Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Mohan Z Mani

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On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Reviews
Year : 2021 | Month : August | Volume : 15 | Issue : 8 | Page : ZE01 - ZE05 Full Version

Salivary Metabolic Profiling of Systemic Disorders and Oral Neoplastic and Preneoplastic Conditions- A Narrative Review


Published: August 1, 2021 | DOI: https://doi.org/10.7860/JCDR/2021/46233.15216
Ramya Mahalingam, Vasanthi Vinoth, Ramya Ramadas, Amritha James, Preethi Arunachalam

1. Postgraduate Student, Department of Oral Pathology, SRM Dental College, Chennai, Tamil Nadu, India. 2. Senior Lecturer, Department of Oral Pathology, SRM Dental College, Chennai, Tamil Nadu, India. 3. Reader, Department of Oral Pathology, SRM Dental College, Chennai, Tamil Nadu, India. 4. Postgraduate Student, Department of Oral Pathology, SRM Dental College, Chennai, Tamil Nadu, India. 5. Postgraduate Student, Department of Oral Pathology, SRM Dental College, Chennai, Tamil Nadu, India.

Correspondence Address :
Dr Ramya Mahalingam,
Postgraduate Student, Department of Oral Pathology, SRM Dental College, Chennai, Tamil Nadu, India.
E-mail: jdrramyamds@gmail.com

Abstract

Salivary metabolic profiling has emerged as an important mode of analysing the metabolic markers that aids in early disease detection in various systemic diseases. The metabolomics study states that, the transitional and the end products of interactions that take place between genes, proteins, and the environment are found to be involved in various disease processes. Salivary metabolomics stands as a highly specific and sensitive method in diagnosis of various conditions making it a better alternative to the conventional serum and tissue-based methods well. These metabolomics studies incorporate various analytical technologies for identifying each component that could be used as a biomarker. Hence, we reviewed the current state of salivary metabolomics, diagnostic efficiency and its associated technologies and its future role in identification and monitoring the disease prognosis. The study selection was done by locating those research papers that provided information on salivary diagnostics using metabolic markers for early diagnosis in systemic disorders, neoplastic and preneoplastic conditions with help of search engines like Pubmed, Google Scholar, Web of Science and Cochrane library. The results of each study were critically evaluated to accentuate the principal role played by these biomarkers in the field of salivary diagnostics.

Keywords

Biomarkers, Genomics, Proteomics, Salivary metabolomics, Transcriptomes

Saliva is a biological fluid with an array of metabolites utilised as a prognostic and diagnostic marker. The components present in blood pass into saliva by transcellular, intracellular, paracellular or extracellular routes either by active transport or passive diffusion. Salivary metabolomics is an emerging diagnostic tool that aids in rapid testing, and helps in accomplishing various research laboratory operations (1). Genomics describes the genes, their functions, and their inter-relationships to identify their combined influence on the growth and development of the individual (2). Transcriptomes are the RNA molecules from protein coding genes, which direct the synthesis of the proteome. The rich oral microbiota contributes to the high proportion of the salivary RNA. The comprehensive RNA level in the saliva which is devoid of cells ranges from 0.108 μg/mL to 6.6 μg/mL which plays an integral role in diagnosis (3). Proteomics provides the complete profile of the proteins, proteoforms, and multiple complexes of proteoforms, including their diagnosis, quantification and understanding of various protein characteristics (4). Salivary proteomics discriminates between physiological and pathological conditions as per the state of the individual (5).

Metabolomics is the fingerprint of the metabolite profile in a biological sample. Metabolomics includes the full repertoire of small molecules and explains the pathway of disease progression to help in the early diagnosis (6),(7). Apart from diagnosing the very progress of the disease, the procedure also distinguish between the disease and the normal metabolic state of the organisms that are being subjected to the procedure of metabolomic studies. The metabolome refers to the final product of the interactions that is found to take place among the proteins, genes and the environment where the process takes place in various disease processes (8). The various steps involved proteomics, genomics and metabolomics has been depicted in (Table/Fig 1).

