaserdquo Journal of Periodontal Research vol 33 no 8 pp 491ndash499 1998

[42] M Ohshima K Fujikawa H Akutagawa T Kato K Ito and KOtsuka ldquoHepatocyte growth factor in saliva a possible markerfor periodontal disease statusrdquo Journal of oral science vol 44no 1 pp 35ndash39 2002

[43] U K Gursoy E Kononen P J Pussinen et al ldquoUse of host- andbacteria-derived salivary markers in detection of periodontitisa cumulative approachrdquoDiseaseMarkers vol 30 no 6 pp 299ndash305 2011

[44] K M Jaedicke P M Preshaw and J J Taylor ldquoSalivarycytokines as biomarkers of periodontal diseasesrdquo Periodontol-ogy 2000 vol 70 no 1 pp 164ndash183 2016

[45] P P Costa G L Trevisan G O Macedo et al ldquoSalivaryinterleukin-6 matrix metalloproteinase-8 and osteoprotegerinin patients with periodontitis and diabetesrdquo Journal of Periodon-tology vol 81 no 3 pp 384ndash391 2010

[46] S Liskmann T Vihalemm O Salum K Zilmer K Fischerand M Zilmer ldquoCorrelations between clinical parameters andinterleukin-6 and interleukin-10 levels in saliva from totally

edentulous patients with peri-implant diseaserdquo The Interna-tional Journal of Oral and Maxillofacial Implants vol 21 no 4pp 543ndash550 2006

[47] N Spielmann andDWong ldquoSaliva diagnostics and therapeuticperspectivesrdquo Oral Diseases vol 17 no 4 pp 345ndash354 2011

[48] P Denny F KHagenMHardt et al ldquoThe proteomes of humanparotid and submandibularsublingual gland salivas collectedas the ductal secretionsrdquo Journal of Proteome Research vol 7no 5 pp 1994ndash2006 2008

[49] D V Sculley and S C Langley-Evans ldquoPeriodontal disease isassociated with lower antioxidant capacity in whole saliva andevidence of increased protein oxidationrdquo Clinical Science vol105 no 2 pp 167ndash172 2003

[50] M Takane N Sugano H Iwasaki Y Iwano N Shimizu andK Ito ldquoNew biomarker evidence of oxidative DNA damage inwhole saliva from clinically healthy and periodontally diseasedindividualsrdquo Journal of Periodontology vol 73 no 5 pp 551ndash554 2002

[51] R Diab-Ladki B Pellat and R Chahine ldquoDecrease in thetotal antioxidant activity of saliva in patients with periodontaldiseasesrdquo Clinical Oral Investigations vol 7 no 2 pp 103ndash1072003

[52] M Takane N Sugano T Ezawa T Uchiyama and K ItoldquoA marker of oxidative stress in saliva association withperiodontally-involved teeth of a hopeless prognosisrdquo Journalof Oral Science vol 47 no 1 pp 53ndash57 2005

[53] D-X Tan L C Manchester R J Reiter W-B Qi M Kar-bownik and J R Calvo ldquoSignificance ofmelatonin in antioxida-tive defense system reactions and productsrdquo Biological Signalsand Receptors vol 9 no 3-4 pp 137ndash159 2000

[54] A Cutando G Gomez-Moreno J Villalba M J Ferrera GEscames and D Acuna-Castroviejo ldquoRelationship betweensalivary melatonin levels and periodontal status in diabeticpatientsrdquo Journal of Pineal Research vol 35 no 4 pp 239ndash2442003

[55] C C Tsai H S Chen S L Chen et al ldquoLipid peroxidationa possible role in the induction and progression of chronicperiodontitisrdquo Journal of Periodontal Research vol 40 no 5 pp378ndash386 2005

[56] Y Karincaoglu K Batcioglu T Erdem M Esrefoglu and MGene ldquoThe levels of plasma and salivary antioxidants in thepatient with recurrent aphthous stomatitisrdquo Journal of OralPathology and Medicine vol 34 no 1 pp 7ndash12 2005

