BACKGROUND: Sialolithiasis pathophysiology is multifactorial, with systemic medications often hypothesised as a key contributor, particularly in older adults (Drug-Induced Sialolithiasis). However, robust evidence suppor...BACKGROUND: Sialolithiasis pathophysiology is multifactorial, with systemic medications often hypothesised as a key contributor, particularly in older adults (Drug-Induced Sialolithiasis). However, robust evidence supporting this theory is limited. This study aimed to investigate the association between common medication classes and sialolithiasis in an older Israeli cohort. METHODS: A nationwide retrospective case-control study (2005-2024) was conducted using the Clalit Health Services database. Sialolithiasis cases were matched 1:3 with controls based on age and gender. After stratification using a Gaussian Mixture Model (age > 50.28 years), logistic regression analyses assessed the association between sialolithiasis and antihyperlipidemic, antihypertensive, psychiatric, neurologic and antidiabetic medications. Significance was considered under p-value of 0.05. RESULTS: The cohort included 32,088 individuals (8015 cases). Multivariable analysis revealed significantly increased odds of sialolithiasis associated with neurologic (OR 1.31, p < 0.001), antihyperlipidemic (OR 1.18, p < 0.001), psychiatric (OR 1.16, p < 0.001) and antihypertensive medications (OR 1.08, p = 0.016). Antidiabetics showed no significant association. CONCLUSIONS: This large-scale analysis strongly supports the theory of Drug-Induced Sialolithiasis. The independent association between these four common medication classes and increased odds of sialolithiasis in older adults suggests that medication-induced hyposalivation is a major, quantifiable risk factor in the aetiology of the condition.
OBJECTIVE: Oral squamous cell carcinoma (OSCC), a common subtype of head and neck cancer (HNSC), impairs essential functions such as breathing, swallowing, and speech. This study aimed to evaluate the therapeutic potenti...OBJECTIVE: Oral squamous cell carcinoma (OSCC), a common subtype of head and neck cancer (HNSC), impairs essential functions such as breathing, swallowing, and speech. This study aimed to evaluate the therapeutic potential of targeting mitochondrial pathways via inhibition of Voltage-Dependent Anionic Channel 1 (VDAC1) using itraconazole (ITRA) and to assess the synergistic effect of combining VDAC1 inhibition with autophagy inhibition using hydroxychloroquine (HCQ). METHODS: The effects of ITRA, HCQ, and their combinations with cisplatin were tested in various HNSC models, including monolayer cultures, hypoxic conditions, 3D spheroids, and an in vivo xenograft model. The study also examined the role of the VDAC1-Hexokinase-II complex and the impact of autophagy under metabolic stress. RESULTS: ITRA alone showed limited cytotoxicity, but its combination with HCQ significantly enhanced antitumoral activity. Synergistic effects were observed with HCQ + ITRA, HCQ + cisplatin, and ITRA + cisplatin in all in vitro models. In vivo, HCQ alone and in combination with ITRA reduced tumor growth without adverse effects. CONCLUSIONS: Taken together, these findings support itraconazole as a promising candidate for further in vivo and clinical investigation in selected oral cancers, including HNSCC and OSCC. Nevertheless, the definition of clinical treatment schedules will require additional comprehensive pharmacokinetic, toxicological, and clinical studies.
PURPOSE: Salivary adenoid cystic carcinoma (SACC) is characterized by a jump growth pattern, making complete resection difficult in some cases. The objective of this study is to evaluate the effect of postoperative radio...PURPOSE: Salivary adenoid cystic carcinoma (SACC) is characterized by a jump growth pattern, making complete resection difficult in some cases. The objective of this study is to evaluate the effect of postoperative radiotherapy (PORT) on the prognosis of SACC with positive surgical margins (PSM). METHODS: Patients with SACC were identified from the medical database of Shanghai Ninth people's Hospital. Kaplan-Meier analysis, univariate and multivariate Cox regression were conducted to assess the effect of PORT on the prognosis of SACC among different groups. RESULTS: A total of 104 patients with SACC were retrospectively reviewed. The 5-year OS and DFS rates were 85.6% and 69.8%, respectively. Multivariate analysis indicated that clinical lymph node stage and distant metastasis were independent prognostic factors for both OS and DFS. Furthermore, pairwise comparisons revealed that the OS in the R1/1 group was comparable to that in the R0/0 group (p = 0.362) and significantly higher than that in the R1/0 group (p = 0.028). The DFS of the R1/1 group also showed a superior outcome compared to the R1/0 group, although without statistical significance (p = 0.104). CONCLUSION: PORT is an effective adjuvant treatment for SACC patients with PSM, which is strongly recommended for SACC patients with PSM to improve the prognosis.
