-
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 -
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 -
Pharmaceuticals (Basel, Switzerland) Sep 2022The search for anticancer drugs is of continuous interest. Arecoline is an alkaloid with anticancer activity. Herein, the metabolism of arecoline through fungal...
In Vitro Characterization of Inhibitors for Lung A549 and Leukemia K562 Cell Lines from Fungal Transformation of Arecoline Supported by In Silico Docking to M3-mAChR and ADME Prediction.
The search for anticancer drugs is of continuous interest. Arecoline is an alkaloid with anticancer activity. Herein, the metabolism of arecoline through fungal transformation was investigated for the discovery of potential anticancer drugs with higher activity and selectivity. Compounds - were isolated, and their structures were fully elucidated using various spectroscopic analyses, including 1D and 2D NMR, ESIMS, and HRESIMS. This is the first report for the isolation of compounds and . An MTT assay was performed to determine the cytotoxic activity of arecoline and its metabolites in vitro using non-small-cell lung cancer A549 and leukemia K562 cell lines compared to staurosporine and doxorubicin as positive controls. For the non-small-cell lung A549 cell line, arecoline hydrobromide, staurosporine, and doxorubicin resulted in IC values of 11.73 ± 0.71 µM, 10.47 ± 0.64 µM, and 5.05 ± 0.13 µM, respectively, while compounds , and exhibited IC values of 3.08 ± 0.19 µM, 7.33 ± 0.45 µM, and 3.29 ± 0.20 µM, respectively. For the leukemia K562 cell line, the IC values of arecoline hydrobromide, staurosporine, and doxorubicin were 15.3 ± 1.08 µM, 5.07 ± 0.36 µM, and 6.94 ± 0.21 µM, respectively, while the IC values of compounds , and were 1.56 ± 0.11 µM, 3.33 ± 0.24 µM, and 2.15 ± 0.15 µM, respectively. The selectivity index value of these compounds was higher than 3. These results indicated that compounds , , and are very strong cytotoxic agents with higher activity than the positive controls and good selectivity toward the tested cancer cell lines. Cell cycle arrest was then studied by flow cytometry to investigate the apoptotic mechanism. Docking simulation revealed that most compounds possessed good binding poses and favorable protein-ligand interactions with muscarinic acetylcholine receptor M3-mAChR protein. In silico study of pharmacokinetics using SwissADME predicted compounds - to be drug-like with a high probability of good oral bioavailability.
PubMed: 36297282
DOI: 10.3390/ph15101171 -
Animal Nutrition (Zhongguo Xu Mu Shou... Dec 2023Arecoline is an alkaloid with important pharmacological effects in the plant areca nut, which has been demonstrated to be an agonist of muscarinic receptors (M...
Arecoline is an alkaloid with important pharmacological effects in the plant areca nut, which has been demonstrated to be an agonist of muscarinic receptors (M receptor). This study explored the influences of dietary arecoline on growth performance, intestinal digestion and absorption abilities, antioxidant capacity, and the apical junction complex (AJC) of adult grass carp (). Adult grass carp (608 to 1512 g) were fed at 6 graded levels of dietary arecoline (0, 0.5, 1.0, 1.5, 2.0, and 2.5 mg/kg diet) for 9 weeks. The results suggested that appropriate dietary supplementation of arecoline (1.0 mg/kg) increased growth parameters and intestinal growth in adult grass carp ( < 0.05), enhanced digestion and absorption capacities ( < 0.05), up-regulated muscarinic receptor 3 () mRNA level ( < 0.05), increased the content of neuropeptide fish substance P ( < 0.05), improved antioxidant capacity by activating the Keap1a/Nrf2 signaling pathway ( < 0.05), reduced intestinal mucosal permeability ( < 0.05), and increased mRNA levels of tight junction (TJ) and adherent junction AJ-related proteins in fish by inhibiting the RhoA/ROCK signaling pathway (RhoA/ROCK/MLCK/NMII) ( < 0.05). In addition, the appropriate arecoline supplementation for adult grass carp was determined to be 1.20, 1.21, 1.07, and 1.19 mg/kg based on percentage weight gain, lipase activity, serum diamine oxidase, and protein carbonyl, respectively. Overall, to the best of our knowledge, we investigated for the first time the effects and possible mechanisms of dietary arecoline on intestinal digestive and absorptive capacities and structural integrity in fish and evaluated the appropriate level of supplementation.
