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Odontology Jan 2024Oral submucous fibrosis (OSF) is an oral condition characterized by chronic progression, which may lead to the development of malignancy. Currently, available treatments...
Oral submucous fibrosis (OSF) is an oral condition characterized by chronic progression, which may lead to the development of malignancy. Currently, available treatments for OSF only provide temporary relief of symptoms, and there is a limited availability of effective interventions that can effectively cure this condition. In this study, we aimed to investigate whether adiponectin (APN) could ameliorate OSF and the mechanisms involved in it. First, human oral mucosal fibroblasts (HOMFs) were cultured, an OSF model was established using arecoline, and APN and Imiquimod treatment were administered. Then we overexpressed NLRP3 and knocked down FOXO3A. FOXO3A, fibrosis-related factors (ɑ-SMA, COL1A, CTGF), TGF-β1/Smad3 signaling-related factors (TGF-β1, p-Smad3, Smad3), NLRP3 inflammasome-related factors (NLRP3, Caspase-1, IL-1β), and ROS levels were evaluated. Finally, we explored the effect of APN on OSF in mice by in vivo experiments. We found that arecoline significantly increased ɑ-SMA, COL1A, CTGF, and TGF-β1 expressions and promoted Smad3 phosphorylation, while APN significantly inhibited the elevation of these fibrosis-related factors. ROS production was significantly elevated in HOMFs after arecoline treatment, while APN treatment inhibited ROS production. However, the addition of Imiquimod and overexpression of NLRP3 exhibited a trend of elevated ROS, resisting the inhibitory effect of APN. Furthermore, adding Imiquimod and overexpression of NLRP3 elevated ɑ-SMA, COL1A and CTGF and activated TGF-β1/Smad3 signaling pathway. Additionally, knockdown of FOXO3A enhanced APN-inhibited ɑ-SMA and COL1A. In vivo experiments further confirmed that APN ameliorated OSF in mice by inhibiting ROS/NLRP3 inflammatory pathway. In conclusion, APN ameliorated arecoline-induced OSF by promoting FOXO3A expression and downregulating the ROS/NLRP3 pathway.
PubMed: 38217790
DOI: 10.1007/s10266-023-00891-0 -
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 -
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 -
The Chinese Journal of Dental Research Dec 2023Oral submucous fibrosis (OSF) is a chronic, progressive and potentially malignant oral mucosal disease. Patients often have a habit of chewing betel nuts. Areca catechu...
Oral submucous fibrosis (OSF) is a chronic, progressive and potentially malignant oral mucosal disease. Patients often have a habit of chewing betel nuts. Areca catechu has been listed as a Class 1 carcinogen by the International Agency for Research on Cancer (IARC), and its main active component, arecoline, is classified as a Group 2B carcinogen by the IARC. The World Health Organization (WHO) categorises OSF as an oral potentially malignant disorder (OPMD). The present guideline describes the risk factors, clinical symptoms and clinical signs of OSF. Clinical staging, auxiliary examination methods, basis for diagnosis and differential diagnosis and the need to improve bad lifestyle habits are proposed and addressed, and local treatment drugs, therapies, dosage and course of treatment, possible adverse reactions, and oral treatment drugs, dosage and course of treatment are proposed. The guideline also addresses the indications for surgical treatment, alternative non-drug treatment methods, selection of treatment plans for different clinical stages, criteria for efficacy evaluation, and preventive measures.
Topics: Humans; Oral Submucous Fibrosis; Mouth Diseases; Risk Factors; Precancerous Conditions; Areca; Carcinogens
PubMed: 38126373
DOI: 10.3290/j.cjdr.b4784075 -
Zhongguo Zhong Yao Za Zhi = Zhongguo... Nov 2023This study comprehensively analyzed the active components of Sanhan Huashi Formula using qualitative and quantitative mass spectrometry techniques, laying the foundation...