OBJECTIVE: To investigate the therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) preconditioned with low-magnitude high-frequency (LMHF) vibration on temporomandibular joint osteoarthritis (TMJOA). METHODS...OBJECTIVE: To investigate the therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) preconditioned with low-magnitude high-frequency (LMHF) vibration on temporomandibular joint osteoarthritis (TMJOA). METHODS: BMSCs with/without LMHF vibration were intra-articularly injected into TMJOA model rats. After 8 weeks, joint diameter was measured. Pathological alterations were observed through histological staining techniques (CXCR4, SOX9). In vitro, BMSCs and chondrocytes were co-cultured with LMHF vibration. Chondrocyte proliferation was assessed by CCK-8. In a tumor necrosis factor-α (TNF-α)-induced inflammatory microenvironment, signal transduction-related and autophagy-related proteins were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. RESULTS: The injection of LMHF vibrated BMSCs increases the joint diameter and alleviates TMJ tissue damage. The OA model led to an elevation in CXCR4 levels and a reduction in SOX9 in condyle cartilage, while vibrated BMSCs upregulated both. In vitro experiments, appropriate cyclic sinusoidal dynamic mechanical vibration enhanced the proliferative capacity of chondrocytes co-cultured with BMSCs. In inflammation, the vibration group downregulated chondrocyte MMP-13 and upregulated chondrocyte Collagen II/BMP7/β-catenin/Atg3, as well as BMSC Collagen X/BMP7/β-catenin/CXCR4/Beclin-1/Atg5-all protein levels exceeded those in the LiCl group. CONCLUSION: For cartilage tissue engineering, LMHF vibration serves as a promising strategy to rapidly expand cells with a reinforced chondrogenic phenotype.
BACKGROUND: This research was designed to establish an innovative diagnostic strategy employing whole-slide imaging (WSI) technology to address the diagnostic difficulties arising from the intricate histological architec...BACKGROUND: This research was designed to establish an innovative diagnostic strategy employing whole-slide imaging (WSI) technology to address the diagnostic difficulties arising from the intricate histological architecture and morphological diversity observed in oral squamous cell carcinoma (OSCC). METHODS: We proposed a cutting-edge multi-task learning architecture (MILGDF) that combines local-global attention mechanisms with dynamic weighted fusion. This model utilizes instance-level category-specific attention to enhance feature extraction efficacy while overcoming the limitations inherent in traditional bag-level attention methods. An adaptive weighting system was incorporated to dynamically adjust the contribution of local and global features, ensuring optimal performance in diverse prediction tasks. RESULTS: Rigorous validation on the HIDOC and TCGA-OSCC datasets revealed the exceptional predictive performance of our model. The MILGDF framework attained an AUC of 0.952 (accuracy: 0.909) on HIDOC and 0.745 (accuracy: 0.725) on TCGA-OSCC, demonstrating statistically significant superiority over existing comparative models in both staging classification and diagnostic prediction. CONCLUSIONS: The MILGDF model is capable of effectively utilizing information from wide-field images (WSI) for the accurate diagnosis and staging of oral squamous cell carcinoma (OSCC); its performance surpasses that of existing methods, demonstrating significant potential for clinical application.
OBJECTIVE: Periodontitis is a chronic inflammatory disorder affecting periodontal tissues; diosmetin, exhibiting anti-inflammatory and anti-osteoporotic properties, emerges as a promising novel agent for periodontitis pr...OBJECTIVE: Periodontitis is a chronic inflammatory disorder affecting periodontal tissues; diosmetin, exhibiting anti-inflammatory and anti-osteoporotic properties, emerges as a promising novel agent for periodontitis prevention. METHODS: In this study, we utilized in vitro primary hPDLCs cultures and in vivo ligature-induced periodontitis models in rats to demonstrate the dual anti-inflammatory and osteogenic effects of diosmetin, alongside its protective role against alveolar bone resorption in periodontal disease. RESULTS: CCK-8 assays demonstrated that diosmetin exhibited no cytotoxicity in hPDLCs at concentrations up to 100 μM. Diosmetin significantly suppressed LPS-induced mRNA and protein expression of pro-inflammatory mediators, including COX-2, IL-1β, and IL-6. The MAPK and NF-κB signaling pathways may represent the underlying mechanisms for its anti-inflammatory effects. Quantitative analysis further revealed upregulated mRNA and protein levels of osteogenic markers-RUNX-2, BMP-2, and BSP, which may be associated with Wnt/β-catenin signaling activation. Alkaline phosphatase (ALP) and alizarin red S (ARS) staining validate the osteogenic differentiation potential of diosmetin in hPDLCs. In the rat ligature-induced periodontitis model, administration of diosmetin significantly reduced the RANKL/OPG ratio, potentially contributing to its inhibition of alveolar bone resorption. CONCLUSION: This study demonstrated the dual roles of diosmetin's anti-inflammatory and osteogenic differentiation effects in preventing periodontitis, along with a preliminary exploration of its underlying mechanisms.
OBJECTIVE: The use of smokeless tobacco (SLT) is associated with significant harm to oral health and salivary biomarkers have recently emerged as potential indicators of such harm. This study evaluated levels of key sali...OBJECTIVE: The use of smokeless tobacco (SLT) is associated with significant harm to oral health and salivary biomarkers have recently emerged as potential indicators of such harm. This study evaluated levels of key salivary proteins, including inflammatory cytokines and vascular dysfunction biomarkers, among SLT users and examined the influence of usage characteristics on these levels. METHODS: A total of 62 male participants, aged 24-55 years, were equally allocated to either SLT users or controls (non-users) groups. Expression of salivary interleukin 1β (IL-1β), tumor necrosis factor alpha (TNF-α), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), endothelin-1 (ET1), and transferrin (TF) was evaluated using ELISA. Multiple linear regression assessed effects of mixed SLT use, areca-nut content, duration and frequency of use on biomarker expression. RESULTS: SLT users exhibited significantly elevated levels of VEGF, EGF, and ET1 (p < 0.0001), TF, and IL-1β (p < 0.05) compared to controls. Additionally, using more than one type of SLT was significantly associated with higher expression of VEGF and TF. CONCLUSIONS: SLT consumption is associated with significant upregulation of pro-inflammatory cytokines and biomarkers of endothelial dysfunction, while mixed use of SLT products may further potentiate these effects. These findings highlight the potential pathogenic impact of SLT on oral health.
AIM: This review provides a comprehensive summary of the mechanisms of action and pharmacological activities of baicalin and baicalein in the therapy of oral squamous cell carcinoma (OSCC). METHODS: A comprehensive liter...AIM: This review provides a comprehensive summary of the mechanisms of action and pharmacological activities of baicalin and baicalein in the therapy of oral squamous cell carcinoma (OSCC). METHODS: A comprehensive literature search was conducted using multiple electronic databases to find relevant publications. RESULTS: Baicalin and its aglycone form, baicalein, are two bioflavonoids from Scutellaria baicalensis, which exhibit selective cytotoxicity in OSCC cells by inducing apoptosis through Bax/Bcl-2 ratio modulation and caspase-3 activation with negligible toxicity to normal cells. They also suppress metastatic activities by inducing the expression of E-cadherin and reducing the expression of vimentin, MMP2, MMP9, and EMT. Antiproliferative effects are mediated by cyclin D1 and p53 inhibition, resulting in cell cycle arrest. Baicalin induces ferroptosis through ferritin heavy chain 1 and glutathione peroxidase 4 inhibition, inducing chemosensitivity. Despite their therapeutic promise, challenges such as poor solubility and low bioavailability hinder clinical translation. Innovative drug delivery systems, including nanoencapsulation, offer promising answers to these challenges. Preclinical investigations confirm their good safety profile, with few adverse effects at therapeutic doses. CONCLUSIONS: These findings underscore the potential of baicalin and baicalein as anti-cancer agents for OSCC. However, further research and clinical trials are necessary to elucidate their mechanisms.
BACKGROUND: The cumulative evidence from meta-analyses on interventions for oral submucous fibrosis (OSF) remains uncertain in terms of strength, precision, and quality. This umbrella review synthesizes the current evide...BACKGROUND: The cumulative evidence from meta-analyses on interventions for oral submucous fibrosis (OSF) remains uncertain in terms of strength, precision, and quality. This umbrella review synthesizes the current evidence on available interventions and assesses the certainty. METHODS: We searched PubMed, Scopus, Epistemonikos, and CINAHL for meta-analyses on OSF interventions. The effect sizes of the outcome measures were used to assess the credibility employing a random-effects model, and the evidence quality was analyzed using the GRADE criteria. RESULTS: Nine meta-analyses encompassing 64 randomized controlled trials were included, detailing 72 associations between available interventions and health outcomes in OSF. Only 17 of the 72 assessed associations were statistically significant (p ≤ 0.05). Lycopene was shown to be statistically effective in improving mouth opening in both the short-term (1-3 months) and long-term (6 months) follow-ups. The evidence regarding other interventions and outcomes remains inconclusive. Using GRADE, 9 associations were supported by low-quality evidence. The remaining 63 associations were substantiated as very low-quality evidence. CONCLUSION: No pharmacological intervention for oral submucous fibrosis is supported by evidence exceeding low certainty, with most evidence rated as very low certainty. This underscores the need for robust long-term studies on other interventions rather than additional meta-analyses.
