Emerging roles of the renin-angiotensin system in select oral diseases.

OBJECTIVES: The renin-angiotensin system (RAS) plays essential roles in cardiovascular and renal function regulation. Recent studies have shown that the RAS components are widely expressed in oral tissues, but their roles in oral diseases remain underexplored. This review aims to summarize the effects of the RAS in select oral diseases including oral squamous cells carcinoma (OSCC), periodontitis, oral submucous fibrosis (OSF), and ageusia/dysgeusia. SUBJECTS AND METHODS: Data searches were performed using PubMed, Web of Science and Scopus through July 2024. A narrative overview of current literature was undertaken to synthesize the contexts with elaboration and summary. RESULTS: In OSCC, ACE/Ang II/AT1R promotes OSCC by inducing angiogenesis, cell proliferation and invasiveness. Conversely, ACE/Ang II/AT2R and ACE2/Ang (1-7)/MasR inhibit OSCC progressions. In periodontitis, ACE/Ang II/AT1R upregulates inflammatory cytokines and promotes osteoclast differentiation factor RANKL, whereas ACE2/Ang (1-7)/MasR exerts opposite effects by preventing inflammation and alveolar bone loss. In OSF, Ang (1-7) counters the profibrotic and proinflammatory action of Ang II. In dysgeusia, Ang II suppresses salt taste responses and enhances sweet taste sensitivities, while Ang (1-7) exhibits opposite effects. CONCLUSIONS: The RAS cascade plays crucial roles in OSCC, periodontitis, OSF and ageusia/dysgeusia. The imbalanced RAS may aggravate the progression of these diseases.

The role of M1 (CD11c) and M2 (CD163) interplay in the pathogenesis of oral submucous fibrosis and its malignant transformation: An immunohistochemical analysis.

OBJECTIVES: The M1/M2 macrophage framework is crucial in organ fibrosis and its progression to malignancy. This study investigated the possible role of M1/M2 macrophage interplay in the pathogenesis of oral submucous fibrosis (OSF) and its malignant transformation by analysing immunohistochemical expression of CD11c (M1) and CD163 (M2) markers. METHODS: Immunohistochemistry was performed using primary antibodies against CD11c and CD163 on ten formalin-fixed paraffin-embedded tissue blocks for each group: (i) Stage 1 OSF, (ii) Stage 2 OSF, (iii) Stage 3 OSF, (iv) Stage 4 OSF, (v) well-differentiated squamous cell carcinoma (WDSCC) with OSF, and (vi) WDSCC without OSF. Ten cases of healthy buccal mucosa (NOM) served as controls. RESULTS: Epithelial quick scores of M1 (CD11c) in NOM, Stages 1-4 OSF, and WDSCC with and without OSF were 0, 1.8, 2.9, 0.4, 0, 0, and 0, while connective tissue scores were 0, 3.2, 4.3, 2.7, 0.5, 1.2, and 2.4, respectively. Epithelial scores for M2 (CD163) were 0, 0.8, 0.8, 2.1, 0.6, 0.8, and 0.2, and connective tissue scores were 0, 1.8, 2.6, 3.9, 2.2, 5, and 4.4, respectively. Stages 3 and 4 OSF, WDSCC with and without OSF exhibited higher M2/M1 ratios compared to NOM and Stages 1-2 OSF. CONCLUSION: The interaction between M1 (CD11c) and M2 (CD163) macrophages, leading to M2 polarisation, plays a crucial role in the pathogenesis of OSF and its potential malignant transformation.

Novel role of CD34+ stromal cells/telocytes in oral submucous fibrosis development and its malignant transformation.

BACKGROUND: Telocytes are interstitial cells widely distributed in the extracellular matrix of numerous tissues distinguished by their long, thin, and moniliform projections. Telocytes have a role in the stimulation of angiogenesis and contribute to the development and progression of fibrosis. AIM: The current study aimed to assess and compare the telocyte distribution in normal mucosa, oral submucous fibrosis (OSF), and OSCC associated with OSF (OSCCOSF). MATERIALS AND METHODS: Formalin-fixed and paraffin-embedded tissue blocks of 30 OSF cases, 15 OSCCOSF cases, and 15 normal oral mucosae were obtained. Immunohistochemical staining was done with antibodies to CD34 to assess the vasculature and telocytes. The mean vascular density (MVD) and mean telocyte density were compared between the groups using the Kruskal-Walli test. RESULTS: A statistically significant high MVD (3.4 ± 1.22) and mean telocyte density (3.8 ± 1.35) was observed in OSCCOSF cases while it was lowest in advanced OSF cases. MVD was higher in early OSF cases than in normal mucosa. CONCLUSION: This study showed a decrease in CD34-positive telocytes in OSF, indicating that telocyte loss promotes the development of fibrosis.Increased angiogenesis coexisted with an increase in telocytes in OSCCOSF.