Various systemic conditions can be diagnosed with the salivary profile which can be studied by spectroscopic studies using NMR spectroscopy, studies done using gas chromatography along with spectroscopic studies like mass spectrometry (GC-MS). Characterisation of vitamins using liquid chromatography studies paired up with mass spectroscopy studies (LC–MS/MS), High performance liquid chromatography procedures being employed in identification of thiols and nucleotides, the inductively coupled plasma mass spectrometry technique atomises the samples and produce ions in order to analyse the trace elements present in the samples (1). Thus, this review article aimed to analyse and critically evaluate the literature available to bolster the importance of salivary diagnostics in the early diagnosis of systemic disorders and neoplastic conditions.

NEURODEGENERATIVE DISORDERS

The key to manage any kind of neurological disorder is to assess the early symptoms for prompt diagnosis. Invasive procedure such as lumbar puncture is done to aid in diagnosis. Salivary analysis of various metabolic products proves non invasive.

Parkinson’s Disease

Parkinson’s disease is a chronic neurodegenerative disorder which is often characterised by a persistent and progressive loss of related nervous systems. Identification of specific biomarkers at early stages of the disease process is important for the diagnosis followed by the evaluation of disease progression and the development of therapeutic interventions (9).

The proteins alpha-synuclein (α-Syn) and DJ-1 biomarkers are known to play a crucial role in the identification of Parkinson’s disease. Decreased levels of these proteins from cerebrospinal fluid were reported in various studies of Parkinson’s disease (10). Saliva from the submandibular salivary gland often is identified to be involved by synucleinopathy in the initial stages of Parkinson’s disease. Assessment of salivary levels of these proteins would be non invasive and reduce the complications related with CSF collection. The salivary assessment of biomarkers associated with Parkinson’s disease can avert the complications associated with the CSF collection methods. Oral biofluid is yet another ideal biofluid for diagnosis and to assess disease progression of Parkinson’s disease (10),(11).

Alzheimer’s Disease

Alzheimer’s Disease (AD) is the most common neurodegenerative disorder manifested as cognitive impairment and dementia due to the destruction of the neurons in the hippocampus, basal forebrain which is followed by the cortical areas of the brain. “Amyloid beta peptide and Tau protein” (Microtubule Associated Protein T-MAPT) have been identified to be one of the factors that attribute to the aetiology of AD. The neuron cell death in AD is caused due the accumulation of amyloid beta peptides extracellularly along with the intracellular neurofibrillary tangles have been reported (12),(13). Apart from the above mentioned markers, increased levels of amyloid beta peptides and phosphorylated tau protein in comparison with total tau concentration could be used as a biomarker which has shown significant results (12). Salivary lactoferrin levels were significantly reduced in AD and can be used as a potential marker in diagnosis of AD (12). The accumulation of acetyl cholinesterase has been reported to be higher in amyloid plaques and neurofibrillary tangles of AD brains which also can play a role in the diagnosis of the disease.

Huntington’s Disease

Huntington’s Disease (HD) is caused by Huntingtin gene (HTT) mutation which is an autosomal dominant neurodegenerative disorder. Htt protein here serves as vital component in the diagnosis of HD making it a promising marker. The salivary levels of total Htt protein from HD patients were significantly increased when compared to controls. In addition to it, there was significant increase in salivary concentration of mutated HTT in HD patients in comparison to the healthy controls.

Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) also known as Lou Gehrig’s disease is a motor neuron degenerative disorder with frontotemporal dementia and muscle weakness followed by paralysis leading to death. Chromogranin A (CgA) is a neuroendocrine secretory protein which is elevated in patients with terminal ALS.

Multiple Sclerosis

Multiple Sclerosis (MS) is a chronic autoimmune, neurodegenerative disorder of the Central Nervous System (CNS) showing demyelination, in which the myelin sheaths of neurons were targeted by T-lymphocytes (14). In this condition the macrophages, microglia and mitochondrial dysfunction generate free radicals in MS. Reactive oxygen species contribute to the plaque formation and measuring their levels serves as a potential biomarker.

Autism Spectrum Disorders

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with impairments in communication, interaction and display of restricted repetitive patterns of behaviour. Autistic disorder, Rett syndrome, Childhood disintegrative disorder, Asperger’s disorder, Pervasive developmental disorder-not otherwise specified are the group of disorders of ASD. Salivary microRNAs (miRNAs/miR) profiling of ASD patients in comparison to control group expressed 14 different types of miRNAs in saliva samples (12).

