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Journal of Oral Biosciences Jun 2024Oral submucous fibrosis (OSF) is a pathological condition characterized by excessive tissue healing resulting from physical, chemical, or mechanical trauma. Notably,... (Review)
Review
BACKGROUND
Oral submucous fibrosis (OSF) is a pathological condition characterized by excessive tissue healing resulting from physical, chemical, or mechanical trauma. Notably, areca nut consumption significantly contributes to the development of oral fibrosis. The current definition of OSF, recognizing its potential for malignant transformation, necessitates a more comprehensive understanding of its pathophysiology and etiology.
HIGHLIGHTS
Areca nut induces fibrotic pathways by upregulating inflammatory cytokines such as TGF-β and expressing additional cytokines. Moreover, it triggers the conversion of fibroblasts to myofibroblasts, characterized by α-SMA and γSMA expression, resulting in accelerated collagen production. Arecoline, a component of areca nut, has been shown to elevate levels of reactive oxygen species, upregulate the expression of various cytokines, and activate specific signaling pathways (MEK, COX2, PI3K), all contributing to fibrosis. Therefore, we propose redefining OSF as "Areca nut-induced oral fibrosis" (AIOF) to align with current epistemology, emphasizing its distinctive association with areca nut consumption. The refined definition enhances our ability to develop targeted interventions, thus contributing to more effective prevention and treatment strategies for oral submucous fibrosis worldwide.
CONCLUSION
Arecoline plays a crucial role as a mediator in fibrosis development, contributing to extracellular matrix accumulation in OSF. The re-evaluation of OSF as AIOF offers a more accurate representation of the condition. This nuanced perspective is essential for distinguishing AIOF from other forms of oral fibrosis and advancing our understanding of the disease's pathophysiology.
Topics: Oral Submucous Fibrosis; Humans; Areca; Arecoline; Cytokines; Signal Transduction; Nuts
PubMed: 38395254
DOI: 10.1016/j.job.2024.02.005 -
Current Issues in Molecular Biology Feb 2024Carcinogens, such as arecoline, play a crucial role in cancer progression and continuous gene mutations by generating reactive oxygen species (ROS). Antioxidants can...
Carcinogens, such as arecoline, play a crucial role in cancer progression and continuous gene mutations by generating reactive oxygen species (ROS). Antioxidants can reduce ROS levels and potentially prevent cancer progression but may paradoxically enhance the survival of cancer cells. This study investigated whether epigallocatechin-3-gallate (EGCG), an antioxidant from green tea, could resolve this paradox. Prostate cancer cells (PC-3 cell line) were cultured and treated with arecoline combined with NAC (N-acetylcysteine) or EGCG; the combined effects on intracellular ROS levels and cell viability were examined using the MTT and DCFDA assays, respectively. In addition, apoptosis, cell cycle, and protein expression were investigated using flow cytometry and western blot analysis. Our results showed that EGCG, similar to NAC (N-acetylcysteine), reduced the intracellular ROS levels, which were elevated by arecoline. Moreover, EGCG not only caused cell cycle arrest but also facilitated cell apoptosis in arecoline-treated cells in a synergistic manner. These were evidenced by elevated levels of cyclin B1 and p27, and increased fragmentation of procaspase-3, PARP, and DNA. Our findings highlight the potential use of EGCG for cancer prevention and therapy.
PubMed: 38392216
DOI: 10.3390/cimb46020098 -
Addiction Biology Feb 2024Stimulant betel quid (SBQ) containing Piper betle leaf (L), green unripe Areca catechu nut (AN) and the alkalizing agent, slaked lime, is an addictive, carcinogenic...
Stimulant betel quid (SBQ) containing Piper betle leaf (L), green unripe Areca catechu nut (AN) and the alkalizing agent, slaked lime, is an addictive, carcinogenic stimulant, with no pharmacotherapy, chewed by millions of people in the Asia/Pacific region. We compared the in vivo physiological profile of chewing (1) non-stimulant P. betle leaf+AN (LAN), (2) SBQ utilizing slaked lime and (3) a novel SBQ utilizing Mg(OH) , as an alkalizing agent, by measuring physiological parameters of intoxication and these were correlated with in vitro levels of alkaloids measured by UHPLC-MS/MS. Chewing LAN, which contains high levels of arecoline, had no stimulatory physiological effect. Chewing SBQ containing slaked lime or novel SBQ containing Mg(OH) , induced equivalent stimulatory physiological responses. In vitro, slaked lime hydrolyzed muscarinic esters in LAN while Mg(OH) did not. The physiological stimulation induced by chewing both SBQ and the lack of physiology to chewing LAN can be explained by changes in lipid solubility of phytochemicals induced by mouth pH during chewing of basic SBQ or acidic LAN. Since antiquity people have added slaked lime to SBQ to enhance absorption of phyto-chemicals across oral membranes to stimulate physiology. The same physiological changes can be induced by substituting slaked lime for less physically and chemically destructive bases. If attitudes regarding SBQ dependence can advance towards the more progressive attitudes already used to help smokers quit tobacco, modern chemistry has the potential to make chewing SBQ safer and quitting programs may become more accessible and efficacious.
