arecoline / Cogent Pharma - LARVOL DELTA

Ion Channel-Targeting Modulators in Glioma: Pharmacological Advances and Therapeutic Perspectives. (PubMed, Int J Mol Sci) - "This perspective summarizes current evidence for eight representative drugs and phytoconstituents-perampanel, valproic acid, cilostazol, berberine, oxaliplatin, temozolomide, arecoline, and triptolide-that modulate these ion channels. In particular, arecoline is associated with carcinogenicity and neurotoxicity, triptolide with significant systemic toxicity, berberine with poor oral bioavailability and potential drug interactions, and oxaliplatin with dose-limiting neurotoxicity. Overall, this perspective highlights ion channels as promising therapeutic targets in glioma while emphasizing the need for rigorous experimental validation and careful evaluation of safety before clinical translation."

Journal • Review • Brain Cancer • CNS Disorders • Epilepsy • Glioma • Oncology • Solid Tumor

Chronic Exposure to Areca Alkaloids at Environmentally Relevant Concentrations Alters Neurobehavior, Gut Microbiota and Brain Metabolism in Adult Zebrafish. (PubMed, Environ Res) - "In this study, adult zebrafish were chronically exposed to arecoline or arecaidine for 90 days to investigate long-term neurobehavioral toxicity and associated biological alterations...Integrated correlation analyses revealed associations among altered gut bacterial genera, brain metabolic pathways, and behavioral endpoints, suggesting potential links among gut microbial alterations, brain metabolic changes, and behavioral outcomes following areca alkaloid exposure. In summary, these findings reveal that long-term exposure to areca alkaloids at environmental concentrations elicits neurobehavioral and neurotoxic effects in adult zebrafish accompanied by alterations in gut microbiota and brain metabolism, highlighting the potential of areca alkaloids as environmental neurotoxicants relevant to aquatic health risk assessment."

Journal • Inflammation • Solid Tumor

Betel nut sucking is the earliest recorded evidence for the habitual use of a neuroactive plant drug. (PubMed, Sci Adv) - "Previous reports suggested that the main neuroactive alkaloid in betel nut, arecoline, is released by masticating the processed nut with slaked lime...Biomolecular analysis of the ancient human teeth is also consistent with this early form of ingesting betel nut. With the earliest forager dating to 25 to 16 thousand years ago, our findings suggest the use of betel nut as a drug has more ancient origins than previously supposed."

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Molecular effects of areca nut-derived compounds on human oral cancer cells: a systematic review of in vitro evidence. (PubMed, J Oral Biol Craniofac Res) - "Findings for p21 were contradictory across studies. In vitro evidence indicates that areca nut constituents induce coordinated inflammatory, proliferative, oxidative, and signaling alterations that support their carcinogenic role in human oral cancer cells."

Journal • Preclinical • Review • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • CDKN1A • CXCL8 • IL1B • IL6 • NOTCH1 • SIRT1

Isoliquiritigenin represses the pro-fibrotic TGF-β/smad2 signaling and nuclear enriched abundant transcript 1 (NEAT1) in oral submucous fibrosis. (PubMed, J Dent Sci) - "Primary normal BMFs and fibrotic BMFs (fBMFs) were isolated from human buccal mucosa, and cell viability, collagen gel contraction, migration, and wound closure were examined after ISL treatment with or without arecoline...In conclusion, ISL selectively targets OSF-derived fibroblasts and attenuates myofibroblast-like phenotypes by disrupting TGF-β1/Smad2 signaling and NEAT1-driven fibrogenic activity. These findings highlight ISL as a promising candidate for adjunctive therapy in OSF."

Journal • Fibrosis • Immunology • COL1A1 • NEAT1 • TGFB1

Dietary Arecoline Supplementation Enhances Flesh Quality, Muscle Growth, and Protein Deposition in Grass Carp (Ctenopharyngodon idella): Insights Into TOR and FOXO Signaling Pathways. (PubMed, Aquac Nutr) - "Our findings provide novel evidence that arecoline improves fish flesh quality. These findings offer practical insights for aquaculture nutrition and highlight arecoline's potential as a functional feed additive."

Journal • Targeted Protein Degradation

Molecular mechanisms of therapeutic resistance in areca nut-associated oral squamous cell carcinoma: the interplay of chronic inflammation and epithelial-mesenchymal transition. (PubMed, Front Oncol) - "Chronic exposure to areca nut alkaloids, such as arecoline, contributes to oral carcinogenesis by inducing oxidative stress, DNA damage, chronic inflammation, fibrosis, and epithelial-mesenchymal transition (EMT)...Recent evidence indicates that targeting inflammatory mediators, reactive oxygen species (ROS), and EMT related pathways may enhance therapeutic outcomes in OSCC associated with areca nut consumption. This review summarises the molecular mechanisms linking areca nut exposure to OSCC progression, focusing on the interaction between chronic inflammation and EMT, and examines their implications for tumour aggressiveness, therapeutic resistance, and future targeted therapeutic strategies."

