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Diseases of the Salivary Glands—Part II

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Otolaryngology".

Deadline for manuscript submissions: closed (25 July 2022) | Viewed by 32186

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Special Issue Editor

Dr. Margherita Sisto

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Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Medical School, Bari, Italy
Interests: pathophysiology and molecular immunology applied to immunological research lines; molecular processes underlying the interaction between receptors of the immune response, inflammation and characterization of new anti-inflammatory molecules; novel therapies for Sjögren’s syndrome autoimmune disease; evaluation of the molecular mechanisms linking chronic inflammation to fibrosis in Sjögren’s syndrome and others autoimmune diseases
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Special Issue Information

The year 2021 saw the publication of the Special Issue “"Diseases of the Salivary Glands" (https://www.mdpi.com/journal/jcm/special_issues/Salivary_Glands), Part I, covering recent and novel advancements as well as future trends in the field of research evaluating diagnostic and therapeutic treatment of salivary gland (SGs) diseases. Part I includes manuscripts focusing on the most advanced diagnostic techniques for the identification of pathologies affecting the SGs, the molecular mechanisms involved in the autoimmune disease Sjӧgren’s syndrome, SGs tumor diagnosis and treatment, and interesting case reports related to primary or secondary diseases of SGs. Local management with novel therapies and pilot studies in emerging fields was covered, too. The Special Issue, Part I, provides important insight into the diagnosis, pathogenesis, natural history, and management of SG diseases, including 14 articles, written by an impressive group of internationally recognized authorities in the field, comprising both researchers and clinicians.

Given the enormous success of Part I, the Special Issue “Diseases of the Salivary Glands” Part II has been launched, with the firm belief that it will enrich the panorama of world research in this field.

Topics include:

1) Clinical features and presentation of potentially malignant SG disorders;

2) Risk factors and etiopathogenesis of SGs tumors;

3) Etiopathogenesis and molecular mechanisms involved in the chronic inflammatory condition characterizing Sjӧgren’s syndrome;

4) New discoveries in the field of micro RNAs associated with Sjӧgren’s syndrome;

5) Molecular markers linked to development and progression of SG diseases: current knowledge and future implications;

6) More innovative techniques for the study of the SG diseases: current limitations and future directions.

Submissions are welcome, both solicited and unsolicited, which will contribute to this goal.

Prof. Dr. Margherita Sisto
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

oral medicine
oral disease
salivary gland dysfunction
potentially malignant oral disorders
cellular and molecular pathway
autoimmune diseases

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Published Papers (11 papers)

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Editorial

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2 pages, 178 KiB

Open AccessEditorial

Special Issue “Diseases of the Salivary Glands-Part II”

by Margherita Sisto

J. Clin. Med. 2022, 11(19), 5567; https://doi.org/10.3390/jcm11195567 - 22 Sep 2022

Cited by 1 | Viewed by 1030

Abstract

This Special Issue, “Diseases of Salivary Gland-Part II”, was born as a continuation of the volume “Diseases of the Salivary Gland”, published, with great success, in 2021 in the prestigious Journal of Clinical Medicine (JCM) (https://www [...] Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands—Part II)

Research

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10 pages, 3657 KiB

Open AccessArticle

Fluoride Exposure and Salivary Glands: How Is Glandular Morphology Susceptible to Long-Term Exposure? A Preclinical Study

by José Mário Matos-Sousa, Leonardo Oliveira Bittencourt, Maria Karolina Martins Ferreira, Vinicius Ruan Neves dos Santos, Karolyny Martins Balbinot, Sérgio Alves-Júnior, João de Jesus Viana Pinheiro, Senda Charone, Juliano Pelim Pessan and Rafael Rodrigues Lima