Topics: Humans; Areca; Proof of Concept Study; Tandem Mass Spectrometry; Calcium Compounds; Oxides
PubMed: 38380696
DOI: 10.1111/adb.13371 -
Journal of Dental Sciences Jan 2024Transient receptor potential melastatin 8 (TRPM8), a thermosensitive ion channel known for its role in cold sensation and menthol response, has emerged as a potential...
Association of higher transient receptor potential melastatin 8 expression with higher tumor histologic grades, lymph node metastasis, risk factors, and worse survival in patients with head and neck squamous cell carcinoma.
BACKGROUND/PURPOSE
Transient receptor potential melastatin 8 (TRPM8), a thermosensitive ion channel known for its role in cold sensation and menthol response, has emerged as a potential regulator in various cancers. This study aimed to investigate expression trends of TRPM8 in head and neck squamous cell carcinoma (HNSCC) cases and oral squamous cell carcinoma (OSCC) cell lines and its association with clinicopathological features.
MATERIALS AND METHODS
The noncancerous matched tissues and HNSCC paired tissue samples from 84 HNSCC patients were utilized to evaluate the association of with HNSCC clinicopathological features. expression was examined in HNSCC patient tissues and OSCC cell lines treated with arecoline.
RESULTS
Kaplan-Meier survival analysis of TCGA data revealed high expression correlated with unfavorable outcomes and higher tumor histologic grades. mRNA expression was upregulated in HNSCC cell lines and patients' tissue samples. Arecoline treatment led to significantly increased mRNA and protein expression in OSCC cell lines. Lymph node metastasis showed a significant association with upregulated expression in combined OSCC and oropharyngeal squamous cell carcinoma (OPSCC) cases. mRNA expression was upregulated in HNSCC and OSCC patients with alcohol drinking and cigarette smoking habits, but not in betel quid chewing.
CONCLUSION
These findings reveal the involvement of in HNSCC's malignant development and metastasis, suggesting that high expression of TRMP8 may be mutually causal with addiction to tobacco, alcohol, and betel nut in HNSCC patients. Further investigations are needed to determine the underlying pathways of in HNSCC's development and progression.
PubMed: 38303833
DOI: 10.1016/j.jds.2023.09.007 -
Journal of Dental Sciences Jan 2024Oral submucosal fibrosis (OSF) is a premalignant disorder positively associated with betel nut chewing. Recent studies supported the promising benefits of histone...
BACKGROUND/PURPOSE
Oral submucosal fibrosis (OSF) is a premalignant disorder positively associated with betel nut chewing. Recent studies supported the promising benefits of histone deacetylase (HDAC) inhibitors for fibrosis treatment. Here we aim to clarify the pro-fibrogenic role of HDAC9 in regulating OSF.
MATERIALS AND METHODS
Healthy and OSF specimens were collected to investigate the clinical significance of HDAC9. Chronic arecoline treatment process was used to induce arecoline-mediated myofibroblasts-related activation of primary buccal mucosa fibroblasts (BMFs). Functional analysis of collagen gel contraction, transwell migration, and wound-healing assays were performed to assess the change in pro-fibrogenic properties of BMFs and fibrotic BMFs (fBMFs). Lentiviral-mediated HDAC9 knockdown was used to verify the role of HDAC9 in the pro-fibrogenic process.
RESULTS
We found that arecoline significantly increased the mRNA and protein expression of HDAC9 of BMFs in a dose-dependent manner. Knockdown of HDAC9 in BMFs reversed the strengthened effects of arecoline on collagen gel contraction, cell migration, and wound-healing ability. We further demonstrated that knockdown of HDAC9 in fBMFs significantly attenuated its inherent pro-fibrogenic properties. Furthermore, we confirmed a significantly increased expression of HDAC9 mRNA in OSF compared to normal tissues, which suggested a positive correlation between the up-regulation of HDAC9 and OSF.
CONCLUSION
We demonstrated that silencing of HDAC9 inhibited arecoline-induced activation and inherent pro-fibrogenic properties, suggesting potential therapeutics by targeting HDAC9 in the OSF treatment.
