arecoline / Cogent Pharma - LARVOL DELTA

INHBA+ macrophages and Pro-inflammatory CAFs are associated with distinctive immunosuppressive tumor microenvironment in submucous Fibrosis-Derived oral squamous cell carcinoma. (PubMed, BMC Cancer) - "The classic OSF-inducing molecule arecoline significantly increases the expression of INHBA (p < 0.0001) in vitro experiments stimulating THP-1 cells...The increased INHBA+Mac and iCAF in ODSCC are associated with the observed more severe TISME. The upregulated INHBA in ODSCC and its interaction with INHBA-ACVR1/ACVR2A/ACVR2B may mediate the modulation effect of INHBA+ Mac and iCAF on Treg differentiation and functionality."

Biomarker • IO biomarker • Journal • Fibrosis • Immunology • Oncology • Oral Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ACVR1 • ACVR2A • ACVR2B • CD8 • DUSP4 • IDO1 • SPP1 • TDO2

Safety evaluation of Areca catechu L. extract powder in rats: acute and 180-day chronic toxicity test. (PubMed, J Ethnopharmacol) - "The acute toxicity test showed that the LD50 of BLTQS exceeded 15 g/kg bw. The no-observed-effect level (NOEL) for BLTQS in rats was calculated to be 0.32 g/kg bw. These findings support the safety of BLTQS for clinical use, provided that dosages adhere to clinically recommended guidelines."

Journal • Preclinical • Hematological Disorders

Intranasal delivery of drugs to the central nervous system of adult zebrafish. (PubMed, Lab Anim (NY)) - "Intranasally administered arecoline (10 mg/mL) and nicotine (5 and 10 mg/mL) demonstrated overt behavioral profiles, evoking characteristic anxiolytic-like effects in zebrafish similar to those observed here for a standard 20-min water immersion method (10 mg/L arecoline or 30 mg/L nicotine). Overall, we showed that neuroactive drugs can be delivered to adult zebrafish intranasally to exert central effects, which may (at least for some drugs) occur faster and can need smaller drug quantities than for the water immersion delivery."

Journal

Unraveling the Ties Between Betel Nut Chewing, Obstructive Airway Disease, Zenker Diverticulum, and Gastro-esophageal Reflux Disease (ATS 2025) - "Discussion Arecoline, a cholinergic alkaloid is one of the primary components of betel nut (Areca Catechu) and can cause increase in eotaxin-1 levels and chronic inflammatory changes leading to Asthma and COPD respectively. In patients with recurrent COPD exacerbations, a thorough search for culture-specific practices like betel nut chewing amongst others is warranted and abstinence from such practices can aid in reducing morbidity."

Asthma • Cardiovascular • Chronic Obstructive Pulmonary Disease • Cough • Esophageal Cancer • Fibrosis • Gastroenterology • Gastroesophageal Reflux Disease • Gastrointestinal Disorder • Immunology • Oncology • Pulmonary Disease • Pulmonary Emphysema • Respiratory Diseases • CCL11

Haplotype-resolved genome reveals haplotypic variation and the biosynthesis of medicinal ingredients in Areca catechu L. (PubMed, Mol Hortic) - "Further analyses tested the function of AcUGT71CE15, AcUGT74CJ38, AcUGT87EE5 and AcUGT83S982 as glucosyltransferases, and AcUGT78AP14 was identified as a rhamnosyltransferase involved in flavonol glycosylation. Our study provides a high-quality genome of A. catechu, characterizes the arecoline biosynthetic pathway and expands the understanding of the diversity of UDP-glucosyltransferase and UDP-rhamnosyltransferase, offering insights into the potential of A. catechu for the biosynthesis of bioactive compounds."

Journal

Modulation of neural activity and gene expression by arecoline. (PubMed, Front Integr Neurosci) - "These results provide valuable insights into the addictive potential of arecoline and its underlying neurobiological mechanisms, offering crucial information for understanding its broader impact on CNS function. The study's findings hold significant implications for informing public health strategies aimed at addressing arecoline misuse and its potential role in addiction-related disorders."

Journal • CNS Disorders • Psychiatry

Application potential of arecoline hydrobromidefor anti-Toxoplasma gondii. (PubMed, Exp Parasitol) - "Furthemore, the survival and safety evaluation outcome indicated that AH can prolong survival period of mice infected with T. gondii at non-toxic and side-effect dose. Based on these advantages, AH is a candidate compound with great potential for the treatment of T. gondii infection and it may be used clinically in the future."

Journal • Infectious Disease • Oncology

Arecoline Alleviates Depression via Gut-Brain Axis Modulation, Neurotransmitter Balance, Neuroplasticity Enhancement, and Inflammation Reduction in CUMS Mice. (PubMed, J Agric Food Chem) - "These findings demonstrate that arecoline exerts its antidepressant effects via a multitargeted approach involving the gut-brain axis, neurotransmitter modulation, and neuroplasticity enhancement. This study highlights arecoline as a promising therapeutic candidate for depression, emphasizing its potential to address both central and peripheral mechanisms."

