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Special Issue "Oral Inflammations and Systemic Diseases"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2019).

Special Issue Editors

Guest Editor
Dr. Ghazal Aarabi

Universitatsklinikum Hamburg-Eppendorf und Medizinische Fakultat, Department of Prosthetic Dentistry, Hamburg, Germany
Website | E-Mail
Interests: biomarkers; cardiovascular disease; caries dental disease prevention; endodontic lesions; genome-wide association studies gingivitis; intima media thickness periodontitis; oral microbiome surrogate markers; systems medicine
Guest Editor
Prof. Dr. Udo Seedorf

Universitatsklinikum Hamburg-Eppendorf und Medizinische Fakultat, Department of Prosthetic Dentistry, Hamburg, Germany
Website | E-Mail
Interests: autoimmunity; autonomous nervous system; cerebral small vessel disease; coronary heart disease; diabetes; epidemiology; genome-wide association studies; genomics; inflammation; ischemic stroke; metabolomics; microbiomics; oral-brain axis; peripheral arterial disease; proteomics; systems medicine; transcriptomics

Special Issue Information

Dear Colleagues,

Oral infections occur frequently in humans and often lead to chronic inflammations affecting the teeth (i.e., caries), the gingival tissues surrounding the teeth (i.e., gingivitis and endodontic lesions), and the tooth-supporting structures (i.e., periodontitis). It has been proposed that these inflammations are not restricted to their specific sites in the oral cavity, but that they may have a negative impact also on the general health of the affected patients via increasing their risk for several widespread diseases, such as diabetes, coronary heart disease, peripheral arterial disease, ischemic stroke, and small vessel disease in the brain. At least four basic pathogenic mechanisms have been proposed that involve oral inflammations in the pathogenesis of these widespread diseases: (1) low level bacteremia, by which oral bacteria enter the blood stream and invade the body; (2) systemic inflammation induced by inflammatory mediators released from the sites of the oral inflammation into the blood stream; (3) autoimmunity to host proteins caused by the host immune response to specific components of oral pathogens; and (4) pathogenic effects resulting from specific bacterial toxins that are produced by oral pathogenic bacteria.

This Special Issue focuses on several aspects of the interaction between oral infections and widespread systemic diseases, and we invite contributions of reviews and/or original papers reporting recent efforts in this field.

Dr. Ghazal Aarabi
Prof. Dr. Udo Seedorf
Guest Editor

Manuscript Submission Information

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 papers will be 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Autoimmunity
  • Bacterial toxins
  • Biomarker
  • Cancer
  • Cardiovascular disease
  • Cytokines
  • Diabetes
  • Endodontic lesions
  • Gingivitis
  • Inflammation
  • Oral microbiome
  • Oral–brain axis
  • Periodontitis
  • Stroke
  • Systemic inflammation

Published Papers (9 papers)

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Research

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Open AccessArticle
IL-1β Damages Fibrocartilage and Upregulates MMP-13 Expression in Fibrochondrocytes in the Condyle of the Temporomandibular Joint
Int. J. Mol. Sci. 2019, 20(9), 2260; https://doi.org/10.3390/ijms20092260
Received: 14 April 2019 / Revised: 25 April 2019 / Accepted: 1 May 2019 / Published: 7 May 2019
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Abstract
The temporomandibular joint (TMJ), which differs anatomically and biochemically from hyaline cartilage-covered joints, is an under-recognized joint in arthritic disease, even though TMJ damage can have deleterious effects on physical appearance, pain and function. Here, we analyzed the effect of IL-1β, a cytokine [...] Read more.
The temporomandibular joint (TMJ), which differs anatomically and biochemically from hyaline cartilage-covered joints, is an under-recognized joint in arthritic disease, even though TMJ damage can have deleterious effects on physical appearance, pain and function. Here, we analyzed the effect of IL-1β, a cytokine highly expressed in arthritic joints, on TMJ fibrocartilage-derived cells, and we investigated the modulatory effect of mechanical loading on IL-1β-induced expression of catabolic enzymes. TMJ cartilage degradation was analyzed in 8–11-week-old mice deficient for IL-1 receptor antagonist (IL-1RA−/−) and wild-type controls. Cells were isolated from the juvenile porcine condyle, fossa, and disc, grown in agarose gels, and subjected to IL-1β (0.1–10 ng/mL) for 6 or 24 h. Expression of catabolic enzymes (ADAMTS and MMPs) was quantified by RT-qPCR and immunohistochemistry. Porcine condylar cells were stimulated with IL-1β for 12 h with IL-1β, followed by 8 h of 6% dynamic mechanical (tensile) strain, and gene expression of MMPs was quantified. Early signs of condylar cartilage damage were apparent in IL-1RA−/− mice. In porcine cells, IL-1β strongly increased expression of the aggrecanases ADAMTS4 and ADAMTS5 by fibrochondrocytes from the fossa (13-fold and 7-fold) and enhanced the number of MMP-13 protein-expressing condylar cells (8-fold). Mechanical loading significantly lowered (3-fold) IL-1β-induced MMP-13 gene expression by condylar fibrochondrocytes. IL-1β induces TMJ condylar cartilage damage, possibly by enhancing MMP-13 production. Mechanical loading reduces IL-1β-induced MMP-13 gene expression, suggesting that mechanical stimuli may prevent cartilage damage of the TMJ in arthritic patients. Full article
(This article belongs to the Special Issue Oral Inflammations and Systemic Diseases)
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Open AccessCommunication
Molecular Aspects of Drug-Induced Gingival Overgrowth: An In Vitro Study on Amlodipine and Gingival Fibroblasts
Int. J. Mol. Sci. 2019, 20(8), 2047; https://doi.org/10.3390/ijms20082047
Received: 2 April 2019 / Revised: 18 April 2019 / Accepted: 24 April 2019 / Published: 25 April 2019
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Abstract
Gingival overgrowth is a serious side effect that accompanies the use of amlodipine. Several conflicting theories have been proposed to explain the fibroblast’s function in gingival overgrowth. To determine whether amlodipine alters the fibrotic response, we investigated its effects on treated gingival fibroblast [...] Read more.
Gingival overgrowth is a serious side effect that accompanies the use of amlodipine. Several conflicting theories have been proposed to explain the fibroblast’s function in gingival overgrowth. To determine whether amlodipine alters the fibrotic response, we investigated its effects on treated gingival fibroblast gene expression as compared with untreated cells. Materials and Methods: Fibroblasts from ATCC® Cell Lines were incubated with amlodipine. The gene expression levels of 12 genes belonging to the “Extracellular Matrix and Adhesion Molecules” pathway was investigated in treated fibroblasts cell culture, as compared with untreated cells, by real time PCR. Results: Most of the significant genes were up-regulated. (CTNND2, COL4A1, ITGA2, ITGA7, MMP10, MMP11, MMP12, MMP26) except for COL7A1, LAMB1, MMP8, and MMP16, which were down-regulated. Conclusion: These results seem to demonstrate that amlodipine has an effect on the extracellular matrix of gingival fibroblast. In the future, it would be interesting to understand the possible effect of the drug on fibroblasts of patients with amlodipine-induced gingival hyperplasia. Full article
(This article belongs to the Special Issue Oral Inflammations and Systemic Diseases)
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Review

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Open AccessReview
T and B Cells in Periodontal Disease: New Functions in A Complex Scenario
Int. J. Mol. Sci. 2019, 20(16), 3949; https://doi.org/10.3390/ijms20163949
Received: 29 July 2019 / Revised: 9 August 2019 / Accepted: 13 August 2019 / Published: 14 August 2019
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Abstract
Periodontal disease is characterised by a dense inflammatory infiltrate in the connective tissue. When the resolution is not achieved, the activation of T and B cells is crucial in controlling chronic inflammation through constitutive cytokine secretion and modulation of osteoclastogenesis. The present narrative [...] Read more.
Periodontal disease is characterised by a dense inflammatory infiltrate in the connective tissue. When the resolution is not achieved, the activation of T and B cells is crucial in controlling chronic inflammation through constitutive cytokine secretion and modulation of osteoclastogenesis. The present narrative review aims to overview the recent findings of the importance of T and B cell subsets, as well as their cytokine expression, in the pathogenesis of the periodontal disease. T regulatory (Treg), CD8+ T, and tissue-resident γδ T cells are important to the maintenance of gingival homeostasis. In inflamed gingiva, however, the secretion of IL-17 and secreted osteoclastogenic factor of activated T cells (SOFAT) by activated T cells is crucial to induce osteoclastogenesis via RANKL activation. Moreover, the capacity of mucosal-associated invariant T cells (MAIT cells) to produce cytokines, such as IFN-γ, TNF-α, and IL-17, might indicate a critical role of such cells in the disease pathogenesis. Regarding B cells, low levels of memory B cells in clinically healthy periodontium seem to be important to avoid bone loss due to the subclinical inflammation that occurs. On the other hand, they can exacerbate alveolar bone loss in a receptor activator of nuclear factor kappa-B ligand (RANKL)-dependent manner and affect the severity of periodontitis. In conclusion, several new functions have been discovered and added to the complex knowledge about T and B cells, such as possible new functions for Tregs, the role of SOFAT, and MAIT cells, as well as B cells activating RANKL. The activation of distinct T and B cell subtypes is decisive in defining whether the inflammatory lesion will stabilise as chronic gingivitis or will progress to a tissue destructive periodontitis. Full article
(This article belongs to the Special Issue Oral Inflammations and Systemic Diseases)
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Open AccessReview
Periodontal Therapy for Improving Lipid Profiles in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis
Int. J. Mol. Sci. 2019, 20(15), 3826; https://doi.org/10.3390/ijms20153826
Received: 13 June 2019 / Revised: 30 July 2019 / Accepted: 31 July 2019 / Published: 5 August 2019
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Abstract
Periodontitis is a chronic inflammatory disorder often seen in patients with diabetes mellitus (DM). Individuals with diabetes are at a greater risk of developing cardiovascular complications and this may be related, in part, to lipid abnormalities observed in these individuals. The objective of [...] Read more.
Periodontitis is a chronic inflammatory disorder often seen in patients with diabetes mellitus (DM). Individuals with diabetes are at a greater risk of developing cardiovascular complications and this may be related, in part, to lipid abnormalities observed in these individuals. The objective of this systematic review is to compile the current scientific evidence of the effects of periodontal treatment on lipid profiles in patients with type 2 diabetes mellitus. Through a systematic search using MEDLINE, EMBASE, PubMed, and Web of Science, 313 articles were identified. Of these, seven clinical trials which met all inclusion criteria were chosen for analysis. Between baseline and 3-month follow-up, there was a statistically significant reduction in the levels of total cholesterol (mean differences (MD) −0.47 mmol/L (95% confidence interval (CI), −0.75, −0.18, p = 0.001)), triglycerides (MD −0.20 mmol/L (95% CI −0.24, −0.16, p < 0.00001)) favouring the intervention arm, and a statistically significant reduction in levels of high density lipoprotein (HDL) (MD 0.06 mmol/L (95% CI 0.03, 0.08, p < 0.00001)) favouring the control arm. No significant differences were observed between baseline and 6-month follow-up levels for any lipid analysed. The heterogeneity between studies was high. This review foreshadows a potential benefit of periodontal therapy for lipid profiles in patients suffering from type 2 DM, however, well designed clinical trials using lipid profiles as primary outcome measures are warranted. Full article
(This article belongs to the Special Issue Oral Inflammations and Systemic Diseases)
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Open AccessReview
Periodontal Disease in Patients Receiving Dialysis
Int. J. Mol. Sci. 2019, 20(15), 3805; https://doi.org/10.3390/ijms20153805
Received: 9 June 2019 / Revised: 1 August 2019 / Accepted: 1 August 2019 / Published: 3 August 2019
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Abstract
Chronic kidney disease (CKD) is characterized by kidney damage with proteinuria, hematuria, and progressive loss of kidney function. The final stage of CKD is known as end-stage renal disease, which usually indicates that approximately 90% of normal renal function is lost, and necessitates [...] Read more.
Chronic kidney disease (CKD) is characterized by kidney damage with proteinuria, hematuria, and progressive loss of kidney function. The final stage of CKD is known as end-stage renal disease, which usually indicates that approximately 90% of normal renal function is lost, and necessitates renal replacement therapy for survival. The most widespread renal replacement therapy is dialysis, which includes peritoneal dialysis (PD) and hemodialysis (HD). However, despite the development of novel medical instruments and agents, both dialysis procedures have complications and disadvantages, such as cardiovascular disease due to excessive blood fluid and infections caused by impaired immunity. Periodontal disease is chronic inflammation induced by various pathogens and its frequency and severity in patients undergoing dialysis are higher compared to those in healthy individuals. Therefore, several investigators have paid special attention to the impact of periodontal disease on inflammation-, nutrient-, and bone metabolism-related markers; the immune system; and complications in patients undergoing dialysis. Furthermore, the influence of diabetes on the prevalence and severity of manifestations of periodontal disease, and the properties of saliva in HD patients with periodontitis have been reported. Conversely, there are few reviews discussing periodontal disease in patients with dialysis. In this review, we discuss the available studies and review the pathological roles and clinical significance of periodontal disease in patients receiving PD or HD. In addition, this review underlines the importance of oral health and adequate periodontal treatment to maintain quality of life and prolong survival in these patients. Full article
(This article belongs to the Special Issue Oral Inflammations and Systemic Diseases)
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Open AccessReview
The Possible Causal Link of Periodontitis to Neuropsychiatric Disorders: More Than Psychosocial Mechanisms
Int. J. Mol. Sci. 2019, 20(15), 3723; https://doi.org/10.3390/ijms20153723
Received: 22 May 2019 / Revised: 19 July 2019 / Accepted: 25 July 2019 / Published: 30 July 2019
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Abstract
Increasing evidence implies a possible causal link between periodontitis and neuropsychiatric disorders, such as Alzheimer’s disease (AD) and major depression (MD). A possible mechanism underlying such a link can be explained by neuroinflammation induced by chronic systemic inflammation. This review article focuses on [...] Read more.
Increasing evidence implies a possible causal link between periodontitis and neuropsychiatric disorders, such as Alzheimer’s disease (AD) and major depression (MD). A possible mechanism underlying such a link can be explained by neuroinflammation induced by chronic systemic inflammation. This review article focuses on an overview of the biological and epidemiological evidence for a feasible causal link of periodontitis to neuropsychiatric disorders, including AD, MD, Parkinson’s disease, and schizophrenia, as well as the neurological event, ischemic stroke. If there is such a link, a broad spectrum of neuropsychiatric disorders associated with neuroinflammation could be preventable and modifiable by simple daily dealings for oral hygiene. However, the notion that periodontitis is a risk factor for neuropsychiatric disorders remains to be effectively substantiated. Full article
(This article belongs to the Special Issue Oral Inflammations and Systemic Diseases)
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Open AccessReview
Pathological Characteristics of Periodontal Disease in Patients with Chronic Kidney Disease and Kidney Transplantation
Int. J. Mol. Sci. 2019, 20(14), 3413; https://doi.org/10.3390/ijms20143413
Received: 9 June 2019 / Revised: 6 July 2019 / Accepted: 10 July 2019 / Published: 11 July 2019
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Abstract
Chronic kidney disease (CKD) is recognized as an irreversible reduction of functional nephrons and leads to an increased risk of various pathological conditions, including cardiovascular disease and neurological disorders, such as coronary artery calcification, hypertension, and stroke. In addition, CKD patients have impaired [...] Read more.
Chronic kidney disease (CKD) is recognized as an irreversible reduction of functional nephrons and leads to an increased risk of various pathological conditions, including cardiovascular disease and neurological disorders, such as coronary artery calcification, hypertension, and stroke. In addition, CKD patients have impaired immunity against bacteria and viruses. Conversely, kidney transplantation (KT) is performed for patients with end-stage renal disease as a renal replacement therapy. Although kidney function is almost normalized by KT, immunosuppressive therapy is essential to maintain kidney allograft function and to prevent rejection. However, these patients are more susceptible to infection due to the immunosuppressive therapy required to maintain kidney allograft function. Thus, both CKD and KT present disadvantages in terms of suppression of immune function. Periodontal disease is defined as a chronic infection and inflammation of oral and periodontal tissues. Periodontal disease is characterized by the destruction of connective tissues of the periodontium and alveolar bone, which may lead to not only local symptoms but also systemic diseases, such as cardiovascular diseases, diabetes, liver disease, chronic obstructive pulmonary disease, and several types of cancer. In addition, the prevalence and severity of periodontal disease are significantly associated with mortality. Many researchers pay special attention to the pathological roles and clinical impact of periodontal disease in patients with CKD or KT. In this review, we provide information regarding important modulators of periodontal disease to better understand the relationship between periodontal disease and CKD and/or KT. Furthermore; we evaluate the impact of periodontal disease on various pathological conditions in patients with CKD and KT. Moreover, pathogens of periodontal disease common to CKD and KT are also discussed. Finally, we examine the importance of periodontal care in these patients. Thus, this review provides a comprehensive overview of the pathological roles and clinical significance of periodontal disease in patients with CKD and KT. Full article
(This article belongs to the Special Issue Oral Inflammations and Systemic Diseases)
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Open AccessReview
Th17 Cells and the IL-23/IL-17 Axis in the Pathogenesis of Periodontitis and Immune-Mediated Inflammatory Diseases
Int. J. Mol. Sci. 2019, 20(14), 3394; https://doi.org/10.3390/ijms20143394
Received: 23 May 2019 / Revised: 11 June 2019 / Accepted: 8 July 2019 / Published: 10 July 2019
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Abstract
Innate immunity represents the semi-specific first line of defense and provides the initial host response to tissue injury, trauma, and pathogens. Innate immunity activates the adaptive immunity, and both act highly regulated together to establish and maintain tissue homeostasis. Any dysregulation of this [...] Read more.
Innate immunity represents the semi-specific first line of defense and provides the initial host response to tissue injury, trauma, and pathogens. Innate immunity activates the adaptive immunity, and both act highly regulated together to establish and maintain tissue homeostasis. Any dysregulation of this interaction can result in chronic inflammation and autoimmunity and is thought to be a major underlying cause in the initiation and progression of highly prevalent immune-mediated inflammatory diseases (IMIDs) such as psoriasis, rheumatoid arthritis, inflammatory bowel diseases among others, and periodontitis. Th1 and Th2 cells of the adaptive immune system are the major players in the pathogenesis of IMIDs. In addition, Th17 cells, their key cytokine IL-17, and IL-23 seem to play pivotal roles. This review aims to provide an overview of the current knowledge about the differentiation of Th17 cells and the role of the IL-17/IL-23 axis in the pathogenesis of IMIDs. Moreover, it aims to review the association of these IMIDs with periodontitis and briefly discusses the therapeutic potential of agents that modulate the IL-17/IL-23 axis. Full article
(This article belongs to the Special Issue Oral Inflammations and Systemic Diseases)
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Open AccessReview
The Association of Periodontitis and Peripheral Arterial Occlusive Disease—A Systematic Review
Int. J. Mol. Sci. 2019, 20(12), 2936; https://doi.org/10.3390/ijms20122936
Received: 6 May 2019 / Revised: 10 June 2019 / Accepted: 12 June 2019 / Published: 15 June 2019
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Abstract
Background: Observational studies support an association between periodontitis (PD) and atherosclerotic vascular disease, but little is known specifically about peripheral arterial occlusive disease (PAOD). Objectives: To systematically review the evidence for an association between PD and PAOD. Data Sources: Medline via PubMed. [...] Read more.
Background: Observational studies support an association between periodontitis (PD) and atherosclerotic vascular disease, but little is known specifically about peripheral arterial occlusive disease (PAOD). Objectives: To systematically review the evidence for an association between PD and PAOD. Data Sources: Medline via PubMed. Review Methods: We searched the Pubmed database for original studies, case reports, case series, meta-analyses and systematic reviews that assessed whether there is an association between PD (all degrees of severity) and PAOD (all degrees of severity). The reporting of this systematic review was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement following the Population, Intervention, Control, and Outcome (PICO) format. Results: 17 out of 755 detected studies were included in the qualitative synthesis. Nine studies demonstrated associations between PD and PAOD, and two studies reported associations between tooth loss and PAOD. Six studies addressed the pathomechanism regarding PD as a possible trigger for PAOD. No study that dismissed an association could be detected. Odds ratios or hazard ratios ranged from 1.3 to 3.9 in four large cohort studies after adjusting for established cardiovascular risk factors. Conclusions: The presented evidence supports a link between PD and PAOD. Further studies which address the temporality of PD and PAOD and randomized controlled intervention trials examining the causal impact of PD on PAOD are needed. Although our results cannot confirm a causal role of PD in the development of PAOD, it is likely that PD is associated with PAOD and plays a contributing role. Full article
(This article belongs to the Special Issue Oral Inflammations and Systemic Diseases)
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