AUTOIMMUNE DISORDERS

Systemic Lupus Erythematosus

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory and also an autoimmune disease. IL-6 levels were found to be increased in SLE. Salivary Plasminogen xActivator Inhibitor (PAI-1) and Monocyte Chemoattractant Protein (MCP-1) levels were elevated in SLE patients (14).

Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is an autoimmune disease of the bone. Salivary TNF- α level are higher in RA and have been employed in the early diagnosis of the condition (15).

Sjogrens’s Syndrome with Increased Risk Of Developing Lymphoma

Sjogren’s syndrome is an autoimmune disease of salivary glands. There is an increased lymphocytic infiltration resulting in oral and ocular findings. This condition presents with abnormal B-cell hyperactivity (16). Siglecs are a group of transmembrane receptors and are expressed in myeloid restricted manner on the surface of various immune cells. These siglecs are found to be in higher levels in the saliva of primary Sjogren’s syndrome patients (16).

All the important markers associated with the neurological and autoimmune disorders are mentioned in (Table/Fig 2) (10),(12),(14),(17),(18).

INFLAMMATORY DISORDERS

Diabetes Mellitus

Salivary glu¬cose possess promising values that are been explored for a long time now and it can be potentially correlated with glucose levels obtained from the blood re¬sults. Those proteins that are present in blood are present in saliva as well. Therefore, saliva can be functionally compared to that of blood in reflecting the exact physiological status of the body and even the pathology at times (13). Salivary α-amylase level of whole saliva is found to be higher in diabetics, while salivary globulin level is lower in diabetics (17).

Inflammatory Bowel Disease

Inflammatory Bowel Disease (IBD), the term includes two conditions the Crohn’s Disease (CD) and Ulcerative Colitis (UC), the aetiology of which is unknown (18). IBD is diagnosed with the help of the following antibodies atypical perinuclear Anti-neutrophil Cytoplasmic Antibodies (p-ANCA), Anti-Saccharomyces Cerevisiae Antibodies (ASCA), anti-OmpC, ALCAs, ACCAs, AMCAs, anti-L, and anti-C and Pancreatic Autoantibodies (PAB) and are considered as potential biomarkers (2). C-Reactive Protein (CRP) and highly sensitive CRP (Hs-CRP) and β2-microglublin are certain inflammatory markers (17). MiR-21 levels are found to be increased significantly in mucosa of the individual with IBD. Significant rise in M2-Pyruvate Kinase (M2PK) in UC, CD, and Colorectal Cancer (CRC) thus, serves as a potential marker. This also rises in the CRC arising in IBD patients. Intraepithelial neoplasia in the mucosa of UC cryptoepithelium shows rise in the mucosa CHI3L1 levels. This marker also used to monitor the malignant degeneration of UC into CRC as there is significant rise in the mucosa CHI3L1 levels during their progression. Most commonly studied markers in the inflammatory disorders are mentioned in the (Table/Fig 2) (10),(12),(14),(17),(18).

NEOPLASTIC AND PRENEOPLASTIC CONDITIONS

Different Carcinomas

All the commonly associated salivary markers different carcinomas in are mentioned in (Table/Fig 3) (19),(20),(21),(22),(23).