OBJECTIVES: Smoking disrupts oxidative balance and is a major risk factor for periodontitis. Forkhead box protein O-1 (FoxO-1) regulates antioxidant defense, yet its contribution to smoking-associated periodontal breakdo...OBJECTIVES: Smoking disrupts oxidative balance and is a major risk factor for periodontitis. Forkhead box protein O-1 (FoxO-1) regulates antioxidant defense, yet its contribution to smoking-associated periodontal breakdown is unclear. This cross-sectional case-control study assessed reactive oxygen species (ROS), matrix metalloproteinase-9 (MMP-9), and FoxO-1 to clarify how smoking modulates oxidative stress and tissue destruction. METHODS: Four groups were defined: non-smoker controls (NS-C), non-smoker periodontitis (NS-P), smoker controls (S-C), and smoker periodontitis (S-P). Periodontal parameters were recorded, and gingival crevicular fluid ROS, MMP-9, and FoxO-1 were quantified by enzyme-linked immunosorbent assay (ELISA). RESULTS: ROS levels were higher in periodontitis than in controls, regardless of smoking (p < 0.0001). MMP-9 was elevated in S-P versus S-C (p = 0.0456) but did not differ between non-smoker groups. FoxO-1 increased with both smoking (p = 0.0069) and inflammation (p < 0.0001). CONCLUSION: These findings suggest that smoking amplifies periodontal tissue destruction not only by enhancing oxidative burden but also by upregulating FoxO-1-linked pathways associated with proteolysis. The parallel rise of FoxO-1 with MMP-9 might indicate a possible compensatory yet insufficient antioxidant response, positioning FoxO-1 as a mechanistic bridge between inflammation and matrix degradation and a candidate target for host-modulatory therapy.
OBJECTIVE: To quantitatively compare circulating interleukin-6 (IL-6) levels in human periodontitis and mouse models, and to evaluate the impact of experimental induction methods on systemic inflammatory responses. METHO...OBJECTIVE: To quantitatively compare circulating interleukin-6 (IL-6) levels in human periodontitis and mouse models, and to evaluate the impact of experimental induction methods on systemic inflammatory responses. METHODS: A systematic review and meta-analysis was conducted according to PRISMA guidelines. Studies reporting serum or plasma IL-6 levels in periodontitis and controls were included. Human studies involved Stage III or higher periodontitis; mouse studies used ligation or inoculation models. Standardized mean differences (SMDs) were pooled using random-effects models. RESULTS: Thirty-eight studies (26 human, 12 mouse) were included. Periodontitis was associated with elevated circulating IL-6 in humans (SMD = 1.57; 95% CI: 0.61-2.54) and mice (SMD = 3.79; 95% CI: 2.53-5.05), with greater increases in mice (p = 0.006). Ligature-induced models showed the largest elevation (SMD = 4.39), higher than humans (p = 0.002) and inoculation models (p = 0.006), whereas inoculation models did not differ from humans. Meta-regression confirmed stronger IL-6 responses in mice (β = 2.26; p = 0.007) and ligature models (β = 2.85; p = 0.006), indicating amplified responses in ligature-induced models. CONCLUSIONS: Circulating IL-6 is elevated in periodontitis across species but exaggerated in ligation models, suggesting possible overestimation of systemic inflammation in preclinical studies. TRIAL REGISTRATION:PROSPERO: CRD420251101961.
OBJECTIVE(S): This study aimed to elucidate the role of Cathepsin S (CTSS) in periodontitis, focusing on its dual impact on inflammation and osteogenic differentiation of periodontal ligament stem cells (PDLSCs). MATERIA...OBJECTIVE(S): This study aimed to elucidate the role of Cathepsin S (CTSS) in periodontitis, focusing on its dual impact on inflammation and osteogenic differentiation of periodontal ligament stem cells (PDLSCs). MATERIALS AND METHODS: Integrated bioinformatics analysis of GEO datasets was performed, followed by experimental validation using PDLSCs from healthy individuals and periodontitis patients. Functional assays included CTSS knockdown/overexpression, LPS stimulation, osteogenic differentiation assessment, and evaluation of NF-κB signaling and inflammatory cytokines. RESULTS: Bioinformatics and experimental data consistently showed CTSS upregulation in periodontitis. CTSS knockdown enhanced osteogenic differentiation and mineralization while inhibiting LPS-induced NF-κB activation and pro-inflammatory cytokine expression (TNF-α, IL-1β, and IL-6); CTSS overexpression produced opposite effects. CONCLUSION(S): CTSS drives inflammation and suppresses PDLSC regenerative capacity via NF-κB activation, positioning it as a promising therapeutic target for periodontal tissue regeneration.