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1.
Eur J Med Chem ; 268: 116229, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38430852

RESUMO

Betel-quid chewing addiction is the leading cause of oral submucous fibrosis and oral cancer, resulting in significant socio-economic burdens. Vaccination may serve as a promising potential remedy to mitigate the abuse and combat accidental overdose of betel nut. Hapten design is the crucial factor to the development of arecoline vaccine that determines the efficacy of a candidate vaccine. Herein, we reported that two kinds of novel arecoline-based haptens were synthesized and conjugated to Bovine Serum Albumin (BSA) to generate immunogens, which generated antibodies with high affinity for arecoline but reduced binding for guvacoline and no affinity for arecaidine or guvacine. Notably, vaccination with Arec-N-BSA, which via the N-position on the tetrahydropyridine ring (tertiary amine group), led to a higher antibody affinity compared to Arec-CONH-BSA, blunted analgesia and attenuated hypothermia for arecoline.


Assuntos
Arecolina , Transtornos Relacionados ao Uso de Substâncias , Arecolina/farmacologia , Arecolina/metabolismo , Vacinas Conjugadas , Areca/metabolismo
2.
Int J Biol Macromol ; 264(Pt 1): 130504, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38442830

RESUMO

Long non-coding RNA FENDRR possesses both anti-fibrotic and anti-cancer properties, but its significance in the development of premalignant oral submucous fibrosis (OSF) remains unclear. Here, we showed that FENDRR was downregulated in OSF specimens and fibrotic buccal mucosal fibroblasts (fBMFs), and overexpression of FENDRR mitigated various myofibroblasts hallmarks, and vice versa. In the course of investigating the mechanism underlying the implication of FENDRR in myofibroblast transdifferentiation, we found that FENDRR can directly bind to miR-214 and exhibit its suppressive effect on myofibroblast activation via titrating miR-214. Moreover, we showed that mitofusin 2 (MFN2), a protein that is crucial to the fusion of mitochondria, was a direct target of miR-214. Our data suggested that FENDRR was positively correlated with MFN2 and MFN2 was required for the inhibitory property of FENDRR pertaining to myofibroblast phenotypes. Additionally, our results showed that the FENDRR/miR-214 axis participated in the arecoline-induced reactive oxygen species (ROS) accumulation and myofibroblast transdifferentiation. Building on these results, we concluded that the aberrant downregulation of FENDRR in OSF may be associated with chronic exposure to arecoline, leading to upregulation of ROS and myofibroblast activation via the miR-214-mediated suppression of MFN2.


Assuntos
MicroRNAs , Fibrose Oral Submucosa , Humanos , Miofibroblastos/metabolismo , Arecolina/efeitos adversos , Arecolina/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fibrose Oral Submucosa/genética , Fibrose Oral Submucosa/metabolismo , Fibrose Oral Submucosa/patologia , Mucosa Bucal/metabolismo , Fibroblastos , MicroRNAs/genética , MicroRNAs/metabolismo , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , GTP Fosfo-Hidrolases/farmacologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo
3.
Mol Biol Rep ; 51(1): 303, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38356030

RESUMO

BACKGROUND: This study aimed to assess silymarin's anticancer and antifibrotic potential through in silico analysis and investigate its impact on in vitro arecoline-induced fibrosis in primary human buccal fibroblasts (HBF). METHODS & RESULTS: The study utilized iGEMDOCK for molecular docking, evaluating nine bioflavonoids, and identified silymarin and baicalein as the top two compounds with the highest target affinity, followed by subsequent validation through a 100ns Molecular Dynamic Simulation demonstrating silymarin's stable behavior with Transforming Growth Factor Beta. HBF cell lines were developed from tissue samples obtained from patients undergoing third molar extraction. Arecoline, a known etiological factor in oral submucous fibrosis (OSMF), was employed to induce fibrogenesis in these HBFs. The inhibitory concentration (IC50) of arecoline was determined using the MTT assay, revealing dose-dependent cytotoxicity of HBFs to arecoline, with notable cytotoxicity observed at concentrations exceeding 50µM. Subsequently, the cytotoxicity of silymarin was assessed at 24 and 72 h, spanning concentrations from 5µM to 200µM, and an IC50 value of 143µM was determined. Real-time polymerase chain reaction (qPCR) was used to analyze the significant downregulation of key markers including collagen, epithelial-mesenchymal transition (EMT), stem cell, hypoxia, angiogenesis and stress markers in silymarin-treated arecoline-induced primary buccal fibroblast cells. CONCLUSION: Silymarin effectively inhibited fibroblast proliferation and downregulated genes associated with cancer progression and EMT pathway, both of which are implicated in malignant transformation. To our knowledge, this study represents the first exploration of silymarin's potential as a novel therapeutic agent in an in vitro model of OSMF.