PubMed: 38023377
DOI: 10.1016/j.aninu.2023.07.005 -
Drug Testing and Analysis Apr 2024Areca nut (AN) is a carcinogen; its chewing cessation is, therefore, of worldwide interest. However, cessation biomarkers are lacking. We sought to establish arecoline...
Areca nut (AN) is a carcinogen; its chewing cessation is, therefore, of worldwide interest. However, cessation biomarkers are lacking. We sought to establish arecoline in chewers' buccal cells (BCs) as a biomarker for AN dose. Self-reported AN doses, expressed as the average AN load ("AANL"), the product of AN amount, chewing time, and chewing frequency, were correlated by regression analysis with chewers' BC arecoline, measured by liquid chromatography mass spectrometry. We then determined whether associations differed between Class 1 chewers (who consume AN alone or with slaked lime, leaf, and/or spices) and Class 2 chewers (who consume any combination of the aforementioned ingredients plus tobacco). Among the 103 chewers, 28 Class 1 and 39 Class 2 chewers had detectable arecoline levels, which were used for analyses. A linear regression of cube-root transformed AANL on equally transformed BC arecoline levels provided the best model fit; resulting slopes and corresponding correlation coefficients were 0.86 and 0.40 (p < 0.01) for all; 1.09 and 0.51 (p < 0.01) for Class 1 chewers; 0.35 and 0.17 (p = 0.29) for Class 2 chewers; and 0.94 and 0.45 (p < 0.01), and 0.79 and 0.37 (p = 0.08), respectively, for those who included or excluded lime. Relationships between AANL and BC arecoline levels were similar between chewers who included or excluded lime (p = 0.76), but less between chewing classes (p = 0.14). This provides confidence that BC arecoline can generally act as a reliable biomarker for AN dose, useful for estimating efficacy in AN cessation studies and population-based chewing assessments.
PubMed: 38584295
DOI: 10.1002/dta.3684 -
BMC Oral Health Mar 2023Betel nut chewing plays a role in the pathogenesis of oral submucous fibrosis (OSF) and oral squamous cell carcinoma (OSCC). As the major active ingredient of the betel...
BACKGROUND
Betel nut chewing plays a role in the pathogenesis of oral submucous fibrosis (OSF) and oral squamous cell carcinoma (OSCC). As the major active ingredient of the betel nut, the effect of arecoline and its underlying mechanism to OSF and OSCC pathogenesis remain unclear.
METHODS
Next-generation sequencing-based transcriptome and dRRBS analysis were performed on OSF and OSCC cells under low-dose arecoline exposure. Functional analyses were performed to compare the different roles of arecoline during OSF and OSCC pathogenesis, and key genes were identified.
RESULTS
In this study, we identified that low-dose arecoline promoted cell proliferation of both NFs and OSCC cells via the acceleration of cell cycle progression, while high-dose arecoline was cytotoxic to both NFs and OSCC cells. We performed for the first time the transcriptome and methylome landscapes of NFs and OSCC cells under low-dose arecoline exposure. We found distinct transcriptome and methylome profiles mediated by low-dose arecoline in OSF and OSCC cells, as well as specific genes and signaling pathways associated with metabolic disorders induced by low-dose arecoline exposure. Additionally, low-dose arecoline displayed different functions at different stages, participating in the modulation of the extracellular matrix via Wnt signaling in NFs and epigenetic regulation in OSCC cells. After exposure to low-dose arecoline, the node roles of FMOD in NFs and histone gene clusters in OSCC cells were found. Meanwhile, some key methylated genes induced by arecoline were also identified, like PTPRM and FOXD3 in NFs, SALL3 and IRF8 in OSCC cells, indicating early molecular events mediated by arecoline during OSF and OSCC pathogenesis.
