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International Journal of Molecular... Sep 2020Oral submucous fibrosis (OSF) is a collagen deposition disorder that affects a patient's oral function and quality of life. It may also potentially transform into... (Review)
Review
Oral submucous fibrosis (OSF) is a collagen deposition disorder that affects a patient's oral function and quality of life. It may also potentially transform into malignancy. This review summarizes the risk factors, pathogenic mechanisms, and treatments of OSF based on clinical and bio-molecular evidence. Betel nut chewing is a major risk factor that causes OSF in Asia. However, no direct evidence of arecoline-induced carcinogenesis has been found in animal models. Despite identification of numerous biomarkers of OSF lesions and conducting trials with different drug combinations, clinicians still adopt conservative treatments that primarily focus on relieving the symptoms of OSF. Treatments focus on reducing inflammation and improving mouth opening to improve a patient's quality of life. In conclusion, high-quality clinical studies are needed to aid clinicians in developing and applying molecular biomarkers as well as standard treatment guidelines.
Topics: Areca; Arecoline; Biomarkers; Collagen; Humans; Mouth Mucosa; Mouth Neoplasms; Oral Submucous Fibrosis; Risk Factors
PubMed: 33008091
DOI: 10.3390/ijms21197231 -
Journal of Dental Research Sep 2022Areca nut chewing is one of the major risk factors for oral cancer, with large-magnitude risks reported in studies comparing betel quid chewers and never users, and it... (Meta-Analysis)
Meta-Analysis
Areca nut chewing is one of the major risk factors for oral cancer, with large-magnitude risks reported in studies comparing betel quid chewers and never users, and it has been evaluated as a group 1 carcinogen by the International Agency for Research on Cancer. Data from a high-quality meta-analysis examining risk estimates are presented in summary form with additional information from more recent studies (pooled adjusted relative risk, 7.9; 95% CI, 7.1 to 8.7). The risk of oral cancer increases in a dose-response manner with the daily number of quids consumed and the number of years chewing. In the Indian subcontinent and in Taiwan, approximately half of oral cancers reported are attributed to betel quid chewing (population attributable fraction, 53.7% for residents in Taiwan and 49.5% for the Indian population), a disease burden that could be prevented. Oral leukoplakia and oral submucous fibrosis are 2 main oral potentially malignant disorders caused by areca nut chewing that can progress to oral cancer with continued use. Ex-chewers seem to demonstrate lower risks than current chewers, but the impact of areca nut cessation on oral cancer risk has not been scientifically evaluated on the basis of randomized controlled studies. These data strongly reconfirm that betel quid chewing, primarily areca nut use, should be taken into account in assessing the cancer risk of South Asian, East Asian populations and Pacific Islanders for the development of oral cancer.
Topics: Areca; Humans; Mouth Neoplasms; Nuts; Precancerous Conditions; Risk Factors
PubMed: 35459408
DOI: 10.1177/00220345221092751 -
Theranostics 2021NRF2, a redox sensitive transcription factor, is up-regulated in head and neck squamous cell carcinoma (HNSCC), however, the associated impact and regulatory mechanisms...
NRF2, a redox sensitive transcription factor, is up-regulated in head and neck squamous cell carcinoma (HNSCC), however, the associated impact and regulatory mechanisms remain unclear. The protein expression of NRF2 in HNSCC specimens was examined by IHC. The regulatory effect of c-MYC on NRF2 was validated by ChIP-qPCR, RT-qPCR and western blot. The impacts of NRF2 on malignant progression of HNSCC were determined through genetic manipulation and pharmacological inhibition and . The gene-set enrichment analysis (GSEA) on expression data of cDNA microarray combined with ChIP-qPCR, RT-qPCR, western blot, transwell migration/ invasion, cell proliferation and soft agar colony formation assays were used to investigate the regulatory mechanisms of NRF2. NRF2 expression is positively correlated with malignant features of HNSCC. In addition, carcinogens, such as nicotine and arecoline, trigger c-MYC-directed NRF2 activation in HNSCC cells. NRF2 reprograms a wide range of cancer metabolic pathways and the most notable is the pentose phosphate pathway (PPP). Furthermore, glucose-6-phosphate dehydrogenase (G6PD) and transketolase (TKT) are critical downstream effectors of NRF2 that drive malignant progression of HNSCC; the coherently expressed signature NRF2/G6PD/TKT gene set is a potential prognostic biomarker for prediction of patient overall survival. Notably, G6PD- and TKT-regulated nucleotide biosynthesis is more important than redox regulation in determining malignant progression of HNSCC. Carcinogens trigger c-MYC-directed NRF2 activation. Over-activation of NRF2 promotes malignant progression of HNSCC through reprogramming G6PD- and TKT-mediated nucleotide biosynthesis. Targeting NRF2-directed cellular metabolism is an effective strategy for development of novel treatments for head and neck cancer.
Topics: Biomarkers, Tumor; Cell Line; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Gene Expression Regulation, Neoplastic; Glucosephosphate Dehydrogenase; Head and Neck Neoplasms; Humans; Metabolic Networks and Pathways; NF-E2-Related Factor 2; Oxidation-Reduction; Pentose Phosphate Pathway; Prognosis; Proto-Oncogene Proteins c-myc; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Transketolase
PubMed: 33859744
DOI: 10.7150/thno.53417 -
Technology in Cancer Research &... 2022The major predisposing factors of developing oral cancer include smoking, alcohol drinking, and betel quid chewing. Betel quid chewing could cause the abrasion and... (Review)
Review
The major predisposing factors of developing oral cancer include smoking, alcohol drinking, and betel quid chewing. Betel quid chewing could cause the abrasion and damage of oral mucosa by crude fibers, chemical insults by additive slaked lime, and arecoline from areca nut. These would lead to the local consequence of oral submucosal fibrosis, which is regarded clinically as a precancer lesion and a major cause of trismus. In addition, the components and additives in betel quid contain chemical toxins and carcinogens, which would further affect the oral mucosa and gradually develop a malignancy. Following literature review, aside from having a greater total tumor burden and more local diseases in the oral cavity and digestive tract, patients with betel quid-related oral cancer also have more systemic diseases from metabolic syndrome, hypertension, cardiovascular disease, type II diabetes mellitus, and obesity than those without this habit. In conclusion, those patients who have the history of smoking, alcohol drinking, and betel quid chewing would present much more unique clinical characteristics than those who only have a history of smoking and alcohol drinking. More attention should therefore be paid to pretreatment evaluation, treatment strategy, and posttreatment follow-up among betel quid chewers.
Topics: Humans; Areca; Diabetes Mellitus, Type 2; Mouth Neoplasms; Mouth Mucosa; Alcohol Drinking
PubMed: 36575633
DOI: 10.1177/15330338221146870 -
Cells Apr 2023Betel quid and areca nut are complex mixture carcinogens, but little is known about whether their derived single-agent arecoline or arecoline -oxide (ANO) is...
Betel quid and areca nut are complex mixture carcinogens, but little is known about whether their derived single-agent arecoline or arecoline -oxide (ANO) is carcinogenic, and the underlying mechanisms remain unclear. In this systematic review, we analyzed recent studies on the roles of arecoline and ANO in cancer and strategies to block carcinogenesis. In the oral cavity, flavin-containing monooxygenase 3 oxidizes arecoline to ANO, and both alkaloids conjugate with -acetylcysteine to form mercapturic acid compounds, which are excreted in urine, reducing arecoline and ANO toxicity. However, detoxification may not be complete. Arecoline and ANO upregulated protein expression in oral cancer tissue from areca nut users compared to expression levels in adjacent normal tissue, suggesting a causal relationship between these compounds and oral cancer. Sublingual fibrosis, hyperplasia, and oral leukoplakia were diagnosed in mice subjected to oral mucosal smearing of ANO. ANO is more cytotoxic and genotoxic than arecoline. During carcinogenesis and metastasis, these compounds increase the expression of epithelial-mesenchymal transition (EMT) inducers such as reactive oxygen species, transforming growth factor-β1, Notch receptor-1, and inflammatory cytokines, and they activate EMT-related proteins. Arecoline-induced epigenetic markers such as sirtuin-1 hypermethylation, low protein expression of miR-22, and miR-886-3-p accelerate oral cancer progression. Antioxidants and targeted inhibitors of the EMT inducers used reduce the risk of oral cancer development and progression. Our review findings substantiate the association of arecoline and ANO with oral cancer. Both of these single compounds are likely carcinogenic to humans, and their mechanisms and pathways of carcinogenesis are useful indicators for cancer therapy and prognosis.
Topics: Arecoline; Cyclic N-Oxides; Mouth Neoplasms; Carcinogenesis; Humans; Animals; Mice; Areca; Oxygenases; Oxidation-Reduction; Acetylcysteine; Epigenesis, Genetic; Carcinogens
PubMed: 37190117
DOI: 10.3390/cells12081208 -
Evidence-based Complementary and... 2021Betel nut, the fruit of L, has a long medical history in Southeast Asia. It is native to Malaysia and is cultivated and processed extensively in subtropical regions,... (Review)
Review
Betel nut, the fruit of L, has a long medical history in Southeast Asia. It is native to Malaysia and is cultivated and processed extensively in subtropical regions, such as South China and India. Betel nut almost appears as a "snack" in various occasions in most parts of China. Clinically, betel nut can play a certain pharmacology role and was used in malaria, ascariasis, arthritis, enterozoic abdominalgia, stagnation of food, diarrhea, edema, and beriberi. The nervous excitement of betel nut chewing has made it gradually become popular. However, chewing betel nut can induce oral submucosal fibrosis (OSF) and oral cancer (OC). At the same time, long-term chewing of betel nut also causes inhaled asthma, sperm reducing, betel quid dependence (BQD), and uterine and esophageal cancers. The main components of processed betel nut are the goal of this review. This study will mainly start from the pharmacological activity and toxicology study of betel nut in recent years, aiming to seek its advantages and disadvantages. In the meantime, this study will analyze and emphasize that betel nut and arecoline are the high-risk factors for oral cancer, which should arouse attention and vigilance of the public.
PubMed: 34457017
DOI: 10.1155/2021/1808081 -
Frontiers in Immunology 2023Arecoline is an alkaloid extracted from betel nut, which has various pharmacological effects. In the present study, we showed that arecoline aggravated experimental...
Arecoline is an alkaloid extracted from betel nut, which has various pharmacological effects. In the present study, we showed that arecoline aggravated experimental acute ulcerative colitis (UC) induced by dextran sodium sulfate (DSS) in mice. We measured body weight and colon length, evaluated disease activity index, colon pathology sections, and levels of colonic inflammatory factors. Arecoline exacerbated the clinical signs of UC and the colonic inflammatory response in mice. The results of 16S rRNA sequencing of fecal samples showed a significant decrease in the percentage of probiotic bacteria , and and a significant increase in the percentage of conditionally pathogenic bacteria and after arecoline treatment. Serum untargeted metabolomics showed that arecoline intervention reduced the levels of ergothioneine, pentostatin, diadenosine tetraphosphate and other metabolites and modulated nicotinate and nicotinamide metabolism, metabolic pathways, glyoxylate and dicarboxylate metabolism, and other metabolic pathways of intestinal microorganisms. According to the combined microbial and metabolite analysis, arecoline influences metabolite levels by modulating the intestinal microbiota. In summary, it was found that arecoline treatment exacerbated colonic injury and intestinal inflammatory responses in UC mice, disrupted the host's intestinal flora, and affected changes in flora metabolites, thereby exacerbating the development of colonic inflammation. Therefore, the consumption of betel nut can be associated with the risk of aggravating UC.
Topics: Animals; Mice; Colitis, Ulcerative; Arecoline; Gastrointestinal Microbiome; RNA, Ribosomal, 16S
PubMed: 37492574
DOI: 10.3389/fimmu.2023.1197922 -
Prague Medical Report 2020Areca nut consumption is a popular habit in Southeast Asian countries. One of the important biologically active alkaloids of areca nut is arecoline, which plays a role... (Review)
Review
Areca nut consumption is a popular habit in Southeast Asian countries. One of the important biologically active alkaloids of areca nut is arecoline, which plays a role in mediating the development of several pathologies of the primary exposure site, the oral cavity. Studies on the metabolism of arecoline revealed the formation of several metabolites which themselves might be toxic. Moreover, polymorphisms in genes encoding enzymes involved in the metabolism of arecoline might predispose an organism towards the development of oral cancer. The present review tries to accumulate all the relevant existing literature and then elucidate the molecular mechanism by which arecoline plays a role in the development of oral submucous fibrosis and oral cancer. Existing information regarding arecoline metabolism, enzymes involved in the metabolic process and biological effects of the metabolites of arecoline have also been compiled and compared to study the toxicity of metabolites with its parent compound arecoline and whether they play any role in the pathogenesis of oral cancer mediated by areca nut consumption. A repertoire of molecular targets has come up in the discussion whose expression profile is perturbed by arecoline. Construction of induction cascade from existing literature has given an idea about the process of molecular pathogenesis. The summarized and analysed data can help to determine the molecular mechanism and drug targets, which in turn could be helpful in the prevention or treatment of these pathological conditions. It also brings into light areas where further research needs to be directed.
Topics: Areca; Arecoline; Humans; Metabolomics; Oral Submucous Fibrosis
PubMed: 33270010
DOI: 10.14712/23362936.2020.19 -
PloS One 2022Arecoline is known to induce reactive oxygen species (ROS). Our previous studies showed that arecoline inhibited myogenic differentiation and acetylcholine receptor...
Arecoline is known to induce reactive oxygen species (ROS). Our previous studies showed that arecoline inhibited myogenic differentiation and acetylcholine receptor cluster formation of C2C12 myoblasts. N-acetyl-cysteine (NAC) is a known ROS scavenger. We hypothesize that NAC scavenges the excess ROS caused by arecoline. In this article we examined the effect of NAC on the inhibited myoblast differentiation by arecoline and related mechanisms. We found that NAC less than 2 mM is non-cytotoxic to C2C12 by viability analysis. We further demonstrated that NAC attenuated the decreased number of myotubes and nuclei in each myotube compared to arecoline treatment by H & E staining. We also showed that NAC prevented the decreased expression level of the myogenic markers, myogenin and MYH caused by arecoline, using immunocytochemistry and western blotting. Finally, we found that NAC restored the decreased expression level of p-ERK1/2 by arecoline. In conclusion, our results indicate that NAC attenuates the damage of the arecoline-inhibited C2C12 myoblast differentiation by the activation/phosphorylation of ERK. This is the first report to demonstrate that NAC has beneficial effects on skeletal muscle myogenesis through ERK1/2 upon arecoline treatment. Since defects of skeletal muscle associates with several diseases, NAC can be a potent drug candidate in diseases related to defects in skeletal muscle myogenesis.
Topics: Acetylcysteine; Arecoline; Cell Differentiation; MAP Kinase Signaling System; Muscle Development; Myoblasts; Phosphorylation; Reactive Oxygen Species
PubMed: 35901044
DOI: 10.1371/journal.pone.0272231