Oral Squamous Cell Carcinoma

Oral Squamous Cell Carcinoma (OSCC) is reported to be the most common malignant neoplasm involving the oral cavity worldwide. The diagnosis of OSCC is done using a panel of markers from the interleukins family mainly the IL-6, IL-8, IL-1, and TNF- α (24). These proteins were found in high levels in saliva in patients with OSCC. Increased levels of IgG have also been detected in OSCC which ascertains their role in angiogenesis (24). There is an altered levels in salivary levels of Ki-67 and Cyclin D1 in OSCC. Cell-surface glycoprotein such as CD44, CD59, or Carcinoembryonic Antigen (CEA) were found to be over expressed in studies conducted using western blot, or Magnetic Resonance Spectroscopy (MRS) based studies. The zinc finger protein family (ZNF) such as ZNF510, Cyfra 21-1, and CK19 have also been used as a tool in the diagnosis. The salivary levels of ZNF510 have been incorporated to discriminate between the early and stages (T1+T2) and the advanced stages (T3+T4) in OSCC. Many unique proteins or panels obtained from non targeted proteomic techniques are used as oncological markers Liquid Chromatography with tandem mass spectrometry (LC-MS/MS) studies have demonstrated that a panel of proteins namely the Mac-2 Binding Protein (M2BP), Myeloid-related protein 14 (MRP14), CD59, catalase, and profiling have shown 90% sensitivity in the diagnosis of OSCC. A panel using Matrix metalloproteinase-1 (MMP1), Kininogen-1 (KNG1), ANXA2, Heat Shock 70 kDa Protein 5 (HSPA5) were able to predict Oral Potentially Malignant Disorders (OPMDs) which showed malignant transformations (25). Along with these biomarkers that are present in higher amounts in OSCC determine the primary and pathological state of individuals. The biomarkers like Resistin (RETN) are studied best using Sodium Dodecyl Sulphate-Polyacrylamide Gel Electrophoresis (SDS-PAGE) coupled to LC-MS/MS which identifies the biomarkers and are considered to be the best tool in biomarker analysis (5). Using nano-LC-MS/MS and validation by Western blot and Enzyme-Linked Immunosorbent Assay (ELISA), S100A8 was identified as a potential biomarker of OSCC (26).

Other important group of biomarkers that play an important role in the salivary diagnostics of OSCC are the group of “MicroRNAs (miRNA/miR)”. These are useful both in the diagnosis and treatment of OSCC. “microRNA”, also explains the process oncogenesis in the head and neck cancers. MiR-125a and miR-200a levels are found to be down regulated in salivary samples of OSCC patients (27). Association of miR-195-, miR-26b, miR-483-5p, miR-375, miR-143, miR-155-5p with oral cancer has been studied by many authors. The levels of these biomarkers in the saliva play a major role in preoperative diagnosis and follow-up postoperatively. In contrast to others miR-195-5p levels was down regulated in OSCC tissues in comparison to the non tumour samples (28).

Defensins that are present within the granules of polymorphonuclear neutrophils possess increased cytotoxic activity. These peptides are found in increased numbers in OSCC which could be used as a prognostic marker (29). Cathepsin V, ADAM9, kallikrein and MMP-1, levels are found to be comparatively higher in patients with OSCC where the healthy individuals and those with other oral diseases showed reduced levels of these biomarkers. Proteases are considered to be of higher importance when the prognosis of the disease has to be assessed (30),(31).

Different biomarkers in various preneoplastic and neoplastic oral conditions has been summarised in (Table/Fig 4).

Mucoepidermoid Carcinoma

Mucoepidermoid Carcinoma (MEC) is a malignant salivary gland neoplasm that may occur in the oral cavity. They are commonly reported in the palatal region. These tumours present with highly variable biologic behaviour. The miRNA 127 3p in MEC is found to be an anti-proliferative that alters the cell cycle. This could be used as a marker in assessing the prognosis of the neoplasm (28). Salivary microRNA namely mmu-miR-140-5p, hsa-miR-374, hsa-miR-222, hsa-miR-15b, hsa-let-7g, hsa-miR-132, hsa-miR-519b-3p, hsa-miR-223, and hsa-miR-30a-3p were increased in malignant parotid gland neoplasms (36).

Kaposi’s Sarcoma

Kaposi’s Sarcoma (KS) is an angioproliferative sarcoma affecting multiple sites of the skin and oral cavity, associated commonly with Human Immunodeficiency Virus (HIV) and Human Papilloma virus type-8 infections. The incidence of HIV associated kaposi’s sarcoma has drastically come down following the Antiretroviral therapy (ART) treatment. MiR-375, which is considered a potential biomarker is found to be down regulated in patients HIV-KS patients following combined antiretroviral therapy (cART). Whereas, HIV-KS patients who have not taken cART treatment showed upregulated MiR-375 (37).