Assuntos
Arecolina , Fibrose Oral Submucosa , Humanos , Arecolina/efeitos adversos , Arecolina/metabolismo , Mucosa Bucal/metabolismo , Simulação de Acoplamento Molecular , Fibrose Oral Submucosa/induzido quimicamente , Fibrose Oral Submucosa/tratamento farmacológico , Fibrose Oral Submucosa/metabolismo , Fibroblastos/metabolismo , Fibrose
4.
Eur J Pharmacol ; 967: 176353, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38325798

RESUMO

Oral submucous fibrosis (OSF) is a chronic oral mucosal disease. The pathological changes of OSF include epithelial damage and subepithelial matrix fibrosis. This study aimed to reveal the epithelial injury mechanism of OSF. A histopathological method was used to analyze oral mucosal tissue from OSF patients and OSF rats. The expression of PDE12 in the oral epithelium was analyzed by immunohistochemistry. The epithelial-mesenchymal transition (EMT) and tight junction proteins in arecoline-treated HOKs were explored by western blotting. Epithelial leakage was assessed by transepithelial electrical resistance and lucifer yellow permeability. The expression of PDE12 and the mitochondrial morphology, mitochondrial permeability transition pore opening, mitochondrial membrane potential, and mitochondrial reactive oxygen species (mtROS) were evaluated in arecoline-induced HOKs. Oxidative phosphorylation (OXPHOS) complexes and ATP content were also explored in HOKs. The results showed significant overexpression of PDE12 in oral mucosal tissue from OSF patients and rats. PDE12 was also overexpressed and aggregated in mitochondria in arecoline-induced HOKs, resulting in dysfunction of OXPHOS and impaired mitochondrial function. An EMT, disruption of tight junctions with epithelial leakage, and extracellular matrix remodeling were also observed. PDE12 overexpression induced by PDE12 plasmid transfection enhanced the mtROS level and interfered with occludin protein localization in HOKs. Interestingly, knockdown of PDE12 clearly ameliorated arecoline-induced mitochondrial dysfunction and epithelial barrier dysfunction in HOKs. Therefore, we concluded that overexpression of PDE12 impaired mitochondrial OXPHOS and mitochondrial function and subsequently impaired epithelial barrier function, ultimately leading to OSF. We suggest that PDE12 may be a new potential target against OSF.


Assuntos
Doenças Mitocondriais , Fibrose Oral Submucosa , Animais , Humanos , Ratos , Arecolina/efeitos adversos , Arecolina/metabolismo , Mitocôndrias , Doenças Mitocondriais/metabolismo , Fibrose Oral Submucosa/induzido quimicamente , Fibrose Oral Submucosa/metabolismo , Fibrose Oral Submucosa/patologia , Fosforilação Oxidativa
5.
Int J Oral Sci ; 16(1): 17, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38403794

