Publications by authors named "Po-Jan Kuo"

21 Publications

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Recommendations for treating stage I-III periodontitis in the Taiwanese population: A consensus report from the Taiwan Academy of Periodontology.

J Formos Med Assoc 2021 Jul 19. Epub 2021 Jul 19.

Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan. Electronic address:

Background/purpose: Based on the fundamental of the S3-level clinical practice guideline (CPG) for treating stage I-III periodontitis developed by the European Federation of Periodontology (EFP), this consensus report aimed to develop treatment recommendations for treating periodontitis in the Taiwanese population.

Methods: The report was constructed by experts from the Taiwan Academy of Periodontology. The following topics were reviewed: (a) the prevalence of periodontitis in Asia and current status of treatment in Taiwan; (b) specific anatomical considerations for treating periodontitis in Asians; (d) educational and preventive interventions and supragingival plaque control; (d) subgingival instrumentation and adjunctive treatment; (e) surgical periodontal therapy; and (f) maintenance and supportive periodontal care. Recommendations were made according to the evidences from the EFP CPG, the published literature and clinical studies in Asians, and the expert opinions.

Results: The treatment recommendations for the Taiwanese population were generally in parallel with the EFP CPG, and extra cautions during treatment and maintenance phases were advised due to the anatomical variations, such as shorter root trunk, higher prevalence of supernumerary distolingual root and lingual bony concavity in mandibular posteriors, and thinner anterior labial plate, of the Asian population.

Conclusion: The EFP CPG could be adopted for treating periodontitis and maintaining periodontal health of the Taiwanese population, and anatomical variations should be cautious when the treatment is delivered.
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http://dx.doi.org/10.1016/j.jfma.2021.06.029DOI Listing
July 2021

Assessment of the changes in retention and surface topography of attachments for maxillary 4-implant-retained overdentures.

J Prosthet Dent 2021 Jun 11. Epub 2021 Jun 11.

Clinical Professor, Department of Prosthodontics, College of Dental Medicine, Columbia University, New York, NY.

Statement Of Problem: Restoring the edentulous maxilla with an implant-retained overdenture (IRO) can present a challenge because of increased implant divergence and the added wear of the implant abutments and attachments. However, knowledge pertaining to the degree of implant divergence and its effects on the wear pattern of the implant attachments is lacking.

Purpose: The purpose of this in vitro study was to investigate the change in the retention and wear characteristics of unsplinted abutments and attachments when used to retain a maxillary 4-implant palateless complete removable overdenture with different implant angulations.

Material And Methods: Three groups of specimens of 0-, 15-, and 30-degree implant angulations were evaluated, each with 7 specimens. The retention of specimens was recorded after aging cycles equivalent to 1, 2.5, and 6 years of use. The surface of the attachments was examined with light and scanning electron microscope (SEM).

Results: Increasing the interimplant divergence improved the initial retention. After 1 year of use, retention of the 15- and 30-degree groups was significantly higher than that of the 0-degree group (P<.05). No significant difference in retention was found between the 15- and 30-degree groups (P>.05). After 2.5 and 6 years of use, no significant difference in retention was noted between groups (P>.05). Under light and SEM examination, the wear of the abutments and attachments was related to the interimplant divergence.

Conclusions: The initial retention of single attachments increased significantly as the implant divergence increased. The retention of the15- and 30-degree groups was significantly higher than that of the 0-degree group after 1 year of use. No significant difference in retention was found after 2.5 and 6 years, regardless of implant angulation.
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http://dx.doi.org/10.1016/j.prosdent.2021.05.002DOI Listing
June 2021

Estimation of the Effect of Accelerating New Bone Formation of High and Low Molecular Weight Hyaluronic Acid Hybrid: An Animal Study.

Polymers (Basel) 2021 May 24;13(11). Epub 2021 May 24.

School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan.

Osteoconduction is an important consideration for fabricating bio-active materials for bone regeneration. For years, hydroxyapatite and β-calcium triphosphate (β-TCP) have been used to develop bone grafts for treating bone defects. However, this material can be difficult to handle due to filling material sagging. High molecular weight hyaluronic acid (H-HA) can be used as a carrier to address this problem and improve operability. However, the effect of H-HA on bone formation is still controversial. In this study, low molecular weight hyaluronic acid (L-HA) was fabricated using gamma-ray irradiation. The viscoelastic properties and chemical structure of the fabricated hybrids were evaluated by a rheological analysis nuclear magnetic resonance (NMR) spectrum. The L-MH was mixed with H-HA to produce H-HA/L-HA hybrids at ratios of 80:20, 50:50 and 20:80 (/). These HA hybrids were then combined with hydroxyapatite and β-TCP to create a novel bone graft composite. For animal study, artificial bone defects were prepared in rabbit femurs. After 12 weeks of healing, the rabbits were scarified, and the healing statuses were observed and evaluated through micro-computer tomography (CT) and tissue histological images. Our viscoelastic analysis showed that an HA hybrid consisting 20% H-HA is sufficient to maintain elasticity; however, the addition of L-HA dramatically decreases the dynamic viscosity of the HA hybrid. Micro-CT images showed that the new bone formations in the rabbit femur defect model treated with 50% and 80% L-HA were 1.47 ( < 0.05) and 2.26 ( < 0.01) times higher than samples filled with HA free bone graft. In addition, a similar tendency was observed in the results of HE staining. These results lead us to suggest that the material with an H-HA/L-HA ratio of 50:50 exhibited acceptable viscosity and significant new bone formation. Thus, it is reasonable to suggest that it may be a potential candidate to serve as a supporting system for improving the operability of granular bone grafts and enhancing new bone formations.
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http://dx.doi.org/10.3390/polym13111708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197183PMC
May 2021

Porphyromonas gingivalis lipopolysaccharide and gingival fibroblast augment MMP-9 expression of monocytic U937 cells through cyclophilin A.