PubMed: 38303807
DOI: 10.1016/j.jds.2023.05.029 -
Pharmaceuticals (Basel, Switzerland) Dec 2023Arecoline is the primary active carcinogen found in areca nut and has been implicated in the pathogenesis of oral squamous cell carcinoma (OSCC) and oral submucous... (Review)
Review
Arecoline is the primary active carcinogen found in areca nut and has been implicated in the pathogenesis of oral squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSF). For this study, we conducted a stepwise review process by combining iterative scoping reviews with a post hoc search, with the aim of identifying the specific mechanisms by which arecoline initiates and promotes oral carcinogenesis. Our initial search allowed us to define the current trends and patterns in the pathophysiology of arecoline-induced OSF and OSCC, which include the induction of cell proliferation, facilitation of invasion, adhesion, and migration, increased collagen deposition and fibrosis, imbalance in immune and inflammatory mechanisms, and genotoxicity. Key molecular pathways comprise the activation of NOTCH1, MYC, PRDX2, WNT, CYR61, EGFR/Pl3K, DDR1 signaling, and cytokine upregulation. Despite providing a comprehensive overview of potential pathogenic mechanisms of OSF, the involvement of molecules functioning as areca alkaloid receptors, namely, the muscarinic and nicotinic acetylcholine receptors (AChRs), was not elucidated with this approach. Accordingly, our search strategy was refined to reflect these evidence gaps. The results of the second round of reviews with the post hoc search highlighted that arecoline binds preferentially to muscarinic AChRs, which have been implicated in cancer. Consistently, AChRs activate the signaling pathways that partially overlap with those described in the context of arecoline-induced carcinogenesis. In summary, we used a theory-driven interpretive review methodology to inform, extend, and supplement the conventional systematic literature assessment workflow. On the one hand, the results of this critical interpretive synthesis highlighted the prevailing trends and enabled the consolidation of data pertaining to the molecular mechanisms involved in arecoline-induced carcinogenesis, and, on the other, brought up knowledge gaps related to the role of the local cholinergic axis in oral carcinogenesis, thus suggesting areas for further investigation.
PubMed: 38139811
DOI: 10.3390/ph16121684 -
Toxics Dec 2023Arecoline is a pyridine alkaloid derived from areca nut in the Arecaceae family. It has extensive medicinal activity, such as analgesic, anti-inflammatory, and...
Arecoline is a pyridine alkaloid derived from areca nut in the Arecaceae family. It has extensive medicinal activity, such as analgesic, anti-inflammatory, and anti-allergic. However, the toxicity of Arecoline limits its application. Most current studies on its toxicity mainly focus on immunotoxicity, carcinogenesis, and cancer promotion. However, there are few systematic studies on its hepatotoxicity and mechanisms. Therefore, this research explored the mechanism of hepatotoxicity induced by Arecoline in rats and analyzed endogenous metabolite changes in rat plasma by combining network toxicology with metabolomics. The differential metabolites after Arecoline exposure, such as D-Lysine, N4-Acetylaminobutanal, and L-Arginine, were obtained by metabolomics study, and these differential metabolites were involved in the regulation of lipid metabolism, amino acid metabolism, and vitamin metabolism. Based on the strategy of network toxicology, Arecoline can affect the HIF-1 signaling pathway, MAPK signaling pathway, PI3K-Akt signaling pathway, and other concerning pathways by regulating critical targets, such as ALB, CASP3, EGFR, and MMP9. Integration of metabolomics and network toxicology results were further analyzed, and it was concluded that Arecoline may induce hepatotoxicity by mediating oxidative stress, inflammatory response, energy and lipid metabolism, and cell apoptosis.
PubMed: 38133385
DOI: 10.3390/toxics11120984 -
The Chinese Journal of Dental Research Dec 2023Oral submucous fibrosis (OSF) is a chronic, progressive and potentially malignant oral mucosal disease. Patients often have a habit of chewing betel nuts. Areca catechu...
Oral submucous fibrosis (OSF) is a chronic, progressive and potentially malignant oral mucosal disease. Patients often have a habit of chewing betel nuts. Areca catechu has been listed as a Class 1 carcinogen by the International Agency for Research on Cancer (IARC), and its main active component, arecoline, is classified as a Group 2B carcinogen by the IARC. The World Health Organization (WHO) categorises OSF as an oral potentially malignant disorder (OPMD). The present guideline describes the risk factors, clinical symptoms and clinical signs of OSF. Clinical staging, auxiliary examination methods, basis for diagnosis and differential diagnosis and the need to improve bad lifestyle habits are proposed and addressed, and local treatment drugs, therapies, dosage and course of treatment, possible adverse reactions, and oral treatment drugs, dosage and course of treatment are proposed. The guideline also addresses the indications for surgical treatment, alternative non-drug treatment methods, selection of treatment plans for different clinical stages, criteria for efficacy evaluation, and preventive measures.
Topics: Humans; Oral Submucous Fibrosis; Mouth Diseases; Risk Factors; Precancerous Conditions; Areca; Carcinogens
PubMed: 38126373
DOI: 10.3290/j.cjdr.b4784075 -
Biomolecules & Biomedicine Dec 2023Oral submucous fibrosis (OSF) is a prevalent chronic condition, and understanding its pathogenesis is crucial for developing effective therapeutic strategies. This study...
Mechanism of adipose tissue-derived stromal cell-extracellular vesicles in treating oral submucous fibrosis by blocking the TGF-β1/Smad3 pathway via the miR-760-3p/IGF1R axis.
Oral submucous fibrosis (OSF) is a prevalent chronic condition, and understanding its pathogenesis is crucial for developing effective therapeutic strategies. This study explores the potential of adipose tissue-derived stromal cell-extracellular vesicles (ADSC-EVs) in mitigating OSF and investigates the underlying molecular mechanisms. OSF was induced in mice by arecoline feeding. Adipose tissue-derived stromal cells (ADSCs), fibrotic buccal mucosal fibroblasts (fBMFs) isolated from OSF mice, and ADSC-EVs were comprehensively characterized. The treatment effects of extracellular vesicles (EVs) and pcDNA3.1-IGF1R on fBMF proliferation, migration, and invasion were assessed using Cell Counting Kit-8 (CCK-8) assay, transwell assay, and flow cytometry assay. The expression levels of alpha smooth muscle actin (α-SMA), collagen I, collagen III, and insulin-like growth factor 1 receptor (IGF1R) were evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. The interaction between miR-760-3p and IGF1R was investigated. In fBMFs and OSF mice treated with a miR-760-3p inhibitor and/or EVs, the expression patterns of miR-760-3p, IGF1R, and proteins related to the TGF-β1/Smad3 pathway were determined. ADSC-EVs demonstrated the ability to upregulate miR-760-3p, impede cell proliferation, migration, and invasion, and reduce α-SMA, collagen I, and collagen III levels in fBMFs. The expression of miR-760-3p was diminished in ADSC-EVs treated with a miR-760-3p inhibitor. However, silencing miR-760-3p or overexpressing IGF1R partially counteracted the beneficial effects of ADSC-EVs on fBMF fibrosis. miR-760-3p directly targets IGF1R. Significantly, ADSC-EVs exert their suppressive effects on the TGF-β1/Smad3 pathway through the miR-760-3p/IGF1R axis. In summary, ADSC-EVs, by transferring miR-760-3p and inhibiting IGF1R expression, effectively block the TGF-β1/Smad3 pathway, thereby alleviating fibrosis in fBMFs and preventing the progression of OSF.
PubMed: 38059910
DOI: 10.17305/bb.2023.9944 -
ACS Chemical Neuroscience Dec 2023Docosahexaenoic acid [22:6(-3), DHA], a polyunsaturated fatty acid, has an important role in regulating neuronal functions and in normal brain development. Dysregulated...
Synthesis and Preclinical Evaluation of 22-[F]Fluorodocosahexaenoic Acid as a Positron Emission Tomography Probe for Monitoring Brain Docosahexaenoic Acid Uptake Kinetics.
Docosahexaenoic acid [22:6(-3), DHA], a polyunsaturated fatty acid, has an important role in regulating neuronal functions and in normal brain development. Dysregulated brain DHA uptake and metabolism are found in individuals carrying the APOE4 allele, which increases the genetic risk for Alzheimer's disease (AD), and are implicated in the progression of several neurodegenerative disorders. However, there are limited tools to assess brain DHA kinetics that can be translated to humans. Here, we report the synthesis of an ω-radiofluorinated PET probe of DHA, 22-[F]fluorodocosahexaenoic acid (22-[F]FDHA), for imaging the uptake of DHA into the brain. Using the nonradiolabeled 22-FDHA, we confirmed that fluorination of DHA at the ω-position does not significantly alter the anti-inflammatory effect of DHA in microglial cells. Through dynamic PET-MR studies using mice, we observed the accumulation of 22-[F]FDHA in the brain over time and estimated DHA's incorporation coefficient (*) using an image-derived input function. Finally, DHA brain * was validated using intravenous administration of 15 mg/kg arecoline, a natural product known to increase the DHA * in rodents. 22-[F]FDHA is a promising PET probe that can reveal altered lipid metabolism in APOE4 carriers, AD, and other neurologic disorders. This new probe, once translated into humans, would enable noninvasive and longitudinal studies of brain DHA dynamics by guiding both pharmacological and nonpharmacological interventions for neurodegenerative diseases.
Topics: Humans; Mice; Animals; Docosahexaenoic Acids; Apolipoprotein E4; Brain; Positron-Emission Tomography; Biological Transport; Alzheimer Disease
PubMed: 38048230
DOI: 10.1021/acschemneuro.3c00681