CONCLUSIONS
This study elucidated the contribution of low-dose arecoline to OSF and OSCC pathogenesis and identified key molecular events that could be targeted for further functional studies and their potential as biomarkers.
Topics: Humans; Arecoline; Oral Submucous Fibrosis; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Epigenesis, Genetic; Mouth Neoplasms; Signal Transduction; Head and Neck Neoplasms; Mouth Mucosa
PubMed: 36966276
DOI: 10.1186/s12903-023-02887-2 -
Molecular Carcinogenesis Jul 2023Arecoline, the main component of betel nut, induces malignant transformation of oral cells through complicated unclear mechanisms. Thus, we aimed to screen the key genes...
BACKGROUND
Arecoline, the main component of betel nut, induces malignant transformation of oral cells through complicated unclear mechanisms. Thus, we aimed to screen the key genes involved in Arecoline-induced oral cancer and further verify their expressions and roles.
METHODS
This study included a data-mining part, a bioinformatics verification part, and an experimental verification one. First, the key gene related to oral cancer induced by Arecoline was screened. Then, the expression and clinical significance of the key gene in head and neck/oral cancer tissues were verified, and its downstream mechanisms of action were explored. Afterwards, the expression and roles of the key gene were verified by experiments at the histological and cytological levels.
RESULTS
MYO1B was identified as the key gene. Overexpression of MYO1B was associated with lymph node metastasis and unfavorable outcomes in oral cancer. MYO1B may be mainly related to metastasis, angiogenesis, hypoxia, and differentiation. A positive correlation between MYO1B and the infiltration of macrophages, B cells, and dendritic cells was presented. MYO1B might have a close relationship with SMAD3, which may be enriched in the Wnt signaling pathway. MYO1B suppression markedly inhibited the proliferation, invasion, and metastasis abilities of both Arecoline-transformed oral cells and oral cancer cells.
CONCLUSION
This study revealed MYO1B as a key gene in Arecoline-induced oral tumorigenesis. MYO1B might be a novel prognostic indicator and therapeutic target for oral cancer.
Topics: Humans; Arecoline; Prognosis; Mouth Neoplasms; Head and Neck Neoplasms; Cell Transformation, Neoplastic; Biomarkers; Carcinoma; Areca; Myosin Type I
PubMed: 37014156
DOI: 10.1002/mc.23535 -
International Journal of Molecular... May 2023Areca nut (AN) is used for traditional herbal medicine and social activities in several countries. It was used as early as about A.D. 25-220 as a remedy. Traditionally,... (Review)
Review
Areca nut (AN) is used for traditional herbal medicine and social activities in several countries. It was used as early as about A.D. 25-220 as a remedy. Traditionally, AN was applied for several medicinal functions. However, it was also reported to have toxicological effects. In this review article, we updated recent trends of research in addition to acquire new knowledge about AN. First, the history of AN usage from ancient years was described. Then, the chemical components of AN and their biological functions was compared; arecoline is an especially important compound in AN. AN extract has different effects caused by different components. Thus, the dual effects of AN with pharmacological and toxicological effects were summarized. Finally, we described perspectives, trends and challenges of AN. It will provide the insight of removing or modifying the toxic compounds of AN extractions for enhancing their pharmacological activity to treat several diseases in future applications.
Topics: Plant Extracts; Areca; Nuts; Arecoline; Plants, Medicinal
PubMed: 37240342
DOI: 10.3390/ijms24108996 -
International Journal of Biological... Apr 2024Long non-coding RNA FENDRR possesses both anti-fibrotic and anti-cancer properties, but its significance in the development of premalignant oral submucous fibrosis (OSF)...
