[Research Progress of Cellular Lipid Droplets in Oral Diseases]. / ç»†èƒžè„‚æ»´åœ¨å£è ”ç–¾ç— ä¸­çš„ç ”ç©¶è¿›å±•.

Lipid droplets are dynamic multifunctional organelles composed of a neutral lipid core and a phospholipid monolayer membrane modified by a specific set of proteins. PAT family proteins are the most characteristic lipid droplet proteins, playing an important role in regulating lipid droplet structure, function, and metabolism. The biogenesis of lipid droplets involves neutral lipid synthesis and the nucleation, budding, and growth of the lipid droplets. Lipid droplets not only serve as the energy metabolism reserve of cells but also participate in intracellular signal transduction and the development of inflammation and tumor. Lipid droplets are closely connected to and interact with various organelles, regulating the division, the transportation, and the genetics of organelles. The complexity of lipid droplets biogenesis and the diversity of their functions may have provided a physiological basis for the pathogenesis and development of diseases, but further research is needed in order to better understand the relevant processes. Published findings have helped elucidate the association between lipid droplets and diseases, such as obesity, non-alcoholic fatty liver disease, neurodegenerative disease, cancer, and cardiovascular disease, but the relationship between lipid droplets and oral diseases has not been fully studied. Topics that warrant further research include the role and mechanisms of lipid droplets in the pathogenesis and development of oral diseases, the relationship between oral diseases and systemic diseases, and translation of the effect of lipid droplets on oral diseases into valuable clinical diagnostic and treatment methods. Herein, we reviewed the biogenesis and functions of lipid droplets and the progress in research concerning lipid droplets in oral diseases, including mouth neoplasms, periodontitis, and dental caries.

[Expression level and clinical significance of CD44 and CD33 in 77 patients with benign lymphoadenosis of oral mucosa].

PURPOSE: To investigate the expression and clinical significance of CD44 and CD33 in benign lymphoadenosis of oral mucosa(BLOM). METHODS: From January 2017 to March 2020, seventy-seven BLOM wax blocks from the Department of Pathology of Qingdao Traditional Chinese Medicine Hospital were selected as the experimental group, and 63 cases of normal oral mucosal tissue wax blocks during the same period were selected as the control group. Immunohistochemical method was used to detect the positive expression of CD44 and CD33 in the two groups.Spearman correlation analysis was used to analyze the correlation between the positive expression of CD33 and the positive expression of CD44 in the diseased tissues of BLOM patients.The general information about patients were collected.The relationship between the expression of CD33 and CD44 in the diseased tissues of BLOM patients and the clinicopathological characteristics of BLOM patients were analyzed. SPSS 21.0 software package was used for statistical analysis of the data. RESULTS: The positive expression rates of CD33 in the control group and the experimental group were 95.24% and 63.64%, respectively, and the difference was statistically significant(P＜0.05). The positive expression rates of CD44 in the control group and the experimental group were 93.65% and 67.53%, respectively, and the difference was statistically significant(P＜0.05). The results of Spearman correlation analysis showed that the positive expression of CD33 in the diseased tissues of BLOM patients was positively correlated with the positive expression of CD44 (r=0.834, P=0.002). The expression of CD33 and CD44 in the diseased tissues of patients with BLOM were related to clinical type, degree of inflammation, presence or absence of lymphoid follicles, and lymphocyte infiltration(P＜0.05), but not related to age, gender, course of disease, location, and epithelial surface keratinization(P＞0.05). CONCLUSIONS: The positive expression rate of CD33 and CD44 in the BLOM tissues decreased, which was closely related to the clinical type, degree of inflammation, presence or absence of lymphoid follicles, and lymphocyte infiltration.

Role of Hydrogen Sulfide in Oral Disease.