Quantitative Assessment of Receptors of Advanced Glycation End Products Expression in Tissue Samples from Patients with oral Submucous Fibrosis, Leukoplakia, and Oral Squamous Cell Carcinoma.

Background and Aim: Oxidative stress markers have been firmly established as elevated in oral squamous cell carcinomas (OSCCs). These markers play a crucial role in the pathogenic mechanism underlying the accumulation of advanced glycation end products (AGEs) and their respective receptors. The primary objective of this study is to discern and compare the levels of receptors of AGEs (RAGEs) within tissue samples from patients diagnosed with oral submucous fibrosis (OSMF) at varying stages, oral leukoplakia at various stages, and OSCC. Materials and Methods: A cross-sectional investigation was conducted, enrolling a total of 49 patients, distributed across three distinct groups. Tissue samples were meticulously collected from the aforementioned patient groups. Subsequently, these samples underwent a process of homogenization and centrifugation. The supernatant obtained was subjected to enzyme-linked immunosorbent assay analysis to precisely determine the concentration of RAGE. Results: The concentration of RAGEs was found to be significantly higher at various stages of OSMF when compared to the reference group of OSCC (P < 0.05). This difference was statistically significant, indicating a substantial association. In contrast, the levels of RAGE in patients with hyperkeratosis accompanied by epithelial dysplasia at various stages were observed to be lower than those in the OSCC group, with the difference in concentration being statistically insignificant (P > 0.05). Conclusion: This comprehensive study has provided compelling evidence demonstrating the heightened levels of RAGE in OSMF when compared to OSCC. These findings collectively suggest the potential utility of anti-RAGE interventions as a promising avenue for novel therapeutic strategies in potentially malignant disorders such as OSMF.

Targeting MetaLnc9/miR-143/FSCN1 axis inhibits oxidative stress and myofibroblast transdifferentiation in oral submucous fibrosis.

Background/purpose: Persistent activation of myofibroblasts is attributed to various dysregulated biological events conferring multiple types of fibrosis diseases, including oral submucous fibrosis (OSF). Although the significance of non-coding RNAs (ncRNAs) in the occurrence of fibrosis has been appreciated, the detailed mechanisms still have not been fully elucidated. The aim of this study was to identify key dysregulated ncRNAs and elucidate their pro-fibrotic mechanisms in promoting myofibroblast activation and the pathological development of OSF. Materials and methods: Expression of non-coding RNAs and mRNAs in OSF cohort was determined using RNA sequencing and qRT-PCR. The molecular axis of pro-fibrotic ncRNAs were exploited via luciferase reporter activity assay and RNA expression rescue experiments. Functional assays, including collagen gel contraction, wound healing ability, cell migration, and reactive oxygen species (ROS) production, were conducted to assess the changes in the myofibroblastic phenotypes of primary human buccal mucosal fibroblasts. Results: Herein, we found that long non-coding RNA MetaLnc9 was upregulated in OSF specimens and positively associated with several fibrosis markers. Silencing of MetaLnc9 diminished the features of activated myofibroblasts and the production of ROS. We not only showed that MetaLnc9 functioned as a competitive endogenous RNA of microRNA (miR)-143, but also demonstrated that the pro-fibrosis effect of MetaLnc9 on myofibroblast activities was mediated by suppression of miR-143. Moreover, our data showed that fascin actin-bundling protein 1 (FSCN1) was a direct target of miR-143 and positively related to MetaLnc9. Conclusion: Upregulation of MetaLnc9 may enhance the activation of myofibroblasts by sponging miR-143 and titrating its inhibitory property on FSCN1.

A scientometric study on research trends and characteristics of oral submucous fibrosis.