RESUMO

A decline in mucosal vascularity is a histological hallmark of oral submucous fibrosis (OSF), a premalignant disease that is largely induced by betel quid chewing. However, the lack of available models has challenged studies of angiogenesis in OSF. Here, we found that the expression of thrombospondin 1 (THBS1), an endogenous angiostatic protein, was elevated in the stroma of tissues with OSF. Using a fibroblast-attached organoid (FAO) model, the overexpression of THBS1 in OSF was stably recapitulated in vitro. In the FAO model, treatment with arecoline, a major pathogenic component in areca nuts, enhanced the secretion of transforming growth factor (TGF)-ß1 by epithelial cells, which then promoted the expression of THBS1 in fibroblasts. Furthermore, human umbilical vein endothelial cells (HUVECs) were incorporated into the FAO to mimic the vascularized component. Overexpression of THBS1 in fibroblasts drastically suppressed the sprouting ability of endothelial cells in vascularized FAOs (vFAOs). Consistently, treatment with arecoline reduced the expression of CD31 in vFAOs, and this effect was attenuated when the endothelial cells were preincubated with neutralizing antibody of CD36, a receptor of THBS1. Finally, in an arecoline-induced rat OSF model, THBS1 inhibition alleviated collagen deposition and the decline in vascularity in vivo. Overall, we exploited an assembled organoid model to study OSF pathogenesis and provide a rationale for targeting THBS1.


Assuntos
Fibrose Oral Submucosa , Humanos , Animais , Ratos , Fibrose Oral Submucosa/patologia , Arecolina/efeitos adversos , Arecolina/metabolismo , Mucosa Bucal/patologia , Trombospondina 1/metabolismo , Trombospondina 1/farmacologia , 60489 , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fibroblastos , Fator de Crescimento Transformador beta1/metabolismo
6.
J Ethnopharmacol ; 326: 117929, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38373661

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ya-Samarn-Phlae (YaSP) has traditionally been widely used in southern Thailand for treating chronic and infected wounds, including diabetic foot ulcers. However, there are only a limited number of clinical studies supporting the use of this polyherbal formulation. Therefore, the present work aims to provide clinical evidence to support the application of YaSP, prepared according to a standardized traditional procedure (T-YaSP). Additionally, its potential chemical markers and wound healing-related biological activities were examined. MATERIALS AND METHODS: The in vitro wound healing-related biological activities of YaSP ethanol extract and T-YaSP, including antibacterial activity against Staphylococcus epidermidis, inhibition and eradication of staphylococcal biofilm, anti-inflammatory effects, and enhancement of human dermal fibroblast migration in scratch wounds, were examined using well-established protocols. The chemical profiles of the ethanol extract of YaSP and T-YaSP were compared, and with promising chemical markers, arecoline, alpha-mangostin, and curcumin were selected and quantified using the HPLC method. A prospective, multicenter, randomized, controlled, parallel-group study was conducted over 12 weeks to evaluate the efficacy of the YaSP solution as an adjunct therapy, combined with standard wound care, for diabetic ulcers compared to standard treatment. RESULTS: The YaSP extract reduces NO production and can scavenge NO radicals in LPS-induced RAW 264.7 macrophage cells. Additionally, in a scratch assay, this extract and one of its herbal components, Curcuma longa, enhance the migration of human dermal fibroblasts. T-YaSP, containing 2.412 ± 0.002 mg/g of arecoline, 2.399 ± 0.005 mg/g of curcumin, and 0.017 ± 0.000 mg/g of α-mangostin, has shown the ability to inhibit the development and eradicate the mature biofilm of S. epidermidis. The use of T-YaSP as an adjunct therapy led to a significantly higher proportion of patients achieving healing within six weeks compared to the standard treatment group (36%/9 patients vs. 4%/1 patient; p = 0.013). After 12 weeks, 19 out of 25 patients in the T-YaSP group experienced complete healing, whereas only four patients in the standard treatment group achieved complete wound healing (76% in the T-YaSP group vs. 16% in the control group; p < 0.001). CONCLUSION: The results presented here represent the first randomized controlled trial to demonstrate the effectiveness of the traditional polyherbal solution, T-YaSP, which exhibits a wide range of wound healing-related activities. Utilizing T-YaSP as an adjunctive treatment resulted in a significant improvement in the number of type 2 diabetic patients achieving complete healing. However, to explore and utilize YaSP further, conducting a double-blind, randomized controlled trial with a larger population is necessary.


