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Evidence-based Complementary and... 2021Betel nut, the fruit of L, has a long medical history in Southeast Asia. It is native to Malaysia and is cultivated and processed extensively in subtropical regions,... (Review)
Review
Betel nut, the fruit of L, has a long medical history in Southeast Asia. It is native to Malaysia and is cultivated and processed extensively in subtropical regions, such as South China and India. Betel nut almost appears as a "snack" in various occasions in most parts of China. Clinically, betel nut can play a certain pharmacology role and was used in malaria, ascariasis, arthritis, enterozoic abdominalgia, stagnation of food, diarrhea, edema, and beriberi. The nervous excitement of betel nut chewing has made it gradually become popular. However, chewing betel nut can induce oral submucosal fibrosis (OSF) and oral cancer (OC). At the same time, long-term chewing of betel nut also causes inhaled asthma, sperm reducing, betel quid dependence (BQD), and uterine and esophageal cancers. The main components of processed betel nut are the goal of this review. This study will mainly start from the pharmacological activity and toxicology study of betel nut in recent years, aiming to seek its advantages and disadvantages. In the meantime, this study will analyze and emphasize that betel nut and arecoline are the high-risk factors for oral cancer, which should arouse attention and vigilance of the public.
PubMed: 34457017
DOI: 10.1155/2021/1808081 -
The Cochrane Database of Systematic... Mar 2018Tardive dyskinesia (TD) remains a troublesome adverse effect of conventional antipsychotic (neuroleptic) medication. It has been proposed that TD could have a component... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Tardive dyskinesia (TD) remains a troublesome adverse effect of conventional antipsychotic (neuroleptic) medication. It has been proposed that TD could have a component of central cholinergic deficiency. Cholinergic drugs have been used to treat TD.
OBJECTIVES
To determine the effects of cholinergic drugs (arecoline, choline, deanol, lecithin, meclofenoxate, physostigmine, RS 86, tacrine, metoxytacrine, galantamine, ipidacrine, donepezil, rivastigmine, eptastigmine, metrifonate, xanomeline, cevimeline) for treating antipsychotic-induced TD in people with schizophrenia or other chronic mental illness.
SEARCH METHODS
An electronic search of the Cochrane Schizophrenia Group's Study-Based Register of Trials (16 July 2015 and April 2017) was undertaken. This register is assembled by extensive searches for randomised controlled trials in many electronic databases, registers of trials, conference proceedings and dissertations. References of all identified studies were searched for further trial citations.
SELECTION CRITERIA
We included reports identified by the search if they were of controlled trials involving people with antipsychotic-induced TD and chronic mental illness, who had been randomly allocated to either a cholinergic agent or to a placebo or no intervention. Two review authors independently assessed the methodological quality of the trials.
DATA COLLECTION AND ANALYSIS
Two review authors extracted data and, where possible, estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We analysed data on an intention-to-treat basis, with the assumption that people who left early had no improvement. We assessed risk of bias and created a 'Summary of findings' table using GRADE.
MAIN RESULTS
We included 14 studies investigating the use of cholinergic drugs compared with placebo published between 1976 and 2014. All studies involved small numbers of participants (five to 60 people). Three studies that investigated the new cholinergic Alzheimer drugs for the treatment of TD are new to this update. Overall, the risk of bias in the included studies was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, studies were not clearly blinded, we are unsure if data are incomplete, and data were often poorly or selectively reported.We are uncertain about the effect of new or old cholinergic drugs on no clinically important improvement in TD symptoms when compared with placebo; the quality of evidence was very low (RR 0.89, 95% CI 0.65 to 1.23; 27 people, 4 RCTs). Eight trials found that cholinergic drugs may make little or no difference to deterioration of TD symptoms (low-quality evidence, RR 1.11, 95% CI 0.55 to 2.24; 147 people). Again, due to very low-quality evidence, we are uncertain about the effects on mental state (RR 0.50, 95% CI 0.10 to 2.61; 77 people, 5 RCTs), adverse events (RR 0.56, 95% CI 0.15 to 2.14; 106 people, 4 RCTs), and leaving the study early (RR 1.09,95% CI 0.56 to 2.10; 288 people 12 RCTs). No study reported on social confidence, social inclusion, social networks, or personalised quality of life.
AUTHORS' CONCLUSIONS
TD remains a major public health problem. The clinical effects of both older cholinergic drugs and new cholinergic agents, now used for treating Alzheimer's disease, are unclear, as too few, too small studies leave many questions unanswered. Cholinergic drugs should remain of interest to researchers and currently have little place in routine clinical work. However, with the advent of new cholinergic agents now used for treating Alzheimer's disease, scope exists for more informative trials. If these new cholinergic agents are to be investigated for treating people with TD, their effects should be demonstrated in large well-designed, conducted and reported randomised trials.
Topics: Antipsychotic Agents; Cholinergic Agents; Dyskinesia, Drug-Induced; Humans; Patient Dropouts; Randomized Controlled Trials as Topic
PubMed: 29553158
DOI: 10.1002/14651858.CD000207.pub2 -
Archives of Toxicology May 2021
Topics: Areca; Arecoline; Nuts; Plant Extracts; Toxicokinetics
PubMed: 33846819
DOI: 10.1007/s00204-021-03039-7 -
Cancer Letters May 2020Betel quid (BQ) and areca nut use are at risk of cancer. This review includes the latest evidence of carcinogenesis caused by BQ exposure, suggests possible prevention... (Review)
Review
Betel quid (BQ) and areca nut use are at risk of cancer. This review includes the latest evidence of carcinogenesis caused by BQ exposure, suggests possible prevention strategies. We conducted a systematic literature search in the PubMed and Web of Science databases to identify relevant articles published in the past 10 years according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Arecoline N-oxide, a metabolite of areca nut, is likely an initiator in carcinogenesis and is detoxified by N-acetylcysteine. Oral potentially malignant disorder and reactive oxygen species involved in carcinogenesis pathways may be treatable using antioxidants. Screening programs conducted by trained physicians are useful for identifying patients with early stages of oral cancer in high-risk groups. Anti-inflammatory medications may be used as chemopreventive agents in the disease-free stage after surgery. The association between survival and tumor somatic mutations in patients who chew BQ should be addressed in cancer studies. Current evidence on the natural course from BQ exposure to cancer occurrence and development provides information for developing primary, secondary, and tertiary prevention strategies against BQ-associated cancer at clinical or translational levels.
Topics: Acetylcysteine; Anti-Inflammatory Agents, Non-Steroidal; Areca; Arecoline; Carcinogens; Cyclic N-Oxides; Humans; Inactivation, Metabolic; Mass Screening; Mouth Neoplasms; Mutation
PubMed: 32112902
DOI: 10.1016/j.canlet.2020.02.030 -
International Journal of Molecular... Mar 2023Areca nut has been listed as one of the most addictive substances, along with tobacco, alcohol and caffeine. Areca nut contains seven psychoactive alkaloids; however,...
Areca nut has been listed as one of the most addictive substances, along with tobacco, alcohol and caffeine. Areca nut contains seven psychoactive alkaloids; however, the effects of these alkaloids on embryonic development and motor behavior are rarely addressed in zebrafish embryo-larvae. Herein, we investigated the effects of exposure to three alkaloids (arecoline and secondary metabolites-arecaidine and arecoline -oxide) on the developmental parameters, locomotive behavior, oxidative stress and transcriptome of zebrafish embryos. Zebrafish embryos exposed to different concentrations (0, 0.1, 1, 10, 100 and 1000 μM) of arecoline, arecaidine and arecoline -oxide showed no changes in mortality and hatchability rates, but the malformation rate of zebrafish larvae was significantly increased in a dose-dependent manner and accompanied by changes in body length. Moreover, the swimming activity of zebrafish larvae decreased, which may be due to the increase in reactive oxygen species and the imbalance between oxidation and antioxidation. Meanwhile, transcriptome analysis showed that endoplasmic reticulum stress and the apoptosis p53 signaling pathway were significantly enriched after exposure to arecoline and arecoline -oxide. However, arecaidine exposure focuses on protein synthesis and transport. These findings provide an important reference for risk assessment and early warning of areca nut alkaloid exposure.
Topics: Animals; Arecoline; Zebrafish; Alkaloids; Oxidative Stress; Endoplasmic Reticulum Stress; Areca
PubMed: 37047326
DOI: 10.3390/ijms24076327 -
Journal of Environmental Pathology,... 2016Oral submucous fibrosis (OSF) is prevalent mostly in Southeast Asia, particularly in the Indian subcontinent. Chewing betel nuts and betel leaves, with or without... (Review)
Review
Oral submucous fibrosis (OSF) is prevalent mostly in Southeast Asia, particularly in the Indian subcontinent. Chewing betel nuts and betel leaves, with or without tobacco, has been associated with OSF. Betel quid contents including guvacine, arecoline, guvacoline, arecaidine, and chavibetol are considered to play an important part in the occurrence of OSF. Transformation of OSF to squamous cell carcinoma (SCC) is variable, but up to 13% conversion of OSF to SCC has been reported. Various genetic and molecular mechanisms impact the malignant transformation of OSF, causing changes in the cell cycle, DNA, keratinocytes, and keratin; tumor-cell proliferation and survival; angiogenesis; fibrosis through epithelial-mesenchymal transitions (EMTs), and tissue hypoxia. All are reviewed here, including potential biomarkers for malignant transformation of OSF. These interactions are not fully understood, but a critical mass of knowledge is building up to ultimately allow the understanding of all mechanisms involved.
Topics: Areca; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Humans; Oral Submucous Fibrosis
PubMed: 27910776
DOI: 10.1615/JEnvironPatholToxicolOncol.2016014024 -
PloS One 2022Arecoline is known to induce reactive oxygen species (ROS). Our previous studies showed that arecoline inhibited myogenic differentiation and acetylcholine receptor...
