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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 -
Toxics Dec 2023Arecoline is a pyridine alkaloid derived from areca nut in the Arecaceae family. It has extensive medicinal activity, such as analgesic, anti-inflammatory, and...
Arecoline is a pyridine alkaloid derived from areca nut in the Arecaceae family. It has extensive medicinal activity, such as analgesic, anti-inflammatory, and anti-allergic. However, the toxicity of Arecoline limits its application. Most current studies on its toxicity mainly focus on immunotoxicity, carcinogenesis, and cancer promotion. However, there are few systematic studies on its hepatotoxicity and mechanisms. Therefore, this research explored the mechanism of hepatotoxicity induced by Arecoline in rats and analyzed endogenous metabolite changes in rat plasma by combining network toxicology with metabolomics. The differential metabolites after Arecoline exposure, such as D-Lysine, N4-Acetylaminobutanal, and L-Arginine, were obtained by metabolomics study, and these differential metabolites were involved in the regulation of lipid metabolism, amino acid metabolism, and vitamin metabolism. Based on the strategy of network toxicology, Arecoline can affect the HIF-1 signaling pathway, MAPK signaling pathway, PI3K-Akt signaling pathway, and other concerning pathways by regulating critical targets, such as ALB, CASP3, EGFR, and MMP9. Integration of metabolomics and network toxicology results were further analyzed, and it was concluded that Arecoline may induce hepatotoxicity by mediating oxidative stress, inflammatory response, energy and lipid metabolism, and cell apoptosis.
PubMed: 38133385
DOI: 10.3390/toxics11120984 -
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 -
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 -
Cureus Oct 2023Oral submucous fibrosis (OSMF) is a precancerous disorder of the submucosa that causes inflammation and progressive fibrosis, leading to pronounced stiffness and... (Review)
Review
Oral submucous fibrosis (OSMF) is a precancerous disorder of the submucosa that causes inflammation and progressive fibrosis, leading to pronounced stiffness and trismus. Chewing betel nuts is a significant risk factor for OSMF in India. Arecoline from betel nuts and copper, which causes fibroblast dysfunction and the development of fibrotic bands, are the main components of betel quid. OSMF is distinguished by fibrosis in the submucosal region, which affects the majority of the oral cavity and results in advanced lockjaw due to rigidity in the lips, pharynx, cheeks, and upper third of the oesophageal canal, which progresses to dysphagia. The prevalence of OSMF is rising, particularly among younger generations, as more commercially available areca nut products like gutka (chewing tobacco) and others are being introduced. The severity of OSMF develops as the practice continues and is permanent. It also persists even after chewing has been stopped. The hallmark of oral submucous fibrosis (OSF) is abnormal collagen deposition. It is a precancerous condition and progresses to malignant tumours. Symptoms include ulcers, xerostomia, submucous fibrosis, burning sensation, and a reduction in mouth opening. Each of these drastically reduces the patient's quality of life. In the past, many treatment modalities have been tried but none of them has resulted in a cure for the disease. The primary focus of the treatment is to reduce the signs and symptoms so that the patient can have a better quality of life. Along with principles, conservative, medical, and surgical management issues have also been covered.
PubMed: 38022118
DOI: 10.7759/cureus.47259 -
Drug Design, Development and Therapy 2023Arecoline is one of the main toxic components of arecoline to cause oral mucosal lesions or canceration, which seriously affects the survival and life quality of...
Jiawei Danxuan Koukang Alleviates Arecoline Induced Oral Mucosal Lesions: Network Pharmacology and the Combined Ultra-High Performance Liquid Chromatography (UPLC) and Mass Spectrometry (MS).
PURPOSE
Arecoline is one of the main toxic components of arecoline to cause oral mucosal lesions or canceration, which seriously affects the survival and life quality of patients. This study analyzed the mechanism of Jiawei Danxuan Koukang (JDK) in alleviating arecoline induced oral mucosal lesions, to provide new insights for the treatment of oral submucosal fibrosis (OSF) or cancerosis.
METHODS
Metabolomics was applied to analyze the composition of JDK and serum metabolites. The active ingredients of JDK were analyzed by the combined ultra-high performance liquid chromatography and mass spectrometry. The target network of JDK, metabolites and OSF was analyzed by network pharmacology, and molecular docking. Oral mucosal lesions and fibrosis were analyzed by HE and Masson staining. Cell differentiation, proliferation and apoptosis were detected. The expressions of α-SMA, Collagen I, Vimentin, Snail, E-cadherin, AR and NOTCH1 were detected by Western blot.
RESULTS
Arecoline induced the gradual atrophy and thinning of rat oral mucosal, collagen accumulation, the increase expressions of fibrosis-related proteins and Th17/Treg ratio. JDK inhibited arecoline-induced oral mucosal lesions and inflammatory infiltration. Arecoline induced changes of serum metabolites in Aminoacyl-tRNA biosynthesis, Alanine, aspartate and glutamate metabolism and Arginine biosynthesis pathways, which were reversed by M-JDK. Quercetin and AR were the active ingredients and key targets of JDK, metabolites and OSF interaction. Arecoline promoted the expression of AR protein, and the proliferation of oral fibroblasts. Quercetin inhibited the effect of arecoline on oral fibroblasts, but was reversed by AR overexpression. Arecoline induced NOTCH1 expression in CAL27 and SCC-25 cells, and promoted cell proliferation, but was reversed by M-JDK or quercetin.
CONCLUSION
JDK improved the arecoline-induced OSF and serum metabolite functional pathway. Quercetin targeted AR protein to improve arecoline-induced OSF. JDK and quercetin inhibited arecoline-induced NOTCH1 protein expression in CAL27 and SCC-25 cells to play an anti-oral cancer role.
Topics: Humans; Rats; Animals; Arecoline; Chromatography, High Pressure Liquid; Network Pharmacology; Molecular Docking Simulation; Quercetin; Oral Submucous Fibrosis; Mouth Mucosa; Fibroblasts; Collagen; Fibrosis; Mass Spectrometry
PubMed: 37854130
DOI: 10.2147/DDDT.S413897 -
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 -
Ecotoxicology and Environmental Safety Oct 2023This study aimed to investigate the effects of arecoline on constipation by intervening at different times to explore its preventive and therapeutic effects. Symptoms...
This study aimed to investigate the effects of arecoline on constipation by intervening at different times to explore its preventive and therapeutic effects. Symptoms related to constipation, gut microbes, short-chain fatty acid (SCFA) content in the cecum, and gene expression in the colon were measured to examine the effect of arecoline on relieving constipation. The results showed that arecoline intervention alleviated loperamide-induced constipation, as evidenced by significantly shortened intestinal transit time, increased fecal water content, improved small bowel propulsion, and increased defecation frequency. In addition, arecoline significantly reduced the levels of gastrointestinal regulatory peptides such as somatostatin and vasoactive intestinal peptide in the serum, thereby regulating intestinal peristalsis. Histopathological analysis showed that arecoline ameliorated intestinal injury caused by constipation. Gut microbial analysis indicated that arecoline altered the taxonomic composition and levels of its metabolite SCFAs in the gut microbiota. Furthermore, the colonic transcriptome results indicated that genes expression related to intestinal diseases were significantly down-regulated by arecoline intervention. In conclusion, the results of the correlation analysis propose a possible mechanism of arecoline in alleviating constipation by modulating the gut microbes and their metabolites and regulating the gut genome.
PubMed: 37666200
DOI: 10.1016/j.ecoenv.2023.115423 -
Scientific Reports Apr 2024A series of arecoline derivatives with amino acid moieties were designed and synthesised using an acylamide condensation strategy, taking arecoline as the foundational...
A series of arecoline derivatives with amino acid moieties were designed and synthesised using an acylamide condensation strategy, taking arecoline as the foundational structure. The insecticidal efficacy of these compounds against Aphis craccivora and Tetranychus cinnabarinus was evaluated. Notably, derivatives 3h and 3i demonstrated superior insecticidal activity compared with arecoline. Additionally, 3h and 3i showed good fungicidal effectiveness against two types of plant fungi. Moreover, molecular docking analyses suggested that 3h and 3i could affect the nervous systems of A. craccivora and T. cinnabarinus by binding to neuronal nicotinic acetylcholine receptors. These findings suggest that compounds 3h and 3i represent promising leads for further development in insecticide and fungicide research.
Topics: Insecticides; Animals; Antifungal Agents; Molecular Docking Simulation; Amino Acids; Drug Design; Aphids; Tetranychidae; Structure-Activity Relationship; Receptors, Nicotinic; Microbial Sensitivity Tests
PubMed: 38658769
DOI: 10.1038/s41598-024-60053-2 -
Ecotoxicology and Environmental Safety Jul 2023Arecoline is a critical bioactive component in areca nuts with toxicity and pharmacological activities. However, its effects on body health remain unclear. Here, we...
Arecoline is a critical bioactive component in areca nuts with toxicity and pharmacological activities. However, its effects on body health remain unclear. Here, we investigated the effects of arecoline on physiologic and biochemical parameters in mouse serum, liver, brain, and intestine. The effect of arecoline on gut microbiota was investigated based on shotgun metagenomic sequencing. The results showed that arecoline promoted lipid metabolism in mice, manifested as significantly reduced serum TC and TG and liver TC levels and a reduction in abdominal fat accumulation. Arecoline intake significantly modulated the neurotransmitters 5-HT and NE levels in the brain. Notably, arecoline intervention significantly increased serum IL-6 and LPS levels, leading to inflammation in the body. High-dose arecoline significantly reduced liver GSH levels and increased MDA levels, which led to oxidative stress in the liver. Arecoline intake promoted the release of intestinal IL-6 and IL-1β, causing intestinal injury. In addition, we observed a significant response of gut microbiota to arecoline intake, reflecting significant changes in diversity and function of the gut microbes. Further mechanistic exploration suggested that arecoline intake can regulate gut microbes and ultimately affect the host's health. This study provided technical help for the pharmacochemical application and toxicity control of arecoline.
Topics: Animals; Mice; Arecoline; Interleukin-6; Gastrointestinal Microbiome; Lipid Metabolism; Liver
PubMed: 37224782
DOI: 10.1016/j.ecoenv.2023.115055