[57] C SMiller J D Foley A L Bailey et al ldquoCurrent developmentsin salivary diagnosticsrdquo Biomarkers inMedicine vol 4 no 1 pp171ndash189 2010

[58] X Gao S Jiang D Koh and C S Hsu ldquoSalivary biomarkersfor dental cariesrdquo Periodontology 2000 vol 70 no 1 pp 128ndash141 2016

[59] Y Hassona and C Scully ldquoSalivary changes in oral mucosaldiseasesrdquo Periodontology 2000 vol 70 no 1 pp 111ndash127 2016

[60] A M Schmidt E Weidman E Lalla et al ldquoAdvanced glycationendproducts (AGEs) induce oxidant stress in the gingiva apotential mechanism underlying accelerated periodontal dis-ease associated with diabetesrdquo Journal of Periodontal Researchvol 31 no 7 pp 508ndash515 1996

[61] S AMorenkova ldquoComparative analysis of dependence of salivasorbitol and fructoseamine levels on blood glucose level inpatients with diabetesrdquo Biomeditsinskaya Khimiya vol 50 no6 pp 612ndash614 2004 (Russian)

8 Disease Markers

[62] F Astaneie M Afshari A Mojtahedi et al ldquoTotal antioxidantcapacity and levels of epidermal growth factor and nitric oxidein blood and saliva of insulin-dependent diabetic patientsrdquoArchives of Medical Research vol 36 no 4 pp 376ndash381 2005

[63] M E Lopez M E Colloca R G Paez J N Schallmach M AKoss andA Chervonagura ldquoSalivary characteristics of diabeticchildrenrdquoBrazilianDental Journal vol 14 no 1 pp 26ndash31 2003

[64] R Wolfram A Oguogho B Palumbo and H SinzingerldquoEnhanced oxidative stress in coronary heart disease andchronic heart failure as indicated by an increased 8-epi-PGF2120572rdquoEuropean Journal of Heart Failure vol 7 no 2 pp 167ndash172 2005

[65] S Xiang R Denver M Bailey and H Krum ldquoPhysiologicdeterminants of endothelin concentrations in human salivardquoClinical Chemistry vol 49 no 12 pp 2012ndash2019 2003

[66] N Christodoulides F N Pierre X Sanchez et al ldquoPro-grammable bio-nanochip technology for the diagnosis of car-diovascular disease at the point-of-carerdquo Methodist DeBakeyCardiovascular Journal vol 8 no 1 pp 6ndash12 2012

[67] E J Franzmann E P Reategui K L Carraway K L HamiltonD T Weed and W J Goodwin ldquoSalivary soluble CD44 apotential molecular marker for head and neck cancerrdquo CancerEpidemiology Biomarkers and Prevention vol 14 no 3 pp 735ndash739 2005

[68] L-P Zhong G-F Chen Z-F Xu X Zhang F-Y Ping and S-F Zhao ldquoDetection of telomerase activity in saliva from oralsquamous cell carcinoma patientsrdquo International Journal of Oraland Maxillofacial Surgery vol 34 no 5 pp 566ndash570 2005

[69] A K Markopoulos E Z Michailidou and G TzimagiorgisldquoSalivary markers for oral cancer detectionrdquo Open DentistryJournal no 4 pp 172ndash178 2010

[70] F D Shah R Begum B N Vajaria et al ldquoA review on salivarygenomics and proteomics biomarkers in oral cancerrdquo IndianJournal of Clinical Biochemistry vol 26 no 4 pp 326ndash334 2011

[71] C F Streckfus L Bigler T Dellinger M Kuhn N Chouinardand X Dai ldquoThe expression of the c-erbB-2 receptor proteinin glandular salivary secretionsrdquo Journal of Oral Pathology andMedicine vol 33 no 10 pp 595ndash600 2004

[72] M Markman ldquoNormal CA-125 and the risk of progression inovarian cancerrdquo Journal of Clinical Oncology vol 24 no 20 p3310 2006

[73] L Zhang J J Farrell H Zhou et al ldquoSalivary transcriptomicbiomarkers for detection of resectable pancreatic cancerrdquo Gas-troenterology vol 138 no 3 pp 949ndash957 2010

