Publications by authors named "Lijian Jin"

113 Publications

Periodontal disease increases the host susceptibility to COVID-19 and its severity: a Mendelian randomization study.

J Transl Med 2021 12 24;19(1):528. Epub 2021 Dec 24.

The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Background: Emerging evidence shows that periodontal disease (PD) may increase the risk of Coronavirus disease 2019 (COVID-19) complications. Here, we undertook a two-sample Mendelian randomization (MR) study, and investigated for the first time the possible causal impact of PD on host susceptibility to COVID-19 and its severity.

Methods: Summary statistics of COVID-19 susceptibility and severity were retrieved from the COVID-19 Host Genetics Initiative and used as outcomes. Single nucleotide polymorphisms associated with PD in Genome-wide association study were included as exposure. Inverse-variance weighted (IVW) method was employed as the main approach to analyze the causal relationships between PD and COVID-19. Three additional methods were adopted, allowing the existence of horizontal pleiotropy, including MR-Egger regression, weighted median and weighted mode methods. Comprehensive sensitivity analyses were also conducted for estimating the robustness of the identified associations.

Results: The MR estimates showed that PD was significantly associated with significantly higher susceptibility to COVID-19 using IVW (OR = 1.024, P = 0.017, 95% CI 1.004-1.045) and weighted median method (OR = 1.029, P = 0.024, 95% CI 1.003-1.055). Furthermore, it revealed that PD was significantly linked to COVID-19 severity based on the comparison of hospitalization versus population controls (IVW, OR = 1.025, P = 0.039, 95% CI 1.001-1.049; weighted median, OR = 1.030, P = 0.027, 95% CI 1.003-1.058). No such association was observed in the cohort of highly severe cases confirmed versus those not hospitalized due to COVID-19.

Conclusions: We provide evidence on the possible causality of PD accounting for the susceptibility and severity of COVID-19, highlighting the importance of oral/periodontal healthcare for general wellbeing during the pandemic and beyond.
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http://dx.doi.org/10.1186/s12967-021-03198-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8708510PMC
December 2021

lipopolysaccharide enhances the proliferation of human periodontal ligament cells via upregulation of cyclin D1, cyclin A and cyclin B1.

Exp Ther Med 2022 Jan 26;23(1). Epub 2021 Oct 26.

Division of Paediatric Dentistry and Orthodontics, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR 999077, P.R. China.

Human periodontal ligament cells (hPDLCs) play a notable role in periodontal tissue homeostasis and regeneration. However, the effect of lipopolysaccharide (-LPS) on the proliferation of hPDLCs remains unclear. The present study investigated the effects of -LPS on the proliferation profile of hPDLCs, and the involvement of cyclins and cyclin-dependent kinases in the process. hPDLCs were treated with -LPS, and cell proliferation and cycle were detected using Cell Counting Kit-8 assays and flow cytometry. The mRNA expression levels of the cyclins and cyclin-dependent kinases (CDKs), including cyclins A, B1, D1 and D2 and CDK1, 2 and 4, were detected using reverse transcription-quantitative PCR. The protein expression levels of cyclins A, B1 and D1 were analysed using western blotting. The proliferation of hPDLCs was significantly increased after treatment with -LPS at the concentrations of 0.001, 0.01, 0.1, 1 and 10 µg/ml for 24, 36 and 48 h compared with the cells cultured without LPS (P<0.01). The proliferation index of hPDLCs was significantly enhanced after treatment with -LPS (0.0001, 0.001, 0.01, 0.1, 1 and 10 µg/ml) for 24 h (P<0.01). However, the S-phase fraction (SPF) only significantly increased after treatment with -LPS at 0.01 µg/ml for 24 h (P<0.05), while the G/M-phase fraction increased (P<0.01) and the G/G-phase fraction decreased (P<0.01) compared with the controls. The proliferation index and SPF increased, peaked at 24 h and then decreased at 48 h in both -LPS-stimulated and control groups. Notably, -LPS significantly upregulated the expression levels of cyclins D1, A and B1 after 24 h compared with those in the controls. Overall, the present study indicated that -LPS may enhance the proliferation of hPDLCs, potentially through upregulation of cyclins D1, A and B1.
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http://dx.doi.org/10.3892/etm.2021.10925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593868PMC
January 2022

Eradication of Persisters Through Colloidal Bismuth Subcitrate Synergistically Combined With Metronidazole.

Front Microbiol 2021 20;12:748121. Epub 2021 Oct 20.

Division of Periodontology and Implant Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

Microbial persisters enable the development of certain intrinsic strategies for survival with extreme tolerance to multiple antimicrobials. is considered to be the "keystone" periodontopathogen. Indeed, periodontitis, as a highly common inflammatory disease, is the major cause of severe tooth loss and edentulism in adults globally, and yet it is crucially involved in various systemic comorbidities like diabetes. We have recently revealed persisters-induced perturbation of immuno-inflammatory responses and effective suppression of this key pathogen by bismuth drugs. This study further explored novel approaches to eradicating persisters through synergistic combination of colloidal bismuth subcitrate (CBS) with traditional antibiotics. (ATCC 33277) cells in planktonic and biofilm states were cultured to stationary phase, and then treated with metronidazole (100 mg/L), amoxicillin (100 mg/L), CBS, (100 μM) and combinations of these medications, respectively. Persister survival rate was calculated by colony-forming unit. Cell viability and cytotoxicity of CBS were assessed in human gingival epithelial cells (HGECs). Notably, CBS combined with metronidazole enabled the effective eradication of persisters in planktonic mode, and nearly eliminated their existence in biofilm mode. Importantly, CBS exhibited no effects on the viability of HGECs, along with minimal cytotoxicity (<5%) even at a high concentration (400 μM). This pioneering study shows that persisters could be well eliminated via the synergistic combination of CBS with metronidazole. Our findings may contribute to developing novel approaches to tackling periodontitis and inflammatory systemic comorbidities.
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http://dx.doi.org/10.3389/fmicb.2021.748121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8565575PMC
October 2021

Oral Hygiene is Associated with Orthodontic Pain in Patients with Treated and Stabilised Periodontitis.

Oral Health Prev Dent 2021 Jan;19(1):555-564

Purpose: This prospective cohort study aimed to 1) determine whether oral hygiene (OH) is a factor affecting orthodontic pain and 2) reveal whether orthodontic pain affects OH practice during orthodontic treatment.

Materials And Methods: 35 adults aged 22-59 years with treated and stabilised periodontitis were recruited. The pre-bonding (baseline) and 1-month post-bonding OH as well as periodontal status were recorded. The experience, duration and maximum intensity of orthodontic pain within the first week after bonding were documented. In addition, the concentrations of cytokines in the gingival crevicular fluid (GCF) were recorded at baseline, 1 day and 1 week after bonding.

Results: Patients who experienced orthodontic pain in the first week of orthodontic treatment had a higher baseline gingival index (GI) than patients who never experienced orthodontic pain (p < 0.05), and patients who experienced a longer duration and higher intensity of orthodontic pain in the first week of orthodontic treatment also had a higher baseline GI (p < 0.05). Patients who experienced orthodontic pain in the first week of orthodontic treatment had statistically significantly higher concentrations of interleukin 1β (IL-1β) in GCF at 1 day post bonding than those who never experienced pain, while baseline GI was positively associated with cytokine concentrations in GCF at 1 week post bonding (p < 0.05). In addition, neither the experience of orthodontic pain nor its duration and intensity were associated with the level of post-bonding OH (p > 0.05).

Conclusions: The finding that increased gingival inflammation accounted for the longer duration and higher intensity of orthodontic pain in treated and stabilised periodontal patient shows that oral hygiene instructions and supportive periodontal care are of great importance prior to and during adjunctive orthodontic treatment in periodontally compromised individuals.
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http://dx.doi.org/10.3290/j.ohpd.b2183027DOI Listing
January 2021

Study of the Cycloaddition of CO with Styrene Oxide Over Six-Connected spn Topology MOFs (Zr, Hf) at Room Temperature.

Chemistry 2021 Oct 5;27(60):14947-14963. Epub 2021 Oct 5.

Guangxi Key Laboratory of Petrochemical Resource Processing and Process Intensification Technology, School of Chemistry and Chemical Engineering, Guangxi University, Nanning, 530004, P. R. China.

A series of MOFs with a 6-connected spn topology were synthesized (MOF-808-(Zr, Hf), PCN-777-(Zr, Hf), MOF-818-(Zr, Hf)). Through the in situ DRIFTS of NH adsorption-desorption, we found that the activated catalyst mainly contains Lewis acid sites. The effects of different organic ligands on the Lewis acid of the Zr cluster were analyzed by XPS and NH -TPD, and the relative Lewis acidity of the same metal was obtained: PCN-777>MOF-808>MOF-818. In the Py-FTIR results, we confirmed that MOF-818 has a higher acid site density. In the activity test, MOFs with mesoporous structure showed better catalytic activity under normal temperature and pressure. Among them, MOF-818 can still maintain a high degree of crystallinity after catalysis. Finally, we use density functional theory to propose the mechanism of the cycloaddition reaction of carbon dioxide and styrene oxide. The results show that the metal is coordinated with styrene oxide and halogens attack the β carbon of the epoxide.
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http://dx.doi.org/10.1002/chem.202102408DOI Listing
October 2021

Gingival bleeding on brushing as a sentinel sign of gingival inflammation: A diagnostic accuracy trial for the discrimination of periodontal health and disease.

J Clin Periodontol 2021 12 4;48(12):1537-1548. Epub 2021 Oct 4.

Division of Periodontology and Implant Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

Aim: To assess the accuracy of self-reported gingival bleeding on brushing (GBoB) for differentiating between periodontal health and disease and explore the optimal haemoglobin concentration that enables visual detection of GBoB.

Materials And Methods: Self-assessment of GBoB was conducted in supervised sessions for 408 consecutive adults. The haemoglobin levels in saliva/toothpaste slurry (TPS) were analysed, followed by a full-mouth periodontal examination. Periodontal diagnoses were made based on the 2017 classification of periodontal diseases. Gingival inflammation was defined as presence of at least 10% of sites with bleeding on probing (BOP). Logistic regression and area under the receiver operating characteristic curve (AUROC) analyses were applied to assess the accuracy of GBoB.

Results: Overall, 37.1% of the subjects claimed self-reported GBoB, and they had higher values of BOP (median: 25.0%; interquartile range (IQR): 16.0%-37.5%) than those without GBoB (median: 13.5%; IQR: 8.0%-24.8%, p < .001). The concentration/total amount of haemoglobin in TPS was positively correlated with the number of bleeding sites (r = .409/r = .520, p < .001). Haemoglobin concentration of 90.58 μg/ml or 0.51 μl blood volume enabled visual detection of GBoB with an AUROC of 0.848. Self-reported GBoB exhibited significantly increased values of diagnostic odds ratios (3-8) for varying degrees of gingival inflammation and periodontal disease (gingivitis and periodontitis). It showed low to moderate accuracy for discriminating periodontitis and gingivitis from periodontal health, with a sensitivity of 37.1% and 61.3% and a specificity of 84.8% and 84.4%, respectively. Absence of self-reported GBoB and low levels of haemoglobin had 93%-98% predictive values for periodontal health.

Conclusions: Despite its low sensitivity for the discrimination of periodontitis, self-reported GBoB is a promising sentinel sign for periodontal health and disease, and gingival inflammation in particular. It is visually detectable after minor blood loss. After validation in an independent population, identification of GBoB may promote earlier detection and better prevention and treatment of periodontal disease, thereby eventually reducing the global burden of the disease.
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http://dx.doi.org/10.1111/jcpe.13545DOI Listing
December 2021

Authors' Response: "Diagnostic accuracy of a point-of-care aMMP-8 test in the discrimination of periodontal health and disease".

J Clin Periodontol 2021 11 29;48(11):1499-1500. Epub 2021 Jul 29.

Division of Periodontology and Implant Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China.

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http://dx.doi.org/10.1111/jcpe.13522DOI Listing
November 2021

mRNA and long non-coding RNA expression profiling of human periodontal ligament cells under tension loading.

Eur J Orthod 2021 Dec;43(6):698-707

Division of Paediatric Dentistry and Orthodontics, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

Objective: This study explored the expression profiles of messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs) in human periodontal ligament (PDL) cells subjected to tensile loading.

Methods: PDL cells were isolated from the teeth of five healthy individuals, cultured and then exposed to tensile loading. RNA sequencing was performed to explore the mRNA and lncRNA expression profiles with or without tensile loading. Differential expression, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to reveal enriched biological functions and signal transduction pathways. Quantitative polymerase chain reaction (qPCR) was performed to validate the expression of specific mRNAs and lncRNAs associated with the enriched pathways.

Results: Tensile loading significantly enhanced the osteogenic potential of PDL cells. Overall, 1438 mRNAs (860 up- and 578 down-regulated) and 195 lncRNAs (107 up- and 88 down-regulated) were differentially expressed (adjusted P-value <0.05) in the tensile loading group versus the control group. GO and KEGG analyses of the differentially expressed genes indicated significant enrichment in osteogenesis-related biological processes and intracellular signal transduction pathways (e.g. the PI3K-Akt pathway), respectively. The qPCR analysis validated the expression levels of five selected mRNAs (EGFR, FGF5, VEGFA, HIF1A, and FOXO1) and three selected lncRNAs (CYTOR, MIR22HG, and SNHG3).

Limitation: Further studies are warranted to validate the mechanisms regulating tension-induced bone remodelling in PDL cells and potential regulation by the identified lncRNAs.

Conclusion: The notably altered mRNA and lncRNA expression profiles in PDL cells under tensile loading enhance our mechanistic understanding of tension-induced osteogenesis.
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http://dx.doi.org/10.1093/ejo/cjab043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8643418PMC
December 2021

Diagnostic accuracy of a point-of-care aMMP-8 test in the discrimination of periodontal health and disease.

J Clin Periodontol 2021 08 10;48(8):1051-1065. Epub 2021 Jun 10.

Division of Periodontology and Implant Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

Aim: To assess the diagnostic utility of an oral rinse active matrix metalloproteinase-8 (aMMP-8) point-of-care test (POCT) for differentiating periodontal health, gingivitis, as well as different stages and grades of periodontitis.

Materials & Methods: The aMMP-8 index test was undertaken in 408 consecutive adults, followed by a full-mouth periodontal examination. The reference standard was the 2017 World Workshop classification of periodontal diseases. Sensitivity, specificity, and the area under the receiver operating characteristic curve (AUROC) were assessed.

Results: 68.6% of the participants were diagnosed with periodontitis, including Stages I (15.9%), II (15.9%), III (29.7%) and IV (7.1%). A positive aMMP-8 POCT was associated with periodontitis after adjusting for age, gender, tobacco smoking and systemic diseases, while it was unable to differentiate among the stages/grades of periodontitis and between gingivitis/periodontal health. This test showed a sensitivity of 33.2% and a specificity of 93.0% for detecting periodontitis (threshold level >10 ng/ml). The levels of aMMP-8 adjusted by the number of teeth present (aMMP-8/NTP) performed better for periodontitis (sensitivity: 67.1%; specificity: 68.8%). Notably, aMMP-8/NTP were strongly predictive for Stage IV periodontitis (threshold level =0.4312 ng/ml) (sensitivity: 89.7%; specificity: 73.6%; and AUROC: 0.856). The test performance greatly improved in combination with age and smoking, with a sensitivity of 82.5%, a specificity of 84.4%, and an AUROC of 0.883.

Conclusion: This aMMP-8 POCT is able to detect periodontitis with better specificity than sensitivity across the spectrum of its severity. This test may be useful for periodontal screening in conjunction with subject characteristics and/or other sensitive screening tools. Further validation studies are needed.
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http://dx.doi.org/10.1111/jcpe.13485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362205PMC
August 2021

Diagnostic accuracy of self-reported measures of periodontal disease: A clinical validation study using the 2017 case definitions.

J Clin Periodontol 2021 08 1;48(8):1037-1050. Epub 2021 Jun 1.

Division of Periodontology and Implant Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

Aim: To clinically validate a self-reported questionnaire for periodontal disease and assess its accuracy for differentiating periodontal health and different stages of periodontitis.

Methods: A Chinese (Cantonese) version of a self-reported questionnaire was prepared by translating and validating the original English questions proposed by the Centers for Disease Control and Prevention/American Academy of Periodontology (CDC/AAP). The utility of the CDC/AAP questionnaire and its individual questions was assessed against a full-mouth periodontal examination. Periodontal case definition was based on the 2017 World Workshop classification of periodontal diseases. Multivariable logistic regression and the area under the receiver operating characteristic curve (AUROC) analysis were performed to assess the accuracy of the questionnaire.

Results: 408 subjects enrolled in this study, including those with periodontal health (16.2%), gingivitis (15.2%), Stages I/II periodontitis (31.8%) and Stages III/IV periodontitis (36.8%). Overall, the questionnaire had poor accuracy in detecting the presence of Stages I/II periodontitis with an AUROC 0.608. While it showed moderate to high accuracy for identifying periodontal disease (gingivitis and periodontitis), periodontitis and Stages III/IV periodontitis with an AUROC of 0.837, 0.803 and 0.870, respectively. Self-reported measures in combination with age and tobacco smoking showed excellent performance for identifying Stages III/IV periodontitis with a high AUROC of 0.953, a sensitivity of 95.7%, and a specificity of 89.0%. Specific questions and combinations provided greater utility to discriminate the various periodontal case definitions.

Conclusions: The self-reported CDC/AAP questionnaire may be a feasible tool for detecting periodontitis, and its combination with demographic and lifestyle factors is useful for the identification of individuals with Stages III/IV periodontitis. This questionnaire seems less helpful in screening of Stages I/II periodontitis. Further studies are needed to test the validity in larger community-based populations.
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http://dx.doi.org/10.1111/jcpe.13484DOI Listing
August 2021

Lipopolysaccharides affect compressed periodontal ligament cells via Eph-ephrin signaling.

Oral Dis 2021 Apr 19. Epub 2021 Apr 19.

Faculty of Dentistry, University of Hong Kong, Hong Kong, China.

Objectives: The aim of this study is to investigate the underlying mechanism of the recovery of periodontal ligament cells (PDLCs) sequentially exposed to inflammation and mechanical loading.

Materials And Methods: We divided PDLCs into four groups: control; compressive force (CF) alone (2.0 g/cm ); lipopolysaccharides (LPS) pretreatment (0.1 μg/ml) followed by simultaneous LPS and CF stimulation, simulating uncontrolled periodontitis; and LPS pretreatment followed by CF exposure, simulating controlled periodontitis. The expression of EphB4-ephrinB2 and EphA2-ephrinA2, and the level of osteoclastogenesis and osteogenesis were evaluated.

Results: Simultaneous stimulation by LPS and CF, compared with CF alone and sequential LPS and CF exposure, significantly suppressed EphB4 and enhanced ephrinA2 expression. Similarly, the most intense osteoclastic differentiation was observed under simultaneous LPS and CF stimulation, while sequential exposure to LPS and CF only slightly increased osteoclastic cell numbers. Both the activation of EphB4 signaling and ephrinA2 silencing lowered osteoclastic differentiation, which had previously been upregulated by simultaneous LPS and CF stimulation. These treatments also increased osteogenic differentiation.

Conclusions: Simultaneous LPS and CF stimulation critically enhances osteoclastogenesis in PDLCs through the suppression of EphB4 and the induction of ephrinA2 signaling. Sequential LPS and CF exposure partially abolishes the osteolytic effects of simultaneous stimulation.
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http://dx.doi.org/10.1111/odi.13875DOI Listing
April 2021

Identification and integrated analysis of differentially expressed long non-coding RNAs associated with periodontitis in humans.

J Periodontal Res 2021 Aug 9;56(4):679-689. Epub 2021 Mar 9.

Orthodontics, Faculty of Dentistry, the University of Hong Kong, Hong Kong SAR.

Background And Objective: Long non-coding RNAs (lncRNAs) can act as competing endogenous RNAs (ceRNAs) to compete for micro-RNAs (miRNAs) in regulation of downstream genes, various biological functions and diseases. Yet, the expression and regulation of lncRNAs in periodontitis are not fully understood. The objective of the study was to identify potential genes (lncRNA, messenger RNA [mRNA] and miRNA) involved in periodontitis, construct lncRNA-miRNA-mRNA ceRNA networks, explore gene functions and validate gene expressions.

Material And Methods: The data sets for the lncRNA, mRNA and miRNA expression profiles in gingival samples from periodontally healthy subjects and chronic periodontitis patients were obtained from the Gene Expression Omnibus. The differentially expressed lncRNAs (DElncRNAs), mRNAs (DEmRNAs) and miRNAs (DEmiRNAs) were identified, and ceRNA networks were then constructed. The expression of DElncRNAs and DEmRNAs was examined by quantitative real-time polymerase chain reaction (qPCR). Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed for exploring the potential functions and biological pathways.

Results: The GSE80715 and GSE54710 data sets were retrieved. Subsequently, 26 DElncRNAs, 436 DEmRNAs and 12 DEmiRNAs were identified (|fold change| ≥2, adjusted p < 0.05). Further bioinformatics analysis contributed to establishment of the ceRNA networks, which consisted of 10 DElncRNAs, 11 DEmiRNAs and 83 DEmRNAs. Notably, the qPCR results showed a marked decrease in the expression of lncRNA H19 and two mRNAs (NOS1 and MAPT) which further supported the identified ceRNA network. The GO results revealed that the up-regulated mRNAs were significantly enriched in inflammatory processes, whilst the down-regulated mRNAs were enriched in cellular potentials.

Conclusion: Non-coding RNAs are critically involved in the regulatory mechanisms in the pathogenesis of periodontitis. Further study is warranted to investigate the specific underlying genetic traits and networks.
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http://dx.doi.org/10.1111/jre.12864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359208PMC
August 2021

Longitudinal Multi-omics and Microbiome Meta-analysis Identify an Asymptomatic Gingival State That Links Gingivitis, Periodontitis, and Aging.

mBio 2021 03 9;12(2). Epub 2021 Mar 9.

Single-Cell Center, Qingdao Institute of BioEnergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, Shandong, China

Most adults experience episodes of gingivitis, which can progress to the irreversible, chronic state of periodontitis, yet roles of plaque in gingivitis onset and progression to periodontitis remain elusive. Here, we longitudinally profiled the plaque metagenome, the plaque metabolome, and salivary cytokines in 40 adults who transited from naturally occurring gingivitis (NG) to healthy gingivae (baseline) and then to experimental gingivitis (EG). During EG, rapid and consistent alterations in plaque microbiota, metabolites, and salivary cytokines emerged as early as 24 to 72 h after oral-hygiene pause, defining an asymptomatic suboptimal health (SoH) stage of the gingivae. SoH features a swift, full activation of 11 salivary cytokines but a steep synergetic decrease of plaque-derived betaine and spp., suggesting an anti-gum inflammation mechanism by health-promoting symbionts. Global, cross-cohort meta-analysis revealed, at SoH, a greatly elevated microbiome-based periodontitis index driven by its convergence of both taxonomical and functional profiles toward the periodontitis microbiome. Finally, post-SoH gingivitis development accelerates oral microbiota aging by over 1 year within 28 days, with spp. depletion and elevation as hallmarks. Thus, the microbiome-defined, transient gum SoH stage is a crucial link among gingivitis, periodontitis, and aging. A significant portion of world population still fails to brush teeth daily. As a result, the majority of the global adult population is afflicted with chronic gingivitis, and if it is left untreated, some of them will eventually suffer from periodontitis. Here, we identified periodontitis-like microbiome dysbiosis in an asymptomatic SoH stage as early as 24 to 72 h after oral-hygiene pause. SoH features a swift, full activation of multiple salivary cytokines but a steep synergetic decrease of plaque-derived betaine and spp. The microbial ecology during early gingivitis is highly similar to that in periodontitis under both taxonomical and functional contexts. Unexpectedly, exposures to gingivitis can accelerate over 10-fold the normal rate of oral microbiota aging. Our findings underscore the importance of intervening at the SoH stage of gingivitis via proper oral-hygiene practices on a daily basis, so as to maintain a periodontitis-preventive plaque and ensure the healthy aging of the oral ecosystem.
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http://dx.doi.org/10.1128/mBio.03281-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092283PMC
March 2021

Proteomic Analysis of Caspofungin-Induced Responses in Planktonic Cells and Biofilms of .

Front Microbiol 2021 18;12:639123. Epub 2021 Feb 18.

Division of Periodontology and Implant Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

biofilms display markedly increased antifungal resistance, and the underlying mechanisms remain unclear. This study investigated the signature profiles of planktonic cells and biofilms in response to caspofungin (CAS) by mass spectrometry-based shotgun proteomics. We found that biofilms were twofold more resistant to CAS with reference to planktonic cells. Notably, 9.6% of biofilm cells survived the lethal treatment of CAS (128 μg/ml), confirmed by LIVE/DEAD staining, confocal laser scanning microscopy (CLSM) and scanning electron microscopy analyses. The responses of planktonic cells and biofilms to CAS treatment at respective minimum inhibitory concentrations (MICs) were assessed by high-throughput proteomics and bioinformatics approaches. There were 148 and 224 proteins with >twofold difference identified from the planktonic cells and biofilms, respectively. CAS treatment downregulated several cell wall- and oxidative stress-related proteins. Whereas, CAS-induced action was compensated by markedly increased expression of many other proteins involved in cell wall integrity and stress response (e.g., heat shock proteins). Moreover, considerable expression changes were identified in metabolism-associated proteins like glycolysis, tricarboxylic acid (TCA) cycle and ATP biosynthesis. Importantly, various key proteins for cell wall integrity, stress response and metabolic regulation (e.g., PIL1, LSP1, HSP90, ICL1, and MLS1) were exclusively enriched and implicated in biofilms. This study demonstrates that biofilms undergo highly complicated yet complex regulation of multiple cellular pathways in response to CAS. Signature proteins essential for modulating cell wall integrity, stress response and metabolic activities may account for the antifungal resistance of biofilms.
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http://dx.doi.org/10.3389/fmicb.2021.639123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931687PMC
February 2021

Evaluation of the FDI Chairside Guide for Assessment of Periodontal Conditions: A Multicentre Observational Study.

Int Dent J 2021 Oct 30;71(5):390-398. Epub 2021 Jan 30.

Department of Periodontology, Zentrum fuer Zahn-, Mund- und Kieferheilkunde, University of Giessen, Geissen, Germany.

Objective: There is a need to develop easy-to-use tools to screen for periodontal conditions in daily practice. This study aimed to evaluate the FDI World Dental Federation "Chairside Guide" (FDI-CG) developed by the Task Team of the FDI Global Periodontal Health Project (GPHP) as a potential tool for screening.

Methods: Databases from 3 centres in Germany, Hong Kong, and Spain (n = 519) were used to evaluate the association of the FDI-CG and its individual items with the periodontitis case definitions proposed by the Centers for Disease Control and Prevention (CDC) and the American Academy of Periodontology (AAP) for population-based surveillance of periodontitis.

Results: Statistically significant differences were observed among the databases for the prevalence of periodontitis and the items included in the FDI-CG. The FDI-CG score and its individual components were significantly associated with the periodontal status in the individual databases and the total sample, with bleeding on probing showing the strongest association with severe periodontitis (odds ratio [OR] = 12.9, 95% CI [5.9; 28.0], P < .001, for those presenting bleeding on probing >50%), followed by age (OR = 4.8, 95% CI [1.7; 4.2], P = .004, for those older than 65 years of age). Those subjects with a FDI-CG score >10 had an OR of 54.0 (95% CI [23.5; 124.2], P < .001) and presented with severe periodontitis. A significant correlation was found between the different FDI-CG scoring categories (mild, moderate, and severe) and the categories for mild, moderate, and severe periodontitis using the Centers for Disease Control and Prevention and the American Academy of Periodontology criteria (r = 0.57, Spearman rank correlation test, P < .001).

Conclusion: The FDI Chairside Guide may represent a suitable tool for screening the periodontal condition by general practitioners in daily dental practice.
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http://dx.doi.org/10.1016/j.identj.2020.12.024DOI Listing
October 2021

MOF-74-M (M = Mn, Co, Ni, Zn, MnCo, MnNi, and MnZn) for Low-Temperature NH-SCR and In Situ DRIFTS Study Reaction Mechanism.

ACS Appl Mater Interfaces 2020 Oct 13;12(43):48476-48485. Epub 2020 Oct 13.

Guangxi Key Laboratory of Petrochemical Resource Processing and Process Intensification Technology, School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, PR China.

Monometallic and bimetallic MOF-74-M (M = Mn, Co, Ni, Zn, MnCo, MnNi, and MnZn) catalysts were prepared by the solvothermal method for NH-SCR. XRD, BET, SEM, and EDS-mapping tests indicate the successful synthesis of the MOF-74-M catalyst with uniform distribution of metal elements and large specific surface area, and the morphology is almost hexagonal. Adding Mn element to a single-metal catalyst can enhance activity, which is mainly because of the existence of various valence states of Mn so that it has excellent redox properties; the catalytic activity of water and sulfur resistance tests showed that the catalytic activity of MOF-74-M increases after adding a proper amount of SO, mainly because of the increase in acidic sites. In situ DRIFTS results indicate that the low-temperature range of MOF-74-MnCo and MOF-74-Mn is dominated by the E-R mechanism and the high-temperature range is dominated by the L-H mechanism. The entire temperature range of MOF-74-Zn is dominated by the L-H mechanism.
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http://dx.doi.org/10.1021/acsami.0c11035DOI Listing
October 2020

Metallodrug ranitidine bismuth citrate suppresses SARS-CoV-2 replication and relieves virus-associated pneumonia in Syrian hamsters.

Nat Microbiol 2020 11 7;5(11):1439-1448. Epub 2020 Oct 7.

Department of Chemistry, State Key Laboratory of Synthetic Chemistry, CAS-HKU Joint Laboratory of Metallomics on Health and Environment, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, Hong Kong, China.

SARS-CoV-2 is causing a pandemic of COVID-19, with high infectivity and significant mortality. Currently, therapeutic options for COVID-19 are limited. Historically, metal compounds have found use as antimicrobial agents, but their antiviral activities have rarely been explored. Here, we test a set of metallodrugs and related compounds, and identify ranitidine bismuth citrate, a commonly used drug for the treatment of Helicobacter pylori infection, as a potent anti-SARS-CoV-2 agent, both in vitro and in vivo. Ranitidine bismuth citrate exhibited low cytotoxicity and protected SARS-CoV-2-infected cells with a high selectivity index of 975. Importantly, ranitidine bismuth citrate suppressed SARS-CoV-2 replication, leading to decreased viral loads in both upper and lower respiratory tracts, and relieved virus-associated pneumonia in a golden Syrian hamster model. In vitro studies showed that ranitidine bismuth citrate and its related compounds exhibited inhibition towards both the ATPase (IC = 0.69 µM) and DNA-unwinding (IC = 0.70 µM) activities of the SARS-CoV-2 helicase via an irreversible displacement of zinc(II) ions from the enzyme by bismuth(III) ions. Our findings highlight viral helicase as a druggable target and the clinical potential of bismuth(III) drugs or other metallodrugs for the treatment of SARS-CoV-2 infection.
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http://dx.doi.org/10.1038/s41564-020-00802-xDOI Listing
November 2020

Microneedles loaded with anti-PD-1-cisplatin nanoparticles for synergistic cancer immuno-chemotherapy.

Nanoscale 2020 Sep 9;12(36):18885-18898. Epub 2020 Sep 9.

Division of Oral and Maxillofacial Surgery, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

Programmed cell death protein-1 (PD-1) on T-cells combined with programmed cell death ligand-1 (PD-L1) critically accounts for tumor immune evasion. Anti-PD-1 (aPD-1) blocks the binding of PD-1 to PD-L1, thus allowing T-cell activation for tumor cell eradication. Currently, the major challenges for cancer immunotherapy are how to improve the response rate and overcome drug resistance. Dermal administration turns out to be a promising route for immunotherapy since skin is a highly active immune organ containing a large population of resident antigen-presenting cells. Microneedle arrays can pierce the immune-cell-rich epidermis, leading to a robust T-cell response in the microenvironment of tumor cells. Herein, we successfully developed a microneedle patch loaded with pH-responsive tumor-targeted lipid nanoparticles (NPs), which allows local delivery of aPD-1 and cisplatin (CDDP) precisely to cancer tissues for cancer therapy. For in vivo studies, aPD-1/[email protected] delivered through microneedles effectively boosted the immune response, thereby a remarkable effect on tumor regression was realized. Synergistic anticancer mechanisms were therefore activated through robust microneedle-induced T-cell response, blockage of PD-1 in T-cells by aPD-1, and an increase in direct cytotoxicity of CDDP in tumor cells. Strikingly, transdermal delivery using MNs increased the response rate in the animal model unresponsive to aPD-1 systemic therapy. This exhibited promise in the treatment of immunotherapy-unresponsive cancers. Taken together, microneedle-mediated local delivery of nano-encapsulated chemotherapeutic and immunotherapeutic agents at tumor skin sites provides a novel treatment strategy and insights into cancer therapy.
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http://dx.doi.org/10.1039/d0nr04213gDOI Listing
September 2020

Th2 cell regulatory and effector molecules single nucleotide polymorphisms and periodontitis.

J Leukoc Biol 2020 11 3;108(5):1641-1654. Epub 2020 Aug 3.

Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

To investigate the association between T helper 2 (Th2) cell regulatory and effector molecules' genetic polymorphisms and periodontitis. Single nucleotide polymorphisms (SNPs) of 11 Th2 cell regulatory or effector molecules genes (CD28, CTLA4, IL4, IL5, IL6, IL9, IL10, IL13, IL4R, GATA3, STAT6, and rs1537415; total 130 SNPs) were studied in Chinese nonsmokers (163 periodontitis-free controls, 141 periodontitis patients) using Sequenom iPlex assays. SNPs potentially associated with periodontitis (adjusted allelic P < 0.1) in this cross-sectional study were further investigated via meta-analysis. Allele G of rs4553808 in promoter of CTLA4 was more frequently detected in periodontitis than controls (P < 0.005), but did not remain significant after age and gender adjustment. Haplotype (GTT) in a block of three CTLA4 SNPs (rs4553808, rs16840252, rs5742909) was significantly associated with periodontitis. Meta-analysis of SNPs identified indicated allele T of CTLA4 rs5742909 (3 studies; 461 control, 369 periodontitis) and allele G of IL6 rs1800796 (18 studies; 2760 control, 2442 periodontitis) were significantly associated with periodontitis (OR = 1.44 and OR = 1.30, respectively). Within limitations of this study, a haplotype of CTLA4 concerning Th2 cell regulation, may be associated with periodontitis in Chinese nonsmokers followed. Meta-analysis indicated rs5742909 of CTLA4 and rs1800796 of IL6 appeared significantly associated with periodontitis.
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http://dx.doi.org/10.1002/JLB.4MA0720-698RRDOI Listing
November 2020

A randomized controlled trial of the effects of non-surgical periodontal therapy on cardiac function assessed by echocardiography in type 2 diabetic patients.

J Clin Periodontol 2020 06 29;47(6):726-736. Epub 2020 Apr 29.

Division of Periodontology & Implant Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

Background: Periodontitis significantly increases the risk of diabetic complications. This clinical trial investigated the effects of periodontal therapy on cardiac function in patients with type 2 diabetes mellitus (T2DM) and periodontitis.

Materials And Methods: Fifty-eight subjects with T2DM and periodontitis were randomly allocated to Treatment Group (n = 29) receiving non-surgical periodontal therapy, and Control Group (n = 29) having only oral hygiene instructions with delayed periodontal treatment until completion of this 6-month study. The left ventricle (LV) diastolic function was assessed by echocardiography with the tissue Doppler imaging index (E/e' ratio); and LV hypertrophy was evaluated by LV mass index (LVMI). Blood samples were collected for biochemical analysis.

Results: The intention-to-treat analysis showed that periodontal treatment significantly reduced the E/e' ratio by 1.66 (95% CI: -2.64 to -0.68, p < .01), along with marked improvement of periodontal conditions (p < .05). LVMI was not altered at the 6-month follow-up. The serum levels of N-terminal pro-B type natriuretic peptide (NT-proBNP) as a cardiac stress biomarker, C-reactive protein and interleukin-6 decreased numerically without reaching statistical significance.

Conclusion: The present study provides the first evidence that non-surgical periodontal therapy may improve cardiac diastolic function in type 2 diabetic patients with periodontitis.
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http://dx.doi.org/10.1111/jcpe.13291DOI Listing
June 2020

Metronidazole-Treated Porphyromonas gingivalis Persisters Invade Human Gingival Epithelial Cells and Perturb Innate Responses.

Antimicrob Agents Chemother 2020 05 21;64(6). Epub 2020 May 21.

Division of Periodontology & Implant Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China

Periodontitis as a biofilm-associated inflammatory disease is highly prevalent worldwide. It severely affects oral health and yet closely links to systemic diseases like diabetes and cardiovascular disease. as a "keystone" periodontopathogen drives the shift of microbe-host symbiosis to dysbiosis and critically contributes to the pathogenesis of periodontitis. Persisters represent a tiny subset of biofilm-associated microbes highly tolerant to lethal treatment of antimicrobials, and, notably, metronidazole-tolerant persisters have recently been identified by our group. This study further explored the interactive profiles of metronidazole-treated persisters (M-PgPs) with human gingival epithelial cells (HGECs). cells (ATCC 33277) at stationary phase were treated with a lethal dosage of metronidazole (100 μg/ml, 6 h) for generating M-PgPs. The interaction of M-PgPs with HGECs was assessed by microscopy, flow cytometry, cytokine profiling, and quantitative PCR (qPCR). We demonstrated that the overall morphology and ultracellular structure of M-PgPs remained unchanged. Importantly, M-PgPs maintained the capabilities to adhere to and invade HGECs. Moreover, M-PgPs significantly suppressed proinflammatory cytokine expression in HGECs at a level comparable to that seen with the untreated cells, through the thermosensitive components. The present report reveals that persisters induced by lethal treatment of antibiotics were able to maintain their capabilities to adhere to and invade human gingival epithelial cells and to perturb the innate host responses. Novel strategies and approaches need to be developed for tackling and favorably modulating the dysregulated immunoinflammatory responses for oral/periodontal health and general well-being.
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http://dx.doi.org/10.1128/AAC.02529-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269468PMC
May 2020

Low-level laser-aided orthodontic treatment of periodontally compromised patients: a randomised controlled trial.

Lasers Med Sci 2020 Apr 12;35(3):729-739. Epub 2019 Dec 12.

Faculty of Dentistry, The University of Hong Kong, 34 Hospital Road, Sai Ying Pun, Hong Kong, SAR, China.

Low-level laser irradiation (LLLI) shows effects in orthodontic pain relief and periodontal inflammation control. The aim of this article is to investigate the analgesic and inflammation-modulatory effects of low-level laser irradiation among orthodontic patients with compromised periodontium. A randomised controlled trial with split-mouth design was conducted in 27 adults with treated and controlled chronic periodontitis over 6 months. One side of the dental arch underwent repeated treatment under a 940-nm diode laser (EZlase; Biolase Technology Inc.) with a beam size of 2.8 cm for 60 seconds at 8.6 J/cm, whilst the other side received pseudo-laser treatment. Laser irradiation was applied repeatedly for 8 times during the first 6 weeks after bracket bonding and monthly thereafter until the end of orthodontic treatment. Subjective pain (assessed by visual analogue scale in pain diary and by chairside archwire activation), periodontal status (assessed by periodontal clinical parameters), cytokines in gingival crevicular fluid (interleukin 1β, prostaglandin E, substance P) and periodontopathic bacteria (Porphyromonas gingivalis and Treponema denticola) in supragingival plaque were assessed. The intensity of pain was lower on the laser-irradiated side at multiple follow-up visits (P < 0.05). The pain subsided 1 day earlier on the laser side, with a lower peak value during the first week after initial archwire placement (P < 0.05). The laser side exhibited a smaller reduction in bite force during the first month (mean difference = 3.17, 95% CI: 2.36-3.98, P < 0.05 at 1-week interval; mean difference = 3.09, 95% CI: 1.87-4.32, P < 0.05 at 1-month interval). A smaller increase was observed in the plaque index scores on the laser side at 1-month (mean difference = 0.19, 95% CI: 0.13-0.24, P < 0.05) and in the gingival index scores at the 3-month follow-up visit (mean difference = 0.18, 95% CI: 0.14-0.21, P < 0.05). Laser irradiation inhibited the elevation of interleukin-1β, prostaglandin E and substance P levels during the first month (P < 0.05). However, no intergroup difference was detected in the bacteria levels. Low-level laser irradiation exhibits benefits in pain relief and inflammation control during the early stage of adjunctive orthodontic treatment in periodontally compromised individuals.
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http://dx.doi.org/10.1007/s10103-019-02923-0DOI Listing
April 2020

Red-Emissive Guanylated Polyene-Functionalized Carbon Dots Arm Oral Epithelia against Invasive Fungal Infections.

ACS Appl Mater Interfaces 2019 Dec 6;11(50):46591-46603. Epub 2019 Dec 6.

Faculty of Dentistry , The University of Hong Kong , 34 Hospital Road , Hong Kong SAR , China.

Oral candidiasis as a highly prevalent and recurrent infection in medically compromised individuals is mainly caused by the opportunistic fungal pathogen . This epithelial infection, if not controlled effectively, can progress to life-threatening systemic conditions and complications. The efficacy of current frontline antifungals is limited due to their poor bioavailability and systemic toxicity. As such, an efficient intervention is essential for controlling disease progression and recurrence. Herein, a theranostic nanoplatform (CD-Gu-AmB) was developed to track the penetration of antifungals and perturb the invasion of at oral epithelial tissues, via decorating the homemade red-emissive carbon dots (CD) with positively charged guanidine groups (Gu) followed by conjugation with antifungal polyene (amphotericin B, AmB) in a reacting site-controllable manner. The generated CD-Gu-AmB favorably gathered within the cells and exhibited potent antifungal effects in both planktonic and biofilm forms. It selectively accumulated in the nuclei of human oral keratinocytes and exhibited undetectable toxicity to the host cells. Moreover, we reported for the first time the penetration and exfoliation profiles of CD in a three-dimensional organotypic model of human oral epithelial tissues, demonstrating that the extra- and intracellular accumulation of CD-Gu-AmB effectively resisted the invasion of by forming a "shielding" layer throughout the entire tissue. This study establishes a multifunctional CD-based theranostic nanoplatform functioning as a traceable and topically applied antifungal to arm oral epithelia, thereby shedding light on early intervention of mucosal candidiasis for oral and general health.
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http://dx.doi.org/10.1021/acsami.9b18003DOI Listing
December 2019

Effect of non-surgical periodontal therapy on renal function in chronic kidney disease patients with periodontitis: a systematic review and meta-analysis of interventional studies.

Clin Oral Investig 2020 Apr 12;24(4):1607-1618. Epub 2019 Nov 12.

Department of Periodontology, Faculty of Dentistry, The University of Hong Kong, 34 Hospital Road, Hong Kong, SAR, China.

Objective: This systematic review evaluated the impacts of non-surgical periodontal therapy (NSPT) in patients with chronic kidney disease (CKD) and periodontitis in order to explore causality and assess the potential benefits of co-management.

Methods: This systematic review and meta-analyses were conducted by searching MEDLINE, EMBASE, PubMed, Cochrane Library, and Open GREY. Interventional studies of adult patients suffering from CKD and periodontitis were investigated. Effect of NSPT on renal function was analyzed.

Results: A total of 109 participants from four case-series studies and 97 participants from one randomized controlled trial were included in this review. Sixty percent of the eligible studies (3/5) aimed at the effect of NSPT on nutritional status and systemic inflammation in dialysis patients. The other two studies concluded a beneficial impact of NSPT on estimated glomerular filtration rate (eGFR) in patients with CKD stages 2-4. Moreover, two meta-analyses were accomplished on eGFR and serum creatinine to evaluate the changes between baseline and 3-month follow-up. The pooled mean of eGFR was not significantly different pre- and post-NSPT using random and fixed-effect models. The change for creatinine was not significant using the random effect model but was significant when the fixed effect model was used (p < 0.001).

Conclusions: There is insufficient evidence to conclude the potential benefit of NSPT on renal function in CKD patients with periodontitis.

Clinical Relevance: Periodontitis contributes to the inflammatory burden and has been associated with impaired kidney function in many observational studies. However, well-designed clinical trials in pre-dialysis patients investigating the impact of NSPT on renal function-related parameters are missing.
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http://dx.doi.org/10.1007/s00784-019-03066-wDOI Listing
April 2020

Species-Level Salivary Microbial Indicators of Well-Resolved Periodontitis: A Preliminary Investigation.

Front Cell Infect Microbiol 2019 11;9:347. Epub 2019 Oct 11.

Faculty of Dentistry, The University of Hong Kong, Hong Kong, China.

To profile the salivary microbiomes of a Hong Kong Chinese cohort at a species-level resolution and determine species that discriminated clinically resolved periodontitis from periodontally healthy cases. Salivary microbiomes of 35 Hong Kong Chinese subjects' under routine supportive dental care were analyzed. All subjects had been treated for any dental caries or periodontal disease with all restorative treatment completed at least 1 year ago and had ≤3 residual pockets. They were categorized based on a past diagnosis of chronic periodontitis into "healthy" (H) or "periodontitis" (P) categories. Unstimulated whole saliva was collected, genomic DNA was isolated, and high throughput Illumina MiSeq sequencing of 16S rRNA (V3-V4) gene amplicons was performed. The sequences were assigned taxonomy at the species level by using a BLASTN based algorithm that used a combined reference database of HOMD RefSeqV14.51, HOMD RefSeqExtended V1.1 and GreenGeneGold. Species-level OTUs were subjected to downstream analysis in QIIME and R. For P and H group comparisons, community diversity measures were compared, differentially abundant species were determined using DESeq2, and disease indicator species were determined using multi-level pattern analysis within the R package "indicspecies." P subjects were significantly older than H subjects ( = 0.003) but not significantly different in their BOP scores ( = 0.82). No significant differences were noted in alpha diversity measures after adjusting for age, gender, and BOP or in the beta diversity estimates. Four species; , and were significantly more abundant in P than in the H group. Indicator species analysis showed 7 significant indicators species of P group. was the sole positive indicator of P group (positive predictive value = 0.9, = 0.04). Significant indicators of the H category were , and . This exploratory study showed salivary microbial species could discriminate treated, well-maintained chronic periodontitis from healthy controls with similar gingival inflammation levels. The findings suggest that certain salivary microbiome features may identify periodontitis-susceptible individuals despite clinical disease resolution.
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http://dx.doi.org/10.3389/fcimb.2019.00347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797555PMC
June 2020

IL-17 alters the mesenchymal stem cell niche towards osteogenesis in cooperation with osteocytes.

J Cell Physiol 2020 05 23;235(5):4466-4480. Epub 2019 Oct 23.

Faculty of Dentistry, The University of Hong Kong, Sai Ying Pun, Hong Kong, China.

Bone remodeling is a strictly regulated dynamic process that cycles between bone formation and resorption, and interleukin-17 (IL-17) critically orchestrates the activation and differentiation of both osteoblasts and osteoclasts. Mesenchymal stem cells (MSCs) within their native environment receive biochemical stimuli from surrounding cells that influences their differentiation into bone precursors, while the roles of osteocytes in regulating the osteogenic differentiation of MSCs remain unclear. This study investigated the specific roles of IL-17 signaling cascades and osteocyte-specific pathways in the osteogenesis of MSCs. Using a transwell coculture (CC) system, we explored the effects of osteocytes and osteoblasts on the osteogenesis of MSCs with and without IL-17 supplementation. A polycaprolactone (PCL) three-dimensional (3D) culture model was used to evaluate their osteogenic potential in the presence of osteocytes and IL-17. Notably, IL-17 induced osteogenesis in MSCs, which could be attenuated by blocking IL-17 receptor A. The osteogenic differentiation of MSCs promoted by IL-17 was further enhanced by CC with osteocytes. Moreover, proinflammatory cytokines IL-6 and IL-1β played an important role in IL-17-dependent differentiation, via the phosphorylation of AKT, signal transducer and activator of transcription 3, and extracellular signal-regulated kinase 1/2 signaling pathways in the MSC niche. The present study confirms a synergistic effect of osteocytes and IL-17 in the production of biochemical signals to stimulate the osteogenic differentiation of MSCs, which could be further promoted in the PCL 3D-scaffold. These findings provide important insight into the mechanisms of MSCs activation and osteogenic differentiation within the native stem cell niche, and suggest a possible role of IL-17 in bone tissue engineering.
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http://dx.doi.org/10.1002/jcp.29323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113695PMC
May 2020

Bismuth drugs tackle Porphyromonas gingivalis and attune cytokine response in human cells.

Metallomics 2019 07;11(7):1207-1218

Discipline of Periodontology, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

Periodontitis is the leading cause of severe tooth loss and edentulism in adults worldwide and is closely linked to systemic conditions such as diabetes and cardiovascular disease. Porphyromonas gingivalis is the key pathogen in periodontitis. Herein, we provided the first evidence that bismuth drugs suppress P. gingivalis in its planktonic, biofilm, and intracellular states. In total, 42 bismuth-associated proteins were identified including its major virulent factors (e.g., gingipains, hemagglutinin HagA, and fimbriae). Bismuth perturbed its iron acquisition, disturbed the energy metabolism and virulence, and deactivated multiple key enzymes (e.g., superoxide dismutase and thioredoxins). Moreover, bismuth inhibited its biofilm formation and disrupted the 3-day matured biofilms. Notably, the internalized P. gingivalis in various human cells (e.g., human gingival epithelium progenitors, HGEPs) was oppressed by bismuth but not the commonly used antibiotic metronidazole. Importantly, bismuth drugs enabled the counteraction of immuno-inflammatory responses in different host cells perturbed by P. gingivalis. The production of IL-6 and IL-8 attenuated by P. gingivalis in both of native and IL-1β-stimulated HGEPs was restored, while the bacterium-enhanced expression of IL-6, IL-1β, and TNFα in THP-1 macrophages was alleviated. This proof-of-concept study brings prospects for the potential reposition of the routinely used anti-Helicobacter pylori bismuth drugs to better manage inflammatory diseases such as periodontitis and P. gingivalis-related complex systemic disorders.
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http://dx.doi.org/10.1039/c9mt00085bDOI Listing
July 2019

Overexpression of ephrinB2 in stem cells from apical papilla accelerates angiogenesis.

Oral Dis 2019 Apr 13;25(3):848-859. Epub 2019 Feb 13.

Endodontology, Faculty of Dentistry, The University of Hong Kong, Hong Kong, Hong Kong.

Objectives: We aimed to accelerate angiogenesis in pulp regeneration by modulating ephrinB2 expression in stem cells from apical papilla (SCAPs).

Materials And Methods: Stem cells from apical papilla were transducted with ephrinB2-lentiviral expression vector (ephrinB2-SCAPs) in experimental group and green fluorescent protein (GFP-SCAPs) in control group. The transduction efficiency was confirmed by real-time PCR and Western blot assays. MTT assay was performed to detect the proliferative capacity of SCAPs after transduction. In vitro Matrigel assay and in vivo Matrigel plug assay were carried out to evaluate the angiogenic capacity.

Results: Results showed that ephrinB2-SCAPs had significantly higher ephrinB2 expression than GFP-SCAPs. EphrinB2-SCAPs upregulated vascular endothelial growth factor (VEGF) secretion under hypoxia. In vitro Matrigel assay demonstrated that human umbilical vein endothelial cells (HUVECs) cocultured with ephrinB2-SCAPs under hypoxia formed vascular-like structures earlier than GFP-SCAPs. Animal experiments confirmed that SCAPs co-transplanted with HUVECs enabled to generate greater amount of blood vessels than SCAPs alone. EphrinB2-SCAPs produced increased number of blood vessels with references to GFP-SCAPs, and those co-transplanted with HUVECs generated vessels with larger and functional tubule volumes.

Conclusions: Regulating ephrinB2 expression in SCAPs may act as a new avenue for enhancing angiogenesis in dental pulp regeneration.
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http://dx.doi.org/10.1111/odi.13042DOI Listing
April 2019

Periodontitis links to exacerbation of myocardial dysfunction in subjects with type 2 diabetes.

J Periodontal Res 2019 Aug 11;54(4):339-348. Epub 2019 Jan 11.

Discipline of Periodontology, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.

Background And Objective: Subjects with diabetes and periodontitis are at high risk of cardiovascular events, while the subclinical alterations of cardiac function in this cohort remain unclear. This cross-sectional study investigated the association of periodontitis with left ventricle (LV) structural and functional abnormalities in subjects with type 2 diabetes mellitus (T2DM).

Material And Methods: A total of 115 subjects with T2DM were divided into Control group (n = 32) with no or mild periodontitis, and the rest with moderate to severe chronic periodontitis (CP) were further categorized into CP-1 (n = 41) and CP-2 (n = 42) based on disease severity. Echocardiography was performed to precisely assess (a) LV hypertrophy by LV mass index (LVMi); (b) LV diastolic function by tissue Doppler imaging index E/e' ratio; and (c) LV systolic function by speckle tracking derived global longitudinal strain (GLS).

Results: Overall, a linear trend in LVMi, E/e', and GLS existed among the Control, CP-1, and CP-2 groups, respectively (P < 0.05). After adjustments of multiple confounders, CP-2 subjects showed significantly higher E/e' (log scale, 2.22 ± 0.05 vs 2.07 ± 0.06, P < 0.01) and GLS (-17.42 ± 0.46% vs -18.95 ± 0.54%, P < 0.05) than the Controls. Multivariate analysis revealed that sites% with probing depth ≥4 mm and sites% with clinical attachment loss ≥5 mm were independent indicators for E/e' (β = 0.005 and β = 0.002, P < 0.01) and GLS (β = 0.03 and β = 0.02, P < 0.05) , respectively. Moreover, the number of missing teeth was significantly associated with LVMi (β = 0.01, P < 0.01).

Conclusion: This study provides the first evidence that severe periodontitis is significantly associated with the exacerbation of LV diastolic and systolic dysfunction in subjects with T2DM.
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http://dx.doi.org/10.1111/jre.12634DOI Listing
August 2019
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