This study comprehensively analyzed the active components of Sanhan Huashi Formula using qualitative and quantitative mass spectrometry techniques, laying the foundation for understanding its pharmacological substance basis. UHPLC-LTQ-Orbitrap-MS and GC-MS technologies were used to analyze and identify the volatile and non-volatile components in Sanhan Huashi Formula. UHPLC-QQQ-MS/MS technology was used to simultaneously determine the content of 27 major active components in the formula. The results showed that 308 major chemical components were identified in Sanhan Huashi Formula, among which 60 compounds were identified by comparing with reference standards, mainly including alkaloids, flavonoids, coumarins, triterpenoid saponins, amino acids, and nucleosides. GC-MS technology preliminarily identified 52 volatile compounds, with γ-eudesmol and β-eudesmol as the main components. The quantitative results demonstrated good linearity(r>0.99) for the 27 active components, indicating the stability, simplicity, and reliability of the established method. Among them, amygdalin, nodakenin, arecoline, ephedrine, and pseudoephedrine had relatively high content and were presumably the main pharmacologically active substances. In conclusion, this study systematically and comprehensively characterized the major chemical components and patterns in Sanhan Huashi Formula, providing a basis for understanding its pharmacological mechanisms and clinical applications.
Topics: Tandem Mass Spectrometry; Chromatography, High Pressure Liquid; Gas Chromatography-Mass Spectrometry; Reproducibility of Results; Drugs, Chinese Herbal
PubMed: 38114213
DOI: 10.19540/j.cnki.cjcmm.20230614.303 -
Oral Diseases Dec 2023The limited understanding of the molecular mechanism for oral submucosal fibrosis (OSF) poses challenges to the development of effective prevention and treatment...
OBJECTIVE
The limited understanding of the molecular mechanism for oral submucosal fibrosis (OSF) poses challenges to the development of effective prevention and treatment strategies. The lack of suitable animal models is a major hindrance. Therefore, this study aimed to address this issue by comparing commonly used arecoline-induced water drinking and injection mouse models.
MATERIALS AND METHODS
The mice were subjected to two protocols: receiving 2 mg/mL arecoline in drinking water and 4 mg/mL arecoline saline solution injections every other day. Tissues were collected at regular 4-week intervals, with a final time point of 20 weeks. Stereo microscopy and histomorphological analysis were performed on live and harvested tissues, respectively.
RESULTS
During arecoline treatment, collagen deposition and myofibroblast proliferation progressively increased in both models. Changes in the collagen I/III ratio indicated that both models exhibited characteristics of the early and intermediate stages of OSF after 20 weeks of arecoline induction. The water-drinking model also demonstrated multi-organ fibrosis involving the tongue, lungs, and small intestine.
CONCLUSION
Both the water drinking and injection mouse models effectively induced OSF, but the water-drinking model better mirrored the observed pathogenesis in patients with OSF. These models provide valuable tools for investigating the mechanisms underlying OSF.
PubMed: 38098250
DOI: 10.1111/odi.14825 -
Biomolecules & Biomedicine Dec 2023Oral submucous fibrosis (OSF) is a prevalent chronic condition, and understanding its pathogenesis is crucial for developing effective therapeutic strategies. This study...
Mechanism of adipose tissue-derived stromal cell-extracellular vesicles in treating oral submucous fibrosis by blocking the TGF-β1/Smad3 pathway via the miR-760-3p/IGF1R axis.
Oral submucous fibrosis (OSF) is a prevalent chronic condition, and understanding its pathogenesis is crucial for developing effective therapeutic strategies. This study explores the potential of adipose tissue-derived stromal cell-extracellular vesicles (ADSC-EVs) in mitigating OSF and investigates the underlying molecular mechanisms. OSF was induced in mice by arecoline feeding. Adipose tissue-derived stromal cells (ADSCs), fibrotic buccal mucosal fibroblasts (fBMFs) isolated from OSF mice, and ADSC-EVs were comprehensively characterized. The treatment effects of extracellular vesicles (EVs) and pcDNA3.1-IGF1R on fBMF proliferation, migration, and invasion were assessed using Cell Counting Kit-8 (CCK-8) assay, transwell assay, and flow cytometry assay. The expression levels of alpha smooth muscle actin (α-SMA), collagen I, collagen III, and insulin-like growth factor 1 receptor (IGF1R) were evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. The interaction between miR-760-3p and IGF1R was investigated. In fBMFs and OSF mice treated with a miR-760-3p inhibitor and/or EVs, the expression patterns of miR-760-3p, IGF1R, and proteins related to the TGF-β1/Smad3 pathway were determined. ADSC-EVs demonstrated the ability to upregulate miR-760-3p, impede cell proliferation, migration, and invasion, and reduce α-SMA, collagen I, and collagen III levels in fBMFs. The expression of miR-760-3p was diminished in ADSC-EVs treated with a miR-760-3p inhibitor. However, silencing miR-760-3p or overexpressing IGF1R partially counteracted the beneficial effects of ADSC-EVs on fBMF fibrosis. miR-760-3p directly targets IGF1R. Significantly, ADSC-EVs exert their suppressive effects on the TGF-β1/Smad3 pathway through the miR-760-3p/IGF1R axis. In summary, ADSC-EVs, by transferring miR-760-3p and inhibiting IGF1R expression, effectively block the TGF-β1/Smad3 pathway, thereby alleviating fibrosis in fBMFs and preventing the progression of OSF.