Background/purpose: Oral submucous fibrosis (OSF) affecting populations is considered a public health issue in South/Southeast Asia. The purpose of this study was to analyze the scientometric characteristics and research trends of OSF. Materials and methods: All the papers on OSF were comprehensively retrieved from the Scopus database. Regional comparison (India versus outside of India) and chronological comparison (before 2015 versus after 2015) were performed. Results: Among all the 1357 papers on OSF, 930 (68.5%) were from India. In India, biology research on antioxidant, oxidative stress, angiogenesis, and extracellular matrix were distinctive keywords. Risk factors of smokeless tobacco and gutkha and the roles of saliva and blood sampling were also distinctive keywords in India. In outside of India, biology research on myofibroblast, alpha smooth muscle actin, microRNA, long untranslated RNA, and protein p53 were distinctive keywords. The trend of biology research on connective tissue, genotype, genetic predisposition, messenger RNA, and cytology before 2015 has changed to research on myofibroblast, biological marker, microRNA, epithelial mesenchymal transition, extracellular matrix, and oxidative stress after 2015. The trend of clinical aspects of surgery and mouth hygiene before 2015 has changed to the aspects of adverse event/effects, complication, and quality of life after 2015. Conclusion: This scientometric study elucidated the current scenario and research trends of OSF, and would help in improving in reciprocal collaboration and communication for this disease control in South/Southeast Asia.

The Role and Significance of Trace Elements in Oral Submucosal Fibrosis.

Oral cancer represents the greatest cause of cancer-related morbidity and death in the majority of areas where tobacco use is common. There is accumulating evidence that the quantities of essential elements change with the beginning and progression of malignant disease. Essential elements operate as a micro-source in numerous metabolic reactions. To provide an area for the particularly important or necessary trace elements like selenium, excess of iodine (I), iron (Fe), zinc (Zn), and other minor elements other trace element disorders such as oculopharyngeal muscular dystrophy (OPMD) are treated using antioxidants. However, even elevated ingestion of these trace elements such as copper could lead to oral submucosa disorder and the advancement of diversified oral diseases and conditions. Trace element enzymes play a very vital role in a variety of biological and chemical events. In redox operations, some trace elements are complicated. Oral potentially malignant fibrosis has a profound influence on the body and early oral symptoms are frequently used to diagnose such disorders. The objective is to elaborate on the role and significance of various trace elements in oral submucous fibrosis.

Computational analysis of phytocompounds in Centella asiatica for its antifibrotic and drug-likeness properties - Herb to drug study.

Oral submucous fibrosis (OSMF) is a potentially malignant disorder with no permanent cure that affects the quality of life due to trismus. Computational pharmacology has accelerated the discovery of drug candidates for the treatment of incurable diseases. The present study aimed to screen the compounds of the miracle herb Centella asiatica with drug-likeness properties based on the absorption, distribution, metabolism, and excretion (ADME) properties. The pharmacological actions of these screened compounds against OSMF were identified by network pharmacology, gene ontology, pathway enrichment analysis, molecular docking, and simulation. Fifteen drug-like ligands were identified after virtual screening viz; asiatic acid, kaempferol, quercetin, luteolin, apigenin, bayogenin, gallic acid, isothankunic acid, madecassic acid, madasiatic acid, arjunolic acid, terminolic acid, catechin, epicatechin, and nobiletin. 850 potential targets were predicted for the ligands, which were analyzed against 354 proteins associated with OSMF. Compound pathway analysis and disease pathway analysis identified 53 common proteins. The GO enrichment analysis identified 472 biological process terms, 76 molecular function terms, and 44 cellular component terms. Pathway enrichment analysis predicted 142 KEGG pathways, 35 Biocarta pathways, and 236 Reactome pathways for the target proteins. The analysis revealed that the herb targets crucial events of fibrosis such as inflammation, oxidative stress, apoptosis, collagen deposition, and epithelial-mesenchymal transition. The common 53 proteins were used for protein-protein interaction (PPI) network analysis, which revealed 4 key proteins interacting with the phytocompounds viz; transforming growth factor-ß1 (TGF-ß1), mothers against decapentaplegic-3 (SMAD-3), mitogen-activated protein kinase-1 (MAPK-1) and proto-oncogene tyrosine-protein kinase (SRC). Molecular docking revealed that all ligands had a good binding affinity to the target proteins. Bayogenin had the highest binding affinity towards MAPK-1 (-9.7 kcal/mol), followed by isothankunic acid towards SRC protein (-9.3 kcal/mol). Madasiatic acid had the highest binding affinity to SMAD-3 (-7.6 kcal/mol) and TGF-ß1 (-7.1 kcal/mol). Molecular dynamics simulation demonstrated stable ligand protein interactions of bayogenin and MAPK complex, isothankunic acid and SRC complex. This in silico study is the first to identify potential phytochemicals present in Centella asiatica and their target molecules, which might be responsible for reversing OSMF.