J Periodontol 2021 May 17. Epub 2021 May 17.

School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan.

Background: Intercellular cross-talking was suggested in matrix metalloproteinase (MMP)-9 expression with unknown mechanisms. Studies showed cyclophilin A (CypA) playing an important role in regulating MMP-9 expression in varied diseases. The aim of the study was to examine the CyPA on the MMP-9 augmentation in monocytic U937 cells after Porphyromonas gingivalis (Pg) lipopolysaccharide (LPS) treatment and human gingival fibroblast (hGF) co-culture.

Methods: In independent culture or co-culture of hGF and U937 cell, quantitative real-time polymerase chain reaction (qPCR) and zymography were selected to examine the mRNA and protein activity of MMP-9, respectively. The CyPA expression was determined by qPCR.

Results: LPS could enhance MMP-9 mRNA expression and enzyme activity in U937 cell. However, the enhancements were not observed in hGF. Similarly, LPS enhanced CyPA mRNA in U937, but not in hGF. After co-cultured with hGF, however, MMP-9 and CyPA in U937 increased regardless of the presence/absence of LPS. In U937 cells, the extra-supplied CyPA increased MMP-9 mRNA and enzyme activity, whereas the CyPA inhibitor, cyclosporine A, suppressed the LPS- and co-culture-enhanced MMP-9. Moreover, the inhibitors for MAP kinase, including PD98059 (ERK) and SP600125 (JNK), suppressed the CyPA-enhanced MMP-9 in U937.

Conclusion: Through the CyPA pathway, the LPS and the hGF could augment the MMP-9 expression in the U937 cells.
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http://dx.doi.org/10.1002/JPER.19-0740DOI Listing
May 2021

2,3,5,4'-tetrahydroxystilbene-2-O-b-D-glucoside triggers the pluripotent-like possibility of dental pulp stem cells by activating the JAK2/STAT3 axis: Preliminary observations.

J Dent Sci 2021 Mar 7;16(2):599-607. Epub 2020 Nov 7.

School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.

Abstract.

Background/purpose: Although 2,3,5,4'-Tetrahydroxystilbene-2-O-beta-glucoside (THSG) reportedly has anti-inflammatory properties, its role in inducing the dedifferentiation of human dental pulp stem cells (DPSC) into pluripotent-like stem cells remains to be determined. The purpose of this study is to evaluate the effects of THSG on the pluripotent-like possibility and mechanism of DPSC.

Materials And Methods: DPSCs were treated with THSG, and cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTS) assay. Real-time polymerase chain reaction was used to analyze the mRNA expression levels of pluripotency-associated genes and oncogenes and to detect telomerase activity in the cells. Embryoid body formation assay was conducted, and pluripotency-related proteins were identified using Western blotting. Data were analyzed using one-way analysis of variance.

Results: Cell viability, telomerase activity, and embryoid body formation were enhanced in THSG-treated DPSCs. The mRNA expression levels of pluripotent-like genes (including Nanog homeobox [], SRY-box 2 [], and POU class 5 homeobox 1 []) significantly increased after THSG treatment. The expression levels of pluripotency-related genes (Janus kinase-signal transducer 2 [] and signal transducer and activator of transcription 3 []) increased, whereas those of oncogenes (, , , and ) decreased. Furthermore, the expression levels of the phosphorylated JAK2 and STAT3 proteins significantly increased after THSG treatment.

Conclusion: THSG treatment may enhance the pluripotent-like possibility of DPSC through the JAK2/STAT3 axis. Hence, it may be used as an alternative cell-based therapeutic strategy in regenerative dentistry.
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http://dx.doi.org/10.1016/j.jds.2020.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025197PMC
March 2021

Antioxidants protect against gingival overgrowth induced by cyclosporine A.

J Periodontal Res 2021 Apr 14;56(2):397-407. Epub 2021 Jan 14.

Department of Dentistry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Xindian, Taiwan.

Objective: We investigated the importance of reactive oxygen species (ROS) on developing gingival overgrowth (GO) and then introduced the antioxidant strategy to prevent, or even reduce GO.

Background: Gingival overgrowth is a common side effect of the patients receiving cyclosporine A (CsA), an immune suppressant. Although it has been broadly investigated, the exact pathogenesis of the induced GO is still uncertain.