Long non-coding RNA FENDRR possesses both anti-fibrotic and anti-cancer properties, but its significance in the development of premalignant oral submucous fibrosis (OSF) remains unclear. Here, we showed that FENDRR was downregulated in OSF specimens and fibrotic buccal mucosal fibroblasts (fBMFs), and overexpression of FENDRR mitigated various myofibroblasts hallmarks, and vice versa. In the course of investigating the mechanism underlying the implication of FENDRR in myofibroblast transdifferentiation, we found that FENDRR can directly bind to miR-214 and exhibit its suppressive effect on myofibroblast activation via titrating miR-214. Moreover, we showed that mitofusin 2 (MFN2), a protein that is crucial to the fusion of mitochondria, was a direct target of miR-214. Our data suggested that FENDRR was positively correlated with MFN2 and MFN2 was required for the inhibitory property of FENDRR pertaining to myofibroblast phenotypes. Additionally, our results showed that the FENDRR/miR-214 axis participated in the arecoline-induced reactive oxygen species (ROS) accumulation and myofibroblast transdifferentiation. Building on these results, we concluded that the aberrant downregulation of FENDRR in OSF may be associated with chronic exposure to arecoline, leading to upregulation of ROS and myofibroblast activation via the miR-214-mediated suppression of MFN2.
Topics: Humans; Myofibroblasts; Arecoline; Reactive Oxygen Species; Oral Submucous Fibrosis; Mouth Mucosa; Fibroblasts; MicroRNAs; GTP Phosphohydrolases; Mitochondrial Proteins
PubMed: 38442830
DOI: 10.1016/j.ijbiomac.2024.130504 -
Drug Design, Development and Therapy 2021Betel nuts have long been used in traditional Chinese medicine. In our study, the bioactive components of betel nut were systematically investigated, and the main...
BACKGROUND
Betel nuts have long been used in traditional Chinese medicine. In our study, the bioactive components of betel nut were systematically investigated, and the main components and their target genes in the treatment of depression were predicted.
METHODS
The metabolites of the kernels and peels were analyzed with a UPLC-MS/MS system. Mass spectrometry outcomes were annotated by MULTIAQUANT. "Compound-disease targets" were utilized to construct a pharmacology network.
RESULTS
A total of 873 metabolites were identified, with a high abundance of flavonoids, alkaloids, and phenols. Moreover, the abundance of flavonoids, alkaloids, and phenols in the kernel was significantly higher than that in the peel. A high abundance of catechin, arginine, and phenylalanine was detected in the kernel, while a high abundance of arginine, arecoline, and aminobutyric acid was detected in the peel. Catechins and cyanoside were the most abundant flavonoids in the kernel and peel, respectively. Arecoline was the most abundant alkaloid. A total of 111 metabolites showed a significant difference between the kernels and peels. The relative abundance of 40 differential metabolites was higher than 100,000, including 14 primary metabolites, 12 flavonoids, 4 phenols, and 4 alkaloids. Among the 40 high abundance metabolites, 20 were higher in the kernel and 20 in the peel. In addition, the enrichment of metabolic pathways found that the kernel and peel of the fruit adopted different metabolic pathways for the synthesis of flavonoids and alkaloids. Network pharmacology prediction showed that 93 metabolites could target 141 depression-related genes. The main components of betel nut intervention in depression were predicted to include L-phenylalanine, protocatechuic acid, okanin, nicotinic acid, L-tyrosine, benzocaine, syringic acid, benzocaine, phloretic acid, cynaroside, and 3,4-dihydroxybenzaldehyde.
CONCLUSION
Betel nuts are rich in natural metabolites, and some of these metabolites can participate in the intervention of depression. In addition, the metabolites showed distinct characteristics between the kernel and peel. Therefore, it is necessary to comprehensively and rationally use betel nuts.
Topics: Alkaloids; Antidepressive Agents; Areca; Chromatography, High Pressure Liquid; Computational Biology; Depression; Flavonoids; Humans; Metabolomics; Network Pharmacology; Phenols; Tandem Mass Spectrometry
PubMed: 34880597
DOI: 10.2147/DDDT.S335312