[74] C T Viet and B L Schmidt ldquoMethylation array analysisof preoperative and postoperative saliva DNA in oral cancerpatientsrdquo Cancer Epidemiology Biomarkers and Prevention vol17 no 12 pp 3603ndash3611 2008

[75] J Wei G Xie Z Zhou et al ldquoSalivary metabolite signatures oforal cancer and leukoplakiardquo International Journal of Cancervol 129 no 9 pp 2207ndash2217 2011

[76] D L Mager A D Haffajee P M Delvin C M Norris M RPosner and J M Goodson ldquoThe salivary microbiota as a diag-nostic indicator of oral cancer a descriptive non-randomizedstudy of cancer-free and oral squamous cell carcinoma subjectsrdquoJournal of Translational Medicine vol 3 article 27 2005

[77] H Xiao L Zhang H Zhou J M Lee E B Garon and D T WWong ldquoProteomic analysis of human saliva from lung cancerpatients using two-dimensional difference gel electrophoresisand mass spectrometryrdquo Molecular amp Cellular Proteomics vol11 no 2 2012

[78] P S Ramsey and W W Andrews ldquoBiochemical predictors ofpreterm labor fetal fibronectin and salivary estriolrdquo Clinics inPerinatology vol 30 no 4 pp 701ndash733 2003

[79] L D Belkien J Bordt P Moller R Hano and E NieschlagldquoEstradiol in saliva for monitoring follicular stimulation in anin vitro fertilization programrdquo Fertility and Sterility vol 44 no3 pp 322ndash327 1985

[80] K Simunkova R Hampl M Hill J Doucha L Starka and KVondra ldquoSalivary cortisol in low dose (1 microg) ACTH test inhealthy women comparison with serum cortisolrdquo PhysiologicalResearch vol 56 no 4 pp 449ndash453 2007

[81] A van Stegeren N Rohleder W Everaerd and O T WolfldquoSalivary alpha amylase asmarker for adrenergic activity duringstress effect of betablockaderdquo Psychoneuroendocrinology vol31 no 1 pp 137ndash141 2006

[82] R S Rittmaster and D L Thompson ldquoEffect of leuprolide anddexamethasone on hair growth and hormone levels in hirsutewomen the relative importance of the ovary and the adrenal inthe pathogenesis of hirsutismrdquo Journal of Clinical Endocrinologyand Metabolism vol 70 no 4 pp 1096ndash1102 1990

[83] I M Goodyer J Herbert and A Tamplin ldquoPsychoendocrineantecedents of persistent first-episode major depression inadolescents a community-based longitudinal enquiryrdquo Psycho-logical Medicine vol 33 no 4 pp 601ndash610 2003

[84] S Yamada ldquoAssessment of mental condition by saliva level of 3-methoxy-4-hydroxyphenylglycolrdquo Seishin Shinkeigaku Zasshivol 107 no 7 pp 712ndash717 2005 (Japanese)

[85] M Tsuruoka J Hara A Hirayama et al ldquoCapillaryelectrophoresis-mass spectrometry-based metabolomeanalysis of serum and saliva from neurodegenerative dementiapatientsrdquo Electrophoresis vol 34 no 19 pp 2865ndash2872 2013

[86] N Pant Pai B Balram S Shivkumar et al ldquoHead-to-headcomparison of accuracy of a rapid point-of-care HIV test withoral versus whole-blood specimens a systematic review andmeta-analysisrdquoThe Lancet Infectious Diseases vol 12 no 5 pp373ndash380 2012

[87] P L CorstjensW RAbrams andDMalamud ldquoSaliva and viralinfectionsrdquo Periodontology 2000 vol 70 no 1 pp 93ndash110 2016

[88] G B L Menezes F A Pereira C A B Duarte et al ldquoHepatitisC virus quantification in serum and saliva of HCV-infectedpatientsrdquo Memorias do Instituto Oswaldo Cruz vol 107 no 5pp 680ndash683 2012

[89] G Yap B K Sil and L-C Ng ldquoUse of saliva for early denguediagnosisrdquo PLoSNeglected Tropical Diseases vol 5 no 5 ArticleID e1046 2011

