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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 -
Addiction Biology Dec 2023As a chewing hobby, areca nut (Areca catechu L.) has become the most common psychoactive substance in the world, besides tobacco, alcohol and caffeinated beverages....
As a chewing hobby, areca nut (Areca catechu L.) has become the most common psychoactive substance in the world, besides tobacco, alcohol and caffeinated beverages. Moreover, as a first-class carcinogen designated by International Agency for Research on Cancer, long-term chewing areca nut can result in oral mucosal diseases and even oral cancer. To clarify the potential mechanism of areca nut addiction, an integrated strategy of metabolomics and network pharmacology was adopted in this study. Network pharmacology study indicated that all the key targets related to areca nut addiction could be regulated by arecoline and pointed out the importance of G-protein coupled receptor signalling pathway. Analysis results of mice plasma metabolome and faeces metabolome intervened by arecoline suggested that the component may affect the dopamine system and 5-HT system by regulating phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, primary bile acid biosynthesis, glycerophospholipid metabolism and intestinal flora structure. Moreover, the potential importance of bile acids in formation of addictive behaviour of chewing areca nut was investigated by integrative analysis of the relationships between metabolites and intestinal flora. The study can provide scientific basis for the addiction intervention and treatment of areca nut chewers.
Topics: Animals; Mice; Arecoline; Areca; Nuts; Network Pharmacology; Behavior, Addictive; Phenylalanine
PubMed: 38017647
DOI: 10.1111/adb.13352 -
Oral Surgery, Oral Medicine, Oral... Feb 2024
Corrigendum to 'Oxidative-protective effect of nuclear receptor coactivator 7 on arecoline induced endothelial-to-mesenchymal transition' [Oral Surg Oral Med Oral Pathol Oral Radio 130(5) (2020) 565-573].
PubMed: 37953131
DOI: 10.1016/j.oooo.2023.11.003 -
Phytomedicine : International Journal... Jan 2024Bacopa monnieri (BM) is traditionally used in human diseases for its antioxidant, anti-inflammatory and neuroprotective effects. However, its anticancer potential has...
BACKGROUND
Bacopa monnieri (BM) is traditionally used in human diseases for its antioxidant, anti-inflammatory and neuroprotective effects. However, its anticancer potential has been poorly understood.
AIM
The aim of this study was to explore the detailed anticancer mechanism of BM against oral cancer and to identify the bioactive BM fraction for possible cancer therapeutics.
RESULTS
We performed bioactivity-guided fractionation and identified that the aqueous fraction of the ethanolic extract of BM (BM-AF) had a potent anticancer potential in both in vitro and in vivo oral cancer models. BM-AF inhibited cell viability, colony formation, cell migration and induced apoptotic cell death in Cal33 and FaDu cells. BM-AF at low doses promoted mitophagy and BM-AF mediated mitophagy was PARKIN dependent. In addition, BM-AF inhibited arecoline induced reactive oxygen species production in Cal33 cells. Moreover, BM-AF supressed arecoline-induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation through mitophagy in Cal33 cells. The in vivo antitumor effect of BM-AF was further validated in C57BL/6J mice through a 4-nitroquinolin-1-oxide and arecoline-induced oral cancer model. The tumor incidence was significantly reduced in the BM-AF treated group. Further, data obtained from western blot and immunohistochemistry analysis showed increased expression of apoptotic markers and decreased expression of inflammasome markers in the tongue tissue obtained from BM-AF treated mice in comparison with the non-treated tumor bearing mice.
CONCLUSION
In conclusion, BM-AF exhibited potent anticancer activity through apoptosis induction and mitophagy-dependent inhibition of NLRP3 inflammasome activation in both in vitro and in vivo oral cancer models. Moreover, we have investigated apoptosis and mitophagy-inducing compounds from this plant extract having anticancer activity against oral cancer cells.
Topics: Mice; Humans; Animals; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Mitophagy; Bacopa; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Arecoline; Mouth Neoplasms; Mice, Inbred C57BL; Apoptosis; Reactive Oxygen Species; Head and Neck Neoplasms
PubMed: 37951147
DOI: 10.1016/j.phymed.2023.155157 -
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 -
Brain Research Jan 2024It is unclear whether acupuncture has a rapid antidepressant effect and what is the main mechanism.
BACKGROUND
It is unclear whether acupuncture has a rapid antidepressant effect and what is the main mechanism.
METHODS
In this study, forced swimming stress test (FST) in mice were divided into five groups: control group, acupuncture group, scopolamine group, arecoline group, and acupuncture + arecoline group. Chronic unpredictable mild stress (CUMS) model rats were divided into six groups: naïve (non-CUMS) group, CUMS group, acupuncture group, scopolamine group, arecoline group, and acupuncture + arecoline group. Twenty-four hours after the end of treatment, FST was conducted in mice and rats. The expression of M1-AchR, AMPA receptors (GluR1 and GluR2), BDNF, mTOR, p-mTOR, synapsin I, and PSD95 in the prefrontal cortex was determined by western blot. The spine density of neurons in the prefrontal cortex was detected by golgi staining.
RESULTS
The results showed that acupuncture reduced the immobility time of FST in two depression models. Acupuncture inhibited the expression of M1-AchR and promoted the expression of GluR1, GluR2, BDNF, p-mTOR, synapsin I, PSD95, and increased the density of neuron dendritic spine in the prefrontal cortex.
CONCLUSIONS
The rapid antidepressant effect of acupuncture may be activating the "glutamate tide" - AMPA receptor activation - BDNF release - mTORC1 pathway activation through inhibiting the expression of M1-AchR in the prefrontal cortex, thereby increasing the expression of synaptic proteins and regulating synaptic plasticity.
Topics: Rats; Mice; Animals; Depression; Brain-Derived Neurotrophic Factor; Synapsins; Arecoline; Antidepressive Agents; TOR Serine-Threonine Kinases; Acupuncture Therapy; Disease Models, Animal; Scopolamine; Prefrontal Cortex; Neuronal Plasticity; Hippocampus; Stress, Psychological
PubMed: 37783259
DOI: 10.1016/j.brainres.2023.148609 -
Tissue Engineering and Regenerative... Jan 2024Oral submucous fibrosis (OSF) is a chronic disease with carcinogenic tendency that poses a non-negligible threat to human health. Exosomes derived from human adipose...
BACKGROUND
Oral submucous fibrosis (OSF) is a chronic disease with carcinogenic tendency that poses a non-negligible threat to human health. Exosomes derived from human adipose mesenchymal stem cells (ADSC-Exo) reduces visceral and cutaneous fibroses, but their role in OSF has received little attention. The aim of this study was to investigate the effects of ADSC-Exo on OSF and elucidate the mechanism.
METHODS
In brief, ADSCs were extracted from adipose tissues and subjected to flow cytometry and induction culture. Fibroblasts were isolated from human buccal mucosa and subjected to immunofluorescence. Myofibroblasts were obtained from fibroblasts induced by arecoline and identified. Immunofluorescence assay confirmed that myofibroblasts could take up ADSC-Exo. The effects of ADSC-Exo on the proliferative and migratory capacities of myofibroblasts were examined using the Cell Counting Kit-8 and scratch assay. Real-time quantitative polymerase chain reaction (qPCR) was performed to evaluate mothers against decapentaplegic homolog 2 (Smad2), Smad3, Smad7, collagen type 1 (Col1), Col3, alpha smooth muscle actin (α-SMA), fibronectin, and vimentin. Western blotting was performed to detect phospho (p)-Smad2, Smad2, p-Smad2/3, Smad2/3, Smad7, Col1, Col3, α-SMA, fibronectin, and vimentin. Furthermore, the dual-luciferase reporter assay was performed to prove that miR-181a-5p in ADSC-Exo directly inhibited the expression of Smad2 mRNA to regulate the transforming growth factor beta (TGF-β) pathway. We also performed qPCR and western blotting to verify the results.
RESULTS
ADSC-Exo could promote the proliferation and migration of myofibroblasts, reduce the expressions of p-smad2, Smad2, p-smad2/3, Smad2/3, Col1, αSMA, fibronectin, and vimentin and elevated the levels of Smad7 and Col3. In addition, miR-181a-5p was highly expressed in ADSC-Exo and bound to the 3'-untranslated region of Smad2. ADSC-Exo enriched with miR-181a-5p reduced collagen production in myofibroblasts and modulated the TGF-β pathway.
CONCLUSIONS
ADSC-Exo promoted the proliferative and migratory capacities of myofibroblasts and inhibited collagen deposition and trans-differentiation of myofibroblasts in vitro. miR-181a-5p in exosomes targets Smad2 to regulate the TGF-β pathway in myofibroblasts. ADSC-Exo perform antifibrotic actions through the miR-181a-5p/Smad2 axis and may be a promising clinical treatment for OSF.
Topics: Humans; Collagen Type I; Exosomes; Fibronectins; Fibrosis; Mesenchymal Stem Cells; MicroRNAs; Oral Submucous Fibrosis; Transforming Growth Factor beta; Vimentin
PubMed: 37755664
DOI: 10.1007/s13770-023-00579-0 -
Oral Diseases May 2024Oral submucous fibrosis (OSF) is associated with malignant disorders. DNA methyltransferase 3A (DNMT3A) is a DNA methylesterase reported to be upregulated in multiple...
BACKGROUND
Oral submucous fibrosis (OSF) is associated with malignant disorders. DNA methyltransferase 3A (DNMT3A) is a DNA methylesterase reported to be upregulated in multiple organs and shown to inhibit fibrosis. However, the detailed effect of DNMT3A on OSF remains unclear.
METHODS
To mimic OSF in vitro, oral fibroblasts were exposed to arecoline and molecular biological experiments were performed to detect the function of DNMT3A in OSF.
RESULTS
We found that von Hippel-Lindau (VHL) was downregulated and highly methylated in OSF. Arecoline remarkably increased the viability, invasiveness, and migration of oral fibroblasts, but upregulation of VHL partially reversed these effects. DNMT3A induces DNA hypermethylation in the VHL promoter, and VHL markedly inhibits the level of tenascin-C (TNC) by inducing the ubiquitination of TNC. TNC reversed the inhibitory effect of VHL upregulation on the differentiation of oral fibroblasts into myofibroblasts.
CONCLUSION
DNMT3A induces OSF by promoting methylation of the VHL promoter. Hence, our study provides novel insights into the discovery of novel strategies that can be employed against OSF.
Topics: Humans; Oral Submucous Fibrosis; DNA Methyltransferase 3A; DNA Methylation; Fibroblasts; DNA (Cytosine-5-)-Methyltransferases; Arecoline; Promoter Regions, Genetic; Von Hippel-Lindau Tumor Suppressor Protein; Cell Movement; Cells, Cultured
PubMed: 37743610
DOI: 10.1111/odi.14725 -
International Immunopharmacology Nov 2023This study investigated the effectiveness of arecoline hydrobromide (AH) on the functions of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and...
OBJECTIVE
This study investigated the effectiveness of arecoline hydrobromide (AH) on the functions of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and collagen-induced arthritis (CIA) mice.
METHODS
Immunofluorescence was used to identify RA-FLSs. Cell Counting Kit-8 (CCK-8) was used to determine the viability of RA-FLSs and the half maximal inhibitory concentration (IC) of AH. The 5-ethynyl-2'-deoxyuridine (EdU) assay was used to detect DNA replication in RA-FLSs. Cell cycle and apoptosis were examined by flow cytometry. Migration and invasion, as well as wound healing assays, were employed to determine cell migration and invasion ability. Proteins and mRNA expression levels were investigated using Western blot, quantitative real-time PCR (RT-qPCR), and immunofluorescence. The CIA mice model was used to assess the effect of AH in vivo. RNA-sequencing (RNA-seq) was used to find the potential signaling pathways of AH against RA, and Western blot was used to verify the key signaling pathway of AH on RA-FLSs. Network pharmacology and molecular docking were used to predict drug targets.
RESULTS
AH inhibited the proliferation and DNA replication of RA-FLSs, promoted cell cycle arrest by reducing the levels of cyclin-dependent kinase 1 (CDK1), cyclin A2, and cyclin B1, promoted apoptosis by suppressing B-cell lymphoma-2 (Bcl-2) expression, and suppressed migration and invasion by inhibiting vimentin expression in RA-FLSs. AH was also effective in relieving arthritis in vivo. RNA sequencing analyses suggested that AH inhibited the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway in RA-FLSs, which was also confirmed in Western blot analysis. Furthermore, network pharmacology and molecular docking suggested that F2, MAPK14, SRC, AKT1, and CTSK might be the direct targets of AH.
CONCLUSION
AH can modulate the pathological process of RA-FLSs by blocking the PI3K/AKT pathway and relieve CIA in mice, making it a potential new small molecule candidate.
Topics: Animals; Mice; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Arthritis, Experimental; Molecular Docking Simulation; Cell Proliferation; Arthritis, Rheumatoid; Fibroblasts; Synoviocytes; Cells, Cultured
PubMed: 37742366
DOI: 10.1016/j.intimp.2023.110925 -
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