J. Clin. Med. 2022, 11(18), 5373; https://doi.org/10.3390/jcm11185373 - 13 Sep 2022

Cited by 1 | Viewed by 1565

Abstract

Despite a strong body of evidence attesting to the effectiveness of fluoride (F) in preventing and controlling caries, some studies have sought to investigate the influence of F exposure on the salivary glands, organs that are essential for the maintenance of cavity homeostasis through salivary production, finding that exposure to F can cause biochemical and proteomic changes. Thus, this study aimed to investigate the morphological effects of prolonged exposure to F on the salivary glands of mice, at concentrations that would correspond to optimally fluoridated water (suitable for human consumption) and to fluorosis-endemic regions. Twenty-four male mice (Mus musculus) were divided into three groups, according to F levels in the drinking water: 0 (control), 10, or 50 mg F/L, with an exposure period of 60 days. The glands were morphometrically analyzed for the total acinar area, parenchyma area, and stromal area, as well as for the immunohistochemical analysis of myoepithelial cells. The results showed that prolonged exposure to F at 10 mg F/L did not promote significant changes in the morphometry of the salivary glands of mice, which reinforces the safety of the chronic use of F in low doses. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands—Part II)

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11 pages, 3147 KiB

Open AccessArticle

The Expression of Follistatin-like 1 Protein Is Associated with the Activation of the EMT Program in Sjögren’s Syndrome

by Margherita Sisto, Domenico Ribatti, Giuseppe Ingravallo and Sabrina Lisi

J. Clin. Med. 2022, 11(18), 5368; https://doi.org/10.3390/jcm11185368 - 13 Sep 2022

Cited by 7 | Viewed by 1721

Abstract

Background: The activation of the epithelial to mesenchymal transition (EMT) program is a pathological response of the Sjögren’s syndrome (SS) salivary glands epithelial cells (SGEC) to chronic inflammation. Follistatin-like 1 protein (FSTL1) is a secreted glycoprotein induced by transforming growth factor-β1 (TGF-β1), actively involved in the modulation of EMT. However, the role of FSTL1 in the EMT program activation in SS has not yet been investigated. Methods: TGF-β1-stimulated healthy human SGEC, SS SGEC, and SS salivary glands (SGs) biopsies were used to assess the effect of FSTL1 on the activation of the EMT program. FSTL1 gene activity was inhibited by the siRNA gene knockdown technique. Results: Here we reported that FSTL1 is up-regulated in SS SGs tissue in a correlated manner with the inflammatory grade. Blockage of FSTL1 gene expression by siRNA negatively modulates the TGF-β1-induced EMT program in vitro. We discovered that these actions were mediated through the modulation of the SMAD2/3-dependent EMT signaling pathway. Conclusions: Our data suggest that the TGF-β1-FSTL1-SMAD2/3 regulatory circuit plays a key role in the regulation of EMT in SS and targeting FSTL1 may be a strategy for the treatment of SGs EMT-dependent fibrosis. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands—Part II)

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12 pages, 1005 KiB

Open AccessArticle

Imaging Activated-T-Lymphocytes in the Salivary Glands of Patients with Sjögren’s Syndrome by ^99mTc-Interleukin-2: Diagnostic and Therapeutic Implications

by Giuseppe Campagna, Luz Kelly Anzola, Michela Varani, Chiara Lauri, Guido Gentiloni Silveri, Lorenzo Chiurchioni, Francesca Romana Spinelli, Roberta Priori, Fabrizio Conti and Alberto Signore