Arecoline promotes fibroblast activation and M2-macrophage polarization by up-regulating the expression of IL-4.

OBJECTIVE: To determine the biological effects of arecoline on oral submucous fibrosis (OSF). DESIGN: The differential genes between OSF tissue and normal oral tissue were collected form GSE64216 dataset, analyzed by Gene Expression Omnibus (GEO) database. Real-time PCR and immunohistochemistry were used to analyze the expression of IL-4 gene and protein in oral tissue. Enzyme-linked immunosorbent assay (ELISA) was used to analyze the expression of exocrine IL-4 protein in human oral fibroblasts (HOF) pre-treated by arecoline. Cell Counting Kit-8 (CCK-8) and transwell assays were used to analyze the proliferation and migration of HOF cells, respectively. After IL-4 was knocked down by short hairpin (sh) plasmid, the proliferation and migration of HOF cells were detected. Flow cytometry was used to analyze the proportion of M2-macrophages. Real-time PCR and immunohistochemistry were used to verify the expression of biomarker proteins of macrophages in OSF tissues. RESULTS: The expression of IL-4 gene and protein were both up-regulated in OSF tissue. Arecoline could enhance the expression of IL-4 gene and exocrine protein in HOF cells, and promote the proliferation and migration of HOF cells. While knockdown of IL-4 could inhibit arecoline-induced proliferation and migration in HOF cells. The results of flow cytometry showed that recombinant human IL-4 (rhIL-4) protein could increase the proportion of M2-macrophages. Similarly, the results of real-time PCR and immunohistochemistry showed the expression of ARG1 (Biomarker proteins of M2-macrophage) was up-regulated in OSF tissues. CONCLUSION: Arecoline promotes activation of fibroblasts and polarization of M2-macrophages by up-regulating the expression of IL-4.

Mechanism of mangiferin in the treatment of oral submucous fibrosis based on Gene Expression Omnibus database chip mining combined with network pharmacology and molecular docking.

OBJECTIVES: This study aims to investigate the primary target and potential mechanism of mangiferin (MF) in treating oral submucous fibrosis (OSF) through Gene Expression Omnibus (GEO) database chip mining, network pharmacology, and molecular docking techniques. METHODS: Potential therapeutic targets for OSF were identified using GEO chip data. The potential targets of MF were predicted, and disease-related targets for OSF were collected from databases. A Venn diagram was created using the EVenn platform to identify overlapping targets. The protein-protein interaction (PPI) network was constructed using the STRING database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the DAVID platform. Cytoscape 3.10.1 software was used to visualize a drug-target-pathway-disease network, while AutoDocktools 1.5.6 software was employed for molecular docking analysis. RESULTS: A total of 356 potential targets for MF and 360 disease-related targets for OSF were obtained from multiple databases. The top 15 key target proteins in the PPI network were selected as significant candidates. GO function and KEGG pathway enrichment analyses revealed that MF treatment primarily involved advanced glycation end products-receptor (AGE-RAGE), epidermal growth factor receptor (EGFR), and other signaling pathways associated with OSF pathogenesis. Molecular docking analysis demonstrated that MF exhibited a strong binding activity toward AKT serine kinase 1 (AKT1), tumor necrosis factor (TNF), and other core targets. CONCLUSIONS: These findings suggest that MF may exert its therapeutic effects on OSF through a multitarget approach involving various signaling pathways.

Alteration of salivary LPO, MDA, LDH, glutathione, GPx, SOD and vitamins in oral submucous fibrosis: A three-level meta-analysis study.

This study aims to investigate the alteration of salivary biomarker profiling in the development of oral submucous fibrosis (OSMF) and to explore the influence of saliva in the diagnosis of OSMF. A systematic search of published articles using the PRISMA guidelines was conducted to identify relevant studies on OSMF and saliva. All eligible studies, including case-control, cross-sectional studies, cohort, and pilot studies, contained the evaluation of salivary biomarker profiling in patients with OSMF. Salivary biomarker data from 28 selected articles were categorized into nine groups, and their mean values were determined. A three-step meta-analysis was performed by grouping salivary biomarker profiling into more heterogeneous categories based on OSMF classification, considering functional, histological, and clinical grading. The salivary biomarker profiling analysis revealed significant alterations in all markers, indicating their efficacy in OSMF diagnosis. Subgroup analyses highlighted significant associations in oxidative stress and protein with increased mean values, particularly emphasizing lipid peroxidase (LPO), malondialdehyde (MDA), and lactate dehydrogenase (LDH). Conversely, decreased mean values were observed in glutathione, glutathione peroxidase (GPx), superoxide dismutase (SOD), and vitamins. Notably, OSMF grading analysis demonstrated a significant difference in weighted effect sizes for histological grading, particularly in stage IV. The study underscores the alteration of specific salivary biomarkers, particularly those associated with LPO, MDA, LDH, glutathione, GPx, SOD, and vitamins, in diagnosing and grading OSMF.

A Case of Advanced Oral Submucous Fibrosis Management: Beyond Conventional Approach.

A chronic, persistent, possibly cancerous condition that mostly affects the oral cavity is called oral submucous fibrosis (OSMF) and causes severe functional impairment. Due to its complex nature, OSMF requires a comprehensive strategy that includes both surgical and medication therapies. Multidisciplinary treatment was started, which included a complete stoppage of habit, dental hygiene precautions, dietary counselling, surgical intervention, supportive medicinal therapy, and physiotherapy. Following surgery and adjunct therapy, the patient's mouth opening and functional results were improved. The patient is kept for regular follow-up to assess the recurrence of fibrosis or any incidence of malignant transformation. This case emphasizes the difficulties in treating advanced OSMF and emphasizes how crucial it is to improve patient outcomes by early detection, stopping betel nut chewing, and thorough multidisciplinary care.

Epidemiological Trends and Clinicopathological Characteristics of Oral Leukoplakia: A Retrospective Analysis From a Single Institution in Chennai, Tamil Nadu, India.

Background India has a high prevalence of oral potentially malignant disorders and malignant transformation. Cases of oral leukoplakia are not commonly encountered, and only a small cohort of patients undergo biopsies for the same. This study aims to assess the various etiological factors causing leukoplakia, the clinical features, histopathological findings, and treatment received by the patients who were histopathologically diagnosed with oral leukoplakia. Methodology Oral leukoplakia cases were included in this study from total biopsy samples received in the oral pathology department. Details were collected from the Dental Information Archival Software of our institution. The period analyzed was from January 1, 2021, to December 31, 2023. Relevant clinical and histopathological details were retrieved and tabulated. Statistical analysis (chi-square test) was used to assess the association between the clinicopathological parameters using SPSS software version 21.0 (IBM Corp., Armonk, NY, USA) with a significance level set at a p-value <0.05. Results A total of 76 oral leukoplakia cases were retrieved from 2,600 biopsy samples. The prevalence of oral leukoplakia was 3.1% to 3.4% for the three years. Leukoplakia was commonly observed in those aged 51 to 60 years (33%). Overall, 21% of the patients with leukoplakia showed severe epithelial dysplasia, 22% showed mild epithelial dysplasia, and 39% showed moderate epithelial dysplasia. Moreover, 30% of the patients presented with leukoplakia and oral submucous fibrosis and showed varying degrees of epithelial dysplasia. Finally, 45% of the patients were managed conservatively using pharmacotherapy. Conclusions Severe epithelial dysplasia was commonly associated with oral leukoplakia. Oral submucous fibrosis was also found to be associated with leukoplakia and showed epithelial dysplasia. None of our proliferative verrucous leukoplakia cases showed any association with oral submucous fibrosis. Surgical management was the preferred treatment.

TUSC3, p53 and p21 genetic association with development of oral submucous fibrosis and oral squamous cell carcinoma among addictive tobacco chewers of Pakistan.

