Association between oxidative stress and chronic orofacial pain and potential druggable targets: Evidence from a Mendelian randomization study.

BACKGROUND: Oxidative stress indicators affect chronic orofacial pain (COFP), but how to reduce these effects is uncertain. OBJECTIVES: 11 oxidative stress biomarkers were collected as exposures, while four forms of COFP were chosen as outcomes for Mendelian randomization (MR) study. METHODS: The effect estimates between oxidative stress and COFP were calculated using inverse variance-weighted MR (IVW-MR). Then, functional mapping and annotation (FUMA) was utilized in order to carry out SNP-based functional enrichment analyses. In addition, the IVW-MR method was applied to combine effect estimates when using genetic variants associated with oxidative stress biomarkers as an instrument for exploring potential druggable targets. RESULTS: The results indicated that oxidative stress biomarkers (causal OR of uric acid (UA), 0.998 for myofascial pain, 95% CI 0.996-1.000, p < .05; and OR of glutathione transferase (GST), 1.002 for dentoalveolar pain, 95% CI 1.000-1.003, p < .05) were significantly linked with the probability of COFP. Functional analysis also demonstrated that UA and myofascial pain genes were prominent in nitrogen and uracil metabolism, while GST and dentoalveolar pain genes were enriched in glutathione metabolism. Also, the study provided evidence that solute carrier family 2 member 9 (SLC2A9) and glutathione S-transferase alpha 2 (GSTA2) cause discomfort in the myofascial pain (OR = 1.003, 95% CI 1.000-1.006; p < .05) and dentoalveolar region (OR = 1.001, 95% CI 1.000-1.002; p < .05), respectively. CONCLUSIONS: In conclusion, this MR study indicates that genetically predicted myofascial pain was significantly associated with decreased UA and dentoalveolar pain was significantly associated with increased GST level. SLC2A9 inhibitor and GSTA2 inhibitor were novel chronic orofacial pain therapies and biomarkers, but clinical trials are called to examine if these oxidative biomarkers have the protective effect against orofacial pain, and further research are needed to explore the underlying mechanisms.

Evaluation of the Efficacy of Stem Cells Therapy in the Periodontal Regeneration: A Meta-Analysis and Mendelian Randomization Study.

Stem cell therapy for periodontal defects has shown good promise in preclinical studies. The purpose of this study was to evaluate the impact of stem cell support on the regeneration of both soft and hard tissues in periodontal treatment. PubMed, Cochrane Library, Embase, and Web of Science were searched and patients with periodontal defects who received stem cell therapy were included in this study. The quality of the included articles was assessed using Cochrane's tool for evaluating bias, and heterogeneity was analyzed using the I2 method. An Mendelian randomization investigation was conducted using abstract data from the IEU public databases obtained through GWAS. Nine articles were included for the meta-analysis. Stem cell therapy effectively rebuilds periodontal tissues in patients with periodontal defects, as evidenced by a reduction in probing depth, clinical attachment level  and bone defect depth . And delta-like homolog 1 is a protective factor against periodontal defects alternative indicator of tooth loosening. The findings of this research endorse the utilization of stem cell treatment for repairing periodontal defects in individuals suffering from periodontitis. It is recommended that additional extensive clinical investigations be carried out to validate the efficacy of stem cell therapy and encourage its widespread adoption.

Type 1 diabetes, glycemic traits, and risk of dental caries: a Mendelian randomization study.

Background: Regarding past epidemiological studies, there has been disagreement over whether type 1 diabetes (T1DM) is one of the risk factors for dental caries. The purpose of this study was to determine the causative links between genetic susceptibility to T1DM, glycemic traits, and the risk of dental caries using Mendelian randomization (MR) approaches. Methods: Summary-level data were collected on genome-wide association studies (GWAS) of T1DM, fasting glucose (FG), glycated hemoglobin (HbA1c), fasting insulin (FI), and dental caries. MR was performed using the inverse-variance weighting (IVW) method, and sensitivity analyses were conducted using the MR-Egger method, weighted median, weighted mode, replication cohort, and multivariable MR conditioning on potential mediators. Results: The risk of dental caries increased as a result of genetic susceptibility to T1DM [odds ratio (OR) = 1.044; 95% confidence interval (CI) = 1.015-1.074; p = 0.003], with consistent findings in the replication cohort. The relationship between T1DM and dental caries was stable when adjusted for BMI, smoking, alcohol intake, and type 2 diabetes (T2DM) in multivariable MR. However, no significant correlations between the risk of dental caries and FG, HbA1c, or FI were found. Conclusion: These results indicate that T1DM has causal involvement in the genesis of dental caries. Therefore, periodic reinforcement of oral hygiene instructions must be added to the management and early multidisciplinary intervention of T1DM patients, especially among adolescents and teenagers, who are more susceptible to T1DM.