J. Clin. Med. 2022, 11(15), 4368; https://doi.org/10.3390/jcm11154368 - 27 Jul 2022

Cited by 4 | Viewed by 1525

Abstract

Background: Sjögren’s syndrome (SS) is a progressive autoimmune disease characterized by local mononuclear cell infiltration of the salivary and lachrymal glands. Labial biopsy demonstrates local infiltration by Th1 cells that produce pro-inflammatory cytokines, such as interleukin-2 (IL2). The aim of this study was to assess the utility of ^99mTc-labelled-IL2 (^99mTc-IL2) in evaluating in vivo the extent and severity of lympho-mononuclear cell infiltration in the salivary glands of patients with SS. Methods: We investigated 48 patients with primary SS and 27 control subjects using ^99mTc-IL2 scintigraphy. Furthermore, in a subgroup of 30 patients, we also performed ^99mTc-pertechnetate scintigraphy (^99mTcO₄⁻) for evaluation of the salivary gland function. Results: ^99mTc-IL2 uptake in the salivary glands of SS patients was higher than in the control subjects (1.30 ± 0.16 vs. 0.83 ± 0.08 for parotids and 1.36 ± 0.15 vs. 1.16 ± 0.07 for submandibular glands; p < 0.0001). The salivary gland uptake of ^99mTc-IL2 in patients with a longer history of disease was lower compared with the recently diagnosed patients. A significant direct correlation was found between the uptake of ^99mTc-IL2 and histology. Conclusions: ^99mTc-IL2 scintigraphy showed that the degree of lymphocytic infiltration of major salivary glands is variable in patients with different disease durations. Patients with a high ^99mTc-IL2 uptake could be efficiently treated with immuno-modulatory drugs and the efficacy of treatment could be followed-up by ^99mTc-IL2 scintigraphy. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands—Part II)

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8 pages, 238 KiB

Open AccessArticle

Comparison Benefit between Hydrogen Peroxide and Adrenaline in Tonsillectomy: A Randomized Controlled Study

by Cheng-Yu Hsieh, Chuan-Jen Hsu, Hung-Pin Wu and Chuan-Hung Sun

J. Clin. Med. 2022, 11(10), 2723; https://doi.org/10.3390/jcm11102723 - 11 May 2022

Cited by 6 | Viewed by 2085

Abstract

This study aimed to further evaluate the benefit of topical hemostasis agents in tonsillectomy. We compared the clinical effects of topical application between hydrogen peroxide and adrenaline in tonsillectomy. Overall, 60 patients (120 tonsils) were prospectively enrolled for tonsillectomy between February 2018 and December 2020. The patients were randomly assigned to either the hydrogen peroxide or adrenaline group. Then, tonsillectomy was performed using hydrogen peroxide as a hemostatic agent on the assigned side, while adrenaline was applied to the other side. All procedures were performed by a surgeon who was blinded to the randomization. The outcome measurements of operation time, intraoperative blood loss, postoperative pain, and hemorrhage events were analyzed. The intraoperative blood loss was significantly lower in the hydrogen peroxide group than in the adrenaline group (9.99 ± 4.51 mL vs. 13.87 ± 6.32 mL; p = 0.0). The median operation time was also significantly lower in the hydrogen peroxide group (8.02 ± 3.59 min vs. 9.22 ± 3.88 min; p = 0.019). Meanwhile, the visual analogue scale (VAS) scores were significantly higher in the hydrogen peroxide group (4.98 ± 1.94 vs. 4.27 ± 1.97; p = 0.001). The topical application of hydrogen peroxide as a hemostatic agent effectively decreases the operation time and intraoperative blood loss. Thus, hydrogen peroxide can be used as a routine hemostatic agent for bleeding control in tonsillectomy. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands—Part II)

28 pages, 3145 KiB

Open AccessArticle

Epitope Mapping of Pathogenic Autoantigens on Sjögren’s Syndrome-Susceptible Human Leukocyte Antigens Using In Silico Techniques

