Publications by authors named "Yaping Pan"

98 Publications

lipopolysaccharide induced RIPK3/MLKL-mediated necroptosis of oral epithelial cells and the further regulation in macrophage activation.

J Oral Microbiol 2022 27;14(1):2041790. Epub 2022 Feb 27.

Department of Oral Pathology, China Medical University School of Stomatology, Shenyang, China.

Necroptosis, a new type of regulated cell death with massive release of damage-associated molecular patterns (DAMPs), is involved in the pathogenesis of periodontitis. However, the role of necroptosis in oral epithelial cells and the following effect on macrophages activation remain unknown. Human immortalized oral epithelial cells were stimulated with lipopolysaccharide (LPS). Cell death was assessed while expressions of RIPK3/MLKL and toll-like receptors (TLRs) were evaluated. Necrosulfonamide (NSA), an inhibitor of MLKL was applied to block necroptosis. The expression of DAMPs and the epithelial connection protein were evaluated by qPCR and immunofluorescence, respectively. Immortalized human monocytes U937 were induced into the M0 or M2 subset, and influences of HIOECs-derived DAMPs on macrophage polarization as well as activation of the Mincle/SYK axis were assessed. LPS could be recognized by TLR2 and regulates necroptosis of HIOECs by activating RIPK3/MLKL. NSA inhibited cell death of HIOECs, alleviated impaired epithelial connection, and inhibited expressions of DAMPs. Low dose of DAMPs derived from HIOECs promoted M2-like polarization by activating the Mincle/SYK axis, which was significantly suppressed with increased doses of DAMPs. LPS destructed oral epithelial cells via RIPK3/MLKL-mediated necroptosis, which further regulated macrophage activation via DAMPs from oral epithelial cells.
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http://dx.doi.org/10.1080/20002297.2022.2041790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8890547PMC
February 2022

Butyrate promotes oral squamous cell carcinoma cells migration, invasion and epithelial-mesenchymal transition.

PeerJ 2022 22;10:e12991. Epub 2022 Feb 22.

Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, China.

Background: Oral squamous cell carcinoma (OSCC), the most common type of primary malignant tumor in the oral cavity, is a lethal disease with high recurrence and mortality rates. Butyrate, a metabolite produced by periodontal pathogens, has been linked to oral diseases. The purpose of this study was to evaluate the effect of sodium butyrate (NaB) on the proliferation, migration, and invasion of OSCC cells and to explore the potential mechanism.

Methods: Two OSCC cell lines (HSC-4 and SCC-9) were treated with NaB at different concentrations. The cell proliferation was assayed by CCK-8, ethylene deoxyuridine (EdU), and flow cytometry. Wound healing and transwell assay were performed to detect cell migration and invasion. Changes in epithelial-mesenchymal transition (EMT) markers, including E-cadherin, Vimentin, and SNAI1, were evaluated by quantitative real-time PCR (qRT-PCR), western blot, and immunofluorescent staining. The expression levels of matrix metalloproteinases (MMPs) were analyzed by qRT-PCR and gelatin zymography.

Results: Our results showed that NaB inhibited the proliferation of OSCC cells and induced cell cycle arrest at G1 phase, but NaB significantly enhanced cell migration and invasion compared with the control group. Further mechanistic investigation demonstrated that NaB induced EMT by increasing the expression of Vimentin and SNAI1, decreasing the expression of membrane-bound E-cadherin, and correspondingly promoting E-cadherin translocation from the membrane to the cytoplasm. In addition, the overexpression of MMP1/2/9/13 was closely related to NaB treatment.

Conclusions: Our study conclude that butyrate may promote the migration and invasion of OSCC cells by inducing EMT. These findings indicate that butyrate may contribute to OSCC metastasis.
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http://dx.doi.org/10.7717/peerj.12991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8877342PMC
February 2022

Motivations and future plans of the final year students in a Chinese dental school.

BMC Med Educ 2022 Feb 9;22(1):90. Epub 2022 Feb 9.

Department of Periodontics, School of Stomatology, China Medical University, Shenyang City, Liaoning province, China.

Background: Understanding dental students' future career choice and motivation could provide beneficial references for both educators and students, but there were few studies on students in a Chinese dental school. The study aimed to investigate Chinese final year dental students' the short-term and long-term plans, motivations, and identify the influence of gender on the future plans.

Methods: A total of 265 final year dental school students of the School of Stomatology, China Medical University from 2016 through 2020 were invited to complete an anonymous, 27-item questionnaire. Moreover, almost all of questions were in multiple-choice formats. Data were categorized and analysed using chi-square comparative analyses.

Results: 88.3% of respondents decided to pursue a graduate degree after graduating from dental school. Moreover, the single most important reason influencing their plans was "eligible for better jobs" (42.8%). More females than males studied dentistry (222 vs 111), and gender had an influence on the choice of specialty.

Conclusions: This study listed the selection tendency and influencing factors of students in a Chinese dental school for the reference of educators and students. And the results could raise some useful influence and feedback effect on current health and education policy, and on the career development of practicing dentists or dental students.
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http://dx.doi.org/10.1186/s12909-022-03156-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8829983PMC
February 2022

Role of PG0192 and PG0193 in the modulation of pro-inflammatory cytokines in macrophages in response to Porphyromonas gingivalis.

Eur J Oral Sci 2022 04 20;130(2):e12851. Epub 2022 Jan 20.

Department of Periodontology, School of Stomatology, China Medical University, Shenyang, Liaoning Province, China.

Porphyromonas gingivalis is the main pathogen of chronic periodontitis. However, the specific mechanisms through which P. gingivalis induces immune and inflammatory responses in periodontitis have not been completely elucidated. In this study, we investigated the effects of the P. gingivalis outer membrane protein OmpH (encoded by PG0192 and PG0193) on interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) expression in macrophages to assess the pro-inflammatory cytokine responses. A PG0192-PG0193 deletion mutant strain and a com△PG0192-0193 strain were constructed. Furthermore, rOmpH-1 and rOmpH-2 encoded by PG0192 and PG0193, respectively, were cloned, expressed, and purified for subsequent experiments. Notably, the expression of IL-6 and TNF-α at mRNA and protein levels was downregulated upon treatment of macrophages with the PG0192-PG0193 deletion mutant strain, whereas treatment of macrophages with P. gingivalis W83 co-incubated with rOmpH-1 or rOmpH-2 upregulated IL-6 and TNF-α mRNA levels. The addition of C5aR antagonist blocked this induction. Overall, our findings provided important insights into the roles of PG0192 and PG0193 for promoting IL-6 and TNF-α expression in macrophages exposed to P. gingivalis and revealed the involvement of C5aR in the pro-inflammatory response.
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http://dx.doi.org/10.1111/eos.12851DOI Listing
April 2022

Correction to: Porphyromonas gingivalis infection promotes mitochondrial dysfunction through Drp1-dependent mitochondrial fission in endothelial cells.