[90] P L A M Corstjens and D Malamud ldquoPoint-of-care diagnos-tics for infectious diseasesrdquo in Salivary Diagnostics D T WongEd chapter 13 pp 136ndash149Wiley-Blackwell Ames Iowa USA2008

[91] J W Galloway B J F Keijser and D M Williams ldquoSaliva instudies of epidemiology of human disease the UK Biobankprojectrdquo Periodontology 2000 vol 70 no 1 pp 184ndash195 2016

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

8 Disease Markers

[62] F Astaneie M Afshari A Mojtahedi et al ldquoTotal antioxidantcapacity and levels of epidermal growth factor and nitric oxidein blood and saliva of insulin-dependent diabetic patientsrdquoArchives of Medical Research vol 36 no 4 pp 376ndash381 2005

[63] M E Lopez M E Colloca R G Paez J N Schallmach M AKoss andA Chervonagura ldquoSalivary characteristics of diabeticchildrenrdquoBrazilianDental Journal vol 14 no 1 pp 26ndash31 2003

[64] R Wolfram A Oguogho B Palumbo and H SinzingerldquoEnhanced oxidative stress in coronary heart disease andchronic heart failure as indicated by an increased 8-epi-PGF2120572rdquoEuropean Journal of Heart Failure vol 7 no 2 pp 167ndash172 2005

[65] S Xiang R Denver M Bailey and H Krum ldquoPhysiologicdeterminants of endothelin concentrations in human salivardquoClinical Chemistry vol 49 no 12 pp 2012ndash2019 2003

[66] N Christodoulides F N Pierre X Sanchez et al ldquoPro-grammable bio-nanochip technology for the diagnosis of car-diovascular disease at the point-of-carerdquo Methodist DeBakeyCardiovascular Journal vol 8 no 1 pp 6ndash12 2012

[67] E J Franzmann E P Reategui K L Carraway K L HamiltonD T Weed and W J Goodwin ldquoSalivary soluble CD44 apotential molecular marker for head and neck cancerrdquo CancerEpidemiology Biomarkers and Prevention vol 14 no 3 pp 735ndash739 2005

[68] L-P Zhong G-F Chen Z-F Xu X Zhang F-Y Ping and S-F Zhao ldquoDetection of telomerase activity in saliva from oralsquamous cell carcinoma patientsrdquo International Journal of Oraland Maxillofacial Surgery vol 34 no 5 pp 566ndash570 2005

[69] A K Markopoulos E Z Michailidou and G TzimagiorgisldquoSalivary markers for oral cancer detectionrdquo Open DentistryJournal no 4 pp 172ndash178 2010

[70] F D Shah R Begum B N Vajaria et al ldquoA review on salivarygenomics and proteomics biomarkers in oral cancerrdquo IndianJournal of Clinical Biochemistry vol 26 no 4 pp 326ndash334 2011

[71] C F Streckfus L Bigler T Dellinger M Kuhn N Chouinardand X Dai ldquoThe expression of the c-erbB-2 receptor proteinin glandular salivary secretionsrdquo Journal of Oral Pathology andMedicine vol 33 no 10 pp 595ndash600 2004

[72] M Markman ldquoNormal CA-125 and the risk of progression inovarian cancerrdquo Journal of Clinical Oncology vol 24 no 20 p3310 2006

[73] L Zhang J J Farrell H Zhou et al ldquoSalivary transcriptomicbiomarkers for detection of resectable pancreatic cancerrdquo Gas-troenterology vol 138 no 3 pp 949ndash957 2010

[74] C T Viet and B L Schmidt ldquoMethylation array analysisof preoperative and postoperative saliva DNA in oral cancerpatientsrdquo Cancer Epidemiology Biomarkers and Prevention vol17 no 12 pp 3603ndash3611 2008

[75] J Wei G Xie Z Zhou et al ldquoSalivary metabolite signatures oforal cancer and leukoplakiardquo International Journal of Cancervol 129 no 9 pp 2207ndash2217 2011