Oral diseases are among the most common human diseases yet less studied. These diseases affect both the physical, mental, and social health of the patients resulting in poor quality of life. They affect all ages, although severe stages are mostly observed in older individuals. Poor oral hygiene, genetics, and environmental factors contribute enormously to the development and progression of these diseases. Although there are available treatment options for these diseases, the recurrence of the diseases hinders their efficiency. Oral volatile sulfur compounds (VSCs) are highly produced in oral cavity as a result of bacteria activities. Together with bacteria components such as lipopolysaccharides, VSCs participate in the progression of oral diseases by regulating cellular activities and interfering with the immune response. Hydrogen sulfide (H2S) is a gaseous neurotransmitter primarily produced endogenously and is involved in the regulation of cellular activities. The gas is also among the VSCs produced by oral bacteria. In numerous diseases, H2S have been reported to have dual effects depending on the cell, concentration, and donor used. In oral diseases, high production and subsequent utilization of this gas have been reported. Also, this high production is associated with the progression of oral diseases. In this review, we will discuss the production of H2S in oral cavity, its interaction with cellular activities, and most importantly its role in oral diseases.

PANoptosis: A New Insight Into Oral Infectious Diseases.

The oral microbiome, one of the most complex and intensive microbial ecosystems in the human body, comprises bacteria, archaea, fungi, protozoa, and viruses. Dysbiosis of the oral microbiome is the initiating factor that leads to oral infectious diseases. Infection is a sophisticated biological process involving interplay between the pathogen and the host, which often leads to activation of programmed cell death. Studies suggest that pyroptosis, apoptosis, and necroptosis are involved in multiple oral infectious diseases. Further understanding of crosstalk between cell death pathways has led to pyroptosis, apoptosis, and necroptosis being integrated into a single term: PANoptosis. PANoptosis is a multifaceted agent of the immune response that has important pathophysiological relevance to infectious diseases, autoimmunity, and cancer. As such, it plays an important role in innate immune cells that detect and eliminate intracellular pathogens. In addition to the classical model of influenza virus-infected and Yersinia-infected macrophages, other studies have expanded the scope of PANoptosis to include other microorganisms, as well as potential roles in cell types other than macrophages. In this review, we will summarize the pathophysiological mechanisms underlying inflammation and tissue destruction caused by oral pathogens. We present an overview of different pathogens that may induce activation of PANoptosis, along with the functional consequences of PANoptosis in the context of oral infectious diseases. To advance our understanding of immunology, we also explore the strategies used by microbes that enable immune evasion and replication within host cells. Improved understanding of the interplay between the host and pathogen through PANoptosis will direct development of therapeutic strategies that target oral infectious diseases.

Detection of Endogenous DNA Double-strand Breaks in Oral Squamous Epithelial Lesions by P53-binding Protein 1.

BACKGROUND/AIM: P53-binding protein 1 (53BP1) is one of the DNA damage response (DDR) molecules. This study aimed to assess 53BP1 expression by immunofluorescence (IF) as a biomarker to differentiate between oral squamous epithelial lesions (OSELs). MATERIALS AND METHODS: We analyzed 129 archival oral biopsy samples, including 18 benign squamous lesions (BSLs), 37 low-grade dysplasias (LGDs), 22 high-grade dysplasias (HGDs), and 52 oral squamous cell carcinomas (OSCCs). 53BP1 and Ki-67 expressions were examined by double IF to assess the type of 53BP1 expression. RESULTS: We found that OSCC exhibited several 53BP1 nuclear foci, particularly high-DNA damage response (HDDR) and large focus (LF)-type, suggesting the presence of endogenous DNA double-strand breaks in the cancer genome, which could disrupt DDR and induce genomic injury. We also found a difference in 53BP1 expression between LGD and HGD, but not between BSL and LGD. Among the Ki-67-positive cells, HDDR- and LF-type expressions were higher in OSELs of higher grades. CONCLUSION: 53BP1 expression can be a valuable biomarker for OSELs to help estimate the grade of oral epithelial dysplasia.

Ubiquitination and Deubiquitination in Oral Disease.

Oral health is an integral part of the general health and well-being of individuals. The presence of oral disease is potentially indicative of a number of systemic diseases and may contribute to their early diagnosis and treatment. The ubiquitin (Ub) system has been shown to play a role in cellular immune response, cellular development, and programmed cell death. Ubiquitination is a post-translational modification that occurs in eukaryotes. Its mechanism involves a number of factors, including Ub-activating enzymes, Ub-conjugating enzymes, and Ub protein ligases. Deubiquitinating enzymes, which are proteases that reversely modify proteins by removing Ub or Ub-like molecules or remodeling Ub chains on target proteins, have recently been regarded as crucial regulators of ubiquitination-mediated degradation and are known to significantly affect cellular pathways, a number of biological processes, DNA damage response, and DNA repair pathways. Research has increasingly shown evidence of the relationship between ubiquitination, deubiquitination, and oral disease. This review investigates recent progress in discoveries in diseased oral sites and discusses the roles of ubiquitination and deubiquitination in oral disease.