Causal effects of the gut microbiome on COVID-19 susceptibility and severity: a two-sample Mendelian randomization study.

Background: The coronavirus disease 2019 (COVID-19) caused a global pandemic, with potential severity. We aimed to investigate whether genetically predicted gut microbiome is associated with susceptibility and severity of COVID-19 risk. Methods: Mendelian randomization (MR) analysis of two sets with different significance thresholds was carried out to infer the causal relationship between the gut microbiome and COVID-19. SNPs associated with the composition of the gut microbiome (n = 5,717,754) and with COVID-19 susceptibility (n = 14,328,058), COVID-19 severity (n = 11,707,239), and COVID-19 hospitalization (n = 12,018,444) from publicly available genome-wide association studies (GWAS). The random-effect inverse variance weighted (IVW) method was used to determine causality. Three more MR techniques-MR Egger, weighted median, and weighted mode-and a thorough sensitivity analysis were also used to confirm the findings. Results: IVW showed that 18 known microbial taxa were causally associated with COVID-19. Among them, six microbial taxa were causally associated with COVID-19 susceptibility; seven microbial taxa were causally associated with COVID-19 severity ; five microbial taxa were causally associated with COVID-19 hospitalization. Sensitivity analyses showed no evidence of pleiotropy or heterogeneity. Then, the predicted 37 species of the gut microbiome deserve further study. Conclusion: This study found that some microbial taxa were protective factors or risky factors for COVID-19, which may provide helpful biomarkers for asymptomatic diagnosis and potential therapeutic targets for COVID-19.

Factorial structure and measurement invariance of the Chinese version of the Oral Health Impact Profile-14 among clinical populations and non-clinical populations: an evidence for public oral investigations.

OBJECTIVE: Oral health-related quality of life (OHRQoL) is a multidimensional concept that is commonly used to examine the impact of oral health status on quality of life. The purpose of this study was to examine the optimal factor model of the Chinese version of the Oral Health Impact Profile (OHIP-14) questionnaire in clinical populations, measurement invariance across clinical status and gender cohorts. This would ensure equal validity of the Chinese version of OHIP-14 in different populations and further support public oral investigations. METHODS: The Chinese version of OHIP-14 was used to investigate 490 dental patients and 919 college students. Confirmatory factor analysis (CFA), item analysis and reliability, measurement invariance, and the t-test were used for data analyses. RESULTS: We found that the 7-factor structure had the best-fit index in the sample (CFI = 0.970, TLI = 0.952; SRMR = 0.029, RMSEA = 0.052(0.040,0.063)). The reliability of the scales was satisfactory (Cronbach's α = 0.942). The error variance invariance fitted the data adequately in measurement invariance, indicating that measurement invariance is acceptable both across the clinical and non-clinical populations (∆CFI=-0.017, ∆RMSEA = 0.010) and across genders in the clinical population (∆CFI = 0.000, ∆RMSEA=-0.003). T-test for scores showed that the clinical populations scored significantly higher than the non-clinical populations, as did the overall score (t = 7.046, p < 0.001, d = 0.396), in terms of functional limitation (t = 2.178, p = 0.030, d = 0.125), physical pain (t = 7.880, p < 0.001,d = 0.436), psychological discomfort (t = 8.993, p < 0.001, d = 0.514), physical disability (t = 6.343, p < 0.001, d = 0.358), psychological disability (t = 5.592, p < 0.001, d = 0.315), social disability (t = 5.301, p < 0.001,d = 0.304), social handicap (t = 4.452, p < 0.001, d = 0.253), and that in the non-clinical populations, females scored significantly higher than males, as did in terms of physical pain (t = 3.055, p = 0.002, d = 0.280), psychological discomfort (t = 2.478, p = 0.014, d = 0.222), and psychological disability (t = 2.067, p = 0.039, d = 0.188). CONCLUSION: This study found that the Chinese version of OHIP-14 has measurement invariance between the clinical and non-clinical populations and across genders in the clinical populations, and can be widely used in OHRQoL assessment for public oral investigations.

