The potential impact of salivary peptides in periodontitis

Abstract Periodontitis is a complex immune-inflammatory condition characterized by the disruption of the periodontal ligament and subsequent formation of periodontal pockets, and by alveolar bone loss, often resulting in tooth loss. A myriad of factors, namely, genetic, metabolic, immunological, and inflammatory, is associated with progression of periodontitis. Periodontitis is also associated with systemic conditions such as neoplastic disorders, obesity, and diabetes. The current diagnosis of this disease relies on clinical measurements such as clinical attachment loss and probing depth, which have poor precision due to patient, operator and probe-related factors. Thus, there is a need to develop reliable, objective, and reproducible biomarkers for early diagnosis of periodontitis. In this regard, saliva, with contributions from the gingival crevicular fluid, holds great potential. However, most of the information on biomarkers of periodontium-related salivary proteins has come from studies on the molecular pathogenesis of periodontitis. In periodontitis, a more holistic approach, such as the use of -omics technologies, for biomarker discovery, is needed. Herein, we review the biomarkers proposed to date for the assessment of periodontitis, with emphasis on the role of salivary peptides in periodontitis and their assessment by high-throughput saliva proteomics. We also discuss the challenges pertaining to the identification of new periodontitis biomarkers in saliva.

[1]  Muhammad Sohail Zafar,et al.  Biochemical analysis of oral fluids for disease detection. , 2020, Advances in clinical chemistry.

[2]  Z. Khurshid,et al.  Evaluation of Osteocalcin Levels in Saliva of Periodontitis Patients and Their Correlation with the Disease Severity: A Cross-Sectional Study , 2020, European Journal of Dentistry.

[3]  J. Preisser,et al.  Flossing Is Associated with Improved Oral Health in Older Adults , 2020, Journal of dental research.

[4]  Z. Khurshid,et al.  Human Saliva: Non-Invasive Fluid for Detecting Novel Coronavirus (2019-nCoV) , 2020, International journal of environmental research and public health.

[5]  Pietro Salvo,et al.  Saliva sampling: Methods and devices. An overview , 2020 .

[6]  C. Vlachopoulos,et al.  Periodontitis and cardiovascular diseases: Consensus report , 2020, Journal of clinical periodontology.

[7]  U. Gursoy,et al.  Salivary human beta-defensins and cathelicidin levels in relation to periodontitis and type 2 diabetes mellitus , 2020, Acta odontologica Scandinavica.

[8]  J. Vincent,et al.  The Future of Biomarkers. , 2020, Critical care clinics.

[9]  P. Papapanou,et al.  Clinical application of the new classification of periodontal diseases: Ground rules, clarifications and "gray zones". , 2019, Journal of periodontology.

[10]  S. K. Vashist,et al.  Chemistry of Biotin–Streptavidin and the Growing Concern of an Emerging Biotin Interference in Clinical Immunoassays , 2019, ACS omega.

[11]  D. Nebel,et al.  Antimicrobial peptide LL-37 and its pro-form, hCAP18, in desquamated epithelial cells of human whole saliva. , 2019, European journal of oral sciences.

[12]  Hao Feng,et al.  The association between chronic periodontitis and oral Helicobacter pylori: A meta-analysis , 2019, PloS one.

[13]  S. Gangloff,et al.  Cationic antimicrobial peptides and periodontal physiopathology: A systematic review. , 2019, Journal of periodontal research.

[14]  V. Salomaa,et al.  Salivary Cytokine Biomarker Concentrations in Relation to Obesity and Periodontitis , 2019, Journal of clinical medicine.

[15]  D. Sakellari,et al.  Saliva proteomics updates in biomedicine , 2019, Journal of Biological Research-Thessaloniki.

[16]  Ali I. Al-Gareeb,et al.  Endothelin-1 is a surrogate biomarker link severe periodontitis and endothelial dysfunction in hypertensive patients: The potential nexus , 2019, Journal of International Oral Health.

[17]  N. Buduneli,et al.  Effects of Smoking on Non-surgical Periodontal Therapy in Patients with Periodontitis Stage III or IV, and Grade C. , 2019, Journal of periodontology.

[18]  Rahila Ikram,et al.  The effects of aspirin gel and mouthwash on levels of salivary biomarkers PGE2, TNF-α and nitric oxide in patients with periodontal diseases. , 2019, Pakistan journal of pharmaceutical sciences.

[19]  G. Dahlén,et al.  Importance of Virulence Factors for the Persistence of Oral Bacteria in the Inflamed Gingival Crevice and in the Pathogenesis of Periodontal Disease , 2019, Journal of clinical medicine.

[20]  Antoine Piau,et al.  Current State of Digital Biomarker Technologies for Real-Life, Home-Based Monitoring of Cognitive Function for Mild Cognitive Impairment to Mild Alzheimer Disease and Implications for Clinical Care: Systematic Review , 2019, Journal of medical Internet research.

[21]  Victoria E. Lawson,et al.  A Prototype Antibody-based Biosensor for Measurement of Salivary MMP-8 in Periodontitis using Surface Acoustic Wave Technology , 2019, Scientific Reports.

[22]  James A. Fellows Yates,et al.  Microbial differences between dental plaque and historic dental calculus are related to oral biofilm maturation stage , 2019, Microbiome.

[23]  D. Michaud,et al.  Oral Health and Cancer , 2019, Current Oral Health Reports.

[24]  K. Kaczor‐Urbanowicz,et al.  Salivaomics in oral cancer. , 2019, Current opinion in otolaryngology & head and neck surgery.

[25]  K. Tabeta,et al.  β 2-Microglobulin and Neutrophil Gelatinase-Associated Lipocalin, Potential Novel Urine Biomarkers in Periodontitis: A Cross-Sectional Study in Japanese , 2019, International journal of dentistry.

[26]  Sean Khozin,et al.  Developing and adopting safe and effective digital biomarkers to improve patient outcomes , 2019, npj Digital Medicine.

[27]  Seba Abraham,et al.  Critical Appraisal of Bidirectional Relationship between Periodontitis and Hyperlipidemia , 2019, Journal of International Society of Preventive & Community Dentistry.

[28]  M. Amerikova,et al.  Antimicrobial activity, mechanism of action, and methods for stabilisation of defensins as new therapeutic agents , 2019, Biotechnology & Biotechnological Equipment.

[29]  Biju Thomas,et al.  A comparative evaluation of the micronutrient profile in the serum of diabetes mellitus Type II patients and healthy individuals with periodontitis , 2019, Journal of Indian Society of Periodontology.

[30]  Yun-Gon Kim,et al.  Deep sequencing salivary proteins for periodontitis using proteomics , 2018, Clinical Oral Investigations.

[31]  T. Sorsa,et al.  The Use of Serum MMP-9 and TIMP-1 in Acute Coronary Syndrome , 2018, Journal of Cardiovascular Translational Research.

[32]  N. Buduneli Hyperglycemia and periodontitis: Possible mechanisms of interaction. , 2018, Oral diseases.

[33]  M. Nieminen,et al.  Salivary biomarkers in association with periodontal parameters and the periodontitis risk haplotype , 2018, Innate immunity.

[34]  Sonalee Shah Salivaomics: The current scenario , 2018, Journal of oral and maxillofacial pathology : JOMFP.

[35]  M. Nieminen,et al.  Saliva and serum biomarkers in periodontitis and coronary artery disease , 2018, Journal of clinical periodontology.

[36]  C. Cutler,et al.  From manual periodontal probing to digital 3-D imaging to endoscopic capillaroscopy: Recent advances in periodontal disease diagnosis. , 2018, Journal of periodontal research.

[37]  M. Napimoga,et al.  Levels of Pro and Anti-inflammatory Citokynes and C-Reactive Protein in Patients with Chronic Periodontitis Submitted to Nonsurgical Periodontal Treatment , 2018, Asian Pacific journal of cancer prevention : APJCP.

[38]  R. Mohamed,et al.  Hepatitis Screening and Treatment Campaign in Malaysia-Validation of Low-cost Point of Care Screening Tests and Nucleic Acid Tests for Hepatitis B and C , 2018, Euroasian journal of hepato-gastroenterology.

[39]  Yannis A. Guzman,et al.  High‐throughput proteomic analysis of candidate biomarker changes in gingival crevicular fluid after treatment of chronic periodontitis , 2018, Journal of periodontal research.

[40]  K. Kornman,et al.  Staging and grading of periodontitis: Framework and proposal of a new classification and case definition , 2018, Journal of periodontology.

[41]  Zhuoneng Li,et al.  Protective role of flavonoid baicalin from Scutellaria baicalensis in periodontal disease pathogenesis: A literature review. , 2018, Complementary therapies in medicine.

[42]  P. Papapanou,et al.  A new classification scheme for periodontal and peri‐implant diseases and conditions – Introduction and key changes from the 1999 classification , 2018, Journal of periodontology.

[43]  K. Kornman,et al.  Staging and grading of periodontitis: Framework and proposal of a new classification and case definition , 2018, Journal of periodontology.

[44]  Muhammad Sohail Zafar,et al.  Human Oral Defensins Antimicrobial Peptides: A Future Promising Antimicrobial Drug. , 2018, Current pharmaceutical design.

[45]  S. Gangloff,et al.  Antimicrobial peptide gene expression in periodontitis patients: A pilot study , 2018, Journal of clinical periodontology.

[46]  Jonas Grossmann,et al.  Targeted Proteomics Guided by Label-free Quantitative Proteome Analysis in Saliva Reveal Transition Signatures from Health to Periodontal Disease * , 2018, Molecular & Cellular Proteomics.

[47]  N. Ghallab,et al.  Diagnostic potential and future directions of biomarkers in gingival crevicular fluid and saliva of periodontal diseases: Review of the current evidence. , 2018, Archives of oral biology.

[48]  R. Boyapati,et al.  Association of pentraxin and high-sensitive C-reactive protein as inflammatory biomarkers in patients with chronic periodontitis and peripheral arterial disease , 2018, Journal of Indian Society of Periodontology.

[49]  Julia Eliette Goeke,et al.  Sensitivity of caries pathogens to antimicrobial peptides related to caries risk , 2018, Clinical Oral Investigations.

[50]  C. Bertozzi,et al.  Antibody detection by agglutination–PCR (ADAP) enables early diagnosis of HIV infection by oral fluid analysis , 2018, Proceedings of the National Academy of Sciences.

[51]  Mercedes Argüello Casteleiro,et al.  Unveiling antimicrobial peptide-generating human proteases using PROTEASIX. , 2018, Journal of proteomics.

[52]  J. Costa-Cruz,et al.  Immune complex detection in saliva samples: an innovative proposal for the diagnosis of human strongyloidiasis , 2017, Parasitology.

[53]  Hadley D Sikes,et al.  Detection of Biomarkers of Periodontal Disease in Human Saliva Using Stabilized, Vertical Flow Immunoassays. , 2017, ACS sensors.

[54]  P. Agrawal,et al.  Antimicrobial peptides: The miraculous biological molecules , 2017, Journal of Indian Society of Periodontology.

[55]  V. Nerurkar,et al.  Detection of Plasmodium falciparum DNA in saliva samples stored at room temperature: potential for a non-invasive saliva-based diagnostic test for malaria , 2017, Malaria Journal.

[56]  F. Silvestre,et al.  Association between obesity and periodontal disease. A systematic review of epidemiological studies and controlled clinical trials , 2017, Medicina oral, patologia oral y cirugia bucal.

[57]  Sanjay Gupta,et al.  Simultaneous Detection of Oral Pathogens in Subgingival Plaque and Prostatic Fluid of Men With Periodontal and Prostatic Diseases , 2017, Journal of periodontology.

[58]  C. la Vecchia,et al.  Hormone factors play a favorable role in female head and neck cancer risk , 2017, Cancer medicine.

[59]  Ting Huang,et al.  Comparison of Fecal Microbial Composition and Antibiotic Resistance Genes from Swine, Farm Workers and the Surrounding Villagers , 2017, Scientific Reports.

[60]  F. Nomura,et al.  Ubiquitination in Periodontal Disease: A Review , 2017, International journal of molecular sciences.

[61]  K. Matsushita,et al.  Porphyromonas gingivalis-induced IL-33 down-regulates hCAP-18/LL-37 production in human gingival epithelial cells. , 2017, Biomedical research.

[62]  Lei Cui,et al.  Exposure to fermentation supernatant of Staphylococcus aureus accelerated dedifferentiation of chondrocytes and production of antimicrobial peptides , 2017, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[63]  A. Banerjee,et al.  The oral health of individuals with dental phobia: a multivariate analysis of the Adult Dental Health Survey, 2009 , 2017, BDJ.

[64]  T. Mulli,et al.  Association of salivary RANKL and osteoprotegerin levels with periodontal health , 2017, Clinical and experimental dental research.

[65]  Siqi Liu,et al.  Disease Biomarkers for Precision Medicine: Challenges and Future Opportunities , 2017, Genom. Proteom. Bioinform..

[66]  H. Atmaca,et al.  Gingival crevicular fluid and serum hCAP18/LL-37 levels in generalized aggressive periodontitis , 2017, Clinical Oral Investigations.

[67]  B. Sulijaya,et al.  Existence of Human Beta Defensin-1 Peptide on Periodontal Disease: An Updated Review Based on Case-control and Cross-sectional Studies , 2017 .

[68]  Praveen Sharma,et al.  Global epidemiology of dental caries and severe periodontitis – a comprehensive review , 2017, Journal of clinical periodontology.

[69]  S. Gorr,et al.  Antimicrobial Peptides: Mechanisms of Action and Resistance , 2017, Journal of dental research.

[70]  Mustafa Naseem,et al.  Human Gingival Crevicular Fluids (GCF) Proteomics: An Overview , 2017, Dentistry journal.

[71]  Shamala Devi Sekaran,et al.  Intracellular Targeting Mechanisms by Antimicrobial Peptides , 2017, Antimicrobial Agents and Chemotherapy.

[72]  C. Borrebaeck Precision diagnostics: moving towards protein biomarker signatures of clinical utility in cancer , 2017, Nature Reviews Cancer.

[73]  R. Vitorino,et al.  Human Antimicrobial Peptides in Bodily Fluids: Current Knowledge and Therapeutic Perspectives in the Postantibiotic Era , 2017, Medicinal research reviews.

[74]  B. Buszewski,et al.  Saliva – Volatile Biomarkers and Profiles , 2017, Critical reviews in analytical chemistry.

[75]  T. Nguyen,et al.  Salivary oxidative stress biomarkers in chronic periodontitis and acute coronary syndrome , 2016, Clinical Oral Investigations.

[76]  Fuhua Yan,et al.  Biomarker levels in gingival crevicular fluid of subjects with different periodontal conditions: A cross-sectional study. , 2016, Archives of oral biology.

[77]  T. V. Van Dyke,et al.  Propolis Improves Periodontal Status and Glycemic Control in Patients With Type 2 Diabetes Mellitus and Chronic Periodontitis: A Randomized Clinical Trial. , 2016, Journal of periodontology.

[78]  Amit Patel Management of Peri-implant Diseases. , 2016, Dentistry today.

[79]  S. Zope,et al.  Estimation and Comparison of Salivary Calcium, Phosphorous, Alkaline Phosphatase and pH Levels in Periodontal Health and Disease: A Cross-sectional Biochemical Study. , 2016, Journal of clinical and diagnostic research : JCDR.

[80]  T. Sorsa,et al.  Oral fluid matrix metalloproteinase (MMP)-8 as a diagnostic tool in chronic periodontitis , 2016 .

[81]  A. Creese,et al.  Longitudinal quantification of the gingival crevicular fluid proteome during progression from gingivitis to periodontitis in a canine model , 2016, Journal of clinical periodontology.

[82]  P. Preshaw,et al.  Salivary cytokines as biomarkers of periodontal diseases. , 2016, Periodontology 2000.

[83]  T. Morelli,et al.  Gingival crevicular fluid as a source of biomarkers for periodontitis. , 2016, Periodontology 2000.

[84]  J. Kinney,et al.  Personalized medicine: an update of salivary biomarkers for periodontal diseases. , 2016, Periodontology 2000.

[85]  R. Redman,et al.  Salivary and serum procalcitonin and C-reactive protein as biomarkers of periodontitis in United States veterans with osteoarthritis or rheumatoid arthritis , 2016, Biotechnic & histochemistry : official publication of the Biological Stain Commission.

[86]  Vural Özdemir,et al.  A Systems Biology Approach to Reveal Putative Host-Derived Biomarkers of Periodontitis by Network Topology Characterization of MMP-REDOX/NO and Apoptosis Integrated Pathways , 2016, Front. Cell. Infect. Microbiol..

[87]  T. Sorsa,et al.  Neutrophil proteolytic activation cascades: a possible mechanistic link between chronic periodontitis and coronary heart disease , 2016, Innate immunity.

[88]  G. Genta,et al.  Probing depth in periodontal pockets: In vitro evaluation of contributions to variability due to probe type and operator skill , 2015, Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine.

[89]  A. Mariotti,et al.  Defining periodontal health , 2015, BMC oral health.

[90]  Š. Podzimek,et al.  C-Reactive Protein in Peripheral Blood of Patients with Chronic and Aggressive Periodontitis, Gingivitis, and Gingival Recessions , 2015, Mediators of inflammation.

[91]  E. Diamandis,et al.  Toward an integrated pipeline for protein biomarker development. , 2015, Biochimica et biophysica acta.

[92]  Malarvili Balakrishnan,et al.  Saliva-Based Biosensors: Noninvasive Monitoring Tool for Clinical Diagnostics , 2014, BioMed research international.

[93]  D. Gillam,et al.  Periodontal Probing: A Review , 2014, Primary dental journal.

[94]  H. Meng,et al.  Vitamin D-Binding Protein Levels in Plasma and Gingival Crevicular Fluid of Patients with Generalized Aggressive Periodontitis , 2014, International journal of endocrinology.

[95]  John J. Taylor Protein Biomarkers of Periodontitis in Saliva , 2014, ISRN inflammation.

[96]  Uwe Völker,et al.  Identification of periodontitis associated changes in the proteome of whole human saliva by mass spectrometric analysis. , 2013, Journal of clinical periodontology.

[97]  C. Punyadeera,et al.  Saliva as an emerging biofluid for clinical diagnosis and applications of MEMS/NEMS in salivary diagnostics , 2012, Nanobiomaterials in Clinical Dentistry.

[98]  Christina M. Bonebreak,et al.  The potential of salivary point of care diagnostics , 2011, Journal of Applied Oral Science.

[99]  O. Aruoma,et al.  The future of biomarkers. , 2010, Toxicology.

[100]  Y Wu,et al.  Initial comparison of proteomic profiles of whole unstimulated saliva obtained from generalized aggressive periodontitis patients and healthy control subjects. , 2009, Journal of periodontal research.

[101]  J Highfield,et al.  Diagnosis and classification of periodontal disease. , 2009, Australian dental journal.

[102]  D. Wong,et al.  Saliva as a diagnostic tool for periodontal disease: current state and future directions. , 2009, Periodontology 2000.

[103]  D. Wong,et al.  Salivary diagnostics. , 2006, Orthodontics & craniofacial research.

[104]  O. Ohlsson,et al.  High-sensitivity serum C-reactive protein levels in subjects with or without myocardial infarction or periodontitis. , 2005, Journal of clinical periodontology.

[105]  E. Rimm,et al.  Alcohol Consumption Increases Periodontitis Risk , 2003, Journal of dental research.

[106]  G. Armitage,et al.  Development of a classification system for periodontal diseases and conditions. , 1999, Annals of periodontology.

[107]  G. Armitage Manual periodontal probing in supportive periodontal treatment. , 1996, Periodontology 2000.

[108]  Kevin Saraiya,et al.  Dental calculus – An evergrowing heap of periodontal pathogens , 2019, Journal of Integrated Health Sciences.

[109]  Muhammad Sohail Zafar,et al.  Role of Salivary Biomarkers in Oral Cancer Detection. , 2018, Advances in clinical chemistry.

[110]  A. Khudhur Identification and characterization of novel salivary biomarkers for oral inflammatory disease , 2017 .

[111]  Madhu Gupta,et al.  Salivary IgA, Interleukin-1β and MMP-8 as Salivary Biomarkers in Chronic Periodontitis Patients. , 2017, The Chinese journal of dental research : the official journal of the Scientific Section of the Chinese Stomatological Association.

[112]  Simon D Tran,et al.  Saliva as a diagnostic tool for oral and systemic diseases. , 2016, Journal of oral biology and craniofacial research.

[113]  E. Lesaffre,et al.  Diagnostic accuracy for apical and chronic periodontitis biomarkers in gingival crevicular fluid: an exploratory study. , 2016, Journal of clinical periodontology.

[114]  D. Wong Salivary Diagnostics: Amazing as it might seem, doctors can detect and monitor diseases using molecules found in a sample of spit. , 2008, American scientist.

[115]  E. Rimm,et al.  Increased physical activity decreases periodontitis risk in men , 2004, European Journal of Epidemiology.