Journal • Review • Fibrosis • Head and Neck Cancer • Immunology • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • CDH1 • CDH2 • TGFB1 • VIM

Investigation into the presence of alkaloids in Areca catechu based single use food-contact articles (FCA) (ACS-Fall 2026) - "The seeds of Areca catechu palm, commonly referred to as the betel nut, are known to contain high concentrations of four toxic alkaloids as described by the International Agency for Cancer Research (IARC): arecoline, guvacoline, areciadine, and guvacine...Tests were also conducted to determine the effect of microwave heating on migration concentrations. Palm leaf bowls were heated using a 1000W microwave for one minute resulting in quantifiable amounts of alkaloids which increased approximately three-fold after 20 minutes of exposure to heated simulant."

Beyond a dual role: how Purpureocillium lilacinum reprograms citrus metabolism for integrated biocontrol and growth promotion. (PubMed, J Sci Food Agric) - "These findings provide novel insights into the biochemical mechanisms underlying P. lilacinum-citrus interactions. They confirm the role of the fungus in orchestrating a synergized growth-and-defense response in citrus, highlighting its strong potential as a sustainable, multi-functional bioinoculant for citrus production systems."

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Multi-Targeted Neuroprotection by Areca catechu Against Cisplatin-Induced Neurotoxicity: Cellular, Caenorhabditis elegans, and Metabolomic Evidence. (PubMed, Int J Mol Sci) - "While AC-EA shows neuroprotective potential, arecoline's toxicity demands caution. To our knowledge, this is the first study to demonstrate the neuroprotective activity of A. catechu against cisplatin-induced neurotoxicity, laying the foundation for developing plant-derived adjunct therapies for chemotherapy-associated neuropathy."

Journal • Lung Cancer • Oncology • Pain • Solid Tumor • NFE2L2

Terrestrial jumping assay for adult zebrafish as a potential tool to assess motor, affective and drug-evoked phenotypes. (PubMed, Behav Brain Res) - "Treatment groups including acute exposure to ethanol, arecoline, caffeine, alarm pheromone and live predator (Nandus nandus), as well as chronic exposure to fluoxetine, reserpine, cuprizone and rotenone. Overall, the assay shows high sensitivity to various experimental manipulations, supporting the utility of the terrestrial jumping assay as a fast, low-cost and single-trial behavioral paradigm to assess both motor phenotypes and affective-like responses in zebrafish."

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Arecoline promotes oral submucous fibrosis by enhancing epithelial cell cuproptosis through PUS1-mediated pseudouridylation. (PubMed, 3 Biotech) - "In conclusion, we reveal a previously unrecognized mechanism whereby arecoline promotes OSF via PUS1-dependent pseudouridylation remodeling and epithelial cuproptosis, offering novel therapeutic targets for OSF intervention. The online version contains supplementary material available at 10.1007/s13205-026-04931-8."

Journal • Fibrosis • Immunology • DLAT • FDX1 • FZD6 • LIAS • MYC • SLC25A3

Targeting monoamine oxidases for the treatment of betel quid dependence: a potential pharmacological and neurobiological approach. (PubMed, Front Pharmacol) - "We have analyzed emerging evidence suggesting that arecoline, betel quid's primary psychoactive constituent, functions as a monoamine oxidase A inhibitor, likely modulating dopaminergic and serotonergic pathways involved in addiction and mood regulation...Future research should include investigating specific monoamine oxidase A expression patterns in betel quid users, developing culturally. Appropriate interventions that integrate biological awareness, and exploring the need for carefully timed monoamine oxidase A inhibitors as cessation aids."

Journal • Review • CNS Disorders • Infectious Disease • Psychiatry

Genotype-dependent profile and developmental dynamics of pyridine alkaloids in Areca catechu L. (PubMed, Sci Rep) - "This study quantified the temporal profiles of four key pyridine alkaloids-arecoline, guvacoline, guvacine, and arecaidine- in 15 arecanut genotypes from 6 to 12 months post-anthesis...To contextualize these alkaloid patterns within overall seed composition, physicochemical properties, fatty acid profiles, antioxidant activity, and total polyphenol content were also evaluated across genotypes. These findings provide a biochemical basis for cultivar selection, value addition, and breeding strategies aimed at optimizing arecanut alkaloid composition."

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Generalized Coronary Spasm after Pulsed Field Ablation: Not a device complication alone, but a possible interaction between technology and host biology. (PubMed, Heart Rhythm) - No abstract available

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Development and application of a liquid chromatography-tandem mass spectrometry method for the analysis of Areca nut alkaloids in rat plasma for a toxicokinetic study. (PubMed, J Chromatogr B Analyt Technol Biomed Life Sci) - "The validated method was successfully applied for a toxicokinetic study in rats, and plasma concentration-time profiles of all analytes were characterized. These results show that the developed method is suitable for the quantitative determination of arecoline, arecaidine, and guvacoline in plasma and can be used in toxicokinetic and pharmacokinetic studies."

Journal • Preclinical

Fully synthetic arecoline and arecaidine vaccine candidates with α-Galactosylceramide as built-in adjuvant. (PubMed, Eur J Med Chem) - "In vivo, Arec-αGalCer vaccination caused a modest mitigation of arecoline-induced hypothermia. In addition, a mixed vaccine formulation elicited a broader serological response than the single vaccine."

Journal • CNS Disorders • Psychiatry

Epigallocatechin Gallate Attenuates Arecoline-induced Migration and Invasion in Esophageal Squamous Cell Carcinoma Cells Associated With EGFR/AKT/P38 Signaling. (PubMed, Anticancer Res) - "The attenuation of arecoline-driven metastatic behavior in ESCC cells by EGCG is associated with alterations in EGFR-AKT-P38 signaling, supporting its potential role as a dietary or adjunctive agent in areca-associated esophageal cancer."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • VIM

Exploring the molecular link between arecoline exposure and prostate cancer-related alterations: integrative evidence from network toxicology, single-cell transcriptomics, molecular simulation, and experimental validation. (PubMed, Front Pharmacol) - "Molecular simulation provided computational support for structural compatibility between arecoline and AR, while in vitro experiments showed increased AR mRNA and protein expression after arecoline treatment in LNCaP cells. These findings suggest AR as a plausible candidate molecular node linking arecoline exposure to PCa-related molecular alterations and provide a hypothesis-generating framework for future mechanistic and exposure-focused studies."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

Spatiotemporal Variations in Areca Nut Consumption in Haikou and Wuzhishan Cities Based on Wastewater Monitoring (PubMed, Huan Jing Ke Xue) - "In contrast， the proportions of arecoline and N-methylnipecotic acid notably were lower than those observed in Wuzhishan...In conclusion， wastewater-based epidemiology of areca nut biomarkers can effectively reflect local consumption levels and habits. This provides a reliable tool for monitoring areca nut use."

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Arecoline Facilitates Object Recognition in Mice. (PubMed, Biol Pharm Bull) - "Time-series analysis further revealed that arecoline treatment led to sustained high discrimination ability during the test session, compared to vehicle treatment. These findings demonstrate that acute arecoline administration enhances object recognition even in a healthy physiological state, possibly by facilitating cholinergic-mediated attention and memory encoding."

Journal • Preclinical • Mood Disorders • Psychiatry

Comprehensive Integrated Single-Cell and Spatial Transcriptomics Unveil the Dynamic Landscape of Betel Nut-Associated Oral Mucosal Carcinogenesis and Its Tumor Microenvironment. (PubMed, MedComm (2020)) - "Clinically, LAMC2 expression was significantly elevated in OSCC tissues from betel nut chewers, and arecoline treatment of OSCC cell lines induced LAMC2 upregulation, EMT, and enhanced migratory and invasive capacities in vitro. Collectively, our study delineates a malignant trajectory of epithelial cell progression, highlighting LAMC2+ EpiC6 as a key aggressive subpopulation orchestrated by EMT-related transcriptional regulators and extracellular matrix remodeling. These findings offer mechanistic insights and identify potential therapeutic targets to disrupt tumor-stroma interplay and mitigate disease progression."

Biomarker • Journal • Fibrosis • Oncology • Oral Cancer • Squamous Cell Carcinoma • CAFs • LAMC2

Development of arecoline-induced mouse model for oral submucous fibrosis: An in vitro and in vivo study. (PubMed, Arch Oral Biol) - "The study demonstrates that arecoline induces OSMF-like condition in both cultured cells and mice, providing practical model for preliminary evaluation of potential anti-OSMF therapeutic agents by assessing fibrotic, inflammatory, oxidative stress markers, key molecular regulators of OSMF."

Journal • Preclinical • Fibrosis • Immunology • COL1A2 • IFNG • IL13 • IL1B • IL6 • TGFB1 • TNFA

Activation of peripheral muscarinic receptors rescues depressive-like behaviors via gut-brain-axis, involving parasympathetic excitation. (PubMed, Acta Pharmacol Sin) - "Furthermore, arecoline, an agonist of the peripheral parasympathetic muscarinic (M) receptors, has exhibited significant antidepressant effects in multiple murine depression models, and its antidepressant effects could be blocked by the M receptor antagonist known as atropine, thus indicating that parasympathetic excitability regulates depressive-like behaviors...Notably, pharmacological activation of peripheral parasympathetic M receptors can regulate the activation of the nodose ganglion (NG)-NTS-ACCGlu neural axis and modulate depressive-like behaviors. For the first time, this study indicates that peripheral M receptors are promising targets for antidepressants development and proposes a potential antidepressant strategy involving the pharmacological modulation of peripheral autonomic balance."

Journal • CNS Disorders • Depression • Psychiatry

Arecoline-induced EV-mediated ZNF582 hypermethylation drives IFIT1-PD-L1 immune evasion in oral squamous cell carcinoma. (PubMed, Clin Epigenetics) - "Targeting the EV-mediated ZNF582-IFIT1-PD-L1 pathway may offer new therapeutic strategies for immune modulation in OSCC patients, especially those with a history of areca nut exposure."

IO biomarker • Journal • Immune Modulation • Immunology • Oncology • Oral Cancer • Squamous Cell Carcinoma • CD4 • CD8 • IFIT1 • PD-L1 • ZNF582