Methods: We cultured human primary gingival fibroblasts and used animal model of GO to investigate the ameliorative effects of antioxidants on CsA-induced GO. To examine the CsA-induced oxidative stress, associated genes and protein expression, and the overgrown gingiva of rats by using immunocytochemistry, confocal laser scanning microscopy, real-time PCR, ELISA, gelatin zymography, gingival morphological, and immunohistochemical analysis.

Results: We found for the first time that ROS was responsible for the CsA-induced oxidative stress and TGF-β1 expression in human primary gingival fibroblasts, as well as the GO of rats. The antioxidants (oxidative scavenger of vitamin E and an antioxidative enzyme inducer of hemin) ameliorated CsA-induced pathological and morphological alterations of GO without affected the CsA-suppressed il-2 expression in rats. CsA-induced oxidative stress, HO-1, TGF-β1, and type II EMT were also rescued by antioxidants treatment.

Conclusions: We concluded that CsA repetitively stimulating the production of ROS is the cause of CsA-GO which is ameliorated by treating antioxidants, including vitamin E and sulforaphane. Furthermore, the immunosuppressive effect of CsA is not interfered by antioxidant treatments in rats. This finding may thus help the clinician devise better prevention strategies in patients susceptible to GO.
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http://dx.doi.org/10.1111/jre.12832DOI Listing
April 2021

2,3,5,4'-Tetrahydroxystilbene-2-O-β-d-glucoside promotes the effects of dental pulp stem cells on rebuilding periodontal tissues in experimental periodontal defects.

J Periodontol 2021 02 29;92(2):306-316. Epub 2020 Aug 29.

School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.

Background: This study aimed to investigate the regenerative effects of 2,3,5,4'-tetrahydroxystilbene-2-O-β-d-glucoside (THSG)-treated human dental pulp stem cells (DPSC) on the healing of experimental periodontal defects in rats.

Methods: The maxillary first molars of 30 male Sprague-Dawley rats were extracted, and after healing, bilateral periodontal defects were surgically created mesially in second molars. The defects were treated with Matrigel (as control), DPSC, or DPSC + THSG. After 2 weeks, the healed defects were evaluated using microcomputed tomography and through histological and immunohistochemical analyses.

Results: In the microcomputed tomography analysis, more new bone formation in the DPSC and DPSC + THSG groups was observed compared with the control group. The periodontal bone supporting ratio in site with DPSC + THSG was significantly higher than that in DPSC. Histologically, an enhanced new bone formation and more significant periodontal attachment were observed in the DPSC + THSG group. The expression levels of proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), and osteopontin (OPN) in the DPSC + THSG group were significantly greater than those in other groups.

Conclusions: THSG-revolutionized DPSCs significantly shortened the regenerative period of periodontal defects by enhancing the cell recruitment and possibly the angiogenesis in rat models, which illustrate the critical implications for a clinical application and provide a novel tactic for periodontitis treatment.
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http://dx.doi.org/10.1002/JPER.19-0563DOI Listing
February 2021

A novel design of palatal stent to reduce donor site morbidity in periodontal plastic surgery.

J Dent Sci 2020 Jun 18;15(2):136-140. Epub 2020 Apr 18.

Department of Periodontology, School of Dentistry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Background/ Purpose: The connective tissue graft from hard palate is a reliable graft technique that has been used for achieving root coverage, increasing keratinized tissue width and thickness in periodontal plastic surgeries. Donor site morbidities, including complications from postoperative bleeding, pain during healing phase, difficulties in eating and speaking and unexpecting healing patterns, are always a concern for both doctors and patients. The aim of this study was to investigate a novel design of palatal stent to reduce these complications and provide patient with a smooth healing experience after soft tissue harvesting from hard palate.

Materials And Methods: Eight patients requiring connective tissue graft from palatal site were included in the study. The palatal stents made with light-curing hybrid composite resin were fabricated and tried in for patients prior to the periodontal plastic surgeries. Stent was delivered immediately without other dressing material or suture after the graft harvesting procedure for blood clot stabilization. Bleeding tendency was evaluated at the completion of the procedure. Patients came back for follow up in 1 week, 2 weeks and 1 month after the surgery. In the consecutive clinical cases, all patients reported minimal postoperative pain and discomfort (score ranged between 0 and 2). Both chewing and swallowing were not affected when wearing the stent, while four patients reported speaking inconvenience influenced by the stent.

Results: In the consecutive clinical cases, all patient reported minimal postoperative pain and discomfort (Score ranged between 0 and 2). Both chewing and swallowing were not affected when wearing the stent while four patients reported speaking influenced by the stent.

Conclusion: The novel design of palatal stent reduces donor site morbidity and provides patient with a good healing experience after soft tissue harvesting from hard palate.
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http://dx.doi.org/10.1016/j.jds.2020.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305455PMC
June 2020

Fibroblast-enhanced cyclophilin A releasing from U937 cell upregulates MMP-2 in gingival fibroblast.

J Periodontal Res 2020 Oct 14;55(5):705-712. Epub 2020 May 14.

Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan.

Objective: This in vitro study aimed to evaluate the expression of cyclophilin A (CyPA) in U937 monocytic cells after coculturing with the human gingival fibroblasts (HGFs) and the effect of CyPA on the augmentation of MMP-2 expression in the coculture environment.

Background: Leukocyte infiltration in gingival connective tissue is one of the major findings in the lesions of inflammatory periodontal diseases. A crosstalk between the resident gingival fibroblasts and the recruited inflammatory cells that promote the expression of matrix metalloproteinases (MMPs) was proposed based on recent findings, whereas the cluster of differentiation 147 (CD147)-CyPA pathway was suggested to be involved with the crosstalk.

Material And Methods: CyPA was released into media, in the independent or transwell coculture of HGF and U937 cells, as determined by enzyme-linked immunosorbent assay, whereas intracellular mRNA expressions for CyPA and MMP-2 were examined by quantitative real-time polymerase chain reaction, in the transwell coculture or conditional medium models. Zymography was conducted to analyze the activities of pro-MMP-2/MMP-2 released into the media.

Results: (a) A significantly increased CyPA protein level was observed in the transwell coculture media compared with that in the independent culture. (b) The transwell coculture-enhanced mRNA expression for CyPA was noticed in U937 cells but not in HGFs. After adding with HGF-conditioned medium, the mRNA enhancement in U937 cells occurred in a dose-dependent manner. (c) Although the MMP-2 activities significantly increased after transwell coculturing, the MMP-2 mRNA enhancement was observed only in HGFs. (d) Exogenous CyPA could enhance MMP-2 activities in HGFs in a dose-dependent manner. However, the CyPA antagonist reduced the MMP-2 activities in the transwell cocultures. (e) Moreover, the CyPA-enhanced MMP-2 activity in HGF was decreased significantly by the pathway inhibitor for c-Jun amino-terminal kinase (JNK).

Conclusion: Based on the present findings, we suggest that gingival fibroblasts could enhance the CyPA release from U937 cells, via the JNK pathway, resulting in MMP-2 enhancement in fibroblasts. The finding shed light on a new mechanism of cellular interaction involving MMP-2 and CyPA, in two cells.
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http://dx.doi.org/10.1111/jre.12759DOI Listing
October 2020

CD147 self-regulates matrix metalloproteinase-2 release in gingival fibroblasts after coculturing with U937 monocytic cells.

J Periodontol 2020 05 21;91(5):651-660. Epub 2019 Oct 21.

Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan.

Background: Cluster of differentiation 147 (CD147) is a multifunctional glycoprotein that functions as an inducer of matrix metalloproteinase (MMP) expression in fibroblasts. Synergistically enhanced MMP-2 expression was recently observed in the coculture of human gingival fibroblasts (HGFs) and U937 human monocytic cells; however, the responsible mechanisms have not yet been fully established. The aim of this study was to evaluate the release of soluble CD147 in HGFs after coculturing with U937 cells and its functional effect on the enhancement of MMP-2 expression in HGFs.

Methods: Enzyme-linked immunosorbent assay was used to determine the amount of CD147 protein in media, whereas real-time polymerase chain reaction was performed to evaluate the mRNA levels of CD147 and MMP-2 in HGFs and U937 cells. The enzyme activities of MMP-2 released from cells were examined by zymography. Transwell coculturing and conditioned media treatments were selected to rule out the effect of direct contact of HGFs and U937 cells.

Results: The protein and mRNA expression of CD147 in HGFs were enhanced after transwell coculturing with U937 cells and exposure to U937-conditioned medium. MMP-2 enzyme activities in HGFs were also significantly increased by the coculturing methods. Administration of exogenous CD147 enhanced MMP-2 expression in HGFs, whereas treatment with cyclosporine-A, which inhibited CD147 expression, reduced U937-enhanced MMP-2 expression in HGFs.

Conclusions: CD147 can interact with fibroblasts to stimulate the expression of MMPs associated with periodontal extracellular matrix degradation. This study has demonstrated that CD147 released from fibroblasts might play a role in monocyte-enhanced MMP-2 expression in HGFs.
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http://dx.doi.org/10.1002/JPER.19-0278DOI Listing
May 2020

Risks of angled implant placement on posterior mandible buccal/lingual plated perforation: A virtual immediate implant placement study using CBCT.

J Dent Sci 2019 Sep 20;14(3):234-240. Epub 2019 Mar 20.

Department of Periodontology, School of Dentistry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Background/purpose: Immediate implant placement has been considered to be a successful treatment procedure. The bone plate perforation (BPP) may be one of severe complication and potentially life-threatening situation. The aim of this virtual study is to evaluate the influences of angled implant insertion on BPP during immediate implant installation in the posterior mandible.

Materials And Methods: Cone beam computed tomography images of 488 posterior teeth from 61 patients were selected. Virtual immediate implant placement (VIIP) was performed at each posterior tooth following the appropriate axis with the prosthetic-driven planning and different deviation angles of 3-, 6-, or 9-degree. BPP was then examined from cross-sectional images obtained. Furthermore, the relation of lingual bony morphology and BPP were also determined.

Results: The incidence of buccal and lingual BPP increased as the deviation angle increased in posterior mandible area. Incidence of lingual BPP was significantly influenced by angular deviation and type of lingual bony morphology after adjusting for age, gender, tooth type, and right/left side. An increase in incidence odds of over 6-fold (OR = 6.583) was noted for placements angled by 9° compared with placements made without angulation, and an increase in incidence odds of over 3-fold (OR = 3.622) was noted for teeth with the undercut-type lingual morphology compared with the other types.

Conclusion: The present Results indicate that accurate selection of the implant insertion angle and full awareness of the bony anatomy at the implant recipient site are essential to prevent BPP in the posterior mandible.
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http://dx.doi.org/10.1016/j.jds.2019.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739299PMC
September 2019

Accuracy of cone beam computed tomography in measuring thicknesses of hard-tissue-mimicking material adjacent to different implant thread surfaces.

J Dent Sci 2019 Jun 14;14(2):119-125. Epub 2019 May 14.

School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.

Background/purpose: To evaluate the measurement accuracy of hard-tissue thicknesses adjacent to dental implants with different thread designs on images obtained from cone beam computed tomography (CBCT) using an model.

Materials And Methods: On 4 × 13-mm implant, the neck of the implant was designed with micro-threads, and the apical part was covered by macro-threads; these implants were placed in a vinyl polysiloxane block that mimicked hard-tissue. Models were prepared with various thicknesses of 2.0, 1.0, 0.5 and 0.3 mm adjacent to the dental implant. Each model was scanned using CBCT, and the thickness of the cortical bone from the outer surface of the micro-threads and macro-threads were recorded. Ground sections were prepared, and the thickness was measured with electronic calipers as the gold standard (GS) measurement.

Results: CBCT measurements of the micro-thread surface were consistently underestimated compared to the GS measurement when the thickness of the hard-tissue-mimicking material was ≤1.0 mm. In comparison, CBCT measurements of the macro-thread surface closely approximated the standard measurement, except when the thickness of the hard-tissue-mimicking material was 0.3 mm. The mean percentage errors from the standard measurement for the 2.0-, 1.0-, 0.5-, and 0.3-mm thickness groups were 4.8%, 16.4%, 37.8%, and 92.6%, respectively, for the micro-thread group, and were 0.6%, 2.9%, 9.5%, and 40.8%, respectively, for the macro-thread group.

Conclusion: Within the limitations of this study, we conclude that CBCT may not produce sufficient resolution for thin sections of hard tissue-mimicking materials adjacent to micro-thread surfaces.
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http://dx.doi.org/10.1016/j.jds.2019.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561864PMC
June 2019

Dental Pulp Stem Cell Transplantation with 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside Accelerates Alveolar Bone Regeneration in Rats.

J Endod 2019 Apr 7;45(4):435-441. Epub 2019 Mar 7.

School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan; Center for Tooth Bank and Dental Stem Cell Technology, Taipei Medical University, Taipei, Taiwan; Department of Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei, Taiwan. Electronic address:

Introduction: Although the therapeutic potential of human dental pulp stem cells (hDPSCs) has been studied for bone regeneration, the therapeutic efficiency needs further consideration and examinations for clinical applications. Thus, the aims of this study were to evaluate the effect of 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (THSG) on the osteogenic differentiation of hDPSCs and to examine the therapeutic efficiency of the THSG-enhanced osseous potential of hDPSCs in alveolar bony defects of rats.

Methods: Expressions of osteogenic messenger RNAs (including ALP, RUNX2, BGLAP, and AMBN) were examined by quantitative real-time polymerase chain reaction. Alizarin red S staining was conducted to analyze THSG-induced mineralization of hDPSCs. To investigate the regenerative effects of THSG-treated hDPSCs on dental alveolar bone, bony defects were created in male Sprague-Dawley rats. Defects were treated with Matrigel (Corning Inc, Corning, NY), hDPSCs, or hDPSCs + THSG. After 2 weeks, defect healing was evaluated by micro-computed tomographic and histologic analyses.

Results: In the cell model, THSG induced osteogenesis-associated genes (ALP, RUNX2, and BGLAP) and an enamel-related gene (AMBN), resulting in mineralization as detected by alizarin red S staining after 2 weeks of treatment. In the animal model, THSG increased all parameters of bone formation (the relative bone volume, trabecular thickness, trabecular number, and trabecular separation) in alveolar bony defects of rats. THSG not only improved the quality of newly formed bone but also the quantity of new bone.

Conclusions: These results showed important findings in revealing the THSG-enhanced osteogenic differentiation of hDPSCs and THSG-facilitated bone regeneration, which may provide an alternative option for cell-based regenerative therapy.
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http://dx.doi.org/10.1016/j.joen.2018.12.019DOI Listing
April 2019

Ameliorative effect of hesperidin on ligation-induced periodontitis in rats.

J Periodontol 2019 03 27;90(3):271-280. Epub 2018 Sep 27.

Department of Periodontology, School of Dentistry, National Defense Medical, Center and Tri-Service General Hospital, Taipei, Taiwan.

Background: This study evaluated the ameliorative effect of hesperidin (HES), an anti-inflammatory flavanone, in rats with ligation (Lig)-induced periodontitis.

Methods: A total of 48 rats were randomly divided into non-ligation group (NL), Lig group, and two ligation-plus-HES groups (L+H). HES was administered immediately after ligature placement at a dose of 75 or 150 mg/kg by intragastric feeding. Destruction of the ligated maxillary second and mandibular first molars were evaluated by dental radiography, microcomputed tomography (micro-CT), and histometry performed after sacrificing the rats on the seventh day. The expression levels of interleukin (IL)-1β, IL-6, and inducible nitric oxide synthase (iNOS) messenger (m)RNAs in the gingiva were determined by reverse-transcription polymerase chain reaction. The expression of iNOS was examined by immunohistochemistry.

Results: The dental radiography and micro-CT findings revealed significantly increased alveolar bone loss in the Lig group, which was significantly prevented by HES. The histometry results revealed less gingival inflammation and connective tissue loss in the L+H groups compared with that in the Lig group. The mRNA expression levels of IL-6, IL-1 β, and iNOS were significantly increased in the Lig group but were reduced in the L+H groups. The immunostaining results showed that the ligation-induced iNOS expression was also decreased by HES.

Conclusions: Oral administration of HES promotes an ameliorative effect against the ligation-induced alveolar bone loss and effectively inhibits the production of proinflammatory mediators in rats with experimentally induced periodontitis. Therefore, HES may be a good candidate for modulating oral inflammatory diseases.
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http://dx.doi.org/10.1002/JPER.16-0708DOI Listing
March 2019

Carvacrol Ameliorates Ligation-Induced Periodontitis in Rats.

J Periodontol 2017 07 7;88(7):e120-e128. Epub 2017 Apr 7.

Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan, Republic of China.

Background: This study aims to evaluate the ameliorative effect of carvacrol, an anti-inflammatory monoterpenoid phenol and a major component of Plectranthus amboinicus, on periodontal damage in an experimental rat model of periodontitis.

Methods: Forty Sprague-Dawley rats were divided into ligation (Lig), non-ligation (n-Lig), and two ligation plus carvacrol (Lig+C) groups. Carvacrol (17.5 or 35.0 mg/kg body weight/day) was administered intragastrically from 1 day before ligation. On day 8, dental alveolar bone loss and gingival inflammation in periodontal specimens were examined by dental radiography, microcomputed tomography, and histology. Expressions of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and inducible nitric oxide synthase messenger (m)RNAs, and levels of matrix metalloproteinase (MMP)-2 and MMP-9 in gingiva were examined by reverse transcription-polymerase chain reaction and zymography.

Results: Dental radiography revealed periodontal bone-supporting ratios in Lig and Lig+C groups were lower than the n-Lig group, with Lig group ratios being lowest. Compared with the n-Lig group, the cemento-enamel junction-bone distance was significantly longer in Lig and Lig+C groups, with Lig+C groups showing shorter distances regardless of radiographic methods used. Histology and histometry showed less inflammatory area and stronger connective tissue attachment in Lig+C groups than in the Lig group. Cytokine/mediator mRNA expression and MMP-9 levels were reduced in the Lig+C groups.

Conclusions: Carvacrol reduced tissue damage and bone loss caused by ligation-induced periodontitis. The present results indicate that carvacrol might reduce tissue destruction by downregulating expression of proinflammatory mediators and MMP-9.
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http://dx.doi.org/10.1902/jop.2017.160618DOI Listing
July 2017

The cytokine-cosmc signaling axis upregulates the tumor-associated carbohydrate antigen Tn.

Oncotarget 2016 Sep;7(38):61930-61944

Center for Cancer Research, Taipei Medical University, Taipei, Taiwan.

Tn antigen (GalNAc-α-O-Ser/Thr), a mucin-type O-linked glycan, is a well-established cell surface marker for tumors and its elevated levels have been correlated with cancer progression and prognosis. There are also reports that Tn is elevated in inflammatory tissues. However, the molecular mechanism for its elevated levels in cancer and inflammation is unclear. In the current studies, we have explored the possibility that cytokines may be one of the common regulatory molecules for elevated Tn levels in both cancer and inflammation. We showed that the Tn level is elevated by the conditioned media of HrasG12V-transformed-BEAS-2B cells. Similarly, the conditioned media obtained from LPS-stimulated monocytes also elevated Tn levels in primary human gingival fibroblasts, suggesting the involvement of cytokines and/or other soluble factors. Indeed, purified inflammatory cytokines such as TNF-α and IL-6 up-regulated Tn levels in gingival fibroblasts. Furthermore, TNF-α was shown to down-regulate the COSMC gene as evidenced by reduced levels of the COSMC mRNA and protein, as well as hypermethylation of the CpG islands of the COSMC gene promoter. Since Cosmc, a chaperone for T-synthase, is known to negatively regulate Tn levels, our results suggest elevated Tn levels in cancer and inflammation may be commonly regulated by the cytokine-Cosmc signaling axis.
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http://dx.doi.org/10.18632/oncotarget.11324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308701PMC
September 2016

2,3,5,4'-Tetrahydroxystilbene-2-O-β-glucoside Isolated from Polygoni Multiflori Ameliorates the Development of Periodontitis.

Mediators Inflamm 2016 18;2016:6953459. Epub 2016 Jul 18.

Taipei Cancer Center, Taipei Medical University, 250 Wu-Hsing Street, Taipei 11031, Taiwan.

Periodontitis, a chronic infection by periodontopathic bacteria, induces uncontrolled inflammation, which leads to periodontal tissue destruction. 2,3,5,4'-Tetrahydroxystilbene-2-O-beta-glucoside (THSG), a polyphenol extracted from Polygoni Multiflori, reportedly has anti-inflammatory properties. In this study, we investigated the mechanisms of THSG on the Porphyromonas gingivalis-induced inflammatory responses in human gingival fibroblasts and animal modeling of ligature-induced periodontitis. Human gingival fibroblast cells were treated with lipopolysaccharide (LPS) extracted from P. gingivalis in the presence of resveratrol or THSG to analyze the expression of TNF-α, IL-1β, and IL-6 genes. Increased AMP-activated protein kinase (AMPK) activation and SirT1 expression were induced by THSG. Treatment of THSG decreased the expression of LPS-induced inflammatory cytokines, enhanced AMPK activation, and increased the expression of SirT1. In addition, it suppressed the activation of NF-κB when cells were stimulated with P. gingivalis LPS. The anti-inflammatory effect of THSG and P. Multiflori crude extracts was reproduced in ligature-induced periodontitis animal modeling. In conclusion, THSG inhibited the inflammatory responses of P. gingivalis-stimulated human gingival fibroblasts and ameliorated ligature-induced periodontitis in animal model.
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http://dx.doi.org/10.1155/2016/6953459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967694PMC
May 2017

Crosstalk Between Human Monocytic U937 Cells and Gingival Fibroblasts in Coculturally Enhanced Matrix Metalloproteinase-2 Expression.

J Periodontol 2016 Oct 13;87(10):1228-37. Epub 2016 Jun 13.

Department of Periodontology, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan, Republic of China.

Background: Matrix metalloproteinases (MMPs) play a key role in inflammatory periodontal disease. Synergistically enhanced MMP-2 expression in a coculture of human gingival fibroblasts (HGFs) and human monocytic U937 cells was observed. Crosstalk between these two cells via the extracellular matrix metalloproteinase inducer (EMMPRIN) was demonstrated.

Methods: Enzyme levels of MMP-2 in HGFs and direct coculture with U937 were examined by zymography. MMP-2 and EMMPRIN expressions of HGFs and U937 were determined in coculture and conditioned cultures (using supernatants from HGF- or U937-conditioned medium). The crosstalk was evaluated by EMMPRIN extrasupplement and EMMPRIN inhibition, through pretreatment of U937 with cyclosporine-A.

Results: Direct coculturing of HGFs and U937 enhanced MMP-2 enzyme level and mRNA expression. Coculturing also increased membranous EMMPRIN expression of U937, but not from HGFs. In conditioned cultures, mRNA expression of MMP-2 increased in HGFs which received U937-conditioned medium. Increased MMP-2 was not observed in U937 with HGF-conditioned medium, although mRNA expression of EMMPRIN increased. Enhanced MMP-2 was observed after administration of exogenous EMMPRIN in HGFs; however, reduced MMP-2 enzyme level was noted if EMMPRIN of cocultured U937 was inhibited.

Conclusions: In the coculture of HGFs and U937, upregulated EMMPRIN expression in U937, which may be triggered by HGFs, can enhance MMP-2 expression in HGFs. Crosstalk between HGFs and U937 involving MMP-2 from HGFs was proposed; EMMPRIN from U937 may play a particular role.
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http://dx.doi.org/10.1902/jop.2016.140653DOI Listing
October 2016

Gelatinases and extracellular matrix metalloproteinase inducer are associated with cyclosporin-A-induced attenuation of periodontal degradation in rats.

J Periodontol 2015 Jan;86(1):82-90

Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan.

Background: The present study aims to examine the inhibitory effect of cyclosporin-A (CsA) on periodontal breakdown and to further explore the correlations of CsA-induced attenuation of periodontal bone loss with the expressions of gelatinases (i.e., matrix metalloproteinase [MMP]-2 and MMP-9) and extracellular matrix metalloproteinase inducer (EMMPRIN).

Methods: Forty Sprague-Dawley rats were randomly divided into four groups: 1) control; 2) CsA; 3) ligature (Lig); and 4) ligature plus CsA (Lig + CsA). The CsA group received 10 mg ⋅ Kg(-1) ⋅ d(-1) CsA for 8 days. The Lig group received silk ligature on selected molars. The Lig + CsA group received silk ligature and CsA treatment. The inhibitory effects of CsA on the ligature-induced periodontal breakdown was examined with microcomputed tomography (micro-CT) and histometric analyses to analyze the amount of attachment loss, crestal bone loss, connective tissue attachment, and the surface area with inflammatory cell infiltration. The effects of CsA on ligature-induced expressions of gelatinases and EMMPRIN in gingival tissues were examined with Western blotting and zymography, respectively.

Results: By micro-CT and histology, the Lig + CsA group had significantly more periodontal breakdown than the control and CsA groups but less periodontal breakdown than the Lig group. Consistent results were found for the expressions of gelatinases and EMMPRIN among the groups demonstrating that the Lig + CsA group had significantly less gingival protein expression of gelatinases and EMMPRIN than the Lig group.

Conclusions: CsA inhibited the expressions of gelatinase MMPs and EMMPRIN and partially prevented the periodontal breakdown in ligature-induced experimental periodontitis. The CsA-induced attenuation of periodontal bone loss was strongly correlated positively with the expressions of MMP-2, MMP-9, and EMMPRIN in gingiva.
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http://dx.doi.org/10.1902/jop.2014.140366DOI Listing
January 2015

Epigallocatechin-3-gallate attenuates Porphyromonas gingivalis lipopolysaccharide-enhanced matrix metalloproteinase-1 production through inhibition of interleukin-6 in gingival fibroblasts.

J Periodontol 2014 Jun 11;85(6):868-75. Epub 2013 Nov 11.

Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan, ROC.

Background: Recent studies have shown that epigallocatechin-3-gallate (EGCG), a major constituent of green tea extract, exhibits effects of anti-inflammation and antioxidation on periodontal inflammation. The present in vitro study examines the effect of EGCG on Porphyromonas gingivalis (Pg) lipopolysaccharide (LPS)-enhanced expression of interleukin (IL)-6 and matrix metalloproteinase (MMP)-1, as well as the activation of nuclear factor-kappa B (NF-κB). Furthermore, the role of IL-6 on LPS-enhanced MMP-1 production is evaluated using human gingival fibroblasts (HGFs).

Methods: HGFs were primary cultured from human gingiva specimens. The cytotoxicities of EGCG and LPS were tested by cell viability tests. The cellular mRNA expression of IL-6 was determined by reverse-transcription polymerase chain reaction, and the protein expression of MMP-1 and IL-6 was examined by enzyme-linked immunosorbent assay. The cytosol expression and nuclear translocation of NF-κB was evaluated by immunocytochemistry followed by confocal laser scanning microscopy.

Results: Pg LPS significantly increased MMP-1 production in HGFs, whereas adding EGCG significantly attenuated this enhanced production of MMP-1. LPS treatment also increased the mRNA and protein expression of IL-6 and stimulated NF-κB activation in HGFs. However, the addition of EGCG significantly attenuated the IL-6 expression and NF-κB activation. Supplemental addition of IL-6 significantly enhanced cellular MMP-1 production, whereas anti-IL-6 antibody inhibited LPS-enhanced MMP-1 production.

Conclusion: EGCG could attenuate Pg LPS-enhanced production of MMP-1 in HGFs, whereas this attenuation might be due to the inhibition of IL-6 by EGCG.
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http://dx.doi.org/10.1902/jop.2013.120714DOI Listing
June 2014

Berberine's effect on periodontal tissue degradation by matrix metalloproteinases: an in vitro and in vivo experiment.

Phytomedicine 2013 Oct 16;20(13):1203-10. Epub 2013 Jul 16.

Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan, ROC; Department of Dental Hygiene, China Medical University, Taichung, Taiwan, ROC.

Periodontal disease involves tissue destruction caused by interactions among bacterial antigens and inflammatory mediators including matrix metalloproteinases (MMPs). Berberine, an isoquinoline alkaloid isolated from medicinal herbs, can inhibit the degradative action of extracellular MMPs. The effect of berberine on the periodontal expression of MMPs was examined in vitro and in vivo. Gelatinolytic activity of pro-MMP-2, MMP-2, and MMP-9 in the human gingival fibroblast and/or U-937 was compared after treatment with Porphyromonas gingivalis lipopolysaccharide (P.g. LPS) in four medias containing 0, 1, 10 and 100μM of berberine each. Twelve animals were divided into three groups for the study: (A) non-ligation, (B) ligation, and (C) ligation-plus-berberine (75mg/kg berberine by gastric lavage daily); and the effect of berberine on periodontal destruction was evaluated in the ligature-induced periodontitis in rats for 8 days by micro computerized tomography (micro-CT), histology and immunohistochemistry (IHC). An enhancing effect of P.g. LPS on MMP activities was identified, with a greater effect on fibroblasts/U937 co-culture than on either culture alone. When berberine was added to the LPS-treated cultures, the activities of MMPs were significantly reduced in dose-dependent manner. In the animals, the trends of the following parameters were compared. 1. Micro-CT distances between cemento-enamel junction (CEJ) and dental alveolar bone crest: B>C>A. 2. Histometrically measured crest bone levels: B>C>A. 3. Amount of collagen deposited in tissue areas: A>C>B. 4. Attachment loss: B>C≈A. 5. Connective tissue (CT) attachment: B>either A or C. 6. Expression of cells stained positive for MMP-2 and -9 by IHC: B>C>A. In conclusion, berberine demonstrated in vitro an inhibitory effect on P.g. LPS-enhanced MMP activities of HGF and U937 macrophages, reducing in vivo gingival tissue degradation in periodontitic rats. We thus propose that berberine may slow periodontal degradation through the regulation of MMPs in periodontitis induced by bacterial plaque.
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http://dx.doi.org/10.1016/j.phymed.2013.06.001DOI Listing
October 2013
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