by Shivai Gupta, Danmeng Li, David A. Ostrov and Cuong Q. Nguyen

J. Clin. Med. 2022, 11(6), 1690; https://doi.org/10.3390/jcm11061690 - 18 Mar 2022

Cited by 2 | Viewed by 2488

Abstract

Sjögren’s syndrome (SjS) is characterized by lymphocytic infiltration and the dysfunction of the salivary and lacrimal glands. The autoimmune response is driven by the effector T cells and their cytokines. The activation of the effector helper T cells is mediated by autoantigen presentation by human leukocyte antigen (HLA) class II molecules of antigen-presenting cells. Studies using familial aggregation, animal models, and genome-wide association demonstrate a significant genetic correlation between specific risk HLAs and SjS. One of the key HLA alleles is HLA-DRB1*0301; it is one of the most influential associations with primary SjS, having the highest odds ratio and occurrence across different ethnic groups. The specific autoantigens attributed to SjS remain elusive, especially the specific antigenic epitopes presented by HLA-DRB1*0301. This study applied a high throughput in silico mapping technique to identify antigenic epitopes of known SjS autoantigens presented by high-risk HLAs. Furthermore, we identified specific binding HLA-DRB1*0301 epitopes using structural modeling tools such as Immune Epitope Database and Analysis Resource IEDB, AutoDock Vina, and COOT. By deciphering the critical epitopes of autoantigens presented by HLA-DRB1*0301, we gain a better understanding of the origin of the antigens, determine the T cell receptor function, learn the mechanism of disease progression, and develop therapeutic applications. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands—Part II)

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15 pages, 3425 KiB

Open AccessArticle

A Computational Text Mining-Guided Meta-Analysis Approach to Identify Potential Xerostomia Drug Targets

by Micaela F. Beckman, Elizabeth J. Brennan, Chika K. Igba, Michael T. Brennan, Farah B. Mougeot and Jean-Luc C. Mougeot

J. Clin. Med. 2022, 11(5), 1442; https://doi.org/10.3390/jcm11051442 - 5 Mar 2022

Cited by 4 | Viewed by 3625

Abstract

Xerostomia (subjective complaint of dry mouth) is commonly associated with salivary gland hypofunction. Molecular mechanisms associated with xerostomia pathobiology are poorly understood, thus hampering drug development. Our objectives were to (i) use text-mining tools to investigate xerostomia and dry mouth concepts, (ii) identify associated molecular interactions involving genes as candidate drug targets, and (iii) determine how drugs currently used in clinical trials may impact these genes and associated pathways. PubMed and PubMed Central were used to identify search terms associated with xerostomia and/or dry mouth. Search terms were queried in pubmed2ensembl. Protein–protein interaction (PPI) networks were determined using the gene/protein network visualization program search tool for recurring instances of neighboring genes (STRING). A similar program, Cytoscape, was used to determine PPIs of overlapping gene sets. The drug–gene interaction database (DGIdb) and the clinicaltrials.gov database were used to identify potential drug targets from the xerostomia/dry mouth PPI gene set. We identified 64 search terms in common between xerostomia and dry mouth. STRING confirmed PPIs between identified genes (CL = 0.90). Cytoscape analysis determined 58 shared genes, with cytokine–cytokine receptor interaction representing the most significant pathway (p = 1.29 × 10⁻²³) found in the Kyoto encyclopedia of genes and genomes (KEGG). Fifty-four genes in common had drug interactions, per DGIdb analysis. Eighteen drugs, targeting the xerostomia/dry mouth PPI network, have been evaluated for xerostomia, head and neck cancer oral complications, and Sjögren’s Syndrome. The PPI network genes IL6R, EGFR, NFKB1, MPO, and TNFSF13B constitute a possible biomarker signature of xerostomia. Validation of the candidate biomarkers is necessary to better stratify patients at the genetic and molecular levels to facilitate drug development or to monitor response to treatment. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands—Part II)

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Review

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16 pages, 6836 KiB

Open AccessReview

Sjögren Syndrome: New Insights in the Pathogenesis and Role of Nuclear Medicine

by Anzola Luz Kelly, Rivera Jose Nelson, Ramírez Sara and Signore Alberto

J. Clin. Med. 2022, 11(17), 5227; https://doi.org/10.3390/jcm11175227 - 4 Sep 2022

Cited by 8 | Viewed by 5531

Abstract

In the last years, new insights into the molecular basis of rheumatic conditions have been described, which have generated particular interest in understanding the pathophysiology of these diseases, in which lies the explanation of the diversity of clinical presentation and the difficulty in diagnostic and therapeutic approaches. In this review, we focus on the new pathophysiological findings for Sjögren syndrome and on the derived new SPECT and PET radiopharmaceuticals to detect inflammation of immunological origin, focusing on their role in diagnosis, prognosis, and the evaluation of therapeutic efficacy. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands—Part II)