Int J Oral Sci 2022 Jan 12;14(1). Epub 2022 Jan 12.

Department of Periodontics and Oral Biology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, China.

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http://dx.doi.org/10.1038/s41368-021-00153-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755809PMC
January 2022

Porphyromonas gingivalis exacerbates ulcerative colitis via Porphyromonas gingivalis peptidylarginine deiminase.

Int J Oral Sci 2021 09 30;13(1):31. Epub 2021 Sep 30.

Department of Periodontology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China.

Ulcerative Colitis (UC) has been reported to be related to Porphyromonas gingivalis (P. gingivalis). Porphyromonas gingivalis peptidylarginine deiminase (PPAD), a virulence factor released by P. gingivalis, is known to induce inflammatory responses. To explore the pathological relationships between PPAD and UC, we used homologous recombination technology to construct a P. gingivalis strain in which the PPAD gene was deleted (Δppad) and a Δppad strain in which the PPAD gene was restored (comΔppad). C57BL/6 mice were orally gavaged with saline, P. gingivalis, Δppad, or comΔppad twice a week for the entire 40 days (days 0-40), and then, UC was induced by dextran sodium sulfate (DSS) solution for 10 days (days 31-40). P. gingivalis and comΔppad exacerbated DDS-induced colitis, which was determined by assessing the parameters of colon length, disease activity index, and histological activity index, but Δppad failed to exacerbate DDS-induced colitis. Flow cytometry and ELISA revealed that compared with Δppad, P. gingivalis, and comΔppad increased T helper 17 (Th17) cell numbers and interleukin (IL)-17 production but decreased regulatory T cells (Tregs) numbers and IL-10 production in the spleens of mice with UC. We also cocultured P. gingivalis, Δppad, or comΔppad with T lymphocytes in vitro and found that P. gingivalis and comΔppad significantly increased Th17 cell numbers and decreased Treg cell numbers. Immunofluorescence staining of colon tissue paraffin sections also confirmed these results. The results suggested that P. gingivalis exacerbated the severity of UC in part via PPAD.
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http://dx.doi.org/10.1038/s41368-021-00136-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484350PMC
September 2021

Porphyromonas gingivalis infection promotes mitochondrial dysfunction through Drp1-dependent mitochondrial fission in endothelial cells.

Int J Oral Sci 2021 09 3;13(1):28. Epub 2021 Sep 3.

Department of Periodontics and Oral Biology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, China.

Porphyromonas gingivalis (P. gingivalis), a key pathogen in periodontitis, has been shown to accelerate the progression of atherosclerosis (AS). However, the definite mechanisms remain elusive. Emerging evidence supports an association between mitochondrial dysfunction and AS. In our study, the impact of P. gingivalis on mitochondrial dysfunction and the potential mechanism were investigated. The mitochondrial morphology of EA.hy926 cells infected with P. gingivalis was assessed by transmission electron microscopy, mitochondrial staining, and quantitative analysis of the mitochondrial network. Fluorescence staining and flow cytometry analysis were performed to determine mitochondrial reactive oxygen species (mtROS) and mitochondrial membrane potential (MMP) levels. Cellular ATP production was examined by a luminescence assay kit. The expression of key fusion and fission proteins was evaluated by western blot and immunofluorescence. Mdivi-1, a specific Drp1 inhibitor, was used to elucidate the role of Drp1 in mitochondrial dysfunction. Our findings showed that P. gingivalis infection induced mitochondrial fragmentation, increased the mtROS levels, and decreased the MMP and ATP concentration in vascular endothelial cells. We observed upregulation of Drp1 (Ser616) phosphorylation and translocation of Drp1 to mitochondria. Mdivi-1 blocked the mitochondrial fragmentation and dysfunction induced by P. gingivalis. Collectively, these results revealed that P. gingivalis infection promoted mitochondrial fragmentation and dysfunction, which was dependent on Drp1. Mitochondrial dysfunction may represent the mechanism by which P. gingivalis exacerbates atherosclerotic lesions.
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http://dx.doi.org/10.1038/s41368-021-00134-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413291PMC
September 2021

Porphyromonas gingivalis outer membrane vesicles inhibit the invasion of Fusobacterium nucleatum into oral epithelial cells by downregulating FadA and FomA.

J Periodontol 2022 Apr 5;93(4):515-525. Epub 2021 Oct 5.

Department of Periodontics, Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, China.

Background: Porphyromonas gingivalis (P. gingivalis) and Fusobacterium nucleatum (F. nucleatum) participate in the formation and progression of periodontitis. They can exert virulence by invading into host cells, but the interaction between them and their specific mechanisms remain unclear. The purpose of this study was to study the effect of P. gingivalis outer membrane vesicles (OMVs) on the ability of F. nucleatum to invade oral epithelial cells, and the reasons for the influence.

Methods: The invasion abilities of the two bacteria were detected separately after mixed infection of P. gingivalis and F. nucleatum. Next, P. gingivalis OMVs were extracted with the kit, and their influence on the invasion ability of F. nucleatum was tested. The effects of P. gingivalis OMVs on F. nucleatum were evaluated by assessment of bacterial morphology, growth curves, auto-aggregation morphology, and the expression of adhesion-related proteins FadA and FomA.

Results: Our results showed that P. gingivalis inhibited the invasion of F. nucleatum into oral epithelial cells but F. nucleatum promoted the invasion of P. gingivalis. In subsequent experiments, we extracted P. gingivalis OMVs successfully and revealed that proteases in P. gingivalis OMVs inhibited the invasion of F. nucleatum into oral epithelial cells. Furthermore, P. gingivalis OMVs did not affect the morphology and proliferation of F. nucleatum, but proteases inside decreased the auto-aggregation of F. nucleatum. Additionally, proteases in P. gingivalis OMVs reduced the expression levels of F. nucleatum surface adhesion-related proteins FadA and FomA.

Conclusion: Our study demonstrated that proteases in P. gingivalis OMVs inhibited the invasion of F. nucleatum into oral epithelial cells by downregulating FadA and FomA.
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http://dx.doi.org/10.1002/JPER.21-0144DOI Listing
April 2022

Effect of molecular weight on the antibacterial activity of polysaccharides produced by Chaetomium globosum CGMCC 6882.

Int J Biol Macromol 2021 Oct 14;188:863-869. Epub 2021 Aug 14.

College of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China.

This study investigated the effect of molecular weight on antibacterial activity of polysaccharides. Results showed that low molecular weight (3.105 × 10 Da) polysaccharide (GCP-2) had higher inhibitory effects against Escherichia coli and Staphylococcus aureus than high molecular weight (5.340 × 10 Da) polysaccharide (GCP-1). Meanwhile, antibacterial activities of GCP-2 and GCP-1 against S. aureus were higher than those of E. coli. Minimum inhibitory concentrations (MICs) of GCP-1 against E. coli and S. aureus were 2.0 mg/mL and 1.2 mg/mL, and MICs of GCP-2 against E. coli and S. aureus were 1.75 mg/mL and 0.85 mg/mL, respectively. Antibacterial mechanisms investigation revealed that GCP-2 and GCP-1 influenced cell membrane integrity, Ca-Mg-ATPase activity on cell membrane and calcium ions in cytoplasm of E. coli and S. aureus, but not cell wall. Present work provided important implications for future studies on development of antibacterial polysaccharides based on molecular weight feature.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.08.059DOI Listing
October 2021

Temperature mediates metabolism switching of Bacillus sp. ZT-1: Analysis of the properties and structure of exopolysaccharides.

Microbiol Res 2021 Oct 5;251:126839. Epub 2021 Aug 5.

Frontiers Science Center for Deep Ocean Multispheres and Earth System, and Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, Ocean University of China, Qingdao, 266100, China; College of Chemistry & Chemical Engineering, Ocean University of China, Qingdao, 266100, China.

Microorganism was very sensitive to external temperature change, which also affected its normal metabolism and secretion. Low temperature exopolysaccharides (LT-EPS) and normal temperature exopolysaccharides (NT-EPS) secreted by Bacillus sp. ZT-1 mediated by temperature were studied in this paper. The total carbohydrate in the LT-EPS and NT-EPS were found to be 82.54 ± 2.56 % and 94.23 ± 1.59 % (w/w). The High Performance Liquid Chromatography (HPLC) revealed the mannose and galacturonic acid accounted for 45.52 and 23.49 % in LT-EPS, respectively. In like manner, mannose and galacturonic acid contained 43.99 and 25.24 % in NT-EPS. One-dimensional nuclear magnetic resonance (NMR) revealed the connection mode of sugar chains. NT-EPS exhibited higher viscosity, better emulsification properties and the larger molecular weight than LT-EPS. Scanning electron microscopy (SEM) showed that LT-EPS was sheet-like with sugar chain branches while NT-EPS was showed as network structure. Furthermore, the 2812 differentially expressed genes (DEGs) were analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and located 739 biological pathways. Finally, transcriptome analysis revealed differences in gene expression of the pentose phosphate pathway of carbohydrate metabolism might be the main reason for this difference.
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http://dx.doi.org/10.1016/j.micres.2021.126839DOI Listing
October 2021

Porphyromonas gingivalis survival skills: Immune evasion.

J Periodontal Res 2021 Dec 13;56(6):1007-1018. Epub 2021 Jul 13.

Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, China.

Periodontitis is a chronic inflammatory condition that destroys the tooth-supporting tissues and eventually leads to tooth loss. As one of the most prevalent oral conditions, periodontitis endangers the oral health of 70% of people throughout the world. Periodontitis is also related to various systemic diseases, such as diabetes mellitus, atherosclerosis, and rheumatoid arthritis, which not only has a great impact on population health status and the quality of life but also increases the social burden. Porphyromonas gingivalis (P. gingivalis) is a gram-negative oral anaerobic bacterium that plays a key role in the pathogenesis of periodontitis. Porphyromonas gingivalis can express various of virulence factors to overturn innate and adaptive immunities, which makes P. gingivalis survive and propagate in the host, destroy periodontal tissues, and have connection to systemic diseases. Porphyromonas gingivalis can invade into and survive in host tissues by destructing the gingival epithelial barrier, internalizing into the epithelial cells, and enhancing autophagy in epithelial cells. Deregulation of complement system, degradation of antibacterial peptides, and destruction of phagocyte functions facilitate the evasion of P. gingivalis. Porphyromonas gingivalis can also suppress adaptive immunity, which allows P. gingivalis to exist in the host tissues and cause the inflammatory response persistently. Here, we review studies devoted to understanding the strategies utilized by P. gingivalis to escape host immunity. Methods for impairing P. gingivalis immune evasion are also mentioned.
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http://dx.doi.org/10.1111/jre.12915DOI Listing
December 2021

Clinical diagnosis and treatment of common respiratory tract infections in relation to microbiological profiles in rural health facilities in China: implications for antibiotic stewardship.

BMC Fam Pract 2021 05 6;22(1):87. Epub 2021 May 6.

School, of Public Health, Anhui Medical University, Hefei, Anhui, China.

Background: This paper tries to describe prevalence and patterns of antibiotics prescription and bacteria detection and sensitivity to antibiotics in rural China and implications for future antibiotic stewardship.

Methods: The study was implemented in one village clinic and one township health center in each of four rural residential areas in Anhui Province, China. It used mixed-methods comprising non-participative observations, exit-survey and microbiological study. Observations were conducted to record clinical diagnosis and antibiotic prescription. Semi-structured questionnaire survey was used to collect patient's sociodemographic information and symptoms. Sputum and throat swabs were collected for bacterial culture and susceptibility testing.

Results: A total of 1068 (51.0% male vs 49.0% female) patients completed the study with diagnosis of respiratory tract infection (326,30.5%), bronchitis/tracheitis (249,23.3%), pharyngitis (119,11.1%) and others (374, 35.0%). They provided 683 sputum and 385 throat swab specimens. Antibiotics were prescribed for 88% of the RTI patients. Of all the specimens tested, 329 (31%) were isolated with bacteria. The most frequently detected bacteria were K. pneumonia (24% in all specimens), H. influenza (16%), H. parainfluenzae (15%), P. aeruginosa (6%), S.aureus (5%), M. catarrhalis (3%) and S. pneumoniae (2%).

Conclusions: The study establishes the feasibility of conducting microbiological testing outside Tier 2 and 3 hospitals in rural China. It reveals that prescription of antibiotics, especially broad-spectrum and combined antibiotics, is still very common and there is a clear need for stewardship programs aimed at both reducing the number of prescriptions and promoting single and narrow-spectrum antibiotics.
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http://dx.doi.org/10.1186/s12875-021-01448-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103749PMC
May 2021

Oral Pathogen Coaggregates With to Modulate the Inflammatory Cytotoxicity of Pulmonary Epithelial Cells.

Front Cell Infect Microbiol 2021 19;11:643913. Epub 2021 Mar 19.

Liaoning Provincial Key Laboratory of Oral Diseases, Department of Oral Biology, School and Hospital of Stomatology, China Medical University, Shenyang, China.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality worldwide, and inflammatory damage induced by bacterial infections is an important contributor to the etiology of COPD. , a recognized periodontal pathogen, is considered as a biomarker of lung function deterioration of COPD patients coinfected with , but the underlying mechanism is still unclear. This study established single- and dual-species infection models, bacterial simultaneous and sequential infection models, and found that could coaggregate with to synergistically invade into pulmonary epithelial cells and transiently resist -induced cytotoxic damage to amplify IL-6 and TNF-α associated inflammation in pulmonary epithelial cells simultaneously infected with and . Furthermore, pretreatment or subsequential infection could maintain or even aggravate -induced inflammatory cytotoxicity of pulmonary epithelial cells. These results indicate that oral pathogen coaggregates with to facilitate bacterial invasion and modulates the inflammatory cytotoxicity of pulmonary epithelial cells, which may contribute to lung function deterioration of COPD patients accompanied with and coinfection.
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http://dx.doi.org/10.3389/fcimb.2021.643913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017200PMC
July 2021

sRNA23392 packaged by Porphyromonas gingivalis outer membrane vesicles promotes oral squamous cell carcinomas migration and invasion by targeting desmocollin-2.

Mol Oral Microbiol 2021 06 4;36(3):182-191. Epub 2021 Apr 4.

Department of Periodontics, School and Hospital of Stomatology, Liaoning Provincial Key Laboratory of Oral Diseases, China Medical University, Shenyang, Liaoning, China.

Oral squamous cell carcinoma (OSCC) is the most common head and neck malignant tumor. Periodontitis, a common chronic inflammatory disease, has been proven to increase the risk of oral cancers. Porphyromonas gingivalis (P. gingivalis), the major pathogen in periodontal disease, was recently shown to promote the development of OSCC. However, the underlying mechanisms have not been defined. Emerging evidence suggests that P. gingivalis outer membrane vesicles (OMVs) contain different packaged small RNAs (sRNAs) with the potential to target host mRNA function and/or stability. In this study, we found that P. gingivalis OMVs promote the invasion and migration of OSCC cells in vitro. Further research showed that sRNA23392 was abundant in P. gingivalis OMVs and it promoted the invasion and migration of OSCC cells by targeting desmocollin-2 (DSC2). DSC2, a desmosomal cadherin family member, has been found to be involved in tumor progression. sRNA23392 inhibitors attenuated P. gingivalis OMV-induced migration and invasion of OSCC cells. Collectively, these findings are consistent with the hypothesis that sRNA23392 in P. gingivalis OMVs is a novel mechanism of the host-pathogen interaction, whereby P. gingivalis promotes the invasion and migration of OSCC.
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http://dx.doi.org/10.1111/omi.12334DOI Listing
June 2021

The Role of Outer Membrane Vesicles in Periodontal Disease and Related Systemic Diseases.

Front Cell Infect Microbiol 2020 28;10:585917. Epub 2021 Jan 28.

Department of Periodontics, Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, China.

Periodontal disease is a chronic infectious disease associated with a variety of bacteria, which can cause damage to the periodontal support structure and affect a variety of systemic system diseases such as cancer, cardiovascular disease, diabetes, rheumatoid arthritis, non-alcoholic fatty liver, and Alzheimer's disease. () is the most important pathogenic bacteria for periodontal disease. It can produce outer membrane vesicles (OMVs) and release them into the environment, playing an important role in its pathogenesis. This article focuses on OMVs, reviews its production and regulation, virulence components, mode of action and related diseases, with a view to providing new ideas for the prevention and treatment of diseases related to infections.
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http://dx.doi.org/10.3389/fcimb.2020.585917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877337PMC
June 2021

Analysis of differentially expressed genes in oral epithelial cells infected with Fusobacterium nucleatum for revealing genes associated with oral cancer.

J Cell Mol Med 2021 01 2;25(2):892-904. Epub 2020 Dec 2.

Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China.

Accumulating evidence links Fusobacterium nucleatum with tumorigenesis. Our previous study demonstrated that F. nucleatum infection can induce epithelial-mesenchymal transition (EMT) in oral epithelial cells and elaborated a probable signal pathway involved in the induction of EMT. However, the comprehensive profiling and pathways of other candidate genes involved in F. nucleatum promoting malignant transformation remain largely elusive. Here, we analysed the transcriptome profile of HIOECs exposed to F. nucleatum infection. Totally, 3307 mRNAs (ǀLog2FCǀ >1.5) and 522 lncRNAs (ǀLog2FCǀ >1) were identified to be differentially expressed in F. nucleatum-infected HIOECs compared with non-infected HIOECs. GO and KEGG pathway analyses were performed to investigate the potential functions of the dysregulated genes. Tumour-associated genes were integrated, and top 10 hub genes (FYN, RAF1, ATM, FOS, CREB, NCOA3, VEGFA, JAK2, CREM and ATF3) were identified by protein-protein interaction (PPI) network, and Oncomine was used to validate hub genes' expression. LncRNA-hub genes co-expression network comprising 67 dysregulated lncRNAs were generated. Together, our study revealed the alteration of lncRNA and potential hub genes in oral epithelial cells in response to F. nucleatum infection, which may provide new insights into the shift of normal to malignant transformation initiated by oral bacterial infection.
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http://dx.doi.org/10.1111/jcmm.16142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812288PMC
January 2021

LL-37-Induced Autophagy Contributed to the Elimination of Live Internalized in Keratinocytes.

Front Cell Infect Microbiol 2020 15;10:561761. Epub 2020 Oct 15.

Department of Periodontology, School and Hospital of Stomatology, China Medical University, Shenyang, China.

(), one of the most important pathogens of periodontitis, is closely associated with the aggravation and recurrence of periodontitis and systemic diseases. Antibacterial peptide LL-37, transcribed from the cathelicidin antimicrobial peptide () gene, exhibits a broad spectrum of antibacterial activity and regulates the immune system. In this study, we demonstrated that LL-37 reduced the number of live (ATCC 33277) in HaCaT cells in a dose-dependent manner via an antibiotic-protection assay. LL-37 promoted autophagy of HaCaT cells internalized with . Inhibition of autophagy with 3-methyladenine (3-MA) weakened the inhibitory effect of LL-37 on the number of intracellular . A cluster of orthologous groups (COGs) and a gene ontology (GO) functional analysis were used to individually assign 65 (10%) differentially expressed genes (DEGs) to an "Intracellular trafficking, secretion, and vesicular transport" cluster and 306 (47.08%) DEGs to metabolic processes including autophagy. Autophagy-related genes, a tripartite motif-containing 22 (), and lysosomal-associated membrane protein 3 () were identified as potentially involved in LL-37-induced autophagy. Finally, bioinformatics software was utilized to construct and predict the protein-protein interaction (PPI) network of CAMP-TRIM22/LAMP3-Autophagy. The findings indicated that LL-37 can reduce the quantity of live internalized in HaCaT cells by promoting autophagy in these cells. The transcriptome sequencing and analysis also revealed the potential molecular pathway of LL-37-induced autophagy.
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http://dx.doi.org/10.3389/fcimb.2020.561761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593823PMC
June 2021

Structural basis of ion transport and inhibition in ferroportin.

Nat Commun 2020 11 10;11(1):5686. Epub 2020 Nov 10.

Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.

Ferroportin is an iron exporter essential for releasing cellular iron into circulation. Ferroportin is inhibited by a peptide hormone, hepcidin. In humans, mutations in ferroportin lead to ferroportin diseases that are often associated with accumulation of iron in macrophages and symptoms of iron deficiency anemia. Here we present the structures of the ferroportin from the primate Philippine tarsier (TsFpn) in the presence and absence of hepcidin solved by cryo-electron microscopy. TsFpn is composed of two domains resembling a clamshell and the structure defines two metal ion binding sites, one in each domain. Both structures are in an outward-facing conformation, and hepcidin binds between the two domains and reaches one of the ion binding sites. Functional studies show that TsFpn is an electroneutral H/Fe antiporter so that transport of each Fe is coupled to transport of two H in the opposite direction. Perturbing either of the ion binding sites compromises the coupled transport of H and Fe. These results establish the structural basis of metal ion binding, transport and inhibition in ferroportin and provide a blueprint for targeting ferroportin in pharmacological intervention of ferroportin diseases.
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http://dx.doi.org/10.1038/s41467-020-19458-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655804PMC
November 2020

An Antibacterial Strategy of Mg-Cu Bone Grafting in Infection-Mediated Periodontics.

Biomed Res Int 2020 28;2020:7289208. Epub 2020 Aug 28.

Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, Shenyang, Liaoning 110002, China.

Periodontal diseases are mainly the results of infections and inflammation of the gum and bone that surround and support the teeth. In this study, the alveolar bone destruction in periodontitis is hypothesized to be treated with novel Mg-Cu alloy grafts due to their antimicrobial and osteopromotive properties. In order to study this new strategy using Mg-Cu alloy grafts as a periodontal bone substitute, the degradation and antibacterial performance were examined. The pH variation and Mg and Cu release of Mg-Cu alloy extracts were measured. () and (), two common bacteria associated with periodontal disease, were cultured in Mg-Cu alloy extracts, and bacterial survival rate was evaluated. The changes of bacterial biofilm and its structure were revealed by scanning electron microscopy (SEM) and transmission electronic microscopy (TEM), respectively. The results showed that the Mg-Cu alloy could significantly decrease the survival rates of both and . Furthermore, the bacterial biofilms were completely destroyed in Mg-Cu alloy extracts, and the bacterial cell membranes were damaged, finally leading to bacterial apoptosis. These results indicate that the Mg-Cu alloy can effectively eliminate periodontal pathogens, and the use of Mg-Cu in periodontal bone grafts has a great potential to prevent infections after periodontal surgery.
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http://dx.doi.org/10.1155/2020/7289208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474743PMC
April 2021

The sialidase inhibitor, DANA, reduces Porphyromonas gingivalis pathogenicity and exerts anti-inflammatory effects: An in vitro and in vivo experiment.

J Periodontol 2021 02 21;92(2):286-297. Epub 2020 Jul 21.

School and Hospital of Stomatology, China Medical University, Shenyang, Liaoning, China.

Background: Sialidase has an important role in the pathogenesis of periodontitis and Porphyromonas gingivalis is a sialidase-producing organism implicated in periodontitis development. The aim of this study was to evaluate the anti-virulence and anti-inflammatory properties of the sialidase inhibitor, 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA), in vitro and in vivo.

Methods: The effects of DANA on P. gingivalis sialidase and cell viability were determined, and the effects of DANA on P. gingivalis virulence were evaluated by assessment of growth curves, cell morphology, biofilm formation, fimbriae gene expression, and gingipains and lipopolysaccharide (LPS) activity. Anti-inflammatory effects of DANA on LPS-induced macrophages were assessed by measurement of tumor necrosis factor-alpha (TNF-α), interleukin (IL-1β), inducible nitric oxide synthase (iNOS) secretions. The effect of DANA on P. gingivalis-induced periodontitis in rats was analyzed by radiography, stereoscopic microscopy, histopathology, and immunohistochemistry.

Results: Sialidase inhibition rate of 1mM DANA was 72.01%. Compared with untreated controls, treatment with DANA inhibited P. gingivalis growth and biofilm formation, and significantly decreased expression of the fimA, fimR, and fimS genes, as well as gingipains activity. DANA did not influence macrophage viability, but significantly inhibited TNF-α, IL-1β, and iNOS production in LPS-stimulated macrophages. In the periodontitis rat model, DANA prevented alveolar bone absorption and inhibited TNF-α and IL-1β production.

Conclusion: DANA can reduce the growth, the biofilm formation and the virulence of P. gingivalis and exhibits anti-inflammatory effects, as well as effects against rat periodontitis, suggesting that DANA should be considered for development as a new adjunctive treatment for periodontitis.
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http://dx.doi.org/10.1002/JPER.19-0688DOI Listing
February 2021

Mechanism of ligand activation of a eukaryotic cyclic nucleotide-gated channel.

Nat Struct Mol Biol 2020 07 1;27(7):625-634. Epub 2020 Jun 1.

Department of Biological Sciences, Columbia University, New York, NY, USA.

Cyclic nucleotide-gated (CNG) channels convert cyclic nucleotide (CN) binding and unbinding into electrical signals in sensory receptors and neurons. The molecular conformational changes underpinning ligand activation are largely undefined. We report both closed- and open-state atomic cryo-EM structures of a full-length Caenorhabditis elegans cyclic GMP-activated channel TAX-4, reconstituted in lipid nanodiscs. These structures, together with computational and functional analyses and a mutant channel structure, reveal a double-barrier hydrophobic gate formed by two S6 amino acids in the central cavity. cGMP binding produces global conformational changes that open the cavity gate located ~52 Å away but do not alter the structure of the selectivity filter-the commonly presumed activation gate. Our work provides mechanistic insights into the allosteric gating and regulation of CN-gated and nucleotide-modulated channels and CNG channel-related channelopathies.
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http://dx.doi.org/10.1038/s41594-020-0433-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354226PMC
July 2020

Periodontal disease and Helicobacter pylori infection in oral cavity: a meta-analysis of 2727 participants mainly based on Asian studies.

Clin Oral Investig 2020 Jul 30;24(7):2175-2188. Epub 2020 May 30.

Department of Periodontics and Oral Biology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Heping Distrct, Nanjing North Street No.117, Shenyang, 110002, China.

Objectives: To assess the association between periodontal disease and Helicobacter pylori (H. pylori) infection in oral cavity.

Materials And Methods: We searched PubMed, Embase, Web of Science, Cochrane library, Gray literature, and clinicaltrials.gov for eligible studies up to September 25, 2019. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The random-effects model was used with the software STATA 13.0. The Newcastle-Ottawa-Scale was used for quality evaluation.

Results: Twelve observational studies (eight from Asia, one from Europe, and three from the South America) involving 2727 participants were included in the meta-analysis. The overall pooled results showed that H. pylori infection in oral cavity was associated with periodontal disease (OR 2.53, 95% CI 1.86-3.44, P < 0.05). No significant heterogeneity among the articles was observed (I = 44.3%, P < 0.05). The sensitivity analysis indicated that the result of our meta-analysis was generally stable. The Begg test and the Egger test both showed no publication bias was observed (P = 0.45 and P = 0.18 respectively).

Conclusions: Based on current available evidence, it seemed there was a correlation between oral H. pylori infection and the occurrence of periodontal disease. However, since most of the data comes from Asia, more large-scale investigations with high quality from all over the world are needed to confirm the association.

Clinical Relevance: H. pylori infection in oral may have a positive association with the prevalence of periodontal disease mainly in Asian populations.
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http://dx.doi.org/10.1007/s00784-020-03330-4DOI Listing
July 2020

Intracellular Ca signaling mediates IGF-1-induced osteogenic differentiation in bone marrow mesenchymal stem cells.

Biochem Biophys Res Commun 2020 06 30;527(1):200-206. Epub 2020 Apr 30.

Department of Periodontics, School of Stomatology, China Medical University, Liaoning Province, China. Electronic address:

Insulin-like growth factor 1 (IGF-1), a multifunctional peptide that involves in cell proliferation and differentiation, can induce strong osteogenic differentiation in bone marrow mesenchymal stem cells (BMMSCs). However, it remains unknown whether intracellular Ca signal contributes to the IGF-1-induced osteogenic differentiation of BMMSCs. In this study, we attempted to investigate the effect of IGF-1 on the gene expression of intracellular Ca-handling proteins and figure out whether the intracellular Ca signal affects IGF-1-induced osteogenic differentiation. We found that IGF-1 treatment significantly increased cell proliferation and induced cell morphological changes with an increase of cell surface area. Quantitative PCR and Western blot analysis showed that osteoblast marker proteins, including alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2) and osteocalcin (OCN) were significantly upregulated by IGF-1 treatment, indicating IGF-1 induced osteogenic differentiation in BMMSCs. Interestingly, the expression levels of the sarco/endoplasmic reticulum Ca-ATPase (SERCA) 3 and inositol-1,4,5-triphosphate receptor (IPR) 2 were dramatically elevated during the IGF-1-induced osteogenic differentiation. Consistently, IGF-1-treated cells exhibited greater Ca response to ATP. Importantly, blocking SERCA by thapsigargin markedly impaired IGF-1-induced osteogenic differentiation, indicating that intracellular Ca mediated IGF-1-induced osteogenic differentiation in BMMSCs, probably via Akt signal pathway, which may provide new insight for the treatment of osteoporosis.
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http://dx.doi.org/10.1016/j.bbrc.2020.04.048DOI Listing
June 2020

Composition and function of oral microbiota between gingival squamous cell carcinoma and periodontitis.

Oral Oncol 2020 08 3;107:104710. Epub 2020 May 3.

Department of Periodontology, School of Stomatology, China Medical University, Shenyang, China. Electronic address:

Objectives: Previous studies have proved that periodontitis is an independent risk factor of oral squamous cell carcinoma (OSCC) epidemiologically. Along with the important role of microbiota in the cancer process and the specific anatomical position, our study explored the microbial composition and functions in periodontitis and gingival squamous cell carcinoma (GSCC).

Materials And Methods: GSCC patients (n = 10), matched periodontitis patients (n = 15), and healthy individuals (n = 15) were recruited. Saliva, subgingival plaque, tongue dorsum, buccal mucosa, cancerous tissue, and paracancerous tissue samples were collected. 16S rDNA amplicon sequencing and functional prediction were applied for the taxonomic analysis.

Results: Periodontal pathogens occupied 46% in GSCC. Besides, the mutual operational taxonomy unites (OTU) generated from the subgingival plaque occupied 38.36% and 44.13% from saliva. Fusobacterium, Peptostreptococcus, and Prevotella were more abundant in cancerous tissues, while Streptococcus, Neisseria, and Haemophilus were more enriched in saliva or soft mucosa. PCoA exhibited similar cluster between tongue dorsum and saliva in GSCC. GSCC showed lower richness than periodontitis. In saliva and subgingival plaque, Atopobium was more prevalent in GSCC than periodontitis and controls in descending order. Lipopolysaccharide (LPS) biosynthesis increased in subgingival plaque of GSCC compared with the other two groups.

Conclusion: Periodontal pathogens were abundant in GSCC. Cancerous tissues harbor enriched periodontal pathogens while saliva or soft mucosa harbored more periodontal health related bacteria. A high level of Atopobium in saliva and LPS biosynthesis have the potential for increasing the risk of suffering from GSCC in individuals with periodontitis, which needs more evidence to clarify it.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104710DOI Listing
August 2020

Interaction with Induces Biofilm-Associated Antibiotic Tolerance via Adhesin A.

ACS Infect Dis 2020 07 4;6(7):1686-1696. Epub 2020 May 4.

Liaoning Provincial Key Laboratory of Oral Diseases, Department of Oral Biology, School and Hospital of Stomatology, China Medical University, Nanjing North Street 117, Shenyang, Liaoning 110002, China.

Respiratory infections with or are associated with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and failure in antibiotic treatment. However, the impact of these dual-species interactions on the severity of chronic obstructive pulmonary disease (COPD) and biofilm antibiotic susceptibility remains poorly understood. This study demonstrated that frequently coexisted with in the respiratory tract, and the number of was negatively correlated with the lung function of AECOPD patients. The coculture of and promoted bacterial proliferation and induced antibiotic tolerance through the formation of a dense biofilm surrounded by excessive Pel and Psl polysaccharides. Moreover, adhesin A (FadA), rather than spent medium, induced antibiotic tolerance of the biofilm. These results indicate that is a biomarker of lung function decline in AECOPD patients and interacts with in vitro to resist antibiotics via FadA, which would be a potential anti-infective target of these dual-species infection.
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http://dx.doi.org/10.1021/acsinfecdis.9b00402DOI Listing
July 2020

Reactive oxygen species mediate TNF-α-induced inflammatory response in bone marrow mesenchymal cells.

Iran J Basic Med Sci 2019 Nov;22(11):1296-1301

Department of Periodontics, School of Stomatology, China Medical University, Liaoning Province, China.

Objectives: It is generally believed that the inflammatory response in bone marrow mesenchymal stem cells (BMSCs) transplantation leads to poor survival and unsatisfactory effects, and is mainly mediated by cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α). In this study, we explored the mechanisms underlying the TNF-α-induced inflammatory response in BMSCs.

Materials And Methods: We treated BMSCs with TNF-α (1 and 10 ng/ml) for 5 days. The expression levels of key inflammatory mediators were evaluated by Real-time PCR. Intracellular ROS level was measured by using a 2, 7-dichlorofluorescein diacetate (DCF-DA).

Results: We found that TNF-α treatment dramatically increased the expression levels of some key inflammatory mediators, including IL-6, IL-1β, IFN-γ and transforming growth factor β (TGF-β). Moreover, TNF-α induced intracellular oxidative stress by elevating intracellular reactive oxygen species (ROS) level, which is due to the increase of lipid peroxidation, the reduction of antioxidant Glutathione (GSH) levels and the inhibition of many antioxidant enzyme activities in BMSCs. Interestingly, 5 µM curcumin, a ROS scavenger, dramatically lowered the TNF-α-induced inflammatory response in BMSCs. In addition, TNF-α induced the activation of extracellular-signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK), p38 and their down-stream transcription factors nuclear factor kappa B (NF-κB) pathway.

Conclusion: ROS mediated the TNF-α-induced inflammatory response via MAPK and NF-κB pathway, and may provide a novel strategy to prevent the inflammatory-dependent impairments in BMSCs.
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http://dx.doi.org/10.22038/ijbms.2019.37893.9006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038432PMC
November 2019

The expression of inducible nitric oxide synthase in the gingiva of rats with periodontitis and diabetes mellitus.

Arch Oral Biol 2020 Apr 20;112:104652. Epub 2020 Feb 20.

Department of Periodontics and Oral Biology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Nanjing North Street No. 117, Shenyang, 110002, Liaoning Province, China. Electronic address:

Objective: To ascertain the role of inducible nitric oxide synthase (iNOS) in the periodontitis response during diabetes.

Methods: Twenty-four male SD rats were randomly divided into four groups: control group (Control), diabetes mellitus group (D), diabetes mellitus plus periodontitis group (DP), and periodontitis group (P). Periodontitis and diabetes were established separately. Then the gingival tissue and alveolar bone were collected. A stereomicroscope was used to evaluate bone loss. The expression of iNOS, TNF-α, and NF-κB in the gingiva was detected by immunohistochemical staining, real-time PCR, and western blot analysis.

Results: Significant bone loss was observed in the DP and P groups and more extensive bone resorption was discovered in the DP group than in the P group (P < 0.05). The immunohistochemical staining analysis revealed enhanced expression of iNOS located in the gingiva of the three disease groups compared with the control group (P < 0.05). In particular, the level of iNOS was significantly higher in the DP group than in the P group (P < 0.05). This elevated trend of iNOS was further demonstrated by quantitative PCR and western blot analysis. Similarly, the mRNA and protein expression levels of NF-κB in the D, DP, and P groups were significantly higher than those of the control group, as was the level of TNF-α protein (P < 0.05).

Conclusions: Our results proved diabetes exacerbated alveolar bone resorption in a periodontitis rat model. iNOS may be the inflammatory mediator in the course of periodontal injury promoted by diabetes.
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http://dx.doi.org/10.1016/j.archoralbio.2020.104652DOI Listing
April 2020

Prognostic Factors of Grade 2-3 Endo-Periodontal Lesions Treated Nonsurgically in Patients with Periodontitis: A Retrospective Case-Control Study.

Biomed Res Int 2020 8;2020:1592910. Epub 2020 Feb 8.

School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Disease, No. 117 Nanjing North St., Shenyang 110002, Liaoning Province, China.

Background: Endo-periodontal lesions are bacterial infectious diseases involving both the periodontal and pulp tissues with poor outcomes. It is hard for clinicians to predict their prognosis. The aim of this study is to investigate the factors affecting the prognosis of endo-periodontal lesions.

Methods: A total of 140 teeth diagnosed with grade 2-3 endo-periodontal lesions in patients with periodontitis were recruited in this study. They were divided into high and low responder groups, according to the clinical symptoms and parameters of the teeth involved after nonsurgical treatment of both the endodontic and periodontal components. Clinical parameters and symptoms were compared before and after treatment, and gender, age, smoking, and all clinical parameters were compared between high and low responder groups using univariate analyses. Logistic regression was applied to evaluate the independent effects on endo-periodontal lesion prognosis.

Results: Compared with the clinical parameters at baseline, the values of tooth mobility (TM), periapical index (PAI), and discomfort when chewing were decreased after endodontic therapy, and the values of periodontal probing depth (PD), clinical attachment level (CAL), sulcus bleeding index (SBI), TM, simplified oral hygiene index (OHI-S), full-mouth periodontitis severity, PAI, and discomfort when chewing were decreased after periodontal therapy. Univariate analysis revealed that smoking, PD, CAL, TM, PAI, clinical crown-root ratio (CR), full-mouth periodontitis severities, and the number of root canals were significantly different between the high and low responder groups ( < 0.05). The logistic regression analysis showed that smoking, PD, CAL, full-mouth periodontitis severities, and the number of root canals remained significantly associated with grade 2-3 endo-periodontal lesions in patients with periodontitis ( < 0.05). The logistic regression analysis showed that smoking, PD, CAL, full-mouth periodontitis severities, and the number of root canals remained significantly associated with grade 2-3 endo-periodontal lesions in patients with periodontitis (.

Conclusions: High PD and CAL, multirooted teeth, smoking, and serious full-mouth periodontitis indicated a poor prognosis for teeth with grade 2-3 endo-periodontal lesions.
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http://dx.doi.org/10.1155/2020/1592910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031715PMC
November 2020

Fusobacterium nucleatum promotes epithelial-mesenchymal transiton through regulation of the lncRNA MIR4435-2HG/miR-296-5p/Akt2/SNAI1 signaling pathway.

FEBS J 2020 09 12;287(18):4032-4047. Epub 2020 Feb 12.

Department of Periodontics, School and Hospital of Stomatology, China Medical University, Shenyang, China.

Fusobacterium nucleatum, an anaerobic oral opportunistic pathogen associated with periodontitis, has been considered to be associated with the development of oral squamous cell carcinoma (OSCC). However, the initial host molecular alterations induced by F. nucleatum infection which may promote predisposition to malignant transformation through epithelial-mesenchymal transition (EMT) have not yet been clarified. In the present study, we monitored the ability of F. nucleatum to induce EMT-associated features, and our results showed that F. nucleatum infection promoted cell migration in either noncancerous human immortalized oral epithelial cells (HIOECs) or the two OSCC cell lines SCC-9 and HSC-4, but did not accelerate cell proliferation or cell cycle progression. Mesenchymal markers, including N-cadherin, Vimentin, and SNAI1, were upregulated, while E-cadherin was decreased and was observed to translocate to the cytoplasm. Furthermore, FadA adhesin and heat-inactivated F. nucleatum were found to cause a similar effect as the viable bacterial cells. The upregulated lncRNA MIR4435-2HG identified by the high-throughput sequencing was demonstrated to negatively regulate the expression of miR-296-5p, which was downregulated in F. nucleatum-infected HIOECs and SCC-9 cells. The binding of MIR4435-2HG and miR-296-5p was validated via a dual-luciferase reporter assay. Additionally, knockdown of MIR4435-2HG with siRNA leads to a decrease in SNAI1 expression, while miR-296-5p could further negatively and indirectly regulate SNAI1 expression via Akt2. Therefore, our study demonstrated that F. nucleatum infection could trigger EMT via lncRNA MIR4435-2HG/miR-296-5p/Akt2/SNAI1 signaling pathway, and EMT process may be a probable link between F. nucleatum infection and initiation of oral epithelial carcinomas.
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http://dx.doi.org/10.1111/febs.15233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540502PMC
September 2020

TrkA undergoes a tetramer-to-dimer conversion to open TrkH which enables changes in membrane potential.

Nat Commun 2020 Jan 28;11(1):547. Epub 2020 Jan 28.

Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.

TrkH is a bacterial ion channel implicated in K uptake and pH regulation. TrkH assembles with its regulatory protein, TrkA, which closes the channel when bound to ADP and opens it when bound to ATP. However, it is unknown how nucleotides control the gating of TrkH through TrkA. Here we report the structures of the TrkH-TrkA complex in the presence of ADP or ATP. TrkA forms a tetrameric ring when bound to ADP and constrains TrkH to a closed conformation. The TrkA ring splits into two TrkA dimers in the presence of ATP and releases the constraints on TrkH, resulting in an open channel conformation. Functional studies show that both the tetramer-to-dimer conversion of TrkA and the loss of constraints on TrkH are required for channel gating. In addition, deletion of TrkA in Escherichia coli depolarizes the cell, suggesting that the TrkH-TrkA complex couples changes in intracellular nucleotides to membrane potential.
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http://dx.doi.org/10.1038/s41467-019-14240-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987127PMC
January 2020
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