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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) | Viewed by 92564

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Special Issue Editors

Dr. Ghazal Aarabi

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Guest Editor

Department of Periodontics, Preventive and Restorative Dentistry, Center for Dental and Oral Medicine, University Medical Center Hamburg Eppendorf, 20246 Hamburg, Germany
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

Prof. Dr. Udo Seedorf

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Guest Editor

Universitatsklinikum Hamburg-Eppendorf und Medizinische Fakultat, Department of Prosthetic Dentistry, Hamburg, Germany
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

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Keywords

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

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Published Papers (10 papers)

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Research

Jump to: Review

15 pages, 2602 KiB

Open AccessArticle

IL-1β Damages Fibrocartilage and Upregulates MMP-13 Expression in Fibrochondrocytes in the Condyle of the Temporomandibular Joint

by Hessam Tabeian, Beatriz F. Betti, Cinthya dos Santos Cirqueira, Teun J. de Vries, Frank Lobbezoo, Anouk V. ter Linde, Behrouz Zandieh-Doulabi, Marije I. Koenders, Vincent Everts and Astrid D. Bakker

Int. J. Mol. Sci. 2019, 20(9), 2260; https://doi.org/10.3390/ijms20092260 - 7 May 2019

Cited by 30 | Viewed by 3820

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 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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8 pages, 369 KiB

Open AccessCommunication

Molecular Aspects of Drug-Induced Gingival Overgrowth: An In Vitro Study on Amlodipine and Gingival Fibroblasts

by Dorina Lauritano, Alberta Lucchese, Dario Di Stasio, Fedora Della Vella, Francesca Cura, Annalisa Palmieri and Francesco Carinci

Int. J. Mol. Sci. 2019, 20(8), 2047; https://doi.org/10.3390/ijms20082047 - 25 Apr 2019

Cited by 80 | Viewed by 4990

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 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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18 pages, 1078 KiB

Open AccessReview

The Pathogenic Factors from Oral Streptococci for Systemic Diseases

by Hiromichi Yumoto, Katsuhiko Hirota, Kouji Hirao, Masami Ninomiya, Keiji Murakami, Hideki Fujii and Yoichiro Miyake

Int. J. Mol. Sci. 2019, 20(18), 4571; https://doi.org/10.3390/ijms20184571 - 15 Sep 2019

Cited by 56 | Viewed by 9645

Abstract

The oral cavity is suggested as the reservoir of bacterial infection, and the oral and pharyngeal biofilms formed by oral bacterial flora, which is comprised of over 700 microbial species, have been found to be associated with systemic conditions. Almost all oral microorganisms are non-pathogenic opportunistic commensals to maintain oral health condition and defend against pathogenic microorganisms. However, oral Streptococci, the first microorganisms to colonize oral surfaces and the dominant microorganisms in the human mouth, has recently gained attention as the pathogens of various systemic diseases, such as infective endocarditis, purulent infections, brain hemorrhage, intestinal inflammation, and autoimmune diseases, as well as bacteremia. As pathogenic factors from oral Streptococci, extracellular polymeric substances, toxins, proteins and nucleic acids as well as vesicles, which secrete these components outside of bacterial cells in biofilm, have been reported. Therefore, it is necessary to consider that the relevance of these pathogenic factors to systemic diseases and also vaccine candidates to protect infectious diseases caused by Streptococci. This review article focuses on the mechanistic links among pathogenic factors from oral Streptococci, inflammation, and systemic diseases to provide the current understanding of oral biofilm infections based on biofilm and widespread systemic diseases. Full article

(This article belongs to the Special Issue Oral Inflammations and Systemic Diseases)

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13 pages, 725 KiB

Open AccessReview

T and B Cells in Periodontal Disease: New Functions in A Complex Scenario

by C.M. Figueredo, R. Lira-Junior and R.M. Love

Int. J. Mol. Sci. 2019, 20(16), 3949; https://doi.org/10.3390/ijms20163949 - 14 Aug 2019

Cited by 86 | Viewed by 14100

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 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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13 pages, 1358 KiB

Open AccessReview

Periodontal Therapy for Improving Lipid Profiles in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis

by Siddharth Garde, Rahena Akhter, Mai Anh Nguyen, Clara K. Chow and Joerg Eberhard

Int. J. Mol. Sci. 2019, 20(15), 3826; https://doi.org/10.3390/ijms20153826 - 5 Aug 2019

Cited by 18 | Viewed by 4584

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 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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21 pages, 635 KiB

Open AccessReview

Periodontal Disease in Patients Receiving Dialysis

by Yasuyoshi Miyata, Yoko Obata, Yasushi Mochizuki, Mineaki Kitamura, Kensuke Mitsunari, Tomohiro Matsuo, Kojiro Ohba, Hiroshi Mukae, Tomoya Nishino, Atsutoshi Yoshimura and Hideki Sakai

Int. J. Mol. Sci. 2019, 20(15), 3805; https://doi.org/10.3390/ijms20153805 - 3 Aug 2019

Cited by 35 | Viewed by 7293

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 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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12 pages, 733 KiB

Open AccessReview

The Possible Causal Link of Periodontitis to Neuropsychiatric Disorders: More Than Psychosocial Mechanisms

by Sadayuki Hashioka, Ken Inoue, Tsuyoshi Miyaoka, Maiko Hayashida, Rei Wake, Arata Oh-Nishi and Masatoshi Inagaki

Int. J. Mol. Sci. 2019, 20(15), 3723; https://doi.org/10.3390/ijms20153723 - 30 Jul 2019

Cited by 64 | Viewed by 8441

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 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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19 pages, 561 KiB

Open AccessReview

Pathological Characteristics of Periodontal Disease in Patients with Chronic Kidney Disease and Kidney Transplantation

by Mineaki Kitamura, Yasushi Mochizuki, Yasuyoshi Miyata, Yoko Obata, Kensuke Mitsunari, Tomohiro Matsuo, Kojiro Ohba, Hiroshi Mukae, Atsutoshi Yoshimura, Tomoya Nishino and Hideki Sakai

Int. J. Mol. Sci. 2019, 20(14), 3413; https://doi.org/10.3390/ijms20143413 - 11 Jul 2019

Cited by 47 | Viewed by 9451

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 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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24 pages, 1949 KiB

Open AccessReview

Th17 Cells and the IL-23/IL-17 Axis in the Pathogenesis of Periodontitis and Immune-Mediated Inflammatory Diseases

by Kübra Bunte and Thomas Beikler

Int. J. Mol. Sci. 2019, 20(14), 3394; https://doi.org/10.3390/ijms20143394 - 10 Jul 2019

Cited by 335 | Viewed by 23913

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 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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12 pages, 2362 KiB

Open AccessReview

The Association of Periodontitis and Peripheral Arterial Occlusive Disease—A Systematic Review

by Mark Kaschwich, Christian-Alexander Behrendt, Guido Heydecke, Andreas Bayer, Eike Sebastian Debus, Udo Seedorf and Ghazal Aarabi

Int. J. Mol. Sci. 2019, 20(12), 2936; https://doi.org/10.3390/ijms20122936 - 15 Jun 2019

Cited by 19 | Viewed by 5169

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. 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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