[76] D L Mager A D Haffajee P M Delvin C M Norris M RPosner and J M Goodson ldquoThe salivary microbiota as a diag-nostic indicator of oral cancer a descriptive non-randomizedstudy of cancer-free and oral squamous cell carcinoma subjectsrdquoJournal of Translational Medicine vol 3 article 27 2005

[77] H Xiao L Zhang H Zhou J M Lee E B Garon and D T WWong ldquoProteomic analysis of human saliva from lung cancerpatients using two-dimensional difference gel electrophoresisand mass spectrometryrdquo Molecular amp Cellular Proteomics vol11 no 2 2012

[78] P S Ramsey and W W Andrews ldquoBiochemical predictors ofpreterm labor fetal fibronectin and salivary estriolrdquo Clinics inPerinatology vol 30 no 4 pp 701ndash733 2003

[79] L D Belkien J Bordt P Moller R Hano and E NieschlagldquoEstradiol in saliva for monitoring follicular stimulation in anin vitro fertilization programrdquo Fertility and Sterility vol 44 no3 pp 322ndash327 1985

[80] K Simunkova R Hampl M Hill J Doucha L Starka and KVondra ldquoSalivary cortisol in low dose (1 microg) ACTH test inhealthy women comparison with serum cortisolrdquo PhysiologicalResearch vol 56 no 4 pp 449ndash453 2007

[81] A van Stegeren N Rohleder W Everaerd and O T WolfldquoSalivary alpha amylase asmarker for adrenergic activity duringstress effect of betablockaderdquo Psychoneuroendocrinology vol31 no 1 pp 137ndash141 2006

[82] R S Rittmaster and D L Thompson ldquoEffect of leuprolide anddexamethasone on hair growth and hormone levels in hirsutewomen the relative importance of the ovary and the adrenal inthe pathogenesis of hirsutismrdquo Journal of Clinical Endocrinologyand Metabolism vol 70 no 4 pp 1096ndash1102 1990

[83] I M Goodyer J Herbert and A Tamplin ldquoPsychoendocrineantecedents of persistent first-episode major depression inadolescents a community-based longitudinal enquiryrdquo Psycho-logical Medicine vol 33 no 4 pp 601ndash610 2003

[84] S Yamada ldquoAssessment of mental condition by saliva level of 3-methoxy-4-hydroxyphenylglycolrdquo Seishin Shinkeigaku Zasshivol 107 no 7 pp 712ndash717 2005 (Japanese)

[85] M Tsuruoka J Hara A Hirayama et al ldquoCapillaryelectrophoresis-mass spectrometry-based metabolomeanalysis of serum and saliva from neurodegenerative dementiapatientsrdquo Electrophoresis vol 34 no 19 pp 2865ndash2872 2013

[86] N Pant Pai B Balram S Shivkumar et al ldquoHead-to-headcomparison of accuracy of a rapid point-of-care HIV test withoral versus whole-blood specimens a systematic review andmeta-analysisrdquoThe Lancet Infectious Diseases vol 12 no 5 pp373ndash380 2012

[87] P L CorstjensW RAbrams andDMalamud ldquoSaliva and viralinfectionsrdquo Periodontology 2000 vol 70 no 1 pp 93ndash110 2016

[88] G B L Menezes F A Pereira C A B Duarte et al ldquoHepatitisC virus quantification in serum and saliva of HCV-infectedpatientsrdquo Memorias do Instituto Oswaldo Cruz vol 107 no 5pp 680ndash683 2012

[89] G Yap B K Sil and L-C Ng ldquoUse of saliva for early denguediagnosisrdquo PLoSNeglected Tropical Diseases vol 5 no 5 ArticleID e1046 2011

[90] P L A M Corstjens and D Malamud ldquoPoint-of-care diagnos-tics for infectious diseasesrdquo in Salivary Diagnostics D T WongEd chapter 13 pp 136ndash149Wiley-Blackwell Ames Iowa USA2008

[91] J W Galloway B J F Keijser and D M Williams ldquoSaliva instudies of epidemiology of human disease the UK Biobankprojectrdquo Periodontology 2000 vol 70 no 1 pp 184ndash195 2016

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom