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Review

Salivary Biomarkers and Their Application in the Diagnosis and Monitoring of the Most Common Oral Pathologies

by
Lucía Melguizo-Rodríguez
1,2,
Victor J. Costela-Ruiz
2,3,
Francisco Javier Manzano-Moreno
2,4,
Concepción Ruiz
2,3,5,* and
Rebeca Illescas-Montes
2,3
1
Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences (Ceuta), University of Granada, 51001 Granada, Spain
2
Instituto Investigación Biosanitaria, ibs.Granada, 18012 Granada, Spain
3
Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, University of Granada, 18016 Granada, Spain
4
Biomedical Group (BIO277), Department of Stomatology, School of Dentistry, University of Granada, 18071 Granada, Spain
5
Institute of Neuroscience, University of Granada, 18016 Granada, Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(14), 5173; https://doi.org/10.3390/ijms21145173
Submission received: 17 June 2020 / Revised: 10 July 2020 / Accepted: 15 July 2020 / Published: 21 July 2020
(This article belongs to the Special Issue Salivary Biomarkers and Their Application to Diagnosis and Monitoring Human Diseases)
Browse Figure
Versions Notes

Abstract

:
Saliva is a highly versatile biological fluid that is easy to gather in a non-invasive manner—and the results of its analysis complement clinical and histopathological findings in the diagnosis of multiple diseases. The objective of this review was to offer an update on the contribution of salivary biomarkers to the diagnosis and prognosis of diseases of the oral cavity, including oral lichen planus, periodontitis, Sjögren’s syndrome, oral leukoplakia, peri-implantitis, and medication-related osteonecrosis of the jaw. Salivary biomarkers such as interleukins, growth factors, enzymes, and other biomolecules have proven useful in the diagnosis and follow-up of these diseases, facilitating the early evaluation of malignization risk and the monitoring of disease progression and response to treatment. However, further studies are required to identify new biomarkers and verify their reported role in the diagnosis and/or prognosis of oral diseases.

Graphical Abstract

1. Introduction

The gold standard for the identification and diagnosis of oral mucosal diseases is the clinical examination by dental health professionals, followed by histopathological examination of suspicious areas [1,2]. Many diseases of the oral cavity can undergo malignant transformation. Oral squamous cell carcinoma (OSCC) is one of the most frequent oral cancers and still has a five-year survival rate of only 50–65% despite diagnostic and therapeutic advances, in part attributable to diagnostic delay [3]. In most cases of OSCC, the diagnosis is based on the histopathological study of a biopsy. The analysis of saliva, which does not require an invasive procedure, is an attractive alternative option for the diagnosis and prognosis of this oral disease [4,5]. Samples can be readily obtained in a pain-free manner, their processing is relatively simple, their composition is less complex, and they are more stable in comparison to other sources [6,7]. Saliva also offers real-time results, being produced by exocrine glands, and therefore, yielding information on patients at the time the sample is taken [8]. Besides the components secreted by these glands, saliva contains other molecules that can potentially be associated with the disease phenotype and facilitate diagnosis and prognosis, including metabolites, proteins, mRNA, DNA, enzymes, hormones, antibodies, antimicrobial constituents, and growth factors [8,9]. However, it should be noted that some biomarkers detected in saliva are not specific to a particular disease and can be used for the diagnosis of various pathologies. Therefore, it is necessary to consider the different biomarkers that are affected in each disease in order to make a much more specific diagnosis and prognosis.
Salivary biomarkers used to diagnose/monitor diseases include cortisol for Cushing disease or stress disorders [10,11]; C-reactive protein (CRP), creatine kinase isoform MB, and myoglobin for cardiovascular disease [12]; pathogens, nucleic acids, and antibodies for infectious processes [13,14]; α-2-macroglobulin and glycosylated hemoglobin (HbA1c) for diabetes [15]; and various interleukins (ILs), for cancers, gut diseases, and muscle or joint disorders [16]. Therefore, the objective of this review was to determine the potential usefulness of different salivary biomarkers to assist the diagnosis and prognosis of oral cavity diseases.

2. Biomarkers in Saliva in Different Oral Diseases

Among the numerous diseases of the oral cavity, this review focuses on the following: oral lichen planus (OLP), periodontitis (PD), and primary Sjögren’s syndrome (pSS) for their high prevalence; oral leukoplakia for its malignant transformation potential, also shared by OLP; peri-implantitis for its possible negative effects on the medium- and long-term success of dental implantation; and medication-related osteonecrosis of the jaw (MRONJ) for its potential impact on the oral and general quality of life of patients. Salivary biomarkers can be useful for the diagnosis, monitoring, and even prognosis of all of these diseases (Table 1).

2.1. Oral Lichen Planus

OLP is a chronic inflammatory disease that affects the oral mucosa, including the tongue and gingival tissues. OLP is estimated to affect 1.01% of the population worldwide, with a higher rate in Europe (1.43%) [109]. It is considered a potentially malignant disease and with a 1.14% probability of oral cancer development [110]. Although no consensus has been established on its etiopathogenesis, the onset and progression of OLP have been attributed to an immunological mechanism responsible for cutaneous manifestations such as erythema, white streaks, papillae, or ulcerations [111]. Abnormal activation of the immune system is mediated by the signaling of different molecules that have been investigated as possible salivary biomarkers of OLP.
Cortisol is the main glucocorticoid that regulates processes and behaviors, including immunoregulation. High cortisol levels are attributed to the presence of stress and may trigger immunological disorders [112]. Salivary cortisol values have been widely studied in relation to the effects of stress- and anxiety-related psychological factors on immune diseases. Elevated salivary cortisol values have been observed in patients diagnosed with OLP than in those without this disease [17,18,19], and it has been suggested that there is a link between high cortisol levels and psychological strains as triggering factors of OLP [20]. Given reports that stress can be responsible for the recurrence of OLP, cortisol has been proposed as a possible diagnostic marker for this disease [21].
The role of oxidative stress in OLP has been investigated [113,114], and the pathogenesis of this disease has been related to nitric oxide (NO) and reactive oxygen species (ROS) [22]. Numerous studies have described higher salivary NO levels in patients with OLP than in healthy individuals [19], and elevated levels have been associated with a more severe disease progression through the production of mucosal lesions [22,23]. For their part, ROS have been associated with cellular oxidative stress, but there is no clear consensus on the relationship between their salivary concentrations and oxidative damage in the tissues of patients with OLP [22,24]. CRP is frequently used as a marker of inflammation, and its salivary levels are higher in patients with OLP than in healthy individuals [22,25,26], indicating a potential role in monitoring the progression of this disease [26].
Among cytokines, salivary levels of tumor necrosis factor α (TNF-α), IL1, IL4, IL6, and IL8 have been described as relevant biomarkers for OLP diagnosis and prognosis [19]. TNF-α has been studied in relation to OLP since the last century [115]. This pro-inflammatory and immunomodulatory cytokine stimulates the acute phase of inflammation, leading to the synthesis of other pro-inflammatory cytokines (e.g., IL1 and IL6) and the activation of T and B cells. It is therefore considered to mediate autoimmune and inflammatory processes, including OLP. Elevated salivary TNF-α levels have been observed in patients with OLP [19,31,32,33], and TNF-α is found to act at the onset of OLP and during its progression [31]. IL1α and IL1β both stimulate various cell populations, including T-helper (Th) lymphocytes, by increasing IL2 secretion and IL2 receptor (IL-2R) expression. They can stimulate their own production and that of other cytokines such as IL6 and IL8, playing a major role in mediating inflammation and regulating the immune response [57,58]. Higher levels of both IL1α and IL1β have been recorded in patients with OLP than in healthy individuals [19,32].
IL4 is a cytokine produced mainly by Th2 lymphocytes that exerts anti-inflammatory action by blocking the synthesis of pro-inflammatory cytokines. Although elevated salivary IL4 levels been found in OLP patients [19,61], there is insufficient evidence to support its usefulness as a biomarker of disease progression [32,62]. IL6 is a pleiotropic cytokine secreted by different cells and is considered to be pro-inflammatory and to mediate immune and inflammatory responses [116]. Significantly higher salivary IL6 levels have been found in OLP patients [19,32,64,65], attributed to the overexpression of tripartite motif-containing 21 (TRIM21), which participates in the regulation of intracellular and immune processes [117]. The association of IL6 with the onset of lesions and with advanced stages of OLP has led to its proposal as a biomarker of the response to treatment [32,66]. Another pro-inflammatory cytokine, IL8, is generated in response to damage, and its salivary levels are higher in patients with OLP than in healthy individuals [19,76,77]. Salivary levels of IL6 and IL8 have been related to the severity of OLP [32], although some authors have described salivary IL8 as a more reliable OLP biomarker [66,78].

2.2. Periodontitis

A wide variety of etiological factors have been implicated in PD, a severe gingival infection that can lead to the destruction of periodontal ligament and alveolar bone [118,119]. Most cases have a bacterial etiology, generating an anti-inflammatory response mediated by cytokines, chemokines, and other biomolecules [120,121,122]. IL1β, TNF-α, IL6, and the receptor activator of nuclear factor κB ligand (RANKL), among other cytokines, are known to be involved in immune response regulation in PD and to play a key role in its development [36,37].
IL1α is produced by cells in numerous periodontal tissues and plays an important role in the immune response to plaque bacteria in PD and other oral diseases. This cytokine frequently acts synergistically with TNF-α and prostaglandin E2 (PGE2) to produce various vascular inflammation-related modifications, and this action is especially important in the migration of neutrophils from the bloodstream to the periodontium. The increased expression of IL1β, TNF-α, and PGE2 in oral cavity fluids and tissues in PD suggests their potential use as biomarkers of its presence and progression. These proteins participate in the activation of osteoclasts, the secretion of infiltrating neutrophils, and the resorption of alveolar bone in chronic PD [51,52]. The presence of IL1β in saliva has enabled discrimination of individuals with PD from those without this disease [35,38,39,46,47,48,49,50], and its levels have been correlated with alveolar bone loss levels [53].
Salivary TNF-α levels are very low and frequently undetectable and, therefore, are of little prognostic or diagnostic value [38,39]. In addition, findings have been controversial, with reports of significantly elevated [34] and significantly reduced [35] salivary TNF-α levels in patients with PD.
Another frequently analyzed cytokine in oral cavity disease is IL6. It is produced by numerous cells of the periodontium in response to IL1β and TNF-α secretion, playing a major role in the activity of immune cells and osteoclasts and the inflammatory response to bacterial plaque formation [37,69,70]. Elevated salivary IL6 expression was observed in patients with PD by some authors [38,63,67] but not by others [27,39,49,68]. Among other salivary cytokines studied in this context, elevated IL4 levels and reduced IL17 levels [63] have been reported in patients with PD. Salivary levels of monocyte chemoattractant protein 1 have also been associated with this disease [85,86].
Salivary levels of RANKL, osteoprotegerin (OPG), and osteocalcin (OSC) have also been studied in patients with PD, mainly to explore the relationship of these biomarkers with bone loss. However, the results have been contradictory, with this association being reported by some authors [83] but not by others [34,84].
Many other salivary biomarkers have been studied in relation to PD, including inflammatory markers, cell activity markers, and growth factors. Inflammatory markers found to be elevated in PD patients include CRP and calprotectin, a known marker of inflammatory bowel disease, and frequently analyzed in feces [27,28,29,30]. Among cell activity markers, elevated levels of alkaline phosphatase (ALP), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and matrix metalloproteases (MMPs) have been associated with PD [67,87,88,89,90,91,92]. MMP-8 has been described as a more useful salivary biomarker of PD in comparison to IL1β [27,39,47,48,67,87,93]. In addition, elevated MMP-9 levels [27,35] but reduced tissue inhibitor metalloproteinase-1 (TIMP-1) levels have been detected in the saliva of patients with PD [93,97]. Available data on the association of salivary growth factors with PD are limited and imprecise. On the other hand, hepatocyte growth factor (HGF) has been related to PD as a possible mediator of apical epithelial migration [98,99,100].
Liukkonen studied 220 patients classified by PD type and reported that salivary levels of IL-17A and IL23 were higher in patients with localized periodontitis, whereas IL1β levels were higher in those with generalized periodontitis [54]. Lira Junior et al. observed higher salivary MMP-8 levels in patients with aggressive PD than in healthy individuals [94]. Isaza Guzmán et al. described salivary levels of nod-like receptor family pyrin domain-containing protein 3 (NLRP3) and IL1β as indicators of the presence and severity of chronic or aggressive PD that may be useful for preventive and/or therapeutic purposes [55].
These types of salivary biomarkers may be useful for the diagnosis, follow-up, and even prognosis of PD and support the delivery of optimal care.

2.3. Primary Sjögren’s Syndrome

pSS is a chronic systemic autoimmune disease that damages salivary and lacrimal glands [123]. It is the second most frequent autoimmune rheumatic disease, with a prevalence of around 1% [124,125]. The immunopathogenic mechanism is based on the pathological hyperactivity of B lymphocytes, expressed as a T lymphocyte-mediated increase in antibody production and the activation of interferon production pathways [126]. The glandular destruction can often generate a chronic inflammatory response in the salivary glands that result in xerostomia [127], associated with multiple oral complications such as oral candidiasis, caries, and PD. Early diagnosis of SS is essential to avoid these adverse effects, and clinicians should be alert to its signs and symptoms in their patients.
The diagnosis of pSS is generally based on a series of clinical and histopathological signs and symptoms that are often difficult to interpret, and different classifications have been published [128,129,130]. This has prompted research into the diagnostic and prognostic value of salivary biomarkers for pSS to facilitate early treatment and reduce the associated complications. In comparison to healthy patients, patients with pSS have an increased salivary expression of S100A proteins, directly related to IL-12 production pathways [81]; proteins vital for innate MHC class I cellular regulation (NGAL) and T-cell activation (CD44) [101]; and β-2 macroglobulin (B2M), which has been significantly correlated with lymphocyte infiltration in labial salivary glands [102]. Recently, auto-antibodies to salivary protein-1 (SP-1), parotid secretory protein (PSP), and carbonic anhydrase VI (CA-6) [103,104] have been proposed as biomarkers for an early pSS diagnosis to reduce complications and improve the prognosis. Further studies are warranted to identify salivary biomarkers for the prognosis of patients with pSS and for evaluating their progression and response to treatments.

2.4. Oral Leukoplakia

Oral leukoplakia is characterized by a whitish plaque in oral mucosa that cannot be removed by scraping, and it predisposes patients to oral cancer development [131]. It is closely related to the consumption of tobacco [132] and has also been associated with alcohol use [133], with fungal [134], bacterial [135,136], and viral [137,138] infections, and with hormonal disorders [139,140]. It is one of the most common premalignant lesions of the oral cavity, being responsible for around 11% of squamous cell carcinomas [141] and 3.5% of malignant transformations with a range between 0.13% and 34% [142]. The risk of malignant transformation is evaluated by taking a biopsy for the analysis of histopathological markers, including signs of dysplasia such as asymmetrical epithelial stratification, pleomorphism, myoepithelial basocellular hyperplasia, hyperchromatic nuclei, and dyskeratosis [143]. There is increasing interest in less invasive diagnostic procedures, including the analysis of pro-inflammatory cytokines.
Deepthi et al. reported that TNF-α acts as a prognostic marker of OSCC, observing elevated salivary TNF-α levels in patients with dysplasia and suggesting that this cytokine may be useful to monitor the malignant transformation of oral leukoplakia [40]. Other authors proposed that TNF-α can serve as a biomarker for the early diagnosis of pre-oral cancer, given that the levels of this cytokine and various ILs are higher in patients with more advanced precancerous lesions [41]. TNFα polymorphisms have also been associated with precancerous oral lesions [42]. Numerous authors have explored the use of ILs as salivary markers for the diagnosis and prognosis of oral leukoplakia. It is generally reported that IL6 and IL8 levels are elevated in patients with oral leukoplakia in comparison to healthy individuals [41,71,72,73]. These angiogenic mediators are suggested as potential salivary biomarkers for early cancer detection, and they are associated with tumor growth and increased blood vessel density [74]. Other ILs investigated in relation to this disease include IL37, found to be elevated in patients with oral leukoplakia [82], and IL10, whose levels have not been significantly associated with premalignant oral lesions [42,80]. However, Brailo et al. observed no difference in salivary TNF-α levels between healthy individuals and patients with oral leukoplakia or oral cancer [43]. Wenghoefer et al. also found no positive relationship between the inflammation markers IL1 β, IL6, IL8, IL10, TNF-α, or COX2 and the development of these oral lesions, even observing a lower expression of IL1β and IL10 in patients with these diseases than in healthy individuals [44].
Besides cytokines, it has been reported that salivary levels of the enzyme LDH, whose expression is closely related to cell necrosis, are elevated in patients with oral leukoplakia and even higher in those with OSCC. Therefore, this marker may be useful to evaluate the risk of malignant transformation of oral leukoplakia [105,106]. Endothelins and growth factors such as transforming growth factor β (TGFβ) and epidermal growth factor (EGF) have also been investigated in relation to oral leukoplasia. However, no significant relationship has been found between their salivary levels and the diagnosis or prognosis [80,107,108].
Data on the usefulness of salivary biomarkers in oral leukoplakia are not conclusive, and further research is warranted to verify the results obtained and to explore new candidate biomolecules for this purpose.

2.5. Peri-Implantitis

Peri-implantitis is an inflammatory disease that destroys hard and soft tissues around dental implants and is one of the main causes of medium- and long-term implant failure. It is triggered by the accumulation of bacteria on the implant surface, generating mucosal inflammation [144]. It is a progressive and irreversible peri-implant disease accompanied by bone resorption, reduced osseointegration, the formation of peri-implant pockets, and purulent secretions [145,146,147].
The most widely studied biomarkers of this disease include pro-inflammatory cytokines IL1β, IL6, IL12, IL17, and TNF-α; anti-inflammatory cytokines IL4 and IL10; osteoclastogenic cytokines RANK, RANKL, and OPG; antioxidant proteins (e.g., urate, malondialdehyde, ascorbate, and myeloperoxidase); and the chemokine IL8 [148]. Peri-implantitis has been associated with increased salivary levels of IL1β, [45,56] IL6, and IL10 levels [45,75], and these interleukins have been proposed as potentially useful markers for the early diagnosis and follow-up of this disease [45,75]. Salivary IL8 and IL12 levels were found to be higher in patients with peri-implantitis than in those with peri-implant mucositis [79]. TNF-α levels were also reported to be higher in patients with peri-implantitis than in healthy individuals [45].
Peri-implantitis is a cause of medium- and long-term implant failure, and the identification of biomarkers of this disease would support the implementation of appropriate preventive and therapeutic measures.

2.6. Medication-Related Osteonecrosis of the Jaw

MRONJ is a severe drug-related complication associated with the use of antiresorptive medication (e.g., bisphosphonates [BPs] and RANKL inhibitors) and with anti-angiogenic medication [149]. BP-related osteonecrosis of the jaw was first described by Robert Marx in 2003 [150]. After the implication of other drugs in maxillary osteonecrosis, such as RANKL inhibitors (denosumab) or VEGF-inhibiting anti-angiogenic drugs, the American Association of Oral and Maxillofacial Surgeons changed the term “BRONJ” to “MRONJ” [151]. MRONJ has been associated with various possible etiologies, including reduced bone turnover and the consequent accumulation of microfractures, avascular necrosis due to anti-angiogenic effects, impaired viability of fibroblasts, and oral keratinocytes; and osteoblast physiology disorders [152,153,154,155].
Difficulties in the early diagnosis of MRONJ, which relies exclusively on clinical findings, has led a small number of researchers to study candidate biomarkers for this purpose [156,157]. Yatsuoka et al. found significantly increased salivary levels of hypotaurine in patients with early-stage MRONJ in comparison to healthy individuals [158]. Hypotaurine is an intermediate in the biosynthesis of taurine, which acts as an antioxidant in cellular defense against oxidative stress, and the detection of increased salivary levels may assist the early diagnosis of MRONJ. Bagan et al. observed a significant increase in the levels of IL1ɑ, IL1β, interleukin-1 receptor antagonist (IL-1RA), and IL6 in the saliva of patients with MRONJ in comparison to healthy individuals [59,60]. These ILs are closely related to the inflammatory process and alveolar bone loss produced in MRONJ, and their analysis may, therefore, be useful in the detection of this disease. Thumbigere-Math et al. described elevated salivary levels of MMP-9 in patients with MRONJ, proposing this protein as a biomarker of this disease [95,96].
Measurement of systemic parameters in MRONJ monitoring represents a long-lasting and ongoing debate with no clear results until now. Different bone biomarkers have been proposed for the risk prevention of MRONJ like OSC, C-terminal telopeptide of collagen I, N-terminal telopeptides, ALP, and parathyroid hormone [159,160,161]. However, there is insufficient evidence that these biomarkers are effective in predicting the diagnosis and prognosis of MRONJ. The availability of reliable salivary biomarkers for the early diagnosis of MRONJ could make a major contribution to the correct management of these patients, reducing their morbidity.

3. Conclusions

In conclusion, salivary levels of various biomarkers are known to change in the presence of oral cavity diseases and can, therefore, be useful for their diagnosis and prognosis. Some biomarkers, such as pro-inflammatory cytokines, are common to many of these diseases, whereas others are more specific. Their evaluation in saliva offers clinicians a valuable non-invasive procedure as a complement to clinical findings, and further research is warranted to establish reliable salivary biomarkers for different diseases of the oral cavity.

Author Contributions

L.M.-R. formulated the research question. R.I.-M. and C.R. conceived and designed the study. All authors contributed to discussion and study design. L.M.-R., V.J.C.-R., F.J.M.-M., and R.I.-M. conducted the bibliographic search and the data collection. All authors interpreted the results and drafted the manuscript. L.M.-R., V.J.C.-R., F.J.M.-M., and R.I.-M. created the table. All authors critically reviewed the manuscript and approved the final version.

Funding

This research received no external funding.

Acknowledgments

This study was supported by research group BIO277 (Junta de Andalucía) and the Department of Nursing (University of Granada).

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

OSCCoral squamous cell carcinoma
ILsinterleukins
CRPC-reactive protein
OLPoral lichen planus
PDperiodontitis
pSSprimary Sjögren’s syndrome
MRONJmedication-related osteonecrosis of the jaw
NOnitric oxide
ROSreactive oxygen species
TNF-αtumor necrosis factor α
ThT-helper
IL-2RIL-2 receptor
TRIM21tripartite motif-containing 21
RANKLreceptor activator of nuclear factor κB ligand
PGE2prostaglandin E2
OPGosteoprotegerin
OSCosteocalcin
ALPalkaline phosphatase
LDHlactate dehydrogenase
ASTaspartate aminotransferase
ALTalanine aminotransferase
MMPsmatrix metalloproteases
TIMP-1tissue inhibitor metalloproteinase-1
HGFhepatocyte growth factor
NLRP3nod-like receptor family pyrin domain containing protein 3
SP-1salivary protein-1
PSPparotid secretory protein
CA-6carbonic anhydrase VI
TGFβtransforming growth factor β
EGFepidermal growth factor
BPsbisphosphonates
IL-1RAinterleukin-1 receptor antagonist

References

  1. Wu, J.Y.; Yi, C.; Chung, H.R.; Wang, D.J.; Chang, W.C.; Lee, S.Y.; Lin, C.T.; Yang, Y.C.; Yang, W.C.V. Potential biomarkers in saliva for oral squamous cell carcinoma. Oral Oncol. 2010, 46, 226–231. [Google Scholar] [CrossRef]
  2. Gaba, F.I.; Sheth, C.C.; Veses, V. Salivary biomarkers and their efficacies as diagnostic tools for Oral Squamous Cell Carcinoma: Systematic review and meta-analysis. J. Oral Pathol. Med. 2018. [Google Scholar] [CrossRef] [PubMed]
  3. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2015. CA A Cancer J. Clin. 2015, 65, 5–29. [Google Scholar] [CrossRef] [PubMed]
  4. Saxena, S.; Sankhla, B.; Sundaragiri, K.S.; Bhargava, A. A Review of Salivary Biomarker: A Tool for Early Oral Cancer Diagnosis. Adv. Biomed. Res. 2017, 6, 90. [Google Scholar] [CrossRef]
  5. Prasad, G.; McCullough, M. Chemokines and Cytokines as Salivary Biomarkers for the Early Diagnosis of Oral Cancer. Int. J. Dent. 2013, 2013, 1–7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Zhang, C.-Z.; Cheng, X.Q.; Li, J.-Y.; Zhang, P.; Yi, P.; Xu, X.; Zhou, X.-D. Saliva in the diagnosis of diseases. Int. J. Oral Sci. 2016, 8, 133–137. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Sánchez-Martínez, P.M. La saliva como fluido diagnóstico. Ed. Cont. Lab. Clín. 2013, 16, 93–108. [Google Scholar]
  8. Berga-Hidalgo, M.C. Marcadores Salivales en Lesiones Potencialmente Malignas de la Cavidad oral y en Carcinoma oral de Células Escamosas; Ed Cont Lab Clín Universidad de Zaragoza: Zaragoza, Spain, 2014. [Google Scholar]
  9. Lee, Y.-H.; Wong, D.T. Saliva: An emerging biofluid for early detection of diseases. Am. J. Dent. 2009, 22, 241–248. [Google Scholar]
  10. Pan, X.; Wang, Z.; Wu, X.; Wen, S.W.; Liu, A. Salivary cortisol in post-traumatic stress disorder: A systematic review and meta-analysis. BMC Psychiatry 2018, 18, 324. [Google Scholar] [CrossRef] [Green Version]
  11. Santos, S.; Santos, E.; Gaztambide, S.; Salvador, J. Diagnóstico y diagnóstico diferencial del síndrome de Cushing. Endocrinol. Nutr. 2009, 56, 71–84. [Google Scholar] [CrossRef]
  12. Gohel, V.; Jones, J.; Wehler, C. Salivary biomarkers and cardiovascular disease: A systematic review. Clin. Chem. Lab. Med. 2018, 56, 1432–1442. [Google Scholar] [CrossRef] [PubMed]
  13. Parisi, M.R.; Soldini, L.; Vidoni, G.; Mabellini, C.; Belloni, T.; Brignolo, L.; Negri, S.; Schlusnus, K.; Dorigatti, F.; Lazzarin, A. Point-of-care testing for HCV infection: Recent advances and implications for alternative screening. New Microbiol. 2014, 37, 449–457. [Google Scholar] [PubMed]
  14. Nefzi, F.; Ben Salem, N.A.; Khelif, A.; Feki, S.; Aouni, M.; Gautheret-Dejean, A. Quantitative analysis of human herpesvirus-6 and human cytomegalovirus in blood and saliva from patients with acute leukemia. J. Med. Virol. 2014, 87, 451–460. [Google Scholar] [CrossRef] [PubMed]
  15. Aitken, J.P.; Ortiz, C.; Morales-Bozo, I.; Rojas-Alcayaga, G.; Baeza, M.; Beltran, C.; Escobar, A. α-2-Macroglobulin in Saliva Is Associated with Glycemic Control in Patients with Type 2 Diabetes Mellitus. Dis. Markers 2015, 2015, 1–5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Rathnayake, N.; Åkerman, S.; Klinge, B.; Lundegren, N.; Jansson, H.; Tryselius, Y.; Sorsa, T.; Gustafsson, A. Salivary Biomarkers for Detection of Systemic Diseases. PLoS ONE 2013, 8, e61356. [Google Scholar] [CrossRef] [Green Version]
  17. López-Jornet, P.; Zavattaro, E.; Mozaffari, H.R.; Ramezani, M.; Sadeghi, M. Evaluation of the Salivary Level of Cortisol in Patients with Oral Lichen Planus: A Meta-Analysis. Medicine 2019, 55, 213. [Google Scholar] [CrossRef] [Green Version]
  18. Lopez-Jornet, P.; Cayuela, C.A.; Tvarijonaviciute, A.; Escribano, D.; Cerón, J.; Parra-Perez, F. Oral lichen planus: Salival biomarkers cortisol, immunoglobulin A, adiponectin. J. Oral Pathol. Med. 2015, 45, 211–217. [Google Scholar] [CrossRef]
  19. Humberto, J.S.M.; Pavanin, J.V.; Da Rocha, M.J.A.; Motta, A.C.F. Cytokines, cortisol, and nitric oxide as salivary biomarkers in oral lichen planus: A systematic review. Braz. Oral Res. 2018, 32. [Google Scholar] [CrossRef]
  20. Shah, B.; Ashok, L.; Sujatha, G. Evaluation of salivary cortisol and psychological factors in patients with oral lichen planus. Indian J. Dent. Res. 2009, 20, 288. [Google Scholar] [CrossRef]
  21. Karthikeyan, P.; Aswath, N. Stress as an etiologic co-factor in recurrent aphthous ulcers and oral lichen planus. J. Oral Sci. 2016, 58, 237–240. [Google Scholar] [CrossRef] [Green Version]
  22. Tvarijonaviciute, A.; Aznar-Cayuela, C.; Rubio, C.P.; Ceron, J.J.; López-Jornet, P.; Asta, T.; Cristina, A.C.; Camila, P.R.; Joaquin, C.J. Evaluation of salivary oxidate stress biomarkers, nitric oxide and C-reactive protein in patients with oral lichen planus and burning mouth syndrome. J. Oral Pathol. Med. 2016, 46, 387–392. [Google Scholar] [CrossRef] [PubMed]
  23. Ohashi, M.; Iwase, M.; Nagumo, M. Elevated production of salivary nitric oxide in oral mucosal diseases. J. Oral Pathol. Med. 1999, 28, 355–359. [Google Scholar] [CrossRef] [PubMed]
  24. Darczuk, D.; Krzysciak, W.; Vyhouskaya, P.; Kesek, B.; Galecka-Wanatowicz, D.; Lipska, W.; Kaczmarzyk, T.; Gluch-Lutwin, M.; Mordyl, B.; Chomyszyn-Gajewska, M. Salivary oxidative status in patients with oral lichen planus. J. Physiol. Pharmacol. Off. J. Pol. Physiol. Soc. 2016, 67, 885–894. [Google Scholar]
  25. Shahidi, M.; Jafari, S.; Barati, M.; Mahdipour, M.; Gholami, M.S. Predictive value of salivary microRNA-320a, vascular endothelial growth factor receptor 2, CRP and IL-6 in Oral lichen planus progression. Inflammopharmacology 2017, 25, 577–583. [Google Scholar] [CrossRef]
  26. Shiva, A.; Arab, S.; Mousavi, S.J.; Zamanian, A.; Maboudi, A. Serum and Salivary Level of Nitric Oxide (NOx) and CRP in Oral Lichen Planus (OLP) Patients. J. Dent. Shiraz 2020, 21, 6–11. [Google Scholar]
  27. Ramseier, C.A.; Kinney, J.S.; Herr, A.E.; Braun, T.; Sugai, J.V.; Shelburne, C.A.; Rayburn, L.A.; Tran, H.M.; Singh, A.K.; Giannobile, W.V. Identification of Pathogen and Host-Response Markers Correlated with Periodontal Disease. J. Periodontol. 2009, 80, 436–446. [Google Scholar] [CrossRef]
  28. Ehrchen, J.M.; Sunderkötter, C.; Foell, D.; Vogl, T.; Roth, J. The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J. Leukoc. Boil. 2009, 86, 557–566. [Google Scholar] [CrossRef]
  29. Aurer, A.; Aurer-Kozelj, J.; Stavljenić-Rukavina, A.; Kalenić, S.; Ivić-Kardum, M.; Haban, V. Inflammatory mediators in saliva of patients with rapidly progressive periodontitis during war stress induced incidence increase. Coll. Antropol. 1999, 23, 117–124. [Google Scholar]
  30. Aurer, A.; Jorgić-Srdjak, K.; Plancak, D.; Stavljenić-Rukavina, A.; Aurer-Kozelj, J. Proinflammatory factors in saliva as possible markers for periodontal disease. Coll. Antropol. 2005, 29, 435–439. [Google Scholar]
  31. Mozaffari, H.R.; Ramezani, M.; Mahmoudiahmadabadi, M.; Omidpanah, N.; Sadeghi, M. Salivary and serum levels of tumor necrosis factor-alpha in oral lichen planus: A systematic review and meta-analysis study. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2017, 124, e183–e189. [Google Scholar] [CrossRef]
  32. Lu, R.; Zhang, J.; Sun, W.; Du, G.; Zhou, G. Inflammation-related cytokines in oral lichen planus: An overview. J. Oral Pathol. Med. 2013, 44, 1–14. [Google Scholar] [CrossRef] [PubMed]
  33. Thanthoni, M.; Sathasivasubramanian, S. Quantitative Analysis of Salivary TNF-αin Oral Lichen Planus Patients. Int. J. Dent. 2015, 2015, 1–5. [Google Scholar] [CrossRef]
  34. Frodge, B.D.; Ebersole, J.L.; Kryscio, R.J.; Thomas, M.V.; Miller, C.S. Bone Remodeling Biomarkers of Periodontal Disease in Saliva. J. Periodontol. 2008, 79, 1913–1919. [Google Scholar] [CrossRef]
  35. Wu, Y.-C.; Ning, L.; Tu, Y.; Huang, C.-P.; Huang, N.-T.; Chen, Y.-F.; Chang, P.-C. Salivary biomarker combination prediction model for the diagnosis of periodontitis in a Taiwanese population. J. Formos. Med. Assoc. 2018, 117, 841–848. [Google Scholar] [CrossRef] [PubMed]
  36. Taylor, J. Cytokine regulation of immune responses to Porphyromonas gingivalis. Periodontology 2000 2010, 54, 160–194. [Google Scholar] [CrossRef]
  37. Preshaw, P.; Taylor, J. How has research into cytokine interactions and their role in driving immune responses impacted our understanding of periodontitis? J. Clin. Periodontol. 2011, 38, 60–84. [Google Scholar] [CrossRef]
  38. Ebersole, J.; Schuster, J.L.; Stevens, J.; Dawson, D.; Kryscio, R.J.; Lin, Y.; Thomas, M.V.; Miller, C.S. Patterns of Salivary Analytes Provide Diagnostic Capacity for Distinguishing Chronic Adult Periodontitis from Health. J. Clin. Immunol. 2012, 33, 271–279. [Google Scholar] [CrossRef]
  39. Rathnayake, N.; Åkerman, S.; Klinge, B.; Lundegren, N.; Jansson, H.; Tryselius, Y.; Sorsa, T.; Gustafsson, A. Salivary biomarkers of oral health—A cross-sectional study. J. Clin. Periodontol. 2012, 40, 140–147. [Google Scholar] [CrossRef]
  40. Deepthi, G.; Nandan, S.R.K.; Kulkarni, P.G. Salivary Tumour Necrosis Factor-α as a Biomarker in Oral Leukoplakia and Oral Squamous Cell Carcinoma. Asian Pac. J. Cancer Prev. 2019, 20, 2087–2093. [Google Scholar] [CrossRef] [Green Version]
  41. Kaur, J.; Jacobs, R. Proinflammatory cytokine levels in oral lichen planus, oral leukoplakia, and oral submucous fibrosis. J. Korean Assoc. Oral Maxillofac. Surg. 2015, 41, 171–175. [Google Scholar] [CrossRef] [Green Version]
  42. Hsu, H.J.; Yang, Y.H.; Shieh, T.Y.; Chen, C.H.; Kao, Y.-H.; Yang, C.F.; Ko, E. Role of cytokine gene (interferon-γ, transforming growth factor-β1, tumor necrosis factor-α, interleukin-6, and interleukin-10) polymorphisms in the risk of oral precancerous lesions in Taiwanese. Kaohsiung J. Med. Sci. 2014, 30, 551–558. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Brailo, V.; Vucicevic-Boras, V.; Lukac, J.; Biocina-Lukenda, D.; Alajbeg, I.; Milenovic, A.; Balija, M. Salivary and serum interleukin 1 beta, interleukin 6 and tumor necrosis factor alpha in patients with leukoplakia and oral cancer. Med. Oral Patol. Oral Cir. Bucal 2011, 17, e10–e15. [Google Scholar] [CrossRef] [PubMed]
  44. Wenghoefer, M.; Pantelis, A.; Najafi, T.; Deschner, J.; Allam, J.; Novak, N.; Reich, R.; Martini, M.; Berge, S.; Fischer, H.; et al. Gene expression of oncogenes, antimicrobial peptides, and cytokines in the development of oral leukoplakia. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontol. 2010, 110, 351–356. [Google Scholar] [CrossRef] [PubMed]
  45. Abduljabbar, T.; Vohra, F.; Ullah, A.; Alhamoudi, N.; Khan, J.; Javed, F. Relationship between self-rated pain and peri-implant clinical, radiographic and whole salivary inflammatory markers among patients with and without peri-implantitis. Clin. Implant. Dent. Relat. Res. 2019, 21, 1218–1224. [Google Scholar] [CrossRef] [PubMed]
  46. Arias-Bujanda, N.; Regueira-Iglesias, A.; Blanco-Pintos, T.; Alonso-Sampedro, M.; Relvas, M.; González-Peteiro, M.M.; Balsa-Castro, C.; Tomás, I.; Sampedro-Alonso, M. Diagnostic accuracy of IL1β in saliva: The development of predictive models for estimating the probability of the occurrence of periodontitis in non-smokers and smokers. J. Clin. Periodontol. 2020, 47, 702–714. [Google Scholar] [CrossRef]
  47. Kaushik, R.; Yeltiwar, R.K.; Pushpanshu, K. Salivary Interleukin-1β Levels in Patients with Chronic Periodontitis before and after Periodontal Phase I Therapy and Healthy Controls: A Case-Control Study. J. Periodontol. 2011, 82, 1353–1359. [Google Scholar] [CrossRef] [PubMed]
  48. Mirrielees, J.; Crofford, L.J.; Lin, Y.; Kryscio, R.J.; Dawson, L.R.; Ebersole, J.L.; Miller, C.S. Rheumatoid arthritis and salivary biomarkers of periodontal disease. J. Clin. Periodontol. 2010, 37, 1068–1074. [Google Scholar] [CrossRef]
  49. Gürsoy, U.K.; Könönen, E.; Uitto, V.-J.; Pussinen, P.; Hyvärinen, K.; Knuuttila, M.; Suominen-Taipale, L. Salivary interleukin-1βconcentration and the presence of multiple pathogens in periodontitis. J. Clin. Periodontol. 2009, 36, 922–927. [Google Scholar] [CrossRef]
  50. Tobón-Arroyave, S.I.; Jaramillo-González, P.; Isaza-Guzman, D.M. Correlation between salivary IL-1β levels and periodontal clinical status. Arch. Oral Boil. 2008, 53, 346–352. [Google Scholar] [CrossRef]
  51. Assuma, R.; Oates, T.; Cochran, D.; Amar, S.; Graves, D.T. IL-1 and TNF antagonists inhibit the inflammatory response and bone loss in experimental periodontitis. J. Immunol. 1998, 160, 403–409. [Google Scholar]
  52. Barksby, H.E.; Lea, S.R.; Preshaw, P.M.; Taylor, J. The expanding family of interleukin-1 cytokines and their role in destructive inflammatory disorders. Clin. Exp. Immunol. 2007, 149, 217–225. [Google Scholar] [CrossRef] [PubMed]
  53. Ng, P.Y.B.; Donley, M.; Hausmann, E.; Hutson, A.D.; Rossomando, E.F.; Scannapieco, F. Candidate salivary biomarkers associated with alveolar bone loss: Cross-sectional and in vitro studies. FEMS Immunol. Med. Microbiol. 2007, 49, 252–260. [Google Scholar] [CrossRef] [Green Version]
  54. Liukkonen, J.; Gursoy, U.K.; Pussinen, P.J.; Suominen, A.L.; Könönen, E. Salivary Concentrations of Interleukin (IL)-1β, IL-17A, and IL-23 Vary in Relation to Periodontal Status. J. Periodontol. 2016, 87, 1484–1491. [Google Scholar] [CrossRef] [PubMed]
  55. Isaza-Guzman, D.M.; Medina-Piedrahíta, V.M.; Gutiérrez-Henao, C.; Tobón-Arroyave, S.I. Salivary Levels of NLRP3 Inflammasome-Related Proteins as Potential Biomarkers of Periodontal Clinical Status. J. Periodontol. 2017, 88, 1329–1338. [Google Scholar] [CrossRef] [PubMed]
  56. Rocha, F.S.; Jesus, R.N.R.; Rocha, F.M.S.; Moura, C.C.G.; Zanetta-Barbosa, D. Saliva Versus Peri-implant Inflammation: Quantification of IL-1β in Partially and Totally Edentulous Patients. J. Oral Implant. 2014, 40, 169–173. [Google Scholar] [CrossRef]
  57. Sims, J.; Smith, D.E. The IL-1 family: Regulators of immunity. Nat. Rev. Immunol. 2010, 10, 89–102. [Google Scholar] [CrossRef]
  58. Gabay, C.; Lamacchia, C.; Palmer, G. IL-1 pathways in inflammation and human diseases. Nat. Rev. Rheumatol. 2010, 6, 232–241. [Google Scholar] [CrossRef]
  59. Bagan, J.; Sheth, C.C.; Soria, J.M.; Margaix, M.; Bagan, L. Bisphosphonates-related osteonecrosis of the jaws: A preliminary study of salivary interleukins. J. Oral Pathol. Med. 2012, 42, 405–408. [Google Scholar] [CrossRef]
  60. Bagan, J.; Sáez, G.; Tormos, M.; Hens, E.; Terol, M.; Bagan, L.; Diaz-Fernandez, J.; Lluch, A.; Camps, C. Interleukin-6 concentration changes in plasma and saliva in bisphosphonate-related osteonecrosis of the jaws. Oral Dis. 2013, 20, 446–452. [Google Scholar] [CrossRef]
  61. Mozaffari, H.R.; Zavattaro, E.; Saeedi, M.; Lopez-Jornet, P.; Sadeghi, M.; Safaei, M.; Imani, M.M.; Nourbakhsh, R.; Moradpoor, H.; Golshah, A.; et al. Serum and salivary interleukin-4 levels in patients with oral lichen planus: A systematic review and meta-analysis. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2019, 128, 123–131. [Google Scholar] [CrossRef]
  62. Mozaffari, H.R.; Molavi, M.; López-Jornet, P.; Sadeghi, M.; Safaei, M.; Imani, M.; Sharifi, R.; Moradpoor, H.; Golshah, A.; Jamshidy, L. Salivary and Serum Interferon-Gamma/Interleukin-4 Ratio in Oral Lichen Planus Patients: A Systematic Review and Meta-Analysis. Medicine 2019, 55, 257. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Prakasam, S.; Srinivasan, M. Evaluation of salivary biomarker profiles following non-surgical management of chronic periodontitis. Oral Dis. 2013, 20, 171–177. [Google Scholar] [CrossRef] [PubMed]
  64. Man Gu, G.; Martin, M.D.; Darveau, R.P.; Truelove, E.; Epstein, J. Oral and serum IL-6 levels in oral lichen planus patients. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2004, 98, 673–678. [Google Scholar] [CrossRef]
  65. Liu, J.; Shi, Q.; Yang, S.; Wang, Q.; Xu, J.; Guo, B. The relationship between levels of salivary and serum interleukin-6 and oral lichen planus. J. Am. Dent. Assoc. 2017, 148, 743–749.e9. [Google Scholar] [CrossRef]
  66. Cheng, Y.-S.L.; Jordan, L.; Gorugantula, L.M.; Schneiderman, E.; Chen, H.-S.; Rees, T. Salivary Interleukin-6 and -8 in Patients with Oral Cancer and Patients with Chronic Oral Inflammatory Diseases. J. Periodontol. 2014, 85, 956–965. [Google Scholar] [CrossRef]
  67. Costa, P.P.; Trevisan, G.L.; Macedo, G.O.; Palioto, D.B.; De Souza, S.L.S.; Grisi, M.F.; Novaes, A.B.; Taba, M.; Taba, M., Jr. Salivary Interleukin-6, Matrix Metalloproteinase-8, and Osteoprotegerin in Patients with Periodontitis and Diabetes. J. Periodontol. 2010, 81, 384–391. [Google Scholar] [CrossRef] [PubMed]
  68. Teles, R.; Likhari, V.; Socransky, S.S.; Haffajee, A.D. Salivary cytokine levels in subjects with chronic periodontitis and in periodontally healthy individuals: A cross-sectional study. J. Periodontal Res. 2009, 44, 411–417. [Google Scholar] [CrossRef] [Green Version]
  69. Irwin, C.R.; Myrillas, T.T. The role of IL-6 in the pathogenesis of periodontal disease. Oral Dis. 2008, 4, 43–47. [Google Scholar] [CrossRef]
  70. Bartold, P.M.; Narayanan, A.S. Molecular and cell biology of healthy and diseased periodontal tissues. Periodontology 2000 2006, 40, 29–49. [Google Scholar] [CrossRef]
  71. Juretić, M.; Cerović, R.; Belušić-Gobić, M.; Pršo, I.B.; Kqiku, L.; Špalj, S.; Pezelj-Ribarić, S. Salivary levels of TNF-? and IL-6 in patients with oral premalignant and malignant lesions. Folia Boil. 2013, 59, 99–102. [Google Scholar]
  72. Selvam, N.P.; Sadaksharam, J. Salivary interleukin-6 in the detection of oral cancer and precancer. Asia-Pac. J. Clin. Oncol. 2015, 11, 236–241. [Google Scholar] [CrossRef] [PubMed]
  73. Punyani, S.R.; Sathawane, R.S. Salivary level of interleukin-8 in oral precancer and oral squamous cell carcinoma. Clin. Oral Investig. 2012, 17, 517–524. [Google Scholar] [CrossRef]
  74. Chang, K.P.; Kao, H.K.; Wu, C.C.; Fang, K.H.; Chang, Y.L.; Huang, Y.C.; Liu, S.C.; Cheng, M.H. Pretreatment Interleukin-6 Serum Levels Are Associated with Patient Survival for Oral Cavity Squamous Cell Carcinoma. Otolaryngol. Neck Surg. 2013, 148, 786–791. [Google Scholar] [CrossRef] [PubMed]
  75. Liskmann, S.; Vihalemm, T.; Salum, O.; Zilmer, K.; Fischer, K.; Zilmer, M. Correlations between clinical parameters and interleukin-6 and interleukin-10 levels in saliva from totally edentulous patients with peri-implant disease. Int. J. Oral Maxillofac. Implant. 2006, 21, 543–550. [Google Scholar]
  76. Mozaffari, H.R.; Sharifi, R.; Mirbahari, S.; Montazerian, S.; Sadeghi, M.; Rostami, S. A systematic review and meta-analysis study of salivary and serum interleukin-8 levels in oral lichen planus. Adv. Dermatol. Allergol. 2018, 35, 599–604. [Google Scholar] [CrossRef] [PubMed]
  77. Ghoreishian, F.S.; Tavangar, A.; Ghalayani, P.; Boroujeni, M.A. Salivary levels of interleukin-8 in oral lichen planus and diabetic patients: A biochemical study. Dent. Res. J. 2017, 14, 209–214. [Google Scholar] [CrossRef] [PubMed]
  78. Sun, A.; Wang, J.; Chia, J.-S.; Chiang, C.-P. Serum interleukin-8 level is a more sensitive marker than serum interleukin-6 level in monitoring the disease activity of oral lichen planus. Br. J. Dermatol. 2005, 152, 1187–1192. [Google Scholar] [CrossRef]
  79. Fonseca, F.J.P.O.; Junior, M.M.; Lourenço, E.J.V.; Teles, D.D.M.; Figueredo, C.M.S. Cytokines expression in saliva and peri-implant crevicular fluid of patients with peri-implant disease. Clin. Oral Implant. Res. 2012, 25, 68–72. [Google Scholar] [CrossRef]
  80. Gonçalves, A.S.; Mosconi, C.; Jaeger, F.; Wastowski, I.; Aguiar, M.C.F.; Silva, T.A.; Ribeiro-Rotta, R.; Costa, N.L.; Batista, A.C. Overexpression of immunomodulatory mediators in oral precancerous lesions. Hum. Immunol. 2017, 78, 752–757. [Google Scholar] [CrossRef]
  81. Cecchettini, A.; Finamore, F.; Puxeddu, I.; Ferro, F.; Baldini, C. Salivary extracellular vesicles versus whole saliva: New perspectives for the identification of proteomic biomarkers in Sjögren’s syndrome. Clin. Exp. Rheumatol. 2019, 37 (Suppl. 118), 240–248. [Google Scholar]
  82. Lin, L.; Wang, J.; Liu, N.; Liu, S.; Xu, H.; Ji, N.; Zhou, M.; Zeng, X.; Zhang, D.; Li, J.; et al. Interleukin-37 expression and its potential role in oral leukoplakia and oral squamous cell carcinoma. Sci. Rep. 2016, 6, 26757. [Google Scholar] [CrossRef] [Green Version]
  83. Tobón-Arroyave, S.I.; Isaza-Guzman, D.M.; Restrepo-Cadavid, E.M.; Zapata-Molina, S.M.; Martínez-Pabón, M.C. Association of salivary levels of the bone remodelling regulators sRANKL and OPG with periodontal clinical status. J. Clin. Periodontol. 2012, 39, 1132–1140. [Google Scholar] [CrossRef] [PubMed]
  84. Buduneli, N.; Kinane, D.F. Host-derived diagnostic markers related to soft tissue destruction and bone degradation in periodontitis. J. Clin. Periodontol. 2011, 38, 85–105. [Google Scholar] [CrossRef]
  85. Al-Sabbagh, M.; Alladah, A.; Lin, Y.; Kryscio, R.J.; Thomas, M.V.; Ebersole, J.L.; Miller, C.S. Bone remodeling-associated salivary biomarker MIP-1α distinguishes periodontal disease from health. J. Periodontal Res. 2011, 47, 389–395. [Google Scholar] [CrossRef]
  86. Fine, D.H.; Markowitz, K.; Furgang, D.; Fairlie, K.; Ferrandiz, J.; Nasri, C.; McKiernan, M.; Donnelly, R.; Gunsolley, J. Macrophage Inflammatory Protein-1α: A Salivary Biomarker of Bone Loss in a Longitudinal Cohort Study of Children at Risk for Aggressive Periodontal Disease? J. Periodontol. 2009, 80, 106–113. [Google Scholar] [CrossRef] [PubMed]
  87. Miricescu, D.; Totan, A.; Calenic, B.; Mocanu, B.; Didilescu, A.; Mohora, M.; Spinu, T.; Greabu, M. Salivary biomarkers: Relationship between oxidative stress and alveolar bone loss in chronic periodontitis. Acta Odontol. Scand. 2013, 72, 42–47. [Google Scholar] [CrossRef] [PubMed]
  88. Zappacosta, B.; Manni, A.; Persichilli, S.; Boari, A.; Scribano, D.; Minucci, A.; Raffaelli, L.; Giardina, B.; De Sole, P. Salivary thiols and enzyme markers of cell damage in periodontal disease. Clin. Biochem. 2007, 40, 661–665. [Google Scholar] [CrossRef]
  89. Kugahara, T.; Shosenji, Y.; Ohashi, K. Screening for periodontitis in pregnant women with salivary enzymes. J. Obstet. Gynaecol. Res. 2007, 34, 40–46. [Google Scholar] [CrossRef]
  90. Luke, R.; Khan, S.N.; Iqbal, P.S.; Soman, R.R.; Chakkarayan, J.; Krishnan, V. Estimation of Specific Salivary Enzymatic Biomarkers in Individuals with Gingivitis and Chronic Periodontitis: A Clinical and Biochemical Study. J. Int. Oral Health 2015, 7, 54–57. [Google Scholar]
  91. Dabra, S.; China, K.; Kaushik, A. Salivary enzymes as diagnostic markers for detection of gingival/periodontal disease and their correlation with the severity of the disease. J. Indian Soc. Periodontol. 2012, 16, 358–364. [Google Scholar] [CrossRef]
  92. Nomura, Y.; Tamaki, Y.; Tanaka, T.; Arakawa, H.; Tsurumoto, A.; Kirimura, K.; Sato, T.; Hanada, N.; Kamoi, K. Screening of periodontitis with salivary enzyme tests. J. Oral Sci. 2006, 48, 177–183. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Gürsoy, U.K.; Könönen, E.; Pradhan-Palikhe, P.; Tervahartiala, T.; Pussinen, P.; Suominen-Taipale, L.; Sorsa, T. Salivary MMP-8, TIMP-1, and ICTP as markers of advanced periodontitis. J. Clin. Periodontol. 2010, 37, 487–493. [Google Scholar] [CrossRef] [PubMed]
  94. Lira-Junior, R.; Öztürk, V.Ö.; Emingil, G.; Bostanci, N.; Boström, E.A. Salivary and Serum Markers Related to Innate Immunity in Generalized Aggressive Periodontitis. J. Periodontol. 2017, 88, 1339–1347. [Google Scholar] [CrossRef] [PubMed]
  95. Thumbigere-Math, V.; Michalowicz, B.S.; De Jong, E.P.; Griffin, T.J.; Basi, D.L.; Hughes, P.J.; Tsai, M.L.; Swenson, K.K.; Rockwell, L.; Gopalakrishnan, R. Salivary proteomics in bisphosphonate-related osteonecrosis of the jaw. Oral Dis. 2013, 21, 46–56. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Thumbigere-Math, V.; Michalowicz, B.S.; Hughes, P.J.; Basi, D.L.; Tsai, M.L.; Swenson, K.K.; Rockwell, L.; Gopalakrishnan, R. Serum Markers of Bone Turnover and Angiogenesis in Patients with Bisphosphonate-Related Osteonecrosis of the Jaw after Discontinuation of Long-Term Intravenous Bisphosphonate Therapy. J. Oral Maxillofac. Surg. 2015, 74, 738–746. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Isaza-Guzman, D.M.; Arias-Osorio, C.; Martínez-Pabón, M.C.; Tobón-Arroyave, S.I. Salivary levels of matrix metalloproteinase (MMP)-9 and tissue inhibitor of matrix metalloproteinase (TIMP)-1: A pilot study about the relationship with periodontal status and MMP-9−1562C/T gene promoter polymorphism. Arch. Oral Boil. 2011, 56, 401–411. [Google Scholar] [CrossRef] [PubMed]
  98. Rudrakshi, C.; Srinivas, N.; Mehta, D.S. A comparative evaluation of hepatocyte growth factor levels in gingival crevicular fluid and saliva and its correlation with clinical parameters in patients with and without chronic periodontitis: A clinico-biochemical study. J. Indian Soc. Periodontol. 2011, 15, 147–151. [Google Scholar] [CrossRef] [PubMed]
  99. Wilczyńska-Borawska, M.; Borawski, J.; Baginska, J.; Małyszko, J.; Myśliwiec, M. Hepatocyte Growth Factor in Saliva of Patients with Renal Failure and Periodontal Disease. Ren. Fail. 2012, 34, 942–951. [Google Scholar] [CrossRef]
  100. Wilczyńska-Borawska, M.; Borawski, J.; Kovalchuk, O.; Chyczewski, L.; Stokowska, W. Hepatocyte growth factor in saliva is a potential marker of symptomatic periodontal disease. J. Oral Sci. 2006, 48, 47–50. [Google Scholar] [CrossRef] [Green Version]
  101. Aqrawi, L.A.; Galtung, H.K.; Guerreiro, E.M.; Øvstebø, R.; Thiede, B.; Utheim, T.P.; Chen, X.; Utheim Øygunn, A.; Palm, Ø.; Skarstein, K.; et al. Proteomic and histopathological characterisation of sicca subjects and primary Sjögren’s syndrome patients reveals promising tear, saliva and extracellular vesicle disease biomarkers. Arthritis Res. Ther. 2019, 21, 181. [Google Scholar] [CrossRef] [Green Version]
  102. Garza-García, F.; Delgado-García, G.; Garza-Elizondo, M.; Ceceñas-Falcón, L.Á.; Galarza-Delgado, D.; Riega-Torres, J. Salivary β2-microglobulin positively correlates with ESSPRI in patients with primary Sjögren’s syndrome. Rev. Bras. Reum. Engl. Ed. 2017, 57, 182–184. [Google Scholar] [CrossRef]
  103. Shen, X.; Xi, G.; Maile, L.A.; Wai, C.; Rosen, C.J.; Clemmons, D.R. Insulin-Like Growth Factor (IGF) Binding Protein 2 Functions Coordinately with Receptor Protein Tyrosine Phosphatase β and the IGF-I Receptor to Regulate IGF-I-Stimulated Signaling. Mol. Cell. Boil. 2012, 32, 4116–4130. [Google Scholar] [CrossRef] [Green Version]
  104. Suresh, L.; Malyavantham, K.S.; Shen, L.; Ambrus, J.L. Investigation of novel autoantibodies in Sjogren’s syndrome utilizing Sera from the Sjogren’s international collaborative clinical alliance cohort. BMC Ophthalmol. 2015, 15, 38. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Patel, S.; Metgud, R. Estimation of salivary lactate dehydrogenase in oral leukoplakia and oral squamous cell carcinoma: A biochemical study. J. Cancer Res. Ther. 2015, 11, 119. [Google Scholar] [CrossRef] [PubMed]
  106. Shetty, S.R.; Chadha, R.; Babu, S.; Kumari, S.; Bhat, S.; Achalli, S. Salivary lactate dehydrogenase levels in oral leukoplakia and oral squamous cell carcinoma: A biochemical and clinicopathological study. J. Cancer Res. Ther. 2012, 8, 123. [Google Scholar]
  107. Jaeger, F.; Assunção, A.C.; Caldeira, P.C.; Queiroz-Junior, C.M.; Bernardes, V.F.; Aguiar, M.C.F. Is salivary epidermal growth factor a biomarker for oral leukoplakia? A preliminary study. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2015, 119, 451–458. [Google Scholar] [CrossRef] [Green Version]
  108. Hoffmann, R.R.; Yurgel, L.S.; Campos, M.M. Evaluation of salivary endothelin-1 levels in oral squamous cell carcinoma and oral leukoplakia. Regul. Pept. 2011, 166, 55–58. [Google Scholar] [CrossRef]
  109. González-Moles, M.Á.; Warnakulasuriya, S.; González-Ruiz, I.; González-Ruiz, L.; Ayén, Á.; Lenouvel, D.; Ruiz-Ávila, I.; Ramos-García, P. Worldwide prevalence of oral lichen planus: A systematic review and meta-analysis. Oral Dis. 2020. [Google Scholar] [CrossRef]
  110. González-Moles, M.Á.; Ruiz-Ávila, I.; González-Ruíz, L.; Ayén, Á.; Gil-Montoya, J.A.; Ramos-García, P. Malignant transformation risk of oral lichen planus: A systematic review and comprehensive meta-analysis. Oral Oncol. 2019, 96, 121–130. [Google Scholar] [CrossRef]
  111. Kurago, Z. Etiology and pathogenesis of oral lichen planus: An overview. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2016, 122, 72–80. [Google Scholar] [CrossRef]
  112. Montero-López, E.; Santos-Ruiz, A.; Gonzalez, R.; Navarrete-Navarrete, N.; Ortego-Centeno, N.; Martínez-Augustín, O.; Rodríguez-Blázquez, M.; Peralta-Ramírez, M.I. Analyses of hair and salivary cortisol for evaluating hypothalamic–pituitary–adrenal axis activation in patients with autoimmune disease. Stress 2017, 20, 541–548. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Upadhyay, R.B.; Carnelio, S.; Shenoy, R.; Gyawali, P.; Mukherjee, M. Oxidative stress and antioxidant defense in oral lichen planus and oral lichenoid reaction. Scand. J. Clin. Lab. Investig. 2010, 70, 225–228. [Google Scholar] [CrossRef] [PubMed]
  114. Sezer, E.; Ozugurlu, F.; Ozyurt, H.; Sahin, S.; Etikan, I. Lipid peroxidation and antioxidant status in lichen planus. Clin. Exp. Dermatol. 2007, 32, 430–434. [Google Scholar] [CrossRef] [PubMed]
  115. Sugermann, P.B.; Savage, N.W.; Seymour, G.; Walsh, L.J. Is there a role for tumor necrosis factor-alpha (TNF-alpha) in oral lichen planus? J. Oral Pathol. Med. 1996, 25, 219–224. [Google Scholar] [CrossRef] [PubMed]
  116. Kishimoto, T. IL-6: From its discovery to clinical applications. Int. Immunol. 2010, 22, 347–352. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Wei, W.; Wang, Y.; Sun, Q.; Jiang, C.; Zhu, M.; Song, C.; Li, C.; Du, G.; Deng, Y.; Nie, H.; et al. Enhanced T-cell proliferation and IL-6 secretion mediated by overexpression of TRIM21 in oral lesions of patients with oral lichen planus. J. Oral Pathol. Med. 2019, 49, 350–356. [Google Scholar] [CrossRef] [PubMed]
  118. Slots, J. Periodontitis: Facts, fallacies and the future. Periodontology 2000 2017, 75, 7–23. [Google Scholar] [CrossRef]
  119. Pihlstrom, B.L.; Michalowicz, B.S.; Johnson, N.W. Periodontal diseases. Lancet 2005, 366, 1809–1820. [Google Scholar] [CrossRef] [Green Version]
  120. Page, R.C. The role of inflammatory mediators in the pathogenesis of periodontal disease. J. Periodontal Res. 1991, 26, 230–242. [Google Scholar] [CrossRef]
  121. Birkedal-Hansen, H. Role of cytokines and inflammatory mediators in tissue destruction. J. Periodontal Res. 1993, 28, 500–510. [Google Scholar] [CrossRef]
  122. Di Benedetto, A.; Gigante, I.; Colucci, S.; Grano, M. Periodontal Disease: Linking the Primary Inflammation to Bone Loss. Clin. Dev. Immunol. 2013, 2013, 1–7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Fox, I.R.; Kang, I. Pathogenesis of Sjögren’s syndrome. Rheum. Dis. Clin. N. Am. 1992, 18, 517–538. [Google Scholar]
  124. Tincani, A.; Andreoli, L.; Cavazzana, I.; Doria, A.; Favero, M.; Fenini, M.-G.; Franceschini, F.; Lojacono, A.; Nascimbeni, G.; Santoro, A.; et al. Novel aspects of Sjögren’s syndrome in 2012. BMC Med. 2013, 11, 93. [Google Scholar] [CrossRef] [Green Version]
  125. Venables, P.J. Sjögren’s syndrome. Best Pr. Res. Clin. Rheumatol. 2004, 18, 313–329. [Google Scholar] [CrossRef] [PubMed]
  126. Mavragani, C.P. Mechanisms and New Strategies for Primary Sjögren’s Syndrome. Annu. Rev. Med. 2017, 68, 331–343. [Google Scholar] [CrossRef]
  127. Márton, K.D.; Boros, I.; Varga, G.; Zelles, T.; Fejérdy, P.; Zeher, M.; Nagy, G. Evaluation of palatal saliva flow rate and oral manifestations in patients with Sjogren’s syndrome. Oral Dis. 2006, 12, 480–486. [Google Scholar] [CrossRef] [PubMed]
  128. Vitali, C.; Bombardieri, S.; Jonsson, R.; Moutsopoulos, H.M.; Alexander, E.L.E.; Carsons, S.E.; Daniels, T.; Fox, P.C.I.; Fox, R.; Kassan, S.S.; et al. Classification criteria for Sjogren’s syndrome: A revised version of the European criteria proposed by the American-European Consensus Group. Ann. Rheum. Dis. 2002, 61, 554–558. [Google Scholar] [CrossRef] [Green Version]
  129. Shiboski, S.C.; Shiboski, C.H.; Criswell, L.A.; Baer, A.N.; Challacombe, S.; Lanfranchi, H.; Schiodt, M.; Umehara, H.; Vivino, F.; Zhao, Y.; et al. American College of Rheumatology classification criteria for Sjögren’s syndrome: A data-driven, expert consensus approach in the Sjögren’s International Collaborative Clinical Alliance cohort. Arthritis Rheum. 2012, 64, 475–487. [Google Scholar] [CrossRef]
  130. Shiboski, C.H.; Shiboski, S.C.; Seror, R.A.; Criswell, L.; Labetoulle, M.; Lietman, T.M.; Rasmussen, A.; Scofield, H.; Vitali, C.; Bowman, S.J.; et al. 2016 American College of Rheumatology/European League against Rheumatism classification criteria for primary Sjögren’s syndrome. Ann. Rheum. Dis. 2016, 76, 9–16. [Google Scholar] [CrossRef]
  131. Naushin, T.; Khan, M.M.; Ahmed, S.; Hassan, M.-U.; Iqbal, F.; Bashir, N.; Khan, A.S. Determination of Ki-67 expression in oral leukoplakia in snuff users and non-users in Khyber Pakhtunkhwa province of Pakistan. Prof. Med. J. 2020, 27, 682–687. [Google Scholar] [CrossRef] [Green Version]
  132. Mehta, T.; Shah, S.; Dave, B.; Shah, R.; Dave, R. Socioeconomic and cultural impact of tobacco in India. J. Fam. Med. Prim. Care 2018, 7, 1173–1176. [Google Scholar] [CrossRef] [PubMed]
  133. Sujatha, D.; Hebbar, P.B.; Pai, A. Prevalence and correlation of oral lesions among tobacco smokers, tobacco chewers, areca nut and alcohol users. Asian Pac. J. Cancer Prev. 2012, 13, 1633–1637. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Gupta, V.; Abhisheik, K.; Balasundari, S.; Devendra, N.K.; Shadab, K.; Anupama, M. Identification of Candida albicans using different culture media and its association in leukoplakia and oral squamous cell carcinoma. J. Oral Maxillofac. Pathol. 2019, 23, 28–35. [Google Scholar] [CrossRef] [PubMed]
  135. Sasaki, M.; Yamaura, C.; Ohara-Nemoto, Y.; Tajika, S.; Kodama, Y.; Ohya, T.; Harada, R.; Kimura, S. Streptococcus anginosus infection in oral cancer and its infection route. Oral Dis. 2005, 11, 151–156. [Google Scholar] [CrossRef] [PubMed]
  136. Kazanowska-Dygdała, M.; Duś, I.; Radwan-Oczko, M. The presence of Helicobacter pylori in oral cavities of patients with leukoplakia and oral lichen planus. J. Appl. Oral Sci. 2016, 24, 18–23. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. De La Cour, C.D.; Sperling, C.D.; Belmonte, F.; Syrjänen, S.; Kjaer, S.K. Human papillomavirus prevalence in oral potentially malignant disorders: Systematic review and meta-analysis. Oral Dis. 2020. [Google Scholar] [CrossRef] [PubMed]
  138. Guidry, J.T.; Birdwell, C.E.; Scott, R.S. Epstein-Barr virus in the pathogenesis of oral cancers. Oral Dis. 2017, 24, 497–508. [Google Scholar] [CrossRef]
  139. Kushlinskiĭ, E.; Nagibin, A.A.; Laptev, I.P. Determination of the sensitivity of tumorous and pretumorous processes in the oral mucosa to steroid hormones. Stomatology 1988, 67, 32–33. [Google Scholar]
  140. Sridharan, G.; Ramani, P.; Patankar, S.; Vijayaraghavan, R. Analysis of estrogen metabolites in oral Leukoplakia and oral squamous cell carcinoma. Int. J. Pharm. Bio Sci. 2017, 8. [Google Scholar] [CrossRef]
  141. Mello, F.W.; Miguel, A.F.P.; Dutra-Horstmann, K.L.; Porporatti, A.L.; Warnakulasuriya, S.; Guerra, E.N.S.; Rivero, E.R.C. Prevalence of oral potentially malignant disorders: A systematic review and meta-analysis. J. Oral Pathol. Med. 2018, 47, 633–640. [Google Scholar] [CrossRef]
  142. Warnakulasuriya, S.; Ariyawardana, A. Malignant transformation of oral leukoplakia: A systematic review of observational studies. J. Oral Pathol. Med. 2015, 45, 155–166. [Google Scholar] [CrossRef] [PubMed]
  143. Van Der Waal, I. Oral leukoplakia: A diagnostic challenge for clinicians and pathologists. Oral Dis. 2018, 25, 348–349. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Jung, R.E.; Zembic, A.; Pjetursson, B.E.; Zwahlen, M.; Thoma, D.S. Systematic review of the survival rate and the incidence of biological, technical, and aesthetic complications of single crowns on implants reported in longitudinal studies with a mean follow-up of 5 years. Clin. Oral Implant. Res. 2012, 23, 2–21. [Google Scholar] [CrossRef] [PubMed]
  145. Khammissa, R.A.G.; Feller, L.; Meyerov, R.; Lemmer, J. Peri-implant mucositis and peri-implantitis: Clinical and histopathological characteristics and treatment. SADJ J. S. Afr. Dent. Assoc. = Tydskr. Suid-Afrik. Tandheelkd. Ver. 2012, 67, 124–126. [Google Scholar]
  146. Wilson, V. An Insight into Peri-Implantitis: A Systematic Literature Review. Prim. Dent. J. 2013, 2, 69–73. [Google Scholar] [CrossRef] [PubMed]
  147. Smeets, R.; Henningsen, A.; Jung, O.; Heiland, M.; Hammächer, C.; Stein, J.M. Definition, etiology, prevention and treatment of peri-implantitis—A review. Head Face Med. 2014, 10, 34. [Google Scholar] [CrossRef] [Green Version]
  148. Gomes, A.M.; Douglas-De-Oliveira, D.W.; Costa, F.O. Could the biomarker levels in saliva help distinguish between healthy implants and implants with peri-implant disease? A systematic review. Arch. Oral Boil. 2018, 96, 216–222. [Google Scholar] [CrossRef]
  149. Kolokythas, A.; Karras, M.; Collins, E.; Flick, W.; Miloro, M.; Adami, G. Salivary Biomarkers Associated with Bone Deterioration in Patients with Medication-Related Osteonecrosis of the Jaws. J. Oral Maxillofac. Surg. 2015, 73, 1741–1747. [Google Scholar] [CrossRef]
  150. Marx, R.E. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J. Oral Maxillofac. Surg. 2003, 61, 1115–1117. [Google Scholar] [CrossRef]
  151. Ruggiero, S.L.; Dodson, T.B.; Fantasia, J.; Goodday, R.; Aghaloo, T.; Mehrotra, B.; O’Ryan, F. American Association of Oral and Maxillofacial Surgeons Position Paper on Medication-Related Osteonecrosis of the Jaw—2014 Update. J. Oral Maxillofac. Surg. 2014, 72, 1938–1956. [Google Scholar] [CrossRef]
  152. Manzano-Moreno, F.J.; Ramos-Torrecillas, J.; De Luna-Bertos, E.; Reyes-Botella, C.; Ruiz, C.; García-Martínez, O. Nitrogen-containing bisphosphonates modulate the antigenic profile and inhibit the maturation and biomineralization potential of osteoblast-like cells. Clin. Oral Investig. 2014, 19, 895–902. [Google Scholar] [CrossRef] [PubMed]
  153. Manzano-Moreno, F.J.; Ramos-Torrecillas, J.; De Luna-Bertos, E.; Ruiz, C.; García-Martínez, O. High doses of bisphosphonates reduce osteoblast-like cell proliferation by arresting the cell cycle and inducing apoptosis. J. Cranio-Maxillofac. Surg. 2015, 43, 396–401. [Google Scholar] [CrossRef]
  154. Mashiba, T.; Mori, S.; Komatsubara, S.; Cao, Y.; Manabe, T.; Norimatsu, H.; Burr, D.B. The effects of suppressed bone remodeling by bisphosphonates on microdamage accumulation and degree of mineralization in the cortical bone of dog rib. J. Bone Miner. Metab. 2005, 23, 36–42. [Google Scholar] [CrossRef] [PubMed]
  155. Landesberg, R.; Cozin, M.; Cremers, S.; Woo, V.; Kousteni, S.; Sinha, S.; Garrett-Sinha, L.A.; Raghavan, S. Inhibition of Oral Mucosal Cell Wound Healing by Bisphosphonates. J. Oral Maxillofac. Surg. 2008, 66, 839–847. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  156. Fedele, S.; Porter, S.; D’Aiuto, F.; Aljohani, S.; Vescovi, P.; Manfredi, M.; Arduino, P.G.; Broccoletti, R.; Musciotto, A.; Di Fede, O.; et al. Nonexposed Variant of Bisphosphonate-associated Osteonecrosis of the Jaw: A Case Series. Am. J. Med. 2010, 123, 1060–1064. [Google Scholar] [CrossRef] [Green Version]
  157. O’Ryan, F.; Khoury, S.; Liao, W.; Han, M.M.; Hui, R.L.; Baer, D.; Martin, D.; Donald, L.; Lo, J. Intravenous Bisphosphonate-Related Osteonecrosis of the Jaw: Bone Scintigraphy as an Early Indicator. J. Oral Maxillofac. Surg. 2009, 67, 1363–1372. [Google Scholar] [CrossRef]
  158. Yatsuoka, W.; Ueno, T.; Miyano, K.; Uezono, Y.; Enomoto, A.; Kaneko, M.; Ota, S.; Soga, T.; Sugimoto, M.; Ushijima, T. Metabolomic profiling reveals salivary hypotaurine as a potential early detection marker for medication-related osteonecrosis of the jaw. PLoS ONE 2019, 14, e0220712. [Google Scholar] [CrossRef] [Green Version]
  159. Bagan, J.; Jiménez-Soriano, Y.; Gomez, D.; Sirera, R.; Poveda, R.; Scully, C. Collagen telopeptide (serum CTX) and its relationship with the size and number of lesions in osteonecrosis of the jaws in cancer patients on intravenous bisphosphonates. Oral Oncol. 2008, 44, 1088–1089. [Google Scholar] [CrossRef]
  160. Prá, K.J.D.; Lemos, C.; Okamoto, R.; Soubhia, A.; Pellizzer, E. Efficacy of the C-terminal telopeptide test in predicting the development of bisphosphonate-related osteonecrosis of the jaw: A systematic review. Int. J. Oral Maxillofac. Surg. 2017, 46, 151–156. [Google Scholar] [CrossRef] [Green Version]
  161. Kim, J.W.; Kong, K.A.; Kim, S.J.; Choi, S.K.; Cha, I.H.; Kim, M.-R. Prospective biomarker evaluation in patients with osteonecrosis of the jaw who received bisphosphonates. Bone 2013, 57, 201–205. [Google Scholar] [CrossRef] [Green Version]
Table
Table 1. Salivary Biomarkers involved in main oral pathologies diagnosis and prognosis.
Table 1. Salivary Biomarkers involved in main oral pathologies diagnosis and prognosis.
BiomarkerOral PathologySalivary Levels in Diagnosed PatientsClinical Relevance
CortisolOLPIncreased levels [17,18,19]Diagnosis and recurrence of the pathology [20,21]
Nitric OxideOLPIncreased levels [19]Prognosis and presence of ulcers [22,23]
ROSOLPUnaltered levels [22]Cellular oxidative stress [22,24]
CRPOLPIncreased levels [22,25,26]OLP progression [26]
PDIncreased levels [27,28,29,30]PD prognosis (modulation of the inflammation) [27,28,29,30]
TNF- αOLPIncreased levels [19,31,32,33]OLP diagnosis, commencement and progression [19,31]
PDIncreased levels [34]
Decreased levels [35]		Uncertain diagnosis, and prognosis role [36,37,38,39]
OLIncreased levels [40,41,42]
Unaltered levels [43,44]		OL prognosis (malignant transformation, pre-oral cancer, and precancerous marker) [40,41,42]
PIIncreased levels [45]Diagnosis of the pathology [45]
IL1IL1βPDIncreased levels [35,38,39,46,47,48,49,50]Diagnosis and progression (inflammatory modulation, severity-bone resorption, generalized PD and PD severity) [51,52,53,54,55]
OLUnaltered levels [44]-
PIIncreased levels [45,56]Diagnosis of the pathology [45,56]
IL1α & IL1βOLPIncreased levels [19,32]Immune and inflammatory response modulator [57,58]
MRONJIncreased levels [59,60]MRONJ diagnosis [59,60]
IL1RAMRONJIncreased levels [59,60]MRONJ diagnosis [59,60]
IL4OLPIncreased levels [19,61]IL4 is not a good salivary marker for OLP prognosis [32,62]
PDIncreased levels [63]-
IL6OLPIncreased levels [19,32,64,65]OLP prognosis (severity and wound marker). IL6 salivary marker is a good option for monitoring the treatment response [32,66]
PDIncreased levels [38,63,67]
Unaltered levels [27,39,49,68]		PD prognosis (inflammatory modulator) [37,69,70]
OLIncreased levels [41,71,72,73]
Unaltered levels [44]		OL prognosis (tumor growth and higher blood vessel density) [74]
PIIncreased levels [45,75]Early diagnosis and prognostic value [45,75]
MRONJIncreased levels [59,60]MRONJ diagnosis [59,60]
IL8OLPIncreased Levels [19,76,77]IL8 is a solid salivary biomarker for OLP severity [32,66,78]
OLIncreased levels [41,71,72,73]
Unaltered levels [44]		OL prognosis (tumor growth and higher blood vessel density) [74]
PIIncreased Levels [79]PI diagnosis [79]
IL10OLIncreased Levels [42,80]
Unaltered levels [44]		Uncertain association with premalignant oral lesions [42,80]
PIIncreased levels [45,75]Early diagnosis and prognostic value [45,75]
IL12pSSIncreased Levels [81]Diagnostic and prognostic value [81]
IL17PDIncreased levels [54,63]Localized periodontitis [54]
IL23PDIncreased levels [54]Localized periodontitis [54]
IL37OLIncreased Levels [82]
RANKLPDIncreased levels [83]
Unaltered levels [34,84]		Uncertain prognosis value (bone loss) [34,83,84]
MIP-1PDIncreased levels [85,86]Diagnosis [85,86]
OPGPDDecreased levels [83]
Unaltered levels [34,84]		Uncertain prognosis value (bone loss) [34,83,84]
OSCPDDecreased levels [83]
Unaltered levels [34,84]		Uncertain prognosis value (bone loss) [34,83,84]
ALPPDIncreased levels [67,87,88,89,90,91,92]Diagnosis of the pathology [67,87,88,89,90,91,92]
LDHPDIncreased levels [67,87,88,89,90,91,92]Diagnosis of the pathology [67,87,88,89,90,91,92]
ASTPDIncreased levels [67,87,88,89,90,91,92]Diagnosis of the pathology [67,87,88,89,90,91,92]
ALTPDIncreased levels [67,87,88,89,90,91,92]Diagnosis of the pathology [67,87,88,89,90,91,92]
MMP8PDIncreased levels [27,39,47,48,67,87,93]Very useful salivary biomarker for the diagnosis of PD [27,39,47,48,67,87,93] and PD severity [94]
MMP9PDIncreased levels [27,35]Diagnosis [27,35]
MRONJIncreased levels [95,96]MRONJ diagnosis [95,96]
TIMP1PDDecreased levels [93,97]PD prognosis (advanced PD) [93]
HGFPDIncreased levels [98,99]Prognosis of the pathology [98,99,100]
NLRP3PDIncreased levels [55]PD severity and chronicity. Also useful as a salivary biomarker for preventive or therapeutic purposes [55]
CD44pSSIncreased levels [101]Diagnostic and prognostic value [101]
B2MpSSIncreased levels [102]Diagnostic and prognostic value [102]
SP1pSSIncreased levels [103,104]Early diagnosis and prognostic value [103,104]
PSPpSSIncreased levels [103,104]Early diagnosis and prognostic value [103,104]
CA6pSSIncreased levels [103,104]Early diagnosis and prognostic value [103,104]
LDHOLIncreased levels [105,106]Risk of malignant transformation of OL [105,106]
TGFβOLUnaltered levels [80,107,108]Uncertain diagnosis and prognosis value [80,107,108]
EGFOLUnaltered levels [80,107,108]Uncertain diagnosis and prognosis value [80,107,108]
OLP: Oral Lichen Planus; PD: Periodontitis; pSS: Primary Sjögren Syndrome; OL: Oral Leukoplakia; PI: Periimplantitis; MRONJ: Medication-Related Osteonecrosis of the Jaw.

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Melguizo-Rodríguez, L.; Costela-Ruiz, V.J.; Manzano-Moreno, F.J.; Ruiz, C.; Illescas-Montes, R. Salivary Biomarkers and Their Application in the Diagnosis and Monitoring of the Most Common Oral Pathologies. Int. J. Mol. Sci. 2020, 21, 5173. https://doi.org/10.3390/ijms21145173

AMA Style

Melguizo-Rodríguez L, Costela-Ruiz VJ, Manzano-Moreno FJ, Ruiz C, Illescas-Montes R. Salivary Biomarkers and Their Application in the Diagnosis and Monitoring of the Most Common Oral Pathologies. International Journal of Molecular Sciences. 2020; 21(14):5173. https://doi.org/10.3390/ijms21145173

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Melguizo-Rodríguez, Lucía, Victor J. Costela-Ruiz, Francisco Javier Manzano-Moreno, Concepción Ruiz, and Rebeca Illescas-Montes. 2020. "Salivary Biomarkers and Their Application in the Diagnosis and Monitoring of the Most Common Oral Pathologies" International Journal of Molecular Sciences 21, no. 14: 5173. https://doi.org/10.3390/ijms21145173

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