BACKGROUND: This study delves into the intricate landscape of oral cancer, a global concern with a high incidence in Asian countries. We focus on oral squamous cell carcinoma (OSCC), primarily driven by the consumption of betel nut and its derivatives. OSCC often arises from premalignant lesions like oral submucous fibrosis (OSF). In Pakistan, OSCC is prevalent among men due to various addictive substances, including smokeless tobacco and chewing materials. Mutations in tumor suppressor genes, such as TP53 and p21, play crucial roles in this malignancy's development. We also explore the involvement of TUSC3 gene deletion in OSCC and OSF. METHODS: In this study we investigated demographics, TUSC3 gene expression, deletion analysis, and TP53 and p21 genetic alterations in OSCC and OSF patients (blood and tissue of 50 samples in each condition) who had tobacco derivates usage history. The association analysis was carried out mainly through PCR based genotyping. RESULTS: The study's patient cohort (OSCC and OSF) displayed a wide age range from 13 to 65 years (Mean = 32.96 years). Both conditions were more prevalent in males, with a male-female ratio of approximately 2.5:1. Chewing habits analysis revealed high frequencies of gutka use in both OSF and OSCC patients. TUSC3 expression analysis in OSCC cell lines indicated significant downregulation. Genotyping showed no TUSC3 deletion in OSF cases, but a deletion rate of over 22% in OSCC tissue samples. Analysis supported a significant association of TUSC3 deletion with OSCC development but not with OSF. Polymorphism in p53 exon 4 and p21 (rs1801270) were significantly associated with both OSCC and OSF, adding to their pathogenesis. Our findings further revealed a strong correlation between TUSC3 deletion and the excessive use of tobacco and related products, shedding light on the genetic underpinnings of OSCC development. CONCLUSIONS: Notably, our study provides a crucial insight into genetic aspects underlying OSCC and OSF in response of addictive consumption of areca nut, betel quid, and tobacco derivatives. A significant association between TUSC3 deletion and OSCC development, along with polymorphisms in TP53 and p21, underscores the importance of further research into the molecular mechanisms driving oral cancer progression for improved diagnosis and treatment outcomes.

Oropharyngeal stenosis in patient with oral submucous fibrosis: a case report with 8-year follow-up.

Oral submucous fibrosis (OSF) is a chronic, progressive condition affecting the oral mucosa associated with areca nut consumption. It leads to restricted tongue movement, loss of papillae, blanching and stiffening of the mucosa, difficulty in opening the mouth, and challenges in eating due to inflammation and fibrosis. This report presents a rare case of oropharyngeal stenosis secondary to OSF in a 43-year-old male with a history of chewing betel nut. A surgical procedure similar to Uvulopalatopharyngoplasty was performed to excise the submucous oropharyngeal stenosis and to reconstruct the uvula, palatoglossal arch, and palatopharyngeal arch. At 8 years postoperatively, the patient exhibited a normal mouth opening and oropharyngeal aperture.

Role of Stem Cells in the Pathogenesis and Malignant Transformation of Oral Submucous Fibrosis.

BACKGROUND: Pathogenesis and malignant potential of Oral submucous fibrosis(OSMF) have always been a topic of interest among the researchers. Despite OSMF being a collagen metabolic disorder, the alterations occurring in the connective tissue stroma affects the atrophic surface epithelium in later stages and progresses to malignant phenotypes. The present review aims to summarize the role of stem cells in the pathogenesis and malignant transformation of oral submucous fibrosis. MATERIALS AND METHODS: A literature search was carried out using data banks like Medline and Embase, google scholar and manual method with no time frame, pertinent to the role of mucosal stem cells in OSMF and its malignisation. The relevant literature was reviewed, critically appraised by all the authors and compiled in this narrative review. RESULTS: Critical appraisal and evaluation of the data extracted from the selected articles were compiled in this review. The collated results highlighted the upregulation and downregulation of various stem cell markers during the progression and malignisation of OSMF were depicted in a descriptive and detail manner in the present review. CONCLUSION: We highlight the potential of mucosal stem cells in the regulation and malignisation of OSMF. However, future large-scale clinical studies will be needed to support whether manipulation of this stem cells at molecular level will be sufficient for the treatment and preventing the malignant transformation of OSMF.

The association between betel quid use and oral potentially malignant and malignant disorders in Southeast Asian and Pacific regions: a systematic review and meta-analysis with GRADE evidence profile.