Journal • Preclinical • CNS Disorders • Depression • Inflammation • Mood Disorders • Psychiatry • BDNF • IL1B

Unveiling the Mystery of the Stimulatory Effects of Arecoline: Its Relevance to the Regulation of Neurotransmitters and the Microecosystem in Multi-Ecological Intestinal Sites. (PubMed, Int J Mol Sci) - "The ingestion of arecoline can alter the behavioral patterns of mice, causing significant changes in the 5-HT levels in brain tissue and exerting regulatory effects on the microecosystem in multi-ecological intestinal sites. These findings will provide a reference for the future development and utilization of betel nut."

Journal

Hypoxia amplifies arecoline-induced invasion and metastasis in oral squamous cell carcinoma - Insights into TGF-β1 signaling and collagen production. (PubMed, J Dent Sci) - "Arecoline stimulates SCC-25 cell proliferation and migration, with hypoxia amplifying these effects by promoting TGF-β1 signaling and type I collagen production. These findings suggest that betel quid consumption, in combination with hypoxia, may exacerbate the invasion and metastasis of OSCC."

Journal • Oncology • Oral Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Tongue Carcinoma • HIF1A • TGFB1

A Metabolomics and Proteomics-Based Study on the Metabolic Effects of Arecoline on the Liver. (PubMed, Toxicon) - "We observed that with increasing doses of arecoline, the metabolites of lipids and lipid-like molecules in mice gradually increased. The results suggested arecoline may induce fatty degeneration in the liver of mice through the PPARα/Acox-1 mediated pathways of oxidative stress, inflammatory response, energy, and lipid metabolism."

Journal • Allergy • Hepatology • Immunology • Inflammation • Metabolic Disorders • Oncology • PPARA

Chitosan nanoparticles as a targeted delivery system for anti-fibrotic microRNAs for oral submucosal fibrosis treatment. (PubMed, Colloids Surf B Biointerfaces) - "Human oral submucosal fibroblasts were first subjected to arecoline stimulation to induce myofibroblast differentiation and were then transfected with a miR-145 inhibitor or miR-424 inhibitor using CS NPs...CS NPs are a good delivery vehicle for miR transfection. Transfection of a miR-145 inhibitor and miR-424 inhibitor inhibited the TGF-β signaling pathway and decreased ECM component production, and could thus be a promising treatment for OSF."

Journal • Fibrosis • Immunology • ACTA2 • COL1A1 • COL3A1 • COL4A1 • MIR145 • MIR424 • MMP2 • TGFB1 • ZEB1

Abnormal collagen deposition mediated by cartilage oligomeric matrix protein in the pathogenesis of oral submucous fibrosis. (PubMed, Int J Oral Sci) - "We further demonstrated that hBMFs present heterogeneous responses to arecoline stimulation, of which COMP-positive fibroblasts secrete more collagen I. Since COMP is a molecular bridge with Fibril-associated collagens with Interrupted Triple helices (FACIT) in the collagen network, we further screened and identified collagen XIV, a FACIT member, co-localizing with both COMP and collagen I. Collagen XIV expression increased under arecoline stimulation in wild-type mice, whereas it was hardly expressed in the Comp-/- mice, even with under stimulation. In summary, we found that COMP may mediates abnormal collagen I deposition by functions with collagen XIV during the progression of OSF, suggesting its potential to be targeted in treating OSF."

Journal • Fibrosis • Immunology • COMP

Assessing the carcinogenic potential and molecular mechanisms of arecoline in human lungs: from in silico methods to in vitro validation. (PubMed, Ecotoxicol Environ Saf) - "This study elucidates the molecular mechanism underlying arecoline-induced LUAD, introducing a novel approach for assessing food safety and presenting innovative and promising targets and strategies for cancer intervention and therapy."

IO biomarker • Journal • Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PACERR • PTGS2

Arecoline Alleviates T2DM via Gut Microbiota Modulation and Liver Gene Regulation in Mice. (PubMed, Mol Nutr Food Res) - "Arecoline improves glucose metabolism, lipid profiles, and liver function, while modulating gut microbiota and liver metabolic pathways, showing potential as a therapeutic agent for T2DM."

Journal • Preclinical • Diabetes • Inflammation • Metabolic Disorders • Type 2 Diabetes Mellitus • IL1B • IL6

Comparative effects of arecoline, caffeine, and nicotine on transcription level in the nucleus accumbens of mice. (PubMed, Genomics) - "Furthermore, only acute caffeine treatment significantly increased mouse activity, and only nicotine induced CPP. These results provided a scientific basis for evaluating arecoline, caffeine, and nicotine on the nervous system."

