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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 -
Clinical, Cosmetic and Investigational... 2015Oral submucous fibrosis (OSF) is a premalignant condition caused by betel chewing. It is very common in Southeast Asia but has started to spread to Europe and North... (Review)
Review
Oral submucous fibrosis (OSF) is a premalignant condition caused by betel chewing. It is very common in Southeast Asia but has started to spread to Europe and North America. OSF can lead to squamous cell carcinoma, a risk that is further increased by concomitant tobacco consumption. OSF is a diagnosis based on clinical symptoms and confirmation by histopathology. Hypovascularity leading to blanching of the oral mucosa, staining of teeth and gingiva, and trismus are major symptoms. Major constituents of betel quid are arecoline from betel nuts and copper, which are responsible for fibroblast dysfunction and fibrosis. A variety of extracellular and intracellular signaling pathways might be involved. Treatment of OSF is difficult, as not many large, randomized controlled trials have been conducted. The principal actions of drug therapy include antifibrotic, anti-inflammatory, and antioxygen radical mechanisms. Potential new drugs are on the horizon. Surgery may be necessary in advanced cases of trismus. Prevention is most important, as no healing can be achieved with available treatments.
PubMed: 25914554
DOI: 10.2147/CCID.S80576 -
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 -
The Cochrane Database of Systematic... Mar 2018Tardive dyskinesia (TD) remains a troublesome adverse effect of conventional antipsychotic (neuroleptic) medication. It has been proposed that TD could have a component... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Tardive dyskinesia (TD) remains a troublesome adverse effect of conventional antipsychotic (neuroleptic) medication. It has been proposed that TD could have a component of central cholinergic deficiency. Cholinergic drugs have been used to treat TD.
OBJECTIVES
To determine the effects of cholinergic drugs (arecoline, choline, deanol, lecithin, meclofenoxate, physostigmine, RS 86, tacrine, metoxytacrine, galantamine, ipidacrine, donepezil, rivastigmine, eptastigmine, metrifonate, xanomeline, cevimeline) for treating antipsychotic-induced TD in people with schizophrenia or other chronic mental illness.
SEARCH METHODS
An electronic search of the Cochrane Schizophrenia Group's Study-Based Register of Trials (16 July 2015 and April 2017) was undertaken. This register is assembled by extensive searches for randomised controlled trials in many electronic databases, registers of trials, conference proceedings and dissertations. References of all identified studies were searched for further trial citations.
SELECTION CRITERIA
We included reports identified by the search if they were of controlled trials involving people with antipsychotic-induced TD and chronic mental illness, who had been randomly allocated to either a cholinergic agent or to a placebo or no intervention. Two review authors independently assessed the methodological quality of the trials.
DATA COLLECTION AND ANALYSIS
Two review authors extracted data and, where possible, estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We analysed data on an intention-to-treat basis, with the assumption that people who left early had no improvement. We assessed risk of bias and created a 'Summary of findings' table using GRADE.
MAIN RESULTS
We included 14 studies investigating the use of cholinergic drugs compared with placebo published between 1976 and 2014. All studies involved small numbers of participants (five to 60 people). Three studies that investigated the new cholinergic Alzheimer drugs for the treatment of TD are new to this update. Overall, the risk of bias in the included studies was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, studies were not clearly blinded, we are unsure if data are incomplete, and data were often poorly or selectively reported.We are uncertain about the effect of new or old cholinergic drugs on no clinically important improvement in TD symptoms when compared with placebo; the quality of evidence was very low (RR 0.89, 95% CI 0.65 to 1.23; 27 people, 4 RCTs). Eight trials found that cholinergic drugs may make little or no difference to deterioration of TD symptoms (low-quality evidence, RR 1.11, 95% CI 0.55 to 2.24; 147 people). Again, due to very low-quality evidence, we are uncertain about the effects on mental state (RR 0.50, 95% CI 0.10 to 2.61; 77 people, 5 RCTs), adverse events (RR 0.56, 95% CI 0.15 to 2.14; 106 people, 4 RCTs), and leaving the study early (RR 1.09,95% CI 0.56 to 2.10; 288 people 12 RCTs). No study reported on social confidence, social inclusion, social networks, or personalised quality of life.
AUTHORS' CONCLUSIONS
TD remains a major public health problem. The clinical effects of both older cholinergic drugs and new cholinergic agents, now used for treating Alzheimer's disease, are unclear, as too few, too small studies leave many questions unanswered. Cholinergic drugs should remain of interest to researchers and currently have little place in routine clinical work. However, with the advent of new cholinergic agents now used for treating Alzheimer's disease, scope exists for more informative trials. If these new cholinergic agents are to be investigated for treating people with TD, their effects should be demonstrated in large well-designed, conducted and reported randomised trials.
Topics: Antipsychotic Agents; Cholinergic Agents; Dyskinesia, Drug-Induced; Humans; Patient Dropouts; Randomized Controlled Trials as Topic
PubMed: 29553158
DOI: 10.1002/14651858.CD000207.pub2 -
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