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Pathogens (Basel, Switzerland) Jul 2023Areca nut and slaked lime, with or without tobacco wrapped in leaf, prepared as betel quid, is extensively consumed as a masticatory product in many countries across... (Review)
Review
Areca nut and slaked lime, with or without tobacco wrapped in leaf, prepared as betel quid, is extensively consumed as a masticatory product in many countries across the world. Betel Quid can promote the malignant transformation of oral lesions as well as trigger benign cellular and molecular changes. In the oral cavity, it causes changes at the compositional level in oral microbiota called dysbiosis. This dysbiosis may play an important role in Oral Cancer in betel quid chewers. The abnormal presence and increase of bacteria , , , sp., , and in saliva and/or other oral sites of the cancer patients has attracted frequent attention for its association with oral cancer development. In the present review, the authors have analysed the literature reports to revisit the oncogenic potential of betel quid and oral microbiome alterations, evaluating the potential of oral microbiota both as a driver and biomarker of oral cancer. The authors have also shared a perspective that the restoration of local microbiota can become a potentially therapeutic or prophylactic strategy for the delay or reversal of lip and oral cavity cancers, especially in high-risk population groups.
PubMed: 37623956
DOI: 10.3390/pathogens12080996 -
Biochemical Genetics Apr 2024Oral submucous fibrosis (OSF) is a chronic disorder with a high malignant transformation rate. Epithelial-mesenchymal transition (EMT) and angiogenesis are key events in...
Oral submucous fibrosis (OSF) is a chronic disorder with a high malignant transformation rate. Epithelial-mesenchymal transition (EMT) and angiogenesis are key events in OSF. The Notch signaling plays an essential role in the pathogenesis of various fibrotic diseases, including OSF. Our study aimed to explore the effects of Notch on the EMT and angiogenesis processes during the development of OSF. The expression of Notch in OSF tissues versus normal buccal mucosa samples was compared. Arecoline was used to induce myofibroblast transdifferentiation of buccal mucosal fibroblasts (BMFs). Short hairpin RNA technique was used to knockdown Notch in BMFs. Pirfenidone and SRI-011381 were used to inhibit and activate the TGF-β1 signaling pathway in BMFs, respectively. The expression of Notch was markedly upregulated in OSF tissues and fibrotic BMFs. Knockdown of Notch significantly decreased the viability and promoted apoptosis in BMFs subjected to arecoline stimulation. Downregulation of Notch also significantly suppressed the EMT process, as shown by the reduction of N-cadherin and vimentin with concomitant upregulation of E-cadherin. In addition, knockdown of Notch upregulated VEGF and enhanced the angiogenic activity of fBMFs. Moreover, inhibition of TGF-β1 suppressed viability and EMT, promoted apoptosis, and induced angiogenesis of fBMFs, while activation of TGF-β1 significantly diminished the effects of Notch knockdown on fBMFs. Knockdown of Notch suppressed EMT and induced angiogenesis in OSF by regulating TGF-β1, suggesting that the Notch-TGF-β1 pathway may serve as a therapeutic intervention target for OSF.
Topics: Humans; Oral Submucous Fibrosis; Transforming Growth Factor beta1; Arecoline; Angiogenesis; Epithelial-Mesenchymal Transition; Fibroblasts
PubMed: 37526864
DOI: 10.1007/s10528-023-10452-3 -
Cancer Science Oct 2023The suppressive regulatory T cells (Treg) are frequently upregulated in cancer patients. This study aims to demonstrate the hypothesis that arecoline could induce the...
The suppressive regulatory T cells (Treg) are frequently upregulated in cancer patients. This study aims to demonstrate the hypothesis that arecoline could induce the secretion of mitochondrial (mt) DNA D-loop and programmed cell death-ligand 1 (PD-L1) in extracellular vesicles (EVs), and attenuate T-cell immunity by upregulated Treg cell numbers. However, the immunosuppression could be reversed by whole glucan particle (WGP) β-glucan in oral squamous cell (OSCC) patients. Arecoline-induced reactive oxygen specimen (ROS) production and cytosolic mtDNA D-loop were analyzed in OSCC cell lines. mtDNA D-loop, PD-L1, IFN-γ, and Treg cells were also identified for the surgical specimens and sera of 60 OSCC patients. We demonstrated that higher mtDNA D-loop, PD-L1, and Treg cell numbers were significantly correlated with larger tumor size, nodal metastasis, advanced clinical stage, and areca quid chewing. Furthermore, multivariate analysis confirmed that higher mtDNA D-loop levels and Treg cell numbers were unfavorable independent factors for survival. Arecoline significantly induced cytosolic mtDNA D-loop leakage and PD-L1 expression, which were packaged by EVs to promote immunosuppressive Treg cell numbers. However, WGP β-glucan could elevate CD4 and CD8 T-cell numbers, mitigate Treg cell numbers, and promote oral cancer cell apoptosis. To sum up, arecoline induces EV production carrying mtDNA D-loop and PD-L1, and in turn elicits immune suppression. However, WGP β-glucan potentially enhances dual effects on T-cell immunity and cell apoptosis and we highly recommend its integration with targeted and immune therapies against OSCC.