Clinical • Journal • Preclinical

Synthesis of 3,2'-Pyrrolidinyl Spirooxindole Derivative via 2,3-Rearrangement of Ammonium Ylide. (PubMed, J Org Chem) - "Herein, we reported an efficient method for the construction of 3,2'-pyrrolidinyl spirooxindole by the [2,3]-rearrangement reaction between 3-diazoindolin-2-one and arecoline under mild reaction conditions, which had a good functional group tolerance and high yield. This work not only facilitates the study of selective rearrangement of ammonium ylide but also contributes significantly to the synthesis of spiro compounds."

Journal

VHL ameliorates arecoline-induced oral submucosal fibrosis by promoting HDAC6 ubiquitination and blocking NF-κB pathway. (PubMed, Sci Rep) - "HDAC6 selective inhibitor ACY-1215 inhibited the NF-κB signaling pathway. VHL attenuated arecoline-induced OSF by inhibiting the ubiquitination of HDAC6 and blocking NF-κB pathway. As a result, our study offers new perspectives into the discovery of novel tactics that can be employed against OSF."

Journal • Fibrosis • Immunology • Oncology • Targeted Protein Degradation • Von Hippel-Lindau Syndrome • HDAC6

Investigation into the presence of alkaloids in Areca catechu-based single-use food-contact articles (FCA). (PubMed, Food Addit Contam Part A Chem Anal Control Expo Ri) - "The seeds of Areca catechu palm, commonly referred to as the betel nut, are known to contain high concentrations of four alkaloids: arecoline, guvacoline, areciadine, and guvacine. Migration of these alkaloids into a food simulant was determined using a single-sided migration cell. The results indicate that carboxylic acid alkaloids, arecaidine, and guvacine, preferentially migrate under the experimental conditions which mimic the conditions of use for dinnerware."

Journal

Jiawei Danxuan Koukang and its key component Quercetin intervened in OSF carcinogenesis by inhibiting the AR/eIF5A2 signaling pathway-mediated EMT. (PubMed, Arch Oral Biol) - "JDK and Quercetin inhibited OSF carcinogenesis by inhibiting the AR/eIF5A2 signal-mediated EMT."

Journal • Fibrosis • Immunology • Oncology • Oral Cancer • CDH1 • EIF5A2 • VIM

Epigallocatechin-3-gallate inhibits the collagen accumulation of oral submucous fibrosis induced by arecoline. (PubMed, Front Pharmacol) - "EGCG effectively suppressed the ARE-induced ECM components while concurrently improving the OSF pathological process in vitro and in vivo. The results indicate that the natural product EGCG effectively suppressed the increased ECM components induced by ARE and concurrently improved the OSF pathological process, indicating that EGCG could be potentially a novel anti-fibrotic candidate drug for the treatment of OSF."

Journal • Fibrosis • Immunology

Arechuines A-D, arecoline alkaloids from the peels of Areca catechu L. (PubMed, Nat Prod Res) - "Compounds 1 - 4 were evaluated for their neuroprotective effects in glutamate-induced HT22 cell and 3 revealed potent neuroprotective effects at 10 μM. These are the first reported arecoline alkaloid atropisomers isolated from A. catechu."

Journal

Oleanolic acid inhibits aldo-keto reductase family 1 member B10-induced cancer stemness and avoids cisplatin-based chemotherapy resistance via the Snail signaling pathway in oral squamous cell carcinoma cell lines. (PubMed, J Dent Sci) - "In this study, we investigated whether arecoline, a major alkaloid in betel nuts, can stimulate aldo-keto reductase family 1 member B10 (AKR1B10) levels in OSCC, promoting cancer stemness and leading to resistance to cisplatin (CDDP)-based chemotherapy. Furthermore, AKR1B10 enhanced CDDP resistance in OSCC cells via EMT-inducing markers. Finally, Finally, OA may efficiently target CDDP resistance, reverse stemness in OSCC cells, and have the potential as a novel anticancer drug."

Journal • Preclinical • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • AKR1B1 • AKR1B10 • SMAD3 • TGFB1

Synthesis and antifungal activity of arecoline derivatives containing amino acid fragments. (PubMed, Mol Divers) - "The findings demonstrated that Compound 3s effectively inhibits fungal hyphal growth by compromising the integrity of the hyphal cell membrane. These results indicate that arecoline derivatives containing amino acid benzyl esters have potential as promising fungicides."

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Epithelium-derived exosomal dipeptidyl peptidase-4 involved in arecoline-induced oral submucous fibrosis. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "These findings offer valuable insights into clinical strategies for combating oral fibrotic disease and contribute to the foundation of future research in this field."

Journal • Fibrosis • Immunology • DPP4