PubMed: 38059910
DOI: 10.17305/bb.2023.9944 -
ACS Chemical Neuroscience Dec 2023Docosahexaenoic acid [22:6(-3), DHA], a polyunsaturated fatty acid, has an important role in regulating neuronal functions and in normal brain development. Dysregulated...
Synthesis and Preclinical Evaluation of 22-[F]Fluorodocosahexaenoic Acid as a Positron Emission Tomography Probe for Monitoring Brain Docosahexaenoic Acid Uptake Kinetics.
Docosahexaenoic acid [22:6(-3), DHA], a polyunsaturated fatty acid, has an important role in regulating neuronal functions and in normal brain development. Dysregulated brain DHA uptake and metabolism are found in individuals carrying the APOE4 allele, which increases the genetic risk for Alzheimer's disease (AD), and are implicated in the progression of several neurodegenerative disorders. However, there are limited tools to assess brain DHA kinetics that can be translated to humans. Here, we report the synthesis of an ω-radiofluorinated PET probe of DHA, 22-[F]fluorodocosahexaenoic acid (22-[F]FDHA), for imaging the uptake of DHA into the brain. Using the nonradiolabeled 22-FDHA, we confirmed that fluorination of DHA at the ω-position does not significantly alter the anti-inflammatory effect of DHA in microglial cells. Through dynamic PET-MR studies using mice, we observed the accumulation of 22-[F]FDHA in the brain over time and estimated DHA's incorporation coefficient (*) using an image-derived input function. Finally, DHA brain * was validated using intravenous administration of 15 mg/kg arecoline, a natural product known to increase the DHA * in rodents. 22-[F]FDHA is a promising PET probe that can reveal altered lipid metabolism in APOE4 carriers, AD, and other neurologic disorders. This new probe, once translated into humans, would enable noninvasive and longitudinal studies of brain DHA dynamics by guiding both pharmacological and nonpharmacological interventions for neurodegenerative diseases.
Topics: Humans; Mice; Animals; Docosahexaenoic Acids; Apolipoprotein E4; Brain; Positron-Emission Tomography; Biological Transport; Alzheimer Disease
PubMed: 38048230
DOI: 10.1021/acschemneuro.3c00681 -
Functional Plant Biology : FPB Jan 2024Viscum schimperi is an evergreen hemiparasitic plant that can grow on stems and branches of several tree species. It penetrates the host tissues and forms a vascular...
Viscum schimperi is an evergreen hemiparasitic plant that can grow on stems and branches of several tree species. It penetrates the host tissues and forms a vascular bridge (haustorium) to withdraw the nutritive resources. Its relationships with hosts remain unknown. This study aimed to investigate the physiological and biochemical attributes of the host-hemiparasite association Acacia gerrardii -Viscum schimperi . The hemiparasite exhibited 2.4- and 3.0-fold lower photosynthetic activity and water use efficiency, and 1.2- and 4.1-fold higher transpiration rate and stomatal conductance. Equally, it displayed 4.9- and 2.6-fold greater water potential and osmotic potential, and in least 3.0times more accumulated 39 K, 85 Rb and 51 V, compared to the host. Nevertheless, it had no detrimental effect on photosynthetic activity, water status and multi-element accumulations in the host. Based on metabolome profiling, V. schimperi could use xanthurenic acid and propylparaben to acquire potassium from the host, and N -1-naphthylacetamide and N -Boc-hydroxylamine to weaken or kill the distal part of the infected branch and to receive the total xylem contents. In contrast, A. gerrardii could used N -acetylserotonin, arecoline, acetophenone and 6-methoxymellein to defend against V. schimperi infection.
Topics: Viscum; Acacia; Photosynthesis; Water; Fabaceae
PubMed: 38035483
DOI: 10.1071/FP23206 -
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