Arecoline is known to induce reactive oxygen species (ROS). Our previous studies showed that arecoline inhibited myogenic differentiation and acetylcholine receptor cluster formation of C2C12 myoblasts. N-acetyl-cysteine (NAC) is a known ROS scavenger. We hypothesize that NAC scavenges the excess ROS caused by arecoline. In this article we examined the effect of NAC on the inhibited myoblast differentiation by arecoline and related mechanisms. We found that NAC less than 2 mM is non-cytotoxic to C2C12 by viability analysis. We further demonstrated that NAC attenuated the decreased number of myotubes and nuclei in each myotube compared to arecoline treatment by H & E staining. We also showed that NAC prevented the decreased expression level of the myogenic markers, myogenin and MYH caused by arecoline, using immunocytochemistry and western blotting. Finally, we found that NAC restored the decreased expression level of p-ERK1/2 by arecoline. In conclusion, our results indicate that NAC attenuates the damage of the arecoline-inhibited C2C12 myoblast differentiation by the activation/phosphorylation of ERK. This is the first report to demonstrate that NAC has beneficial effects on skeletal muscle myogenesis through ERK1/2 upon arecoline treatment. Since defects of skeletal muscle associates with several diseases, NAC can be a potent drug candidate in diseases related to defects in skeletal muscle myogenesis.
Topics: Acetylcysteine; Arecoline; Cell Differentiation; MAP Kinase Signaling System; Muscle Development; Myoblasts; Phosphorylation; Reactive Oxygen Species
PubMed: 35901044
DOI: 10.1371/journal.pone.0272231 -
Chemico-biological Interactions Feb 2022Habitual chewing of the areca nut increases the risk of mortality owing to cardiovascular disease, but few reports have revealed the cardiotoxicity mechanism of the...
Habitual chewing of the areca nut increases the risk of mortality owing to cardiovascular disease, but few reports have revealed the cardiotoxicity mechanism of the areca nut. Arecoline has been reported to be the primary toxic constituent in the areca nut. In order to study the acute cardiotoxicity of the areca nut in the development of pathologic heart hypertrophy, we induced heart injury in rats using arecoline. Arecoline at a low dosage (5 mg/kg/day) or a high dosage (50 mg/kg/day) was intraperitoneally injected to Sprague-Dawley rats for 21 days. The change of heart function and biochemical pathways were investigated with echocardiography and Western blot. The results were presented that heart functions were weakened by arecoline stimulation, and western blotting analysis revealed an elevation in BNP levels in the heart after arecoline exposure. Arecoline induced IL-6-mediated activation of the MEK5/ERK5 and JAK2/STAT3 pathways, as well as mitogen-activated protein kinase signaling cascades. Further, arecoline increased the calcineurin and NFATc3 levels in the heart. In summary, our results suggest that arecoline causes significantly cardiotoxicity and heart damage by inducing several hypertrophy-related signaling pathways, including IL-6-induced MEK5/ERK5, JAK2/STAT3, mitogen-activated protein kinases, and calcineurin signaling pathways. The study elucidated, for the first time, the possible cardiac hypertrophy mechanisms underlying the cardiotoxicity of the areca nut.
Topics: Arecoline
PubMed: 34999050
DOI: 10.1016/j.cbi.2022.109810 -
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 -
Cell Biology International Sep 2022Arecoline, a major alkaloid of the areca nut, has potential toxicity to the nervous system. Our previous study reveals that the neurotoxicity of arecoline involves...
Arecoline, a major alkaloid of the areca nut, has potential toxicity to the nervous system. Our previous study reveals that the neurotoxicity of arecoline involves in inhibited endogenous hydrogen sulfide (H S) generation. Therefore, the present study investigated whether exogenous H S protects against arecoline-induced neurotoxicity and further explore the underlying mechanisms focusing on leptin/leptin receptor signaling pathway. The cell viability was measured by CCK-8 kit. The apoptosis were detected by Hoechst 33258 and Annexin V/PI (propidium iodide) staining. The protein expressions were determined by Western blot analysis. Our results demonstrated that NaHS, an exogenous H S donor, significantly increases the cell viability, decreases apoptosis ratio, and reduces caspase-3 activity as well as Bax/Bcl-2 ratio in PC12 cells exposed to arecoline, indicating the protection of H S against arecoline-induced cytotoxicity and apoptosis. Also, NaHS attenuated arecoline-induced endoplasmic reticulum (ER) stress, as evidenced by the decreases in the expressions of glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), and Cleaved caspase-12. Meanwhile, NaHS promoted leptin/leptin receptor signaling pathway in arecoline-exposed PC12 cells, as illustrated by upregulations of leptin and leptin receptor expressions. Furthermore, leptin tA, an antagonist of leptin receptor, obviously abolished the inhibitory effects of NaHS on arecoline-induced cytotoxicity, apoptosis, and ER stress in arecoline-exposed PC12 cells. Taken together, these results suggested that H S prevents arecoline-induced neurotoxicity via enhancing the leptin/leptin receptor signaling pathway.
Topics: Animals; Apoptosis; Arecoline; Endoplasmic Reticulum Stress; Hydrogen Sulfide; Leptin; Rats; Receptors, Leptin; Signal Transduction
PubMed: 35819076
DOI: 10.1002/cbin.11850