Background: Betel quid (BQ) chewing is a prevalent habit in the Asian and Pacific regions. It is deeply intertwined within cultural customs, and has been reported to result in oral potentially malignant disorders (OPMDs) and malignant disorders (MDs). Objective: We aim to present a summative and broad overview of the burden that BQ chewing has imposed on the residents of the Southeast Asian, Pacific, and Australasian regions, allowing us to quantify the level of impact it is currently causing on the risk of people developing oral cancer. Methods: This scoping review and meta-analysis screened databases such as PubMed, MEDLINE, and Google Scholar for publications that investigated the association between BQ and OPMDs and MDs. The search strategy involved MeSH headings relating to BQ, OPMDs, and MDs, and a search for results during the period between January 2010 and June 2023 within the set geographical boundaries of the Southeast Asian and Pacific regions. This systematic review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement for Scoping Reviews (PRISMA-ScR). R software was used to screen outliers. The included studies were further analysed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Results: Nine articles (n = 19,312 participants) presented odds ratio outcomes from 11 regionally different study groups. We indicated a strong correlation between BQ chewing and the increased risk of OMPDs and MDs. The risk was quantified through meta-analyses with an odds ratio (OR) of 8.18 (5.27-12.72) and an increased OR of 9.93 (7.36-13.39) when the outlier was removed. BQ chewing was further identified within various Australian communities and discovered to be produced locally in North Queensland. Discussion: A meta-analysis of two outcomes revealed substantial heterogeneity and minor evidence of publication bias, thus the association effect was included with and without these articles. The overall GRADE quality of evidence ranged from moderate to very high and highlighted five studies with a high level of imprecision. Conclusion: The lingering high prevalence of BQ in the Southeast Asia and Pacific regions, as well as its rising acceptance among non-ethnic Australians, is alarming and requires prompt and rigorous intervention to prevent the risk of oral cancer. Systematic Review Registration: PROSPERO (CRD42023429694).

Role of Antioxidant Vitamins in Oral Submucous Fibrosis: A Narrative Review.

Oral submucous fibrosis (OSMF) has a high rate of malignant transformation and is an insidious chronic inflammatory disease. Though this disorder seems to be multifactorial in origin, betel quid chewing appears to be the main etiologic factor. Various treatment strategies have been attempted but none proven to cure the disorder because of its multimodal pathogenesis. Reactive oxygen species (ROS) appear to have a role in cancer formation. As OSMF is an oral premalignant disorder and found to be associated with carcinogens like areca nut and tobacco, it is believed to have some relationship with ROS. Tissue damage due to ROS along with other mechanisms may result in the complex pathophysiology of OSMF. The antioxidant system in the body helps to prevent damage caused by highly reactive ROS and helps in the repair of tissues. To study the levels of oxidative stress and antioxidant vitamins in OSMF condition, the present review was done. We carried out a thorough literature search to identify original reports and studies determining the status of oxidative stress and antioxidant vitamins in OSMF condition using several databases including Google Scholar, PubMed, and Scopus. Our review observed that the oxidative stress increased in the condition of OSMF as shown by an increase in malonaldehyde (MDA) and a decrease in antioxidant vitamins like vitamin A, vitamin C, and vitamin E. Also, after the intake of antioxidant vitamins, there was symptomatic improvement in OSMF patients. With the help of identifying oxidative stress and antioxidant status, we can assess the clinical stage of OSMF and can develop a comprehensive treatment plan.

Correlation between Vascularity and Advancing Histological Grades of Oral Submucous Fibrosis with a Plausible Role in Malignisation: Systematic review of a persisting matter of conflict.

Objectives: This study aimed to quantify the vascularity in histological grades of oral submucous fibrosis (OSMF) and to determine if there is any connection between vasculogenesis and malignisation. Recent studies show no significant change in vascularity as the stage advances as opposed to the conventional concept. Methods: A comprehensive database search until December 2022 was conducted for published articles on vascularity in OSMF following preferred reporting items for systematic reviews and meta-analyses guidelines. Results: A total of 98 articles were screened of which 13 were included for systematic evaluation. The study included 607 cases, with a definite predilection for the male gender. Of the 13 studies, 11 evaluated mean vascular density. In more than half of the studies, the vascularity decreased as the stage advanced. Similar results were obtained for endothelial cells/µm2, mean vascular area percentage and mean vascular area. Conclusion: The present review supports the prevailing concept that vascularity decreases with the advancement of the OSMF stage. This denies the systemic absorption of carcinogens into the circulation with resultant longer exposure of compromised epithelium and malignisation.