Assuntos
Curcumina , Diabetes Mellitus , Pé Diabético , Humanos , Arecolina/farmacologia , Estudos Prospectivos , Curcumina/farmacologia , Cicatrização , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Pé Diabético/tratamento farmacológico , Método Duplo-Cego , Etanol/farmacologia
7.
Environ Toxicol ; 39(5): 2794-2802, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38282581

RESUMO

Aerobic glycolysis is a typical metabolic rearrangement for tumorigenesis. Arecoline is of explicit carcinogenicity, numerous works demonstrate its mutagenicity, genotoxicity, and cytotoxicity. However, the effects of arecoline on aerobic glycolysis of esophageal epithelial cells remain unclear. In the present study, 5 µM arecoline efficiently increased HK2 expression to induce aerobic glycolysis in Het-1A-Are and NE2-Are cells. The mechanistic analysis showed that arecoline activated the Akt-c-Myc signaling pathway and reduced the GSK3ß-mediated phosphorylation of c-Myc on Thr58 to prevent its ubiquitination and destruction, subsequently promoting HK2 transcription and expression. Taken together, these results suggest that arecoline can induce aerobic glycolysis of esophageal epithelial cells and further confirm that arecoline is a carcinogen harmful to human health.


Assuntos
Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Arecolina , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Células Epiteliais/metabolismo , Glicólise , Linhagem Celular Tumoral , Proliferação de Células
8.
Phytomedicine ; 123: 155157, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37951147

RESUMO

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.


Assuntos
Bacopa , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Camundongos , Humanos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Mitofagia , Bacopa/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Arecolina/farmacologia , Neoplasias Bucais/tratamento farmacológico , Camundongos Endogâmicos C57BL , Apoptose , Espécies Reativas de Oxigênio/metabolismo
9.
Brain Res ; 1822: 148609, 2024 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-37783259

RESUMO

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.


Assuntos
Terapia por Acupuntura , Depressão , Ratos , Camundongos , Animais , Depressão/terapia , Depressão/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sinapsinas/metabolismo , Arecolina/metabolismo , Arecolina/farmacologia , Antidepressivos/farmacologia , Antidepressivos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Modelos Animais de Doenças , Escopolamina/farmacologia , Córtex Pré-Frontal/metabolismo , Plasticidade Neuronal , Hipocampo/metabolismo , Estresse Psicológico/terapia , Estresse Psicológico/metabolismo
10.
Addict Biol ; 28(12): e13352, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-38017647

RESUMO

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.


Assuntos
Arecolina , Comportamento Aditivo , Animais , Camundongos , Arecolina/farmacologia , Areca , Nozes , Farmacologia em Rede , Fenilalanina
11.
Drug Des Devel Ther ; 17: 3085-3101, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37854130

RESUMO

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.


Assuntos
Arecolina , Fibrose Oral Submucosa , Humanos , Ratos , Animais , Arecolina/efeitos adversos , Cromatografia Líquida de Alta Pressão , Farmacologia em Rede , Simulação de Acoplamento Molecular , Quercetina/farmacologia , Fibrose Oral Submucosa/etiologia , Fibrose Oral Submucosa/metabolismo , Fibrose Oral Submucosa/patologia , Mucosa Bucal/patologia , Fibroblastos , Colágeno/farmacologia , Fibrose , Espectrometria de Massas
12.
Cancer Sci ; 114(10): 3857-3872, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37525561