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13 pages, 633 KiB

Open AccessReview

Pleomorphic Adenoma of the Salivary Glands and Epithelial–Mesenchymal Transition

by Yuka Matsumiya-Matsumoto, Yoshihiro Morita and Narikazu Uzawa

J. Clin. Med. 2022, 11(14), 4210; https://doi.org/10.3390/jcm11144210 - 20 Jul 2022

Cited by 13 | Viewed by 4698

Abstract

Pleomorphic adenoma (PA) is a localized tumor that presents pleomorphic or mixed characteristics of epithelial origin and is interwoven with mucoid tissue, myxoid tissue, and chondroid masses. The literature reported that PA most often occurs in adults aged 30–60 years and is a female predilection; the exact etiology remains unclear. Epithelial–mesenchymal transition (EMT) is the transdifferentiation of stationary epithelial cells primarily activated by a core set of transcription factors (EMT-TFs) involved in DNA repair and offers advantages under various stress conditions. Data have suggested that EMTs represent the basic principle of tissue heterogeneity in PAs, demonstrating the potential of adult epithelial cells to transdifferentiate into mesenchymal cells. It has also been reported that multiple TFs, such as TWIST and SLUG, are involved in EMT in PA and that SLUG could play an essential role in the transition from myoepithelial to mesenchymal cells. Given this background, this review aims to summarize and clarify the involvement of EMT in the development of PA, chondrocyte differentiation, and malignant transformation to contribute to the fundamental elucidation of the mechanisms underlying EMT. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands—Part II)

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9 pages, 770 KiB

Open AccessReview

Sjögren’s Syndrome-Related Organs Fibrosis: Hypotheses and Realities

by Margherita Sisto, Domenico Ribatti and Sabrina Lisi

J. Clin. Med. 2022, 11(12), 3551; https://doi.org/10.3390/jcm11123551 - 20 Jun 2022

Cited by 7 | Viewed by 2151

Abstract

Sjögren’s syndrome (SS) is a systemic chronic autoimmune disorder characterized by lymphoplasmacytic infiltration of salivary glands (SGs) and lacrimal glands, causing glandular damage. The disease shows a combination of dryness symptoms found in the oral cavity, pharynx, larynx, and vagina, representing a systemic disease. Recent advances link chronic inflammation with SG fibrosis, based on a molecular mechanism pointing to the epithelial to mesenchymal transition (EMT). The continued activation of inflammatory-dependent fibrosis is highly detrimental and a common final pathway of numerous disease states. The important question of whether and how fibrosis contributes to SS pathogenesis is currently intensely debated. Here, we collect the recent findings on EMT-dependent fibrosis in SS SGs and explore clinical evidence of multi-organ fibrosis in SS to highlight potential avenues for therapeutic investigation. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands—Part II)

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12 pages, 1088 KiB

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E-Cadherin Signaling in Salivary Gland Development and Autoimmunity

by Margherita Sisto, Domenico Ribatti and Sabrina Lisi

J. Clin. Med. 2022, 11(8), 2241; https://doi.org/10.3390/jcm11082241 - 17 Apr 2022

Cited by 11 | Viewed by 4537

Abstract

E-cadherin, the major epithelial cadherin, is located in regions of cell–cell contact known as adherens junctions. E-cadherin contributes to the maintenance of the epithelial integrity through homophylic interaction; the cytoplasmic tail of E-cadherin directly binds catenins, forming a dynamic complex that regulates several intracellular signal transduction pathways, including epithelial-to-mesenchymal transition (EMT). Recent progress uncovered a novel and critical role for this adhesion molecule in salivary gland (SG) development and in SG diseases. We summarize the structure and regulation of the E-cadherin gene and transcript in view of the role of this remarkable protein in SG morphogenesis, focusing, in the second part of the review, on altered E-cadherin expression in EMT-mediated SG autoimmunity. Full article

(This article belongs to the Special Issue Diseases of the Salivary Glands—Part II)

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