Vascular Endothelial Growth Factor: A Translational View in Oral Non-Communicable Diseases.

Vascular endothelial growth factors (VEGFs) are vital regulators of angiogenesis that are expressed in response to soluble mediators, such as cytokines and growth factors. Their physiologic functions include blood vessel formation, regulation of vascular permeability, stem cell and monocyte/macrophage recruitment and maintenance of bone homeostasis and repair. In addition, angiogenesis plays a pivotal role in chronic pathologic conditions, such as tumorigenesis, inflammatory immune diseases and bone loss. According to their prevalence, morbidity and mortality, inflammatory diseases affecting periodontal tissues and oral cancer are relevant non-communicable diseases. Whereas oral squamous cell carcinoma (OSCC) is considered one of the most common cancers worldwide, destructive inflammatory periodontal diseases, on the other hand, are amongst the most prevalent chronic inflammatory conditions affecting humans and also represent the main cause of tooth loss in adults. In the recent years, while knowledge regarding the role of VEGF signaling in common oral diseases is expanding, new potential translational applications emerge. In the present narrative review we aim to explore the role of VEGF signaling in oral cancer and destructive periodontal inflammatory diseases, with emphasis in its translational applications as potential biomarkers and therapeutic targets.

'The Double-Edged Sword' - An hypothesis for Covid-19-induced salivary biomarkers.

Utilising biomarkers for COVID-19 diagnosis, prediction of treatment response and overall prognostication have been investigated recently. However, these ventures have only considered the use of blood-based molecular markers. Saliva is another biofluid that warrants being applied in similar fashion with major advantages that centres on its non-invasive and repeatable collection as well as cost-efficiency. To this end, this article presents a hypothesis for the sources of biomarkers useful clinically for COVID-19 disease outcome estimation and identify the likely implications of their detection in saliva.

Regulation of mucin 1 expression and its relationship with oral diseases.

OBJECTIVE: The aim of this study is to describe the polymorphic mucin 1 (MUC1), and to provide an overview of the known complex and multiple functions of MUC1 in normal oral mucosa and oral mucosal lesions in compromised situations as well as exploring the challenges associated with the heterogeneous nature of MUC1. We will review the current knowledge and provide insights into the future management possibilities of using MUC1 as a therapeutic agent. METHODS: A literature search of the electronic databases included MEDLINE (1966 -December 2019) and hand searches of cross-references were undertaken using terms related to mucins, MUC1. RESULTS: MUC1 is a large transmembrane glycoprotein expressed on the apical surface of most of epithelial cell surfaces. Not only is it involved in lubrication, cell surface hydration, and protection against degrading enzymes, MUC1 also promotes abnormal cellular signalling, angiogenesis, anti-adhesion and tumorigenesis. Aberrant glycosylation, overexpression, loss of apical constraint are characteristics of the transformation of a normal cell to a cancerous cell. This review summarizes studies of MUC1 expression and function with a special emphasis on oral epithelial cells in normal and abnormal conditions. In addition, current knowledge of MUC1 and unexplored areas of MUC1 are presented. CONCLUSION: MUC1 is an archetypical transmembrane protein, the presence of MUC1 in ectopic regions may lead to dysregulation of certain enzymes and activation of various pathways, favouring the development of inflammatory responses and tumour formation. This review examines the potential of MUC1 in the development of future therapeutics.

What can we learn about functional importance of human antimicrobial peptide LL-37 in the oral environment from severe congenital neutropenia (Kostmann disease)?

The human antimicrobial peptide LL-37 is produced by neutrophils and epithelial cells, and the peptide can be detected in plasma as well as saliva. LL-37 is active against both gram-positive and gram-negative bacteria including oral pathogens such as Porphyromonas gingivalis and Streptococcus mutans. Besides its antimicrobial properties, LL-37 modulates the innate immune system, and furthermore, it also affects host cell viability. Although, both structural and functional properties of LL-37 have been extensively investigated, its physiological/pathophysiological importance in-vivo is not completely understood. In this review, Kostmann disease (morbus Kostmann) is highlighted since it may represent a LL-37 knockdown model which can provide new important information and insights about the functional role of LL-37 in the human in-vivo setting. Patients with Kostmann disease suffer from neutropenia, and although they are treated with recombinant granulocyte colony-stimulating factor (G-CSF) to normalize their levels of neutrophils, they lack or have very low levels of LL-37 in plasma, saliva and neutrophils. Interestingly, these patients suffer from severe periodontal disease, linking LL-37-deficiency to oral infections. Thus, LL-37 seems to play an important pathophysiological role in the oral environment antagonizing oral pathogens and thereby prevents oral infections.

N-glycomic Analysis of Z(IgA1) Partitioned Serum and Salivary Immunoglobulin A by Capillary Electrophoresis.

AIMS: Application of capillary electrophoresis with laser induced fluorescence detection (CE-LIF) to identify the N-glycosylation structures of serum and saliva IgA from healthy controls and patients with malignant hematological diseases having cytostatic treatment induced mild oral mucosal lesions. BACKGROUND: Altered N-glycosylation of body fluid glycoproteins can be an effective indicator of most inflammatory processes. Immunoglobulin A (IgA) is the second highest abundant immunoglobulin and has a major role in the immune-defense against potential pathogen attacks. While IgA is abundant in serum, secretory immunoglobulin A (sIgA) is one of the most prevalent proteins in mucosal surfaces, such as in saliva. OBJECTIVE: Our aim was to investigate the changes of IgA glycosylation in serum and saliva as a response to an administered cytostatic treatment in patients with malignant hematological disorders. METHODS: Capillary electrophoresis with laser induced fluorescent detection (CE-LIF) was used to analyze the N-glycosylation profiles of Z(IgA1) partitioned immunoglobulin A in pooled serum and saliva of 10 control subjects and 8 patients with malignant hematological diseases having cytostatic treatment induced mild oral mucosal lesions. RESULTS: Eight of 31 and four of 38 N-glycans in serum and saliva, respectively, showed significant (p<0.05) differences upon comparison to the control group. Thirteen glycans were present in the saliva but not in the serum, on the other hand, six structures were found in the serum samples not present in the saliva. CONCLUSION: The developed Z(IgA1) partitioning and the high resolution CE-LIF based glyocoanalytical methods provided an efficient and sensitive workflow to detect and monitor IgA glycosylation alterations in serum and saliva with the scope for widespread molecular medicinal use.

A Transparent, Wearable Fluorescent Mouthguard for High-Sensitive Visualization and Accurate Localization of Hidden Dental Lesion Sites.

Accurate detection and early diagnosis of oral diseases such as dental caries and periodontitis, can be potentially achieved by detecting the secretion of volatile sulfur compounds (VSCs) in oral cavities. Current diagnostic approaches for VSCs can detect the existence and concentrations, yet are not capable of locating the dental lesion sites. Herein, the development of a unique approach for accurately locating dental lesion sites using a fluorescent mouthguard consisting of the zinc oxide-poly(dimethylsiloxane) (ZnO-PDMS) nanocomposite to detect the local release of VSCs is reported. The ZnO-PDMS mouthguard displays a highly sensitive and selective response to VSCs, and exhibits high fluorescent stability, good biocompatibility, and low biological toxicity in normal physiological environments. Then, the wearable ZnO-PDMS mouthguard is demonstrated to be able to identify the precise locations of lesion sites in human subjects. Combined with image analysis, the mouthguards successfully uncover the precise locations of dental caries, allowing convenient screening of hidden dental lesion sites that are oftentimes omitted by dentists. Due to low cost, long-term stability, and good patient compliance, the proposed wearable mouthguard is suitable for large-scale production and enables widely applicable, preliminary yet accurate screening of dental lesions prior to dental clinics and routine physical examinations.

CD146 expression in oral lichen planus and oral cancer.

