The antitumor effects of herbal medicine Triphala on oral cancer by inactivating PI3K/Akt signaling pathway: based on the network pharmacology, molecular docking, in vitro and in vivo experimental validation.

BACKGROUND: This research aimed to investigate the anti-tumor effects and underlying genetic mechanisms of herbal medicine Triphala (TRP) in oral squamous cell carcinoma (OSCC). METHODS: The target genes of Triphala (TRP) in oral squamous cell carcinoma (OSCC) were identified, and subsequent functional enrichment analysis was conducted to determine the enriched signaling pathways. Based on these genes, a protein-protein interaction network was constructed to identify the top 10 genes with the highest degree. Genes deregulated in OSCC tumor samples were identified to be hub genes among the top 10 genes. In vitro experiments were performed to investigate the influence of TRP extracts on the cell metabolic activity, migration, invasion, apoptosis, and proliferation of two OSCC cell lines (CAL-27 and SCC-9). The functional rescue assay was conducted to investigate the effect of applying the inhibitor and activator of an enriched pathway on the phenotypes of cancer cells. In addition, the zebrafish xenograft tumor model was established to investigate the influence of TRP extracts on tumor growth and metastasis in vivo. RESULTS: The target genes of TRP in OSCC were prominently enriched in the PI3K-Akt signaling pathway, with the identification of five hub genes (JUN, EGFR, ESR1, RELA, and AKT1). TRP extracts significantly inhibited cell metabolic activity, migration, invasion, and proliferation and promoted cell apoptosis in OSCC cells. Notably, the application of TRP extracts exhibited the capacity to downregulate mRNA and phosphorylated protein levels of AKT1 and ESR1, while concomitantly inducing upregulation of mRNA and phosphorylated protein levels in the remaining three hub genes (EGFR, JUN, and RELA). The functional rescue assay demonstrated that the co-administration of TRP and the PI3K activator 740Y-P effectively reversed the impact of TRP on the phenotypes of OSCC cells. Conversely, the combination of TRP and the PI3K inhibitor LY294002 further enhanced the effect of TRP on the phenotypes of OSCC cells. Remarkably, treatment with TRP in zebrafish xenograft models demonstrated a significant reduction in both tumor growth and metastatic spread. CONCLUSIONS: Triphala exerted significant inhibitory effects on cell metabolic activity, migration, invasion, and proliferation in OSCC cell lines, accompanied by the induction of apoptosis, which was mediated through the inactivation of the PI3K/Akt pathway.

The effectiveness of adjunctive measures in managing peri-implant mucositis: an umbrella review.

OBJECTIVES: The purpose of this umbrella review was to gather and summarize the data from published systematic reviews (SRs) that compared non-surgical mechanical debridement (NSMD) with and without the use of adjunctive treatments on the management of peri-implant mucositis (PIM). MATERIALS AND METHODS: A protocol was developed and registered in PROSPERO (CRD42021254350) before the systematic search for the SRs. Seven electronic databases, including Cochrane Library, Embase (via Ovid), MEDLINE (via Pubmed), Proquest, Prospero, Scopus and Web of Science, were searched for published reviews. The search for unpublished and informally published reviews was further attempted in the last four databases. The methodological quality of the included reviews was assessed using AMSTAR 2. RESULTS: Twelve included SRs assessed clinical studies published between 2014 and 2020, including a total of seventeen primary clinical trials. All SRs summarized data from individual studies and provided a narrative conclusion regarding the effectiveness of the adjunctive treatments. Only six SRs performed a meta-analysis (MA) of additional benefits of the adjunctive therapy for PIM, with results indicating no significant difference between the different treatment modalities. The overall confidence was adjudged ranging from critically low to low using AMSTAR 2 and significant additional benefits of any adjunctive treatments in comparison with NSMD were not apparent. CONCLUSION: Overall, the reviewed evidence did not support the use of adjunctive treatments for improvement of clinical outcomes in PM management as compared to NSMD alone.

Impact of design elements of the implant supracrestal complex (ISC) on the risk of peri-implant mucositis and peri-implantitis: A critical review.

OBJECTIVE: The aim of this review was to investigate the evidence correlating the emergence profile (EP) and emergence angle (EA), peri-implant tissue height, implant neck design, abutment and/or prosthesis material, retention and connection types with risk of peri-implant mucositis and peri-implantitis. METHODS: Seven focus questions were identified, and seven electronic search queries were conducted in PubMed. Human studies reporting on bleeding on probing, probing depth or case definitions of peri-implant mucositis and peri-implantitis were included. RESULTS: Emerging evidence with bone-level implants suggests a link between EA combined with convex EP and peri-implantitis. Depth of the peri-implant sulcus of ≥3 mm is shown to be reducing the effectiveness of treatment of established peri-implant mucositis. Modification of the prosthesis contour is shown to be an effective supplement of the anti-infective treatment of peri-implant mucositis. Limited evidence points to no difference with regard to the risk for peri-implant mucositis between tissue- and bone-level implants, as well as the material of the abutment or the prosthesis. Limited evidence suggests the use or not of prosthetic abutments in external connections and does not change the risk for peri-implantitis. Literature with regard to prosthesis retention type and risk for peri-implantitis is inconclusive. CONCLUSIONS: Limited evidence indicates the involvement of EA, EP, sulcus depth and restricted accessibility to oral hygiene in the manifestation and/or management of peri-implant mucositis/peri-implantitis. Conclusions are limited by the lack of consensus definitions and validated outcomes measures, as well as diverse methodological approaches. Purpose-designed studies are required to clarify current observations.

Molecular Subtypes of Oral Squamous Cell Carcinoma Based on Immunosuppression Genes Using a Deep Learning Approach.

Background: The mechanisms through which immunosuppressed patients bear increased risk and worse survival in oral squamous cell carcinoma (OSCC) are unclear. Here, we used deep learning to investigate the genetic mechanisms underlying immunosuppression in the survival of OSCC patients, especially from the aspect of various survival-related subtypes. Materials and methods: OSCC samples data were obtained from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and OSCC-related genetic datasets with survival data in the National Center for Biotechnology Information (NCBI). Immunosuppression genes (ISGs) were obtained from the HisgAtlas and DisGeNET databases. Survival analyses were performed to identify the ISGs with significant prognostic values in OSCC. A deep learning (DL)-based model was established for robustly differentiating the survival subpopulations of OSCC samples. In order to understand the characteristics of the different survival-risk subtypes of OSCC samples, differential expression analysis and functional enrichment analysis were performed. Results: A total of 317 OSCC samples were divided into one inferring cohort (TCGA) and four confirmation cohorts (ICGC set, GSE41613, GSE42743, and GSE75538). Eleven ISGs (i.e., BGLAP, CALCA, CTLA4, CXCL8, FGFR3, HPRT1, IL22, ORMDL3, TLR3, SPHK1, and INHBB) showed prognostic value in OSCC. The DL-based model provided two optimal subgroups of TCGA-OSCC samples with significant differences (p = 4.91E-22) and good model fitness [concordance index (C-index) = 0.77]. The DL model was validated by using four external confirmation cohorts: ICGC cohort (n = 40, C-index = 0.39), GSE41613 dataset (n = 97, C-index = 0.86), GSE42743 dataset (n = 71, C-index = 0.87), and GSE75538 dataset (n = 14, C-index = 0.48). Importantly, subtype Sub1 demonstrated a lower probability of survival and thus a more aggressive nature compared with subtype Sub2. ISGs in subtype Sub1 were enriched in the tumor-infiltrating immune cells-related pathways and cancer progression-related pathways, while those in subtype Sub2 were enriched in the metabolism-related pathways. Conclusion: The two survival subtypes of OSCC identified by deep learning can benefit clinical practitioners to divide immunocompromised patients with oral cancer into two subpopulations and give them target drugs and thus might be helpful for improving the survival of these patients and providing novel therapeutic strategies in the precision medicine area.

Oral Health-Related Quality of Life in Patients With Chronic Respiratory Diseases-Results of a Systematic Review.

Background: This systematic review evaluates the oral health-related quality of life (OHRQoL) of patients with chronic respiratory diseases. Methods: A systematic literature search was performed based on the PubMed, Medline, Web of Science, and Scopus, using the search terms: "oral health-related quality of life" and "respiratory disease" or "lung" and "oral health-related quality of life." Full-text articles published until June 30, 2021 and reporting any OHRQoL measurement in children or adults with a chronic respiratory disease or condition were included and analyzed qualitatively. Results: A total of seven out of 44 studies were included, of which four studies examined adults and three studies investigated children. The respective diseases were chronic obstructive pulmonary disease (COPD) (n = 2), sleep apnea (n = 2), severe asthma (n = 1), cystic fibrosis (n = 1), and lung transplantation (n = 1). Four studies confirmed a worse OHRQoL in the respiratory diseased group compared to healthy controls. The overall OHRQoL was reduced in the included studies. Oral health, health-related quality of life, and disease-related parameters were rarely examined with regard to OHRQoL. Conclusion: Patients with chronic respiratory diseases show a reduced OHRQoL. Oral health should be fostered in these individuals to support their OHRQoL.

Immune Checkpoint Gene Expression Profiling Identifies Programmed Cell Death Ligand-1 Centered Immunologic Subtypes of Oral and Squamous Cell Carcinoma With Favorable Survival.

OBJECTIVE: This study aimed to identify the programmed death ligand-1 (PDL1, also termed as CD274) and its positively correlated immune checkpoint genes (ICGs) and to determine the immune subtypes of CD274-centered ICG combinations in oral and squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Firstly, the 95 ICGs obtained via literature reviews were identified in the Cancer Genome Atlas (TCGA) database in relation to OSCC, and such 88 ICG expression profiles were extracted. ICGs positively correlated with CD274 were utilized for subsequent analysis. The relationship between ICGs positively correlated with CD274 and immunotherapy biomarkers (tumor mutation burden (TMB), and adaptive immune resistance pathway genes) was investigated, and the relationships of these genes with OSCC clinical features were explored. The prognostic values of CD274 and its positively correlated ICGs and also their associated gene pairs were revealed using the survival analysis. RESULTS: Eight ICGs, including CTLA4, ICOS, TNFRSF4, CD27, B- and T-lymphocyte attenuator (BTLA), ADORA2A, CD40LG, and CD28, were found to be positively correlated with CD274. Among the eight ICGs, seven ICGs (CTLA4, ICOS, TNFRSF4, CD27, BTLA, CD40LG, and CD28) were significantly negatively correlated with TMB. The majority of the adaptive immune resistance pathway genes were positively correlated with ICGs positively correlated with CD274. The survival analysis utilizing the TCGA-OSCC data showed that, although CD274 was not significantly associated with overall survival (OS), the majority of ICGs positively correlated with CD274 (BTLA, CD27, CTLA4, CD40LG, CD28, ICOS, and TNFRSF4) were significantly correlated with OS, whereby their low-expression predicted a favorable prognosis. The survival analysis based on the gene pair subtypes showed that the combination subtypes of CD274_low/BTLA_low, CD274_low/CD27_low, CD274_low/CTLA4_low, CD8A_high/BTLA_low, CD8A_high/CD27_low, and CD8A_high/CTLA4_low predicted favorable OS. CONCLUSION: The results in this study provide a theoretical basis for prognostic immune subtyping of OSCC and highlight the importance of developing future immunotherapeutic strategies for treating oral cancer.

The molecular differences between human papillomavirus-positive and -negative oropharyngeal squamous cell carcinoma: A bioinformatics study.

OBJECTIVE: To investigate the genetic and epigenetic differences between human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) and HPV-negative OPSCC. METHODS: Microarray data of HPV-positive and -negative OPSCC were retrieved from NCBI GEO datasets. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DE-miRNAs) were identified by performing differential expression analysis. A functional enrichment analysis was performed to explore the biological processes and signaling pathways that DEGs and DE-miRNAs were involved in, respectively. A protein-protein interaction (PPI) network of DEGs was constructed to identify hub genes. miRNA-target network and miRNA-miRNA functional synergistic network were each constructed in order to identify risk-marker miRNAs. An miRNA-target-pathway network was constructed in order to explore the function of identified risk-marker miRNAs. RESULTS: Microarray data from 3 datasets (GSE39366, GSE40774, and GSE55550) was included and analyzed. The PPI network identified 3 hub genes (VCAM1, UBD, and RPA2). MiR-107 and miR-142-3p were found to play the most significant role in both the DE-miRNA-target network as well as in the miRNA-miRNA functional synergistic network. MiR-107 was involved in HPV-induced tumorigenesis by targeting many genes (CAV1, CDK6, MYB, and SERPINB5) and regulating the p53 signaling pathway, the PI3K-Akt signaling pathway, and the autophagy pathway. In addition, miR-142-3p was implicated in HPV-induced tumorigenesis by targeting the PPFIA1 gene and regulating transcriptional dysregulation and other cancerous pathways. CONCLUSION: Three genes (VCAM1, UBD, and RPA2), two miRNAs (miR-107 and miR-142-3p), and four pathways (p53, PI3K-Akt, autophagy, and transcription dysregulation in cancer) were identified to play critical roles in distinguishing HPV-positive OPSCC from HPV-negative OPSCC.

Shared genetic and epigenetic mechanisms between chronic periodontitis and oral squamous cell carcinoma.

OBJECTIVES: To analyze bioinformatic datasets for detecting genetic and epigenetic mechanisms shared by chronic periodontitis (CP) and oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Datasets from GEO and TCGA databases reporting mRNAs, miRNAs or methylation expression in human CP and OSCC tissues were analyzed. Differential expression, functional enrichment and protein-protein interaction (PPI) network analyses were performed. Differentially expressed miRNAs (DEmiRNAs) and genes (DEG) in CP and OSCC were determined. DEmiRNA-target and DEmiRNA-DEG networks were constructed. Directly and indirectly interacting cross-talk genes were screened, and their prediction accuracy and association with OSCC prognosis was determined. RESULTS: 3 DE-miRNAs (miR-375, miR-3609 and miR-3652) expressed in both CP and OSCC critically regulated most DEGs. Among 12 directly interacting cross-talk genes, NCAPH was significantly related with the prognosis of OSCC. NR2F2 had highest differential expression in CP and OSCC. Among 4 cross-talk genes (FN1, MPPED1, NDEL1, and NR2F2) differentially expressed in CP, 3 (FN1, MPPED1, NDEL1) were also expressed in OSCC. Among 12 indirectly interacting cross-talk genes differentially expressed in OSCC, 3 genes (CDCA8, HIST1H3J, and RAD51) were significantly related to its prognosis. Significant pathways involved in CP and OSCC included: chemokine receptors, class I PI3K signaling events, epithelial-to-mesenchymal transition and signaling events by VEGFR1 and VEGFR2, EGF receptor (ErbB1). CONCLUSION: Bioinformatic analysis of available datasets implicated 1 directly interacting cross-talk gene (NCAPH), 4 indirectly interacting cross-talk genes (NCAPH, NR2F2, FN1, and MPPED1) and 3 DE-miRNAs (hsa-miR-375, miR-3609 and miR-3652) as shared genetic and epigenetic expression patterns between CP and OSCC.

Salivary IL-1ß and red complex bacteria as predictors of the inflammatory status in sub-peri-implant niches of subjects with peri-implant mucositis.

BACKGROUND AND OBJECTIVES: Salivary biomarkers may enhance diagnostic sensitivity for peri-implant disease assessment. This study aimed to investigate the association of salivary periodontopathogen count and salivary interleukin-1beta (IL-1ß) level with the peri-implant crevicular fluid IL-1ß response at peri-implant mucositis (PM) sites among subjects with differing periodontal disease susceptibility. MATERIALS AND METHODS: Eighty-seven partially edentulous subjects having at least one implant with peri-implant mucositis were included: 40 with history of chronic periodontitis (P) and 47 with no history of periodontitis (NP). Salivary IL-1ß, peri-implant crevicular fluid (PICF) IL-1ß, and salivary red complex pathogen counts were recorded. Subjects were scored according to a threshold salivary pathogen level of more than 5log (10) counts and assigned a "red complex score." Quartiles of salivary and PICF IL-1ß levels were also scored. Area under receiver operating curve (AUC) was computed to predict the highest PICF IL-1ß score using salivary biomarker as predictors and age-adjusted logistic regression performed for the significant predictors. RESULTS: In the NP group, red complex score (AUC = 0.758 P = 0.010) (odds ratio = 1.377) and salivary IL-1ß (AUC = 0.708 P = 0.038) (odds ratio = 2.506) were significant predictors of highest PICF IL-1ß quartile score. In the P group, no significant associations were noted. CONCLUSIONS: Salivary biomarkers could distinguish the "high" pro-inflammatory responders at PM sites only in subjects without inherent periodontal disease susceptibility. Periodontal susceptibility may impact the immuno-inflammatory response in sub-peri-implant niches of those with peri-implant mucositis.

Human cytomegalovirus-1 and Epstein-Barr virus-1 viral colonization of titanium and zirconia abutments: a split-mouth study.

AIM: Human cytomegalovirus-1 (HCMV-1) and Epstein-Barr virus-1 (EBV-1) detection in submarginal plaque is linked to diseased states of the periodontium. In the present study, we evaluated the viral colonization of titanium and zirconia abutments by HCMV-1 and EBV-1 in a split-mouth study. METHODS: Forty dental implant abutments placed in 20 non-smokers were evaluated retrospectively. Each participant had received at least one each of titanium and zirconia abutments (in function for at least 1 year). HCMV-1 and EBV-1 were evaluated in these clinically-healthy peri-implant sites' submarginal plaque biofilm at one titanium and one zirconia abutment, one healthy tooth site, and serum using polymerase chain reaction assays. Related-samples McNemar test and Wilcoxon signed-rank test were used to determine the differences in viral detection frequency and load, respectively. RESULTS: EBV-1 was detected at the titanium abutment in 60% of participants, but in none at their zirconia abutment (P = 0.04). HCMV-1 was detected at the titanium abutments in 90% of participants, and at the zirconia abutments in 70% of participants. This difference was not significant (P = 0.25). The differences in HCMV-1 viral load between the abutment types were insignificant (P = 0.075). CONCLUSION: EBV-1 did not colonize the biofilm at the zirconia abutments as opposed to the titanium abutments in the same participants. Abutment material could contribute to differences in biofilm characteristics.

High salivary calcium level associated with periodontal disease in Indian subjects--a pilot study.

OBJECTIVES: To evaluate the association of salivary calcium level with periodontal status in a case-control study model. MATERIALS AND METHODS: Fifty adult non-smoking subjects recruited from an Indian dental educational institution were categorised into case and control groups on the basis of a full-mouth periodontal examination. The case group was comprised of 25 subjects diagnosed with chronic generalised periodontitis and the control group included 25 periodontally healthy individuals. Basic demographic data was obtained and 3 ml of unstimulated saliva was collected. Salivary calcium levels were assayed by the ion selective electrode method. RESULTS: The mean age for cases (46.6 ± 6.9 years) was significantly higher than that for controls (42.4 ± 6.3 years). The mean number of teeth for the case group (28 ± 3) was significantly lower than that for the control group (31 ± 1). The mean salivary calcium level in the case group (2.11 ± 0.24 mmol/L) was significantly higher than in the control group (1.86 ± 0.25 mmol/L) when ANCOVA for age adjustment was applied. CONCLUSIONS: Periodontal disease is associated with higher salivary calcium levels than that in periodontal health, indicating that the calcium level of saliva could possibly be a risk factor for development of periodontal diseases.

Management of multiple and isolated gingival recession sites with periodontal plastic surgical procedures--a case report.

Multiple recession defects in the dentition of an individual are routinely encountered in clinical practice and as such present a challenge for management. Periodontal plastic surgical procedures aim to restore both gingival esthetics as well as function in these defects. This case report highlights four periodontal plastic surgical techniques (the coronally advanced flap for single and multiple recession defects, double papillae with subepithelial connective tissue graft, and envelope technique with subepithelial connective tissue graft) that have been employed for root coverage in isolated Miller Class I recession defects in a 35-year-old individual. Three of the techniques resulted in 100% root coverage in all treated sites, while the site treated with subepithelial connective graft by envelope technique resulted in 83.3% root coverage. Treatment also helped to resolve hypersensitivity and achieved satisfaction of the patient's esthetic concerns.