Tooth ultrastructure changes induced by a nonsense mutation in the FAM83H gene: insights into the diversity of amelogenesis imperfecta.

OBJECTIVES: The current research on single-nucleotide polymorphism (SNP) mutation sites at different positions of the FAM83H gene and their phenotypic changes leading to amelogenesis imperfecta (AI) is inconsistent. We identified a previously reported heterozygous nonsense mutation c.1192C>T (p.Q398*) in the FAM83H gene and conducted a comprehensive analysis of the dental ultrastructure and chemical composition changes induced by this mutation. Additionally, we predicted the protein feature affected by this mutation site. The aim was to further deepen our understanding of the diversity of AI caused by different mutation sites in the FAM83H gene. METHODS: Whole-exome sequencing (WES) and Sanger sequencing were used to confirm the mutation sites. Physical features of the patient's teeth were investigated using various methods including cone beam computer tomography (CBCT), scanning electron microscopy (SEM), contact profilometry (roughness measurement), and a nanomechanical tester (nanoindentation measurement). The protein features of wild-type and mutant FAM83H were predicted using bioinformatics methods. RESULTS: One previously discovered FAM83H heterozygous nonsense mutation c.1192C>T (p.Q398*) was detected in the patient. SEM revealed inconsistent dentinal tubules, and EDS showed that calcium and phosphorus were lower in the patient's dentin but higher in the enamel compared to the control tooth. Roughness measurements showed that AI patients' teeth had rougher occlusal surfaces than those of the control tooth. Nanoindentation measurements showed that the enamel and dentin hardness values of the AI patients' teeth were both significantly reduced compared to those of the control tooth. Compared to the wild-type FAM83H protein, the mutant FAM83H protein shows alterations in stability, hydrophobicity, secondary structure, and tertiary structure. These changes could underlie functional differences and AI phenotype variations caused by this mutation site. CONCLUSIONS: This study expands the understanding of the effects of FAM83H mutations on tooth structure. CLINICAL RELEVANCE: Our study enhances our understanding of the genetic basis of AI and may contribute to improved diagnostics and personalized treatment strategies for patients with FAM83H-related AI.

Chitosan nanoparticles for sustained release of metformin and its derived synthetic biopolymer for bone regeneration.

Background: There are considerable socioeconomic costs associated with bone defects, making regenerative medicine an increasingly attractive option for treating them. Chitosan is a natural biopolymer; it is used in approaches for sustained slow release and osteogenesis, and metformin has osteoinductivity. Our study aimed to synthesize chitosan and human serum albumin (HSA) with a metformin nanoformulation to evaluate the therapeutic effects of this nanoformulation on bone defects in vitro. Methods: A pluripotent differentiation assay was performed in vitro on mouse bone marrow mesenchymal stem cells (BMSCs). Cell Counting Kit-8 was used to detect whether metformin was toxic to BMSCs. The osteogenesis-related gene expression of osteocalcin (OCN) and osteoprotegerin (OPG) from BMSCs was tested by real-time polymerase chain reaction (PCR). HSA, metformin hydrochloride, and chitosan mixtures were magnetically stirred to finish the assembly of metformin/HSA/chitosan nanoparticles (MHC NPs). The MHC NPs were characterized using transmission electron microscopy (TEM), dynamic light scattering (DLS), and Fourier transform infrared spectroscopy (FT-IR). To test the expression of OCN and OPG, western blot were used. MHC NPs were evaluated in vitro for their osteoinductivity using alkaline phosphatase (ALP). Results: BMSCs successfully differentiated into osteogenic and adipogenic lineages in vitro. According to real-time PCR, a 50 µM concentration of metformin promoted osteogenesis in BMSCs most effectively by upregulating the osteogenic markers OCN and OPG. The microstructure of MHC NPs was spherical with an average nanosize of 20 ± 4.7 nm and zeta potential of -8.3 mV. A blueshift and redshift were observed in MHC NPs following exposure to wavelengths of 1,600-1,900 and 2,000-3,700 nm, respectively. The encapsulation (%) of metformin was more than 90%. The simulation study showed that MHC NPs have good stability and it could release metformin slowly in vitro at room temperature. Upon treatment with the studied MHC NPs for 3 days, ALP was significantly elevated in BMSCs. In addition, the MHC NPs-treated BMSCs upregulated the expression of OPG and OCN, as shown by real-time PCR and western blot. Conclusion: MHC NPs have a stable metformin release effect and osteogenic ability. Therefore, as a derived synthetic biopolymer, it is expected to play a role in bone tissue regeneration.

Cross-cultural adaptation and psychometric properties of the Mainland Chinese version of the manchester orofacial pain disability scale (MOPDS) among college students.

BACKGROUND: Orofacial pain (OFP) is a highly prevalent disorder in mainland China that predisposes to an associated physical and psychological disability. There is lack of a good properties mainland Chinese version of instrument to examine OFP. This study aims to cross-cultural adaptation and evaluate psychometrics properties of the Manchester Orofacial Pain Disability Scale (MOPDS) in mainland Chinese Mandarin context. METHODS: Translation and cross-cultural adaption of the mainland Chinese version MOPDS were conducted following accepted guidelines of self-report measures. Chinese college students (N = 1039) completed the mainland Chinese version of the MOPDS for item analysis, reliability and validity tests, and measurement invariance analysis, and after a one-month interval, around 10% of the sample (n = 110) were invited to retest. To conduct the CFA and measurement invariance analysis, Mplus 8.4 was used. IBM SPSS Statistics 26 software were used for all additional studies. RESULTS: We found that the mainland Chinese version of MOPDS contains 25 items, divided into two categories: physical disability and psychological disability. The scale demonstrated excellent internal reliability, test-retest reliability, and validity. The measurement invariance results proved that the scale could be applied to people of different gender, age, and health consultation status. CONCLUSIONS: The results demonstrated the mainland Chinese version of MOPDS has good psychometric properties and can be used to measure the level of physical and psychological disability of Chinese OFP peoples.

Potential interaction between the oral microbiota and COVID-19: a meta-analysis and bioinformatics prediction.

Objectives: The purpose of this study was to evaluate available evidence on the association between the human oral microbiota and coronavirus disease 2019 (COVID-19) and summarize relevant data obtained during the pandemic. Methods: We searched EMBASE, PubMed, and the Cochrane Library for human studies published up to October 2022. The main outcomes of the study were the differences in the diversity (α and ß) and composition of the oral microbiota at the phylum and genus levels between patients with laboratory-confirmed SARS-CoV-2 infection (CPs) and healthy controls (HCs). We used the Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis (GEPIA) database, Protein-protein interaction (PPI) network (STRING) and Gene enrichment analysis (Metascape) to evaluate the expression of dipeptidyl peptidase 4 (DPP4) (which is the cell receptor of SARS CoV-2) in oral tissues and evaluate its correlation with viral genes or changes in the oral microbiota. Results: Out of 706 studies, a meta-analysis of 9 studies revealed a significantly lower alpha diversity (Shannon index) in CPs than in HCs (standardized mean difference (SMD): -0.53, 95% confidence intervals (95% CI): -0.97 to -0.09). Subgroup meta-analysis revealed a significantly lower alpha diversity (Shannon index) in older than younger individuals (SMD: -0.54, 95% CI: -0.86 to -0.23/SMD: -0.52, 95% CI: -1.18 to 0.14). At the genus level, the most significant changes were in Streptococcus and Neisseria, which had abundances that were significantly higher and lower in CPs than in HCs based on data obtained from six out of eleven and five out of eleven studies, respectively. DPP4 mRNA expression in the oral salivary gland was significantly lower in elderly individuals than in young individuals. Spearman correlation analysis showed that DPP4 expression was negatively correlated with the expression of viral genes. Gene enrichment analysis showed that DPP4-associated proteins were mainly enriched in biological processes, such as regulation of receptor-mediated endocytosis of viruses by host cells and bacterial invasion of epithelial cells. Conclusion: The oral microbial composition in COVID-19 patients was significantly different from that in healthy individuals, especially among elderly individuals. DPP4 may be related to viral infection and dysbiosis of the oral microbiome in elderly individuals.

Prognostic biomarker GSTK1 in head and neck squamous cell carcinoma and its correlation with immune infiltration and DNA methylation.

Background: Glutathione S-transferase kappa 1 (GSTK1) is critical in sarcoma and breast cancer (BRCA) development. However, the clinical significance of GSTK1 in head and neck squamous cell carcinoma (HNSC) remains unclear. This study is the first investigation into the role of GSTK1 in HNSC. Methods: All original data were downloaded from the Cancer Genome Atlas (TCGA) dataset and verified by R Base Package 4.2.0. The expression of GSTK1 in various cancers was explored with TIMER and TCGA databases. Prognostic value of GSTK1 was analyzed via survival module of Kaplan-Meier plotter and Human Protein Atlas database and Cox regression analysis. The association between GSTK1 and clinical features was evaluated by Wilcoxon signed-rank test and logistic regression analysis. The relationship between GSTK1 and immune infiltration and methylation level was further explored. The expression of GSTK1 and its correlation with immune cell infiltration was verified by Immunohistochemical staining (IHC). Results: GSTK1 was lower in HNSC, BRCA, Lung squamous cell carcinoma, and Thyroid carcinoma than in para-carcinoma. Low GSTK1 expression was associated with worse overall survival in Bladder urothelial carcinoma, Kidney renal papillary cell carcinoma, BRCA, and HNSC. However, only in BRCA and HNSC, GSTK1 expression in tumors was lower than that in normal tissues. Cox regression analyses confirmed that GSKT1 was an independent prognostic factor of overall survival in HNSC patients. The decrease in GSTK1 expression in HNSC was significantly correlated with high T stage and smoker history. IHC showed that the expression level of GSTK1 in HNSC was lower than that in para-carcinoma. In addition, GSEA showed that three pathways related to immune infiltration were positively correlated, while two pathways related to DNA methylation were negatively correlated with expression of GSTK1. Further analysis showed that GSTK1 was moderately positively correlated with the infiltration level of T cells and Cytotoxic cells, which was further confirmed by IHC. The methylation level of GSTK1 was associated with prognosis in patients with HNSC. Conclusion: Low GSTK1 expression may be a potential molecular marker for poor prognosis in HNSC and provide new insight for the development of diagnostic marker or therapeutic target.

Oral Health-Related Quality of Life among Chinese Chronic Orofacial Pain Patients with Psychological Health Problems: A Moderated Mediation Model.

Psychological therapies are important for comprehensive chronic orofacial pain (COFP) treatment. This study is to validate the effects of psychological factors on oral health-related quality of life (OHRQoL) among COFP patients in China. Pain catastrophizing, which is a subjective cognitive emotion used to manage the psychological aspects of pain among COFP patients, was examined in relation to COFP severity and OHRQoL. All 479 participants were recruited in Changsha, Hunan Province, China. Cronbach's alpha coefficients (0.868-0.960), composite reliability scores (0.924-0.969), and average variance extracted from each construct (0.555-0.753) all indicated a good model fit. Pearson's correlation analysis showed that age and education status have a positive correlation with COFP severity, pain catastrophizing, and anxiety. COFP severity was related to anxiety, depression, and COFP-OHRQoL. Pain catastrophizing was related to employment status. Anxiety and depression symptoms indirectly mediated the correlation between COFP severity and COFP-OHRQoL. As a second-stage moderator, pain catastrophizing moderated the mediating effects of anxiety symptoms and depression symptoms. Our findings suggest that anxiety, depression, and pain catastrophizing should be evaluated jointly to improve COFP-OHRQoL among COFP patients. This evidence will help therapists to comprehensively treat patients for the best treatment effect.