Topics: Humans; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Arecoline; B7-H1 Antigen; Mouth Neoplasms; Glucans; beta-Glucans; DNA, Mitochondrial; Head and Neck Neoplasms; Immunosuppression Therapy; Extracellular Vesicles
PubMed: 37525561
DOI: 10.1111/cas.15919 -
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 -
Journal of Dental Sciences Jul 2023Scientometric analysis is a useful tool that utilizes bibliometric data to measure scientific output of a disease or region in a particular field. In this report, we...
Scientometric analysis is a useful tool that utilizes bibliometric data to measure scientific output of a disease or region in a particular field. In this report, we comprehensively provide bibliometric characteristics of all the papers on betel quid (BQ)-related cancer and precancerous lesions. There are 1403 papers on BQ-related cancer and precancerous lesions published until 2022 in the Scopus database. China (mainland and Taiwan region), India, United States, and United Kingdom contribute 1214 (86.5%) papers and 34,120 (91.9%) citations of all the papers. The number (457), citations (14,573), and index (60) of the papers originated from Taiwan region stably remain in the first. The most frequent research keyword is arecoline, followed by drug, prevalence, metabolism, carcinogenesis, and pathology. Areca nut and BQ cessation program by Taiwan government has demonstrated a significant positive impact on oral cancer prevention. Collectively, the scientific output of BQ-related cancer and precancerous field represents distinct regional characteristic. BQ-related cancer prevention is still a long way off. Encouragingly, Taiwan region is well ahead in this way.
PubMed: 37404660
DOI: 10.1016/j.jds.2023.03.007 -
Oral Diseases May 2024Submucosal fibrosis (OSF) of the oral cavity is a chronic scarring disease. Arecoline (Are) is the driving factor for the occurrence and deterioration of OSF. Curcumin...
BACKGROUND
Submucosal fibrosis (OSF) of the oral cavity is a chronic scarring disease. Arecoline (Are) is the driving factor for the occurrence and deterioration of OSF. Curcumin plays a vital anti-inflammatory role in Are-induced OSF development. However, its potential pharmacological mechanism needs to be elucidated.
METHODS
The relative molecular level was measured via qRT-PCR or Western blot. MTT assay, transwell assay and flow cytometry detected cell proliferation, migration, and apoptosis. The correlation between hypoxia-inducible factor-1α (HIF-1α) and LTBP2 promoter was confirmed through dual-luciferase reporter assay. ELISA was performed to detect inflammatory cytokines levels.
RESULTS
Curcumin alleviated Are-induced oral mucosal fibroblast cells fibrosis by reducing oral mucosa fibroblasts viability, promoting cell apoptosis, suppressing cell migration, and down-regulating the levels of fibrosis markers and inflammatory factors. Curcumin relieved Are-induced OSF via inhibiting HIF-1α. Mechanically, HIF-1α bound to the promoter of LTBP2 to transcriptionally activated LTBP2. LTBP2 knockdown relieved Are-induced OSF, and curcumin down-regulated LTBP2 via inhibiting HIF-1α to relieve Are-induced OSF. Moreover, curcumin decreased NF-κB signal associated proteins via inhibiting LTBP2 to relieve Are-induced OSF.
CONCLUSION
Curcumin reduced the transcription level of LTBP2 by inhibiting HIF-1α, thereby inactivating NF-κB pathway to alleviate Are-induced OSF.
Topics: Curcumin; Oral Submucous Fibrosis; Humans; Arecoline; NF-kappa B; Hypoxia-Inducible Factor 1, alpha Subunit; Apoptosis; Cell Movement; Cell Proliferation; Signal Transduction; Fibroblasts; Mouth Mucosa; Cells, Cultured
PubMed: 37382472
DOI: 10.1111/odi.14656 -
Oral Diseases Apr 2024Fibroblast activating protein (FAP) is associated with various organ fibrosis. However, the expression and molecular function of FAP in oral submucous fibrosis (OSF) is...
OBJECTIVES
Fibroblast activating protein (FAP) is associated with various organ fibrosis. However, the expression and molecular function of FAP in oral submucous fibrosis (OSF) is still unclear.
MATERIALS AND METHODS
The high-performance liquid chromatography was used to detect the presence of alkaloids in areca nut extract (ANE). Real-time qPCR, Western blot, and Immunohistochemistry assay were used to analyze the expression of FAP mRNA or protein in OSF and normal oral tissue. A chi-squared test analyzed the relationship between FAP protein expression and clinicopathological data of OSF patients. CCK-8, Wound-healing, and Transwell migration assay were employed to assess the effect of the proliferation and migration ability of hOMF cells with FAP overexpression or knockdown. The expression level of a-SMA, FSP1, and P13K-Akt signaling pathways-related protein in hOMF cells transfected with FAP overexpression or knockdown plasmid was verified by western blot assay.