RESUMO

The suppressive regulatory T cells (Treg) are frequently upregulated in cancer patients. This study aims to demonstrate the hypothesis that arecoline could induce the secretion of mitochondrial (mt) DNA D-loop and programmed cell death-ligand 1 (PD-L1) in extracellular vesicles (EVs), and attenuate T-cell immunity by upregulated Treg cell numbers. However, the immunosuppression could be reversed by whole glucan particle (WGP) ß-glucan in oral squamous cell (OSCC) patients. Arecoline-induced reactive oxygen specimen (ROS) production and cytosolic mtDNA D-loop were analyzed in OSCC cell lines. mtDNA D-loop, PD-L1, IFN-γ, and Treg cells were also identified for the surgical specimens and sera of 60 OSCC patients. We demonstrated that higher mtDNA D-loop, PD-L1, and Treg cell numbers were significantly correlated with larger tumor size, nodal metastasis, advanced clinical stage, and areca quid chewing. Furthermore, multivariate analysis confirmed that higher mtDNA D-loop levels and Treg cell numbers were unfavorable independent factors for survival. Arecoline significantly induced cytosolic mtDNA D-loop leakage and PD-L1 expression, which were packaged by EVs to promote immunosuppressive Treg cell numbers. However, WGP ß-glucan could elevate CD4+ and CD8+ T-cell numbers, mitigate Treg cell numbers, and promote oral cancer cell apoptosis. To sum up, arecoline induces EV production carrying mtDNA D-loop and PD-L1, and in turn elicits immune suppression. However, WGP ß-glucan potentially enhances dual effects on T-cell immunity and cell apoptosis and we highly recommend its integration with targeted and immune therapies against OSCC.


Assuntos
Carcinoma de Células Escamosas , Vesículas Extracelulares , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , beta-Glucanas , Humanos , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Arecolina , Antígeno B7-H1/genética , Neoplasias Bucais/patologia , Glucanos , beta-Glucanas/farmacologia , DNA Mitocondrial/genética , Terapia de Imunossupressão , Vesículas Extracelulares/metabolismo
13.
Front Immunol ; 14: 1197922, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37492574

RESUMO

Arecoline is an alkaloid extracted from betel nut, which has various pharmacological effects. In the present study, we showed that arecoline aggravated experimental acute ulcerative colitis (UC) induced by dextran sodium sulfate (DSS) in mice. We measured body weight and colon length, evaluated disease activity index, colon pathology sections, and levels of colonic inflammatory factors. Arecoline exacerbated the clinical signs of UC and the colonic inflammatory response in mice. The results of 16S rRNA sequencing of fecal samples showed a significant decrease in the percentage of probiotic bacteria Ligilactobacillus, Limosilactobacillus and Lactobacillus and a significant increase in the percentage of conditionally pathogenic bacteria Odoribacter and Bacteroides after arecoline treatment. Serum untargeted metabolomics showed that arecoline intervention reduced the levels of ergothioneine, pentostatin, diadenosine tetraphosphate and other metabolites and modulated nicotinate and nicotinamide metabolism, metabolic pathways, glyoxylate and dicarboxylate metabolism, and other metabolic pathways of intestinal microorganisms. According to the combined microbial and metabolite analysis, arecoline influences metabolite levels by modulating the intestinal microbiota. In summary, it was found that arecoline treatment exacerbated colonic injury and intestinal inflammatory responses in UC mice, disrupted the host's intestinal flora, and affected changes in flora metabolites, thereby exacerbating the development of colonic inflammation. Therefore, the consumption of betel nut can be associated with the risk of aggravating UC.


Assuntos
Colite Ulcerativa , Microbioma Gastrointestinal , Animais , Camundongos , Colite Ulcerativa/induzido quimicamente , Arecolina , RNA Ribossômico 16S
14.
J Cell Mol Med ; 27(13): 1797-1805, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37337411