Oral Lichen Planus

Oral Lichen Planus (OLP) is a chronic inflammatory disease mucocutaneous disorder. OLP is an inflammation triggered by the apoptosis mediated by the cytotoxic T-lymphocytes against the epithelial cells. The malignant transformation rate of OLP is found to be 1% over a 5-year average period (38). The diagnosis of OLP has been made using cortisol, Oxidative stress related molecules, Igs, and cytokines are mostly protein based. Extensive studies have been conducted to find the relationship between psychological status and levels of cortisol hormone in patients with OLP. Many studies revealed that the elevated levels of this glucocorticoid are common among affected individuals (24). A study done by Lorenzo-Pouso AI et al., reported that the adiponectin levels were higher in OLP patients (24). The levels of IgA and IgG are considerably increased in OLP patients when compared to control population (37),(38).

Oral Leukoplakia

Oral Leukoplakia (OL) is an Oral Potentially Malignant Disorder (OPMD) characterised by white plaque of questionable risk having excluded (other) known diseases or disorders. The annual average of malignant transformations of this condition is 1%.There are no specific markers to predict the malignant transformation of OL (31). The salivary proteomic studies focused on to study the cytokines based on ELISA techniques and the studies mainly studied the following IL-6, IL-8, and TNF- α (24).

Few other proteins that can differentiate between OL and OSCC are C4d, Malondialdehyde (MDA), endothelin-1, and lactate dehydrogenase (39). Camisasca et al., reported that in a 2-DE gel-based proteomic study, 22 spots were more abundant in patients with OL than in controls. One spot corresponded to CK10 (40). The authors later validated this marker by immunohistochemistry.

Oral Submucous Fibrosis

Oral Submucous Fibrosis (OSMF) is a potentially malignant disorder with a high prevalence rate in India. It account for almost 6-8% of the malignant transformation rate ranging from 4.5% to 7.6%. The role of lactate dehydrogenase has been studied widely, and their levels are found to be increased in OSMF. A study done by Kallalli BN et al., highlighted the elevated levels of lactate dehydrogenase in both OSMF as well as in OSCC (33). Alternatively trace elements can be used as a marker in the diagnosis of OSMF. Altered levels of trace elements like zinc, copper and iron can be observed in OSMF. An antioxidant enzyme superoxide dismutase activated by zinc is reduced in OSMF (33).

Salivary albumin and uric acid levels in OSMF patients showed mild decrease in their levels. However, Tiwari P et al., in their study highlighted that the free radicals produced by the areca nut in OSMF have least effect on the albumin present. Similarly, the uric acid levels were also reduced (35). S100A7 levels were assessed in OSCC and OSMF patients. Many researchers have reported the antifibrotic activity and reduction in fibroblast proliferation has been associated with S100A7 (39) Raffat MA et al., reported the increased levels of S100A7 in OSMF patient’s salivary samples which could be used as a potential biomarker (41). The potentially malignant disorders of the oral cavity like leukoplakia and OSMF showed increased levels of salivary miR-21 and miR-31nand is considered to be used as an adjuvant method of screening in OPMD. Hung KF et al., in their study highlighted the increased levels of miR-21 and miR-31 in the saliva in OPMD (42).

Conclusion

In summary, the salivary biomarkers are considered to be a valuable tool in diagnosis of the preliminary stages of the disease. These biomarkers in many neurological disorders and premalignant conditions are considered to play a key role in assessing the condition well ahead in order to promptly treat the condition. The salivary extraction being the highly non invasive procedure, the biomarkers can be easily identified by the help of advanced analysing tools. The overall content of the study lead to the identification of potential biomarkers in various systemic disorders. And thus, the application of these non invasive metabolite panel will help in early and precise risk detection and that which can lead to early risk management and medical intervention.

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DOI and Others

10.7860/JCDR/2021/46233.15216

Date of Submission: Aug 07, 2020
Date of Peer Review: Oct 04, 2020
Date of Acceptance: Feb 26, 2021
Date of Publishing: Aug 01, 2021

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was informed consent obtained from the subjects involved in the study? NA
• For any images presented appropriate consent has been obtained from the subjects. NA

PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Aug 08, 2020
• Manual Googling: Jan 15, 2021
• iThenticate Software: May 29, 2021 (22%)

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