OBJECTIVE: To examine the CD146/METCAM expression on keratinocytes in normal oral mucosa (NOM), oral lichen planus (OLP), oral epithelial dysplasia (OED), and oral squamous cell carcinoma (OSCC). SUBJECTS AND METHODS: Immunohistochemical examination of CD146 was performed on 80 specimens, divided into 20 cases from each group. The number of CD146+ keratinocytes was quantitatively assessed together with the staining intensity. RESULTS: The mean percentage of CD146+ keratinocytes was 19.04±15.32, 59.40±24.48, 60.04±28.87, and 22.13±21.03 in NOM, OLP, OED, and OSCC, respectively. The mean percentages of CD146+ keratinocytes in OLP and OED were significantly higher than those of NOM and OSCC (p≤0.001). Most OED (55%) and OLP (60%) showed strong and moderate staining intensity, respectively, while NOM (50%) and OSCC (45%) predominantly expressed CD146 at mild intensity. CONCLUSIONS: This is the first study to examine CD146 expression in OLP and OED. CD146 is upregulated in OLP and OED but downregulated in OSCC. The alteration in CD146 may be involved in the immunoregulatory response of OLP and the early event of oral carcinogenesis. The loss of this protein may underlie the progression of OED into invasive OSCC. CLINICAL RELEVANCE: Overexpression of CD146 protein may play a role in the pathophysiology of OLP and OED.

Therapeutic effects of bone mesenchymal stem cells on oral and maxillofacial defects: a novel signaling pathway involving miR-31/CXCR4/Akt axis.

Context: Although bone mesenchymal stem cells (BMSCs) have been used for the treatment of oral and maxillofacial defects, the survival rate and limited proliferation reduces the therapeutic efficiency of BMSC.Objective: The aim of our study is to explore the role of miR-31 in regulating survival, proliferation, and migration of BMSC in vitro.Materials and methods: LPS was used in vitro to induce BMSC damage and then miR-31 was used to incubate with BMSC. Subsequently, BMSC proliferation, survival, and migration were determined via ELISA, qPCR, western blots, and immunofluorescence.Results: The expression of miR-31 was downregulated in response to LPS stress. Interestingly, supplementation of miR-31 could reverse the survival, proliferation and migration of BMSC under LPS. Mechanically, miR-31 treatment inhibited the activation of caspase, and thus promoted BMSC survival. Besides, miR-31 upregulated the genes related to cell proliferation, an effect that was followed by an increase in the levels of migratory factors. Further, we found that miR-31 treatment activated the CXCR4/Akt pathway and blockade of CXCR4/Akt could abolish the beneficial effects of miR-31 on BMSC proliferation, survival, and migration.Conclusions: miR-31 could increase the therapeutic efficiency of BMSC via the CXCR4/Akt pathway.

Osteoimmunology of Oral and Maxillofacial Diseases: Translational Applications Based on Biological Mechanisms.

The maxillofacial skeleton is highly dynamic and requires a constant equilibrium between the bone resorption and bone formation. The field of osteoimmunology explores the interactions between bone metabolism and the immune response, providing a context to study the complex cellular and molecular networks involved in oro-maxillofacial osteolytic diseases. In this review, we present a framework for understanding the potential mechanisms underlying the immuno-pathobiology in etiologically-diverse diseases that affect the oral and maxillofacial region and share bone destruction as their common clinical outcome. These otherwise different pathologies share similar inflammatory pathways mediated by central cellular players, such as macrophages, T and B cells, that promote the differentiation and activation of osteoclasts, ineffective or insufficient bone apposition by osteoblasts, and the continuous production of osteoclastogenic signals by immune and local stromal cells. We also present the potential translational applications of this knowledge based on the biological mechanisms involved in the inflammation-induced bone destruction. Such applications can be the development of immune-based therapies that promote bone healing/regeneration, the identification of host-derived inflammatory/collagenolytic biomarkers as diagnostics tools, the assessment of links between oral and systemic diseases; and the characterization of genetic polymorphisms in immune or bone-related genes that will help diagnosis of susceptible individuals.

Histone Lys demethylase KDM3C demonstrates anti-inflammatory effects by suppressing NF-κB signaling and osteoclastogenesis.

Histone Lys-specific demethylases (KDMs) play a key role in many biological processes through epigenetic mechanisms. However, the role of KDMs in inflammatory responses to oral bacterial infection is poorly understood. Here, we show a novel regulatory role of KDM3C in inflammatory responses to oral bacterial infection. KDM3C expression is transiently suppressed in human and mouse macrophages exposed to LPS from Porphyromonas gingivalis (Pg LPS). Loss of KDM3C in both human and mouse macrophages led to notable induction of proinflammatory cytokines in response to Pg LPS stimulation. Also, KDM3C depletion led to strong induction of p65 phosphorylation and accelerated nuclear translocation in cells exposed to Pg LPS. Kdm3C knockout (KO) in mice led to increased alveolar bone destruction upon induction of experimental periodontitis or pulp exposure compared with those of the wild-type (WT) littermates. The Kdm3C KO mice also revealed an increased number of osteoclasts juxtaposed to the bony lesions. We also confirmed enhanced osteoclastogenesis by bone marrow-derived macrophages isolated from the Kdm3C KO compared with the WT controls. These findings suggest an anti-inflammatory function of KDM3C in regulating the inflammatory responses against oral bacterial infection through suppression of NF-κB signaling and osteoclastogenesis.-Lee, J. Y., Mehrazarin, S., Alshaikh, A., Kim, S., Chen, W., Lux, R., Gwack, Y., Kim, R. H., Kang, M. K. Histone Lys demethylase KDM3C demonstrates anti-inflammatory effects by suppressing NF-κB signaling and osteoclastogenesis.

Saliva: An all-rounder of our body.

Saliva is a multifaceted bodily fluid that is often taken for granted but is indispensable for oral health and overall well-being in humans. Although mainly comprised of water (99.5%), proteins, ions and enzymes turn saliva into a viscoelastic solution that performs a variety of vital tasks. This review article gives a brief overview of the salivary gland system, as well as the composition, output and functions of saliva. It also addresses the current applications of saliva for diagnostic purposes, the clinical relevance of saliva in oral diseases as well as current treatment options.

Exposure to air pollution and oxidative stress markers in patients with potentially malignant oral disorders.

The etiopathogenesis of potentially malignant oral disorders (PMOD) has not been fully understood yet. Recent results suggest that oxidative stress may be involved in the etiology of PMOD. Production of oxidants seems to be the major biological effect responsible for tissue injury and inflammatory response to air pollution. The aim of this study was to compare the oxidative stress markers and antioxidant potential in saliva of PMOD subjects and healthy controls in periods of high and low air pollution. Among enrolled 40 participants, there were 20 PMOD patients and 20 healthy volunteers. The exposure to air pollution was assessed by exhaled CO (eCO). Four oxidative status parameters: 8-hydroxy-2'-deoxyguanosine (8-OHdG), malondialdehyde (MDA), reduced glutathione (GSH) and total antioxidant capacity (TAC) were measured in saliva. Measurements were carried out in June (low air pollution) and November (increased air pollution). In both groups, significantly higher concentrations of 8-OHdG (P < 0.001 for PMOD patients and P = 0.001 for healthy controls), MDA (P = 0.002 and P = 0.012 respectively) and eCO (P < 0.001 and P < 0.001 respectively) were observed in periods of high air pollution. The concentration of TAC did not change between visits. The concentration of salivary GSH (P < 0.001 and P < 0.001 for both groups) decreased when compared between consecutive visits. We conclude that exhaled carbon monoxide (reflecting exposure to air pollution) correlated with the oxidative stress markers in patients with PMOD and healthy controls.

A New Approach for the Diagnosis of Systemic and Oral Diseases Based on Salivary Biomolecules.

Early diagnosis represents the target of contemporary medicine and has an important role in the prognosis and further treatment. Saliva is a biofluid that generated a high interest among researchers due to its multiple advantages over other body fluids. The multitude of components that can act as biomarkers influenced the existing technologies to develop protocols that could allow saliva to become the new noninvasive diagnostic method. Saliva as a diagnostic tool can bring substantial addition to the diagnostic armamentarium, providing important information about oral and general health. The diagnostic applications of saliva extended and had a rapid evolution due to the advancement in salivaomics. The present review summarizes the latest researches in saliva-related studies and explores the information and correlations that saliva can offer regarding the systemic and oral diseases, highlighting its great potential of diagnosis. It is expected that in the future specific guidelines and results regarding the salivary diagnostics are to be available, together with high-sensitivity and specificity tests for multiple systemic and oral diseases.