RESUMO

Oral submucous fibrosis (OSF) is a chronic progressive fibrosis disease that affects in oral mucosal tissues. Interleukin (IL)-13 has been implicated in the development of fibrosis in multiple organs. Indeed, it contributes to diseases such as pulmonary fibrosis, liver cirrhosis among others. Currently, its expression in OSF and the specific mechanisms are not well understood. The aim of this study was to investigate the role of IL-13 in OSF and further explore whether IL-13 regulates-polarization of M2-macrophages in OSF. Initially, in the tissues of patients with OSF, we observed a high expression of M2-macrophages and IL-13 protein. Additionally, we found a correlation between the expression of IL-13 and the stage of OSF. Arecoline inhibited the proliferation of fibroblasts (FBs) and promoted IL-13 production in vitro. Furthermore, our observations revealed that M2-macrophages increased upon co-culturing M0-macrophages with supernatants containing the IL-13 cytokine. In conclusion, our study demonstrated that arecoline stimulates FBs leading to increased secretion of IL-13, which in turn IL-13 leads to polarization of M2-macrophages and promotes the occurrence of OSF. This suggests that IL-13 may be a potential therapeutic target of OSF.


Assuntos
Fibrose Oral Submucosa , Humanos , Arecolina/farmacologia , Fibroblastos/metabolismo , Fibrose , Interleucina-13/metabolismo , Mucosa Bucal/metabolismo , Fibrose Oral Submucosa/patologia
15.
Ecotoxicol Environ Saf ; 259: 115055, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-37224782

RESUMO

Arecoline is a critical bioactive component in areca nuts with toxicity and pharmacological activities. However, its effects on body health remain unclear. Here, we investigated the effects of arecoline on physiologic and biochemical parameters in mouse serum, liver, brain, and intestine. The effect of arecoline on gut microbiota was investigated based on shotgun metagenomic sequencing. The results showed that arecoline promoted lipid metabolism in mice, manifested as significantly reduced serum TC and TG and liver TC levels and a reduction in abdominal fat accumulation. Arecoline intake significantly modulated the neurotransmitters 5-HT and NE levels in the brain. Notably, arecoline intervention significantly increased serum IL-6 and LPS levels, leading to inflammation in the body. High-dose arecoline significantly reduced liver GSH levels and increased MDA levels, which led to oxidative stress in the liver. Arecoline intake promoted the release of intestinal IL-6 and IL-1ß, causing intestinal injury. In addition, we observed a significant response of gut microbiota to arecoline intake, reflecting significant changes in diversity and function of the gut microbes. Further mechanistic exploration suggested that arecoline intake can regulate gut microbes and ultimately affect the host's health. This study provided technical help for the pharmacochemical application and toxicity control of arecoline.


Assuntos
Arecolina , Microbioma Gastrointestinal , Animais , Camundongos , Arecolina/farmacologia , Arecolina/toxicidade , Interleucina-6/metabolismo , Metabolismo dos Lipídeos , Fígado
16.
Behav Brain Res ; 450: 114493, 2023 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-37178776

RESUMO

Epidemiological investigations and clinical studies have confirmed that human chewing of betel nut is an addictive behavior, and the proportion of teenagers chewing betel nut is increasing. Previous studies have shown that adolescence shows higher sensitivity to many addictive substances compared with adulthood, and that adult susceptibility to addictive substances is usually changed after exposure to addictive substances during adolescence. However, there are no reports of age-related animal experiments on betel nut or dependence to its active ingredients. Therefore, the two-bottle choice (TBC) (experiment 1 and 2) and conditioned place preference (CPP) (experiment 3 and 4) models with mice were used in this study to explore age-related differences in intake and preference of arecoline, the alkaloid in betel nut with highest content, and to explore the effect of arecoline exposure during adolescence on the re-exposure of arecoline in adulthood in mice. The results of experiment 1 showed that the intake of 80 µg/ml arecoline in adolescent mice was significantly higher than that in adult mice. However, there was no significant difference between adult and adolescent mice in preference for arecoline at any tested concentration (5-80 µg/ml), which may be due to the significantly higher intake of total fluid in adolescent mice compared to adult mice. The preference of arecoline in adolescent mice peaked at 20 µg/ml, and in adult mice peaked at 40 µg/ml. The results of experiment 2 showed that oral arecoline (5-80 µg/ml) in mice during adolescence caused a significant increase in the intake (days 3-16) and preference (days 5-8) for 40 µg/ml arecoline in adulthood. The results of experiment 3 showed that the doses of 0.03 or 0.1 mg/kg of arecoline produced the highest CPP response in adolescent or adult mice, respectively. The results of experiment 4 showed that mice exposed to arecoline in adolescence had significantly increased the CPP scores induced by arecoline in adulthood compared to mice that were not exposed. These data suggested that adolescent mice were more sensitive to arecoline, and exposure of mice to arecoline during adolescence increased the susceptibility to arecoline in adulthood.


Assuntos
Alcaloides , Transtornos Relacionados ao Uso de Substâncias , Humanos , Adulto , Adolescente , Masculino , Animais , Camundongos , Arecolina/farmacologia , Camundongos Endogâmicos C57BL , Fatores Etários
17.
Cells ; 12(8)2023 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-37190117

RESUMO

Betel quid and areca nut are complex mixture carcinogens, but little is known about whether their derived single-agent arecoline or arecoline N-oxide (ANO) is carcinogenic, and the underlying mechanisms remain unclear. In this systematic review, we analyzed recent studies on the roles of arecoline and ANO in cancer and strategies to block carcinogenesis. In the oral cavity, flavin-containing monooxygenase 3 oxidizes arecoline to ANO, and both alkaloids conjugate with N-acetylcysteine to form mercapturic acid compounds, which are excreted in urine, reducing arecoline and ANO toxicity. However, detoxification may not be complete. Arecoline and ANO upregulated protein expression in oral cancer tissue from areca nut users compared to expression levels in adjacent normal tissue, suggesting a causal relationship between these compounds and oral cancer. Sublingual fibrosis, hyperplasia, and oral leukoplakia were diagnosed in mice subjected to oral mucosal smearing of ANO. ANO is more cytotoxic and genotoxic than arecoline. During carcinogenesis and metastasis, these compounds increase the expression of epithelial-mesenchymal transition (EMT) inducers such as reactive oxygen species, transforming growth factor-ß1, Notch receptor-1, and inflammatory cytokines, and they activate EMT-related proteins. Arecoline-induced epigenetic markers such as sirtuin-1 hypermethylation, low protein expression of miR-22, and miR-886-3-p accelerate oral cancer progression. Antioxidants and targeted inhibitors of the EMT inducers used reduce the risk of oral cancer development and progression. Our review findings substantiate the association of arecoline and ANO with oral cancer. Both of these single compounds are likely carcinogenic to humans, and their mechanisms and pathways of carcinogenesis are useful indicators for cancer therapy and prognosis.


Assuntos
Arecolina , Carcinogênese , Carcinógenos , Óxidos N-Cíclicos , Neoplasias Bucais , Arecolina/química , Arecolina/metabolismo , Arecolina/toxicidade , Óxidos N-Cíclicos/toxicidade , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/genética , Neoplasias Bucais/prevenção & controle , Carcinogênese/induzido quimicamente , Carcinogênese/genética , Humanos , Animais , Camundongos , Areca/toxicidade , Oxigenases/metabolismo , Oxirredução , Acetilcisteína/metabolismo , Epigênese Genética/efeitos dos fármacos , Carcinógenos/química , Carcinógenos/metabolismo , Carcinógenos/toxicidade
18.
Nutrients ; 15(10)2023 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-37242285

RESUMO

The areca nut is often consumed as a chewing food in the Asian region. Our previous study revealed that the areca nut is rich in polyphenols with high antioxidant activity. In this study, we further assessed the effects and molecular mechanisms of the areca nut and its major ingredients on a Western diet-induced mice dyslipidemia model. Male C57BL/6N mice were divided into five groups and fed with a normal diet (ND), Western diet (WD), WD with areca nut extracts (ANE), areca nut polyphenols (ANP), and arecoline (ARE) for 12 weeks. The results revealed that ANP significantly reduced WD-induced body weight, liver weight, epididymal fat, and liver total lipid. Serum biomarkers showed that ANP ameliorated WD-enhanced total cholesterol and non-high-density lipoprotein (non-HDL). Moreover, analysis of cellular signaling pathways revealed that sterol regulatory element-binding protein 2 (SREBP2) and enzyme 3-hydroxy-3-methylglutaryld coenzyme A reductase (HMGCR) were significantly downregulated by ANP. The results of gut microbiota analysis revealed that ANP increased the abundance of beneficial bacterium Akkermansias and decreased the abundance of the pathogenic bacterium Ruminococcus while ARE shown the opposite result to ANP. In summary, our data indicated that areca nut polyphenol ameliorated WD-induced dyslipidemia by increasing the abundance of beneficial bacteria in the gut microbiota and reducing the expressions of SREBP2 and HMGCR while areca nut ARE inhibited this improvement potential.


Assuntos
Areca , Hepatopatia Gordurosa não Alcoólica , Masculino , Camundongos , Animais , Areca/química , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Nozes , Dieta Ocidental/efeitos adversos , Camundongos Endogâmicos C57BL , Arecolina/farmacologia , Extratos Vegetais/farmacologia
19.
Int J Mol Sci ; 24(10)2023 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-37240342

RESUMO

Areca nut (AN) is used for traditional herbal medicine and social activities in several countries. It was used as early as about A.D. 25-220 as a remedy. Traditionally, AN was applied for several medicinal functions. However, it was also reported to have toxicological effects. In this review article, we updated recent trends of research in addition to acquire new knowledge about AN. First, the history of AN usage from ancient years was described. Then, the chemical components of AN and their biological functions was compared; arecoline is an especially important compound in AN. AN extract has different effects caused by different components. Thus, the dual effects of AN with pharmacological and toxicological effects were summarized. Finally, we described perspectives, trends and challenges of AN. It will provide the insight of removing or modifying the toxic compounds of AN extractions for enhancing their pharmacological activity to treat several diseases in future applications.


Assuntos
Extratos Vegetais , Plantas Medicinais , Extratos Vegetais/química , Areca/efeitos adversos , Areca/química , Nozes/química , Arecolina/farmacologia
20.
PeerJ ; 11: e15158, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37096061

RESUMO

Objectives: Cellular senescence is strongly associated with fibrosis and tumorigenesis. However, whether the epithelium of oral submucous fibrosis (OSF) undergoes premature senescence remains unclear. This study investigates the roles of senescent epithelial cells in OSF. Methods: The immunohistochemistry and Sudan black B staining were performed to identify epithelium senescence in OSF tissues. Arecoline was used to induce human oral keratinocytes (HOKs) senescence. The cell morphology, senescence-associated ß galactosidase activity, cell counting Kit 8, immunofluorescence, quantitative real-time PCR, and western blot assay were used to identification of senescent HOKs. The enzyme-linked immunosorbent assay was exerted to evaluate the levels of transforming growth factor ß1 (TGF-ß1) in the supernatants of HOKs treated with or without arecoline. Results: The senescence-associated markers, p16 and p21, were overexpressed in OSF epithelium. These expressions were correlated with alpha-smooth actin (α-SMA) positively and proliferating cell nuclear antigen (PCNA) negatively. Moreover, Sudan black staining showed that there was more lipofuscin in OSF epithelium. In vitro, HOKs treated with arecoline showed senescence-associated characteristics including enlarged and flattened morphology, senescence-associated ß galactosidase staining, cell growth arrest, γH2A.X foci, upregulation of p53, p21, and TGF-ß1 protein levels. Moreover, senescent HOKs secreted more TGF-ß1. Conclusions: Senescent epithelial cells are involved in OSF progression and may become a promising target for OSF treatment.


Assuntos
Fibrose Oral Submucosa , Fator de Crescimento Transformador beta1 , Humanos , Fator de Crescimento Transformador beta1/metabolismo , Fibrose Oral Submucosa/metabolismo , Arecolina/metