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Open Life Sciences 2021The areca nut is one of the most commonly consumed psychoactive substances worldwide, with an estimated consumption by approximately 10% of the world's population,...
The areca nut is one of the most commonly consumed psychoactive substances worldwide, with an estimated consumption by approximately 10% of the world's population, especially in some regions of South Asia, East Africa, and the tropical Pacific. Arecoline, the major areca nut alkaloid, has been classified as carcinogenic to humans as it adversely affects various organs, including the brain, heart, lungs, gastrointestinal tract, and reproductive organs. Earlier studies have established a link between areca nut chewing and cardiac arrhythmias, and yet research pertaining to the mechanisms underlying cardiotoxicity caused by arecoline is still preliminary. The main purpose of this study is to test the hypothesis that arecoline causes cardiac fibrosis through transforming growth factor-β (TGF-β)/Smad-mediated signaling pathways. Male Wistar rats were injected intraperitoneally with low (5 mg/kg/day) or high (50 mg/kg/day) doses of arecoline for 3 weeks. Results from Masson's trichrome staining indicated that arecoline could induce cardiac fibrosis through collagen accumulation. Western blot analysis showed that TGF-β and p-Smad2/3 protein expression levels were markedly higher in the arecoline-injected rat hearts than in those of the control rats. Moreover, arecoline upregulated other fibrotic-related proteins, including SP1-mediated connective tissue growth factor expression. Tissue-type plasminogen activator and its inhibitor, plasminogen activator inhibitor, and matrix metalloproteinase (MMP) 9 were upregulated, and the inhibitor of MMP9 was downregulated. This study provides novel insight into the molecular mechanisms underlying arecoline-induced cardiac fibrosis. Taken together, the areca nut is a harmful substance, and the detrimental effects of arecoline on the heart are similar to that caused by oral submucous fibrosis.
PubMed: 34761109
DOI: 10.1515/biol-2021-0116 -
BMC Complementary Medicine and Therapies Nov 2021Gastroesophageal reflux disease (GERD) is associated with lower esophageal sphincter (LES) incompetence. In some patients, GERD is refractory to acid reduction therapy...
BACKGROUND
Gastroesophageal reflux disease (GERD) is associated with lower esophageal sphincter (LES) incompetence. In some patients, GERD is refractory to acid reduction therapy which is the main treatment for GERD. So far, medications that can increase LES tone are few. Arecae pericarpium (A. pericarpium) is a medication in Traditional Chinese Medicine known to promote intestinal motility.
METHODS
We investigated the effect of A. pericarpium extracts on porcine LES motility. In addition, we used tetrodotoxin (TTX) and atropine to study the underlying mechanism of A. pericarpium extracts-induced contractions of LES.
RESULTS
The results of this study showed that A. pericarpium extracts and their main active ingredient, arecoline, can induce the contractions of porcine LES sling and clasp muscles in a dose-response manner. TTX did not have an inhibitory effect on the contractions induced by A. pericarpium extracts and arecoline in LES. However, atropine significantly inhibited A. pericarpium extracts- and arecoline-induced contractions of LES.
CONCLUSION
A. pericarpium extracts can induce the contractions of porcine LES in a dose dependent manner, possibly through muscarinic receptors, and hence, may be worth developing as an alternative therapy for GERD.
Topics: Animals; Areca; Esophageal Sphincter, Lower; Gastroesophageal Reflux; In Vitro Techniques; Plant Extracts; Receptors, Muscarinic; Swine; Taiwan
PubMed: 34736444
DOI: 10.1186/s12906-021-03442-8 -
Paeonol inhibits profibrotic signaling and HOTAIR expression in fibrotic buccal mucosal fibroblasts.Journal of the Formosan Medical... May 2022Betel nut chewing is the major risk factor of oral submucous fibrosis (OSF). Various studies have sought to discover alternative strategies to alleviate oral...
BACKGROUND/PURPOSE
Betel nut chewing is the major risk factor of oral submucous fibrosis (OSF). Various studies have sought to discover alternative strategies to alleviate oral fibrogenesis. In the present study, we aimed to evaluate the anti-fibrosis effect of paeonol, a phenolic component derived from Paeonia Suffruticosa.