RESULTS
The four specific areca alkaloids (Arecoline, Guvacine, Arecaidine, and Guvacoline) were successfully detected in the ANE. The viability of hOMF cells was significantly improved in the 50 μg/mL ANE group and was inhibited in the 5 and 50 mg/mL ANE groups. The expression of FAP was upregulated in OSF tissues, and hOMF cells treated with 50 μg/mL ANE and was related to pathology grade, clinical stage, and history of chewing betel nut. Additionally, FAP may promote the proliferation, migration, and activation of hOMF cells through the P13K-Akt signaling pathway.
CONCLUSIONS
This study found that ANE had a bidirectional effect on the viability of hOMF cells, and the FAP gene was a potential therapeutic target in OSF.
Topics: Humans; Oral Submucous Fibrosis; Cell Movement; Cell Proliferation; Areca; Serine Endopeptidases; Fibroblasts; Membrane Proteins; Male; Endopeptidases; Female; Adult; Arecoline; Signal Transduction; Alkaloids; Plant Extracts; Middle Aged
PubMed: 37357365
DOI: 10.1111/odi.14602 -
Journal of Cellular and Molecular... Jul 2023Oral submucous fibrosis (OSF) is a chronic progressive fibrosis disease that affects in oral mucosal tissues. Interleukin (IL)-13 has been implicated in the development...
Oral submucous fibrosis (OSF) is a chronic progressive fibrosis disease that affects in oral mucosal tissues. Interleukin (IL)-13 has been implicated in the development of fibrosis in multiple organs. Indeed, it contributes to diseases such as pulmonary fibrosis, liver cirrhosis among others. Currently, its expression in OSF and the specific mechanisms are not well understood. The aim of this study was to investigate the role of IL-13 in OSF and further explore whether IL-13 regulates-polarization of M2-macrophages in OSF. Initially, in the tissues of patients with OSF, we observed a high expression of M2-macrophages and IL-13 protein. Additionally, we found a correlation between the expression of IL-13 and the stage of OSF. Arecoline inhibited the proliferation of fibroblasts (FBs) and promoted IL-13 production in vitro. Furthermore, our observations revealed that M2-macrophages increased upon co-culturing M0-macrophages with supernatants containing the IL-13 cytokine. In conclusion, our study demonstrated that arecoline stimulates FBs leading to increased secretion of IL-13, which in turn IL-13 leads to polarization of M2-macrophages and promotes the occurrence of OSF. This suggests that IL-13 may be a potential therapeutic target of OSF.
Topics: Humans; Arecoline; Fibroblasts; Fibrosis; Interleukin-13; Mouth Mucosa; Oral Submucous Fibrosis
PubMed: 37337411
DOI: 10.1111/jcmm.17761 -
Nutrients May 2023The areca nut is often consumed as a chewing food in the Asian region. Our previous study revealed that the areca nut is rich in polyphenols with high antioxidant...
The areca nut is often consumed as a chewing food in the Asian region. Our previous study revealed that the areca nut is rich in polyphenols with high antioxidant activity. In this study, we further assessed the effects and molecular mechanisms of the areca nut and its major ingredients on a Western diet-induced mice dyslipidemia model. Male C57BL/6N mice were divided into five groups and fed with a normal diet (ND), Western diet (WD), WD with areca nut extracts (ANE), areca nut polyphenols (ANP), and arecoline (ARE) for 12 weeks. The results revealed that ANP significantly reduced WD-induced body weight, liver weight, epididymal fat, and liver total lipid. Serum biomarkers showed that ANP ameliorated WD-enhanced total cholesterol and non-high-density lipoprotein (non-HDL). Moreover, analysis of cellular signaling pathways revealed that sterol regulatory element-binding protein 2 (SREBP2) and enzyme 3-hydroxy-3-methylglutaryld coenzyme A reductase (HMGCR) were significantly downregulated by ANP. The results of gut microbiota analysis revealed that ANP increased the abundance of beneficial bacterium and decreased the abundance of the pathogenic bacterium while ARE shown the opposite result to ANP. In summary, our data indicated that areca nut polyphenol ameliorated WD-induced dyslipidemia by increasing the abundance of beneficial bacteria in the gut microbiota and reducing the expressions of SREBP2 and HMGCR while areca nut ARE inhibited this improvement potential.
Topics: Male; Mice; Animals; Areca; Non-alcoholic Fatty Liver Disease; Nuts; Diet, Western; Mice, Inbred C57BL; Arecoline; Plant Extracts
PubMed: 37242285
DOI: 10.3390/nu15102403 -
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