METHODS
The cytotoxicity of paeonol was tested using normal and fibrotic buccal mucosal fibroblasts (fBMFs) derived from OSF tissues. Collagen gel contraction, Transwell migration, invasion, and wound healing capacities were examined. Besides, the activation of TGF-β/Smad2 signaling and expression levels of type I collagen, α-SMA, and long non-coding RNA HOTAIR were measured as well.
RESULTS
Paeonol exerted a higher cytotoxic effect on fBMFs compared to normal BMFs. The arecoline-induced myofibroblast activities, including collagen gel contractility, cell motility, and wound healing ability were all suppressed by paeonol treatment. In addition, the activation of the TGF-β/Smad2 pathway was inhibited along with a lower expression of α-SMA and type I collagen in paeonol-treated cells. Also, the administration of paeonol decreased the mRNA expression of HOTAIR in fBMFs.
CONCLUSION
Our results indicate that paeonol may be a promising compound to attenuate the progression of oral fibrogenesis in OSF patients.
Topics: Acetophenones; Areca; Arecoline; Cell Transdifferentiation; Cells, Cultured; Collagen Type I; Fibroblasts; Fibrosis; Humans; Mouth Mucosa; Oral Submucous Fibrosis; Transforming Growth Factor beta
PubMed: 34696937
DOI: 10.1016/j.jfma.2021.09.027 -
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 -
Journal of Personalized Medicine Jul 2021Oral submucosal fibrosis (OSF) is a precancerous condition in the oral cavity and areca nut consumption has been regarded as one of the etiologic factors implicated in...
Oral submucosal fibrosis (OSF) is a precancerous condition in the oral cavity and areca nut consumption has been regarded as one of the etiologic factors implicated in the development of OSF via persistent activation of buccal mucosal fibroblasts (BMFs). It has been previously reported that an epithelial to mesenchymal transition (EMT) factor, ZEB1, mediated the areca nut-associated myofibroblast transdifferentiation. In the current study, we aimed to elucidate how areca nut affected non-coding RNAs and the subsequent myofibroblast activation via ZEB1. We found that long non-coding RNA LINC00084 was elicited in the BMFs treated with arecoline, a major alkaloid of areca nut, and silencing LINC00084 prevented the arecoline-induced activities (such as collagen gel contraction, migration, and wound healing capacities). The upregulation of LINC00084 was also observed in the OSF tissues and fibrotic BMFs (fBMFs), and positively correlated with several fibrosis factors. Moreover, we showed knockdown of LINC00084 markedly suppressed the myofibroblast features in fBMFs, including myofibroblast phenotypes and marker expression. The results from the luciferase reporter assay confirmed that LINC00084 acted as a sponge of miR-204 and miR-204 inhibited ZEB1 by directly interacting with it. Altogether, these findings suggested that the constant irritation of arecoline may result in upregulation of LINC00084 in BMFs, which increased the ZEB1 expression by sequestering miR-204 to induce myofibroblast transdifferentiation.
PubMed: 34442351
DOI: 10.3390/jpm11080707 -
Behavioural Pharmacology Oct 2021Despite the evidence that the muscarinic agonist arecoline is a drug of abuse throughout Southeast Asia, its stimulus characteristics have not been well studied. The...
Despite the evidence that the muscarinic agonist arecoline is a drug of abuse throughout Southeast Asia, its stimulus characteristics have not been well studied. The goal of this work was to understand more about the mediation of discriminative stimulus effects of arecoline. Arecoline (1.0 mg/kg s.c.) was trained as a discriminative stimulus in a group of eight rats. The ability of various cholinergic agonists and antagonists to mimic or antagonize the discriminative stimulus effects of arecoline and to modify its rate-suppressing effects was evaluated. A muscarinic antagonist, but neither of two nicotinic antagonists, was able to modify the discriminative stimulus effects of arecoline, suggesting a predominant muscarinic basis of arecoline's discriminative stimulus effects in this assay. However, both nicotine itself and two nicotine agonists with selective affinity for the α4β2* receptor (ispronicline and metanicotine) produced full arecoline-like discriminative stimulus effects in these rats. The discriminative stimulus effects of the selective nicotine agonists were blocked by both the general nicotine antagonist mecamylamine and by the selective α4β2* antagonist, dihydro-beta-erythroidine (DHβE). Surprisingly, only DHβE antagonized the rate-suppressing effects of the selective nicotine agonists. These data indicate a selective α4β2* nicotine receptor component to the behavioral effects of arecoline. Although the nicotinic aspects of arecoline's behavior effects could suggest that abuse of arecoline-containing material (e.g. betel nut chewing) is mediated through nicotinic rather than muscarinic actions, further research, specifically on the reinforcing effects of arecoline, is necessary before this conclusion can be supported.
Topics: Animals; Arecoline; Behavior, Animal; Dihydro-beta-Erythroidine; Discrimination Learning; Mecamylamine; Muscarinic Agonists; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Pyridines; Rats; Receptors, Nicotinic; Substance-Related Disorders
PubMed: 34417356
DOI: 10.1097/FBP.0000000000000652 -
BMC Endocrine Disorders Aug 2021Betel-nut consumption is the fourth most common addictive habit globally and there is good evidence linking the habit to obesity, type 2 diabetes (T2D) and the metabolic...
BACKGROUND
Betel-nut consumption is the fourth most common addictive habit globally and there is good evidence linking the habit to obesity, type 2 diabetes (T2D) and the metabolic syndrome. The aim of our pilot study was to identify gene expression relevant to obesity, T2D and the metabolic syndrome using a genome-wide transcriptomic approach in a human monocyte cell line incubated with arecoline and its nitrosated products.
RESULTS
The THP1 monocyte cell line was incubated separately with arecoline and 3-methylnitrosaminopropionaldehyde (MNPA) in triplicate for 24 h and pooled cDNA indexed paired-end libraries were sequenced (Illumina NextSeq 500). After incubation with arecoline and MNPA, 15 and 39 genes respectively had significant changes in their expression (q < 0.05, log fold change 1.5). Eighteen of those genes have reported associations with T2D and obesity in humans; of these genes there was most marked evidence for CLEC10A, MAPK8IP1, NEGR1, NQ01 and INHBE genes.
CONCLUSIONS
Our preliminary studies have identified a large number of genes relevant to obesity, T2D and metabolic syndrome whose expression was changed significantly in human TPH1 cells following incubation with betel-nut derived arecoline or with MNPA. These findings require validation by further cell-based work and investigation amongst betel-chewing communities.
Topics: Areca; Arecoline; Biomarkers; Diabetes Mellitus, Type 2; Follow-Up Studies; Gene Expression Regulation; Humans; Metabolic Syndrome; Monocytes; Obesity; Pilot Projects; Prognosis; Transcriptome
PubMed: 34391409
DOI: 10.1186/s12902-021-00827-1 -
Cancer Medicine Sep 2021Arecoline, a major alkaloid within areca nut extract, is recognized as the primary active carcinogen promoting oral squamous cell carcinoma (OSCC) pathological...
Arecoline, a major alkaloid within areca nut extract, is recognized as the primary active carcinogen promoting oral squamous cell carcinoma (OSCC) pathological development. Dysregulation of N6-methyladenosine (m6A) methyltransferase components (e.g., Fat mass and obesity-associated protein [FTO] and methyltransferase-like 3 [METTL3]) are closely associated with multiple cancer progression, including oral cancer. However, the biological function role of FTO in arecoline-induced oral cancer is largely unknown. We identified that FTO was significantly upregulated in OSCC tissues from patients with areca nut chewing habits and chronic arecoline-treated OSCC cell lines. Depletion of FTO attenuated the arecoline-promoted stemness, chemoresistance, and oncogenicity of OSCC cells. Finally, we revealed that FTO was negatively regulated by a transcription factor forkhead box protein A2 (FOXA2) in OSCC cells. This study, for the first time, demonstrated that FTO plays an oncogenic role in arecoline-induced OSCC progression. Thus, developing new therapeutic agents targeting FTO may serve as a promising method to treatment OSCC patients, especially those with areca nut chewing habits.
Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Areca; Arecoline; Carcinogenesis; Case-Control Studies; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Hepatocyte Nuclear Factor 3-beta; Humans; Methyltransferases; Mouth Mucosa; Mouth Neoplasms; Nuts; Squamous Cell Carcinoma of Head and Neck; Up-Regulation
PubMed: 34378866
DOI: 10.1002/cam4.4188 -
Cells Jul 2021Glioblastoma multiforme (GBM) is characterized by several genetic abnormalities, leading to cell cycle deregulation and abnormal mitosis caused by a defective...
BACKGROUND
Glioblastoma multiforme (GBM) is characterized by several genetic abnormalities, leading to cell cycle deregulation and abnormal mitosis caused by a defective checkpoint. We previously demonstrated that arecaidine propargyl ester (APE), an orthosteric agonist of M2 muscarinic acetylcholine receptors (mAChRs), arrests the cell cycle of glioblastoma (GB) cells, reducing their survival. The aim of this work was to better characterize the molecular mechanisms responsible for this cell cycle arrest.
METHODS
The arrest of cell proliferation was evaluated by flow cytometry analysis. Using immunocytochemistry and time-lapse analysis, the percentage of abnormal mitosis and aberrant mitotic spindles were assessed in both cell lines. Western blot analysis was used to evaluate the modulation of Sirtuin2 and acetylated tubulin-factors involved in the control of cell cycle progression.
RESULTS
APE treatment caused arrest in the M phase, as indicated by the increase in p-HH3 (ser10)-positive cells. By immunocytochemistry, we found a significant increase in abnormal mitoses and multipolar mitotic spindle formation after APE treatment. Time-lapse analysis confirmed that the APE-treated GB cells were unable to correctly complete the mitosis. The modulated expression of SIRT2 and acetylated tubulin in APE-treated cells provides new insights into the mechanisms of altered mitotic progression in both GB cell lines.
CONCLUSIONS
Our data show that the M2 agonist increases aberrant mitosis in GB cell lines. These results strengthen the idea of considering M2 acetylcholine receptors a novel promising therapeutic target for the glioblastoma treatment.
Topics: Acetylation; Arecoline; Cell Line, Tumor; Cell Nucleus; Glioblastoma; Humans; Metaphase; Mitosis; Receptor, Muscarinic M2; Sirtuin 2; Spindle Apparatus; Time-Lapse Imaging; Tubulin
PubMed: 34359896
DOI: 10.3390/cells10071727 -
Oncotarget Jul 2021Head and neck cancers are highly prevalent in south-east Asia, primarily due to betel nut chewing. Arecoline, the primary alkaloid is highly carcinogenic; however its...
Head and neck cancers are highly prevalent in south-east Asia, primarily due to betel nut chewing. Arecoline, the primary alkaloid is highly carcinogenic; however its role in promoting tumorigenesis by disrupting junctional complexes and increasing risk of metastasis is not well delineated. Subsequently, the effects of low and high concentrations of arecoline on the stability of tight junctions and EMT induction were studied. A microarray analysis confirmed involvement of a MAPK component, JunD, in regulating tight junction-associated genes, specifically ZO-1. Results established that although arecoline-induced phosphorylation of JunD downregulated expression of ZO-1, JunD itself was modulated by the lncRNA-NEAT1 in presence of arecoline. Increased NEAT1 in tissues of HNSCC patients significantly correlated with poor disease prognosis. Here we show that NEAT1-JunD complex interacted with ZO-1 promoter in the nuclear compartment, downregulated expression of ZO-1 and destabilized tight junction assembly. Consequently, silencing NEAT1 in arecoline-exposed cells not only downregulated the expression of JunD and stabilized expression of ZO-1, but also reduced expression of the EMT markers, Slug and Snail, indicating its direct regulatory role in arecoline-mediated TJ disruption and disease progression.
PubMed: 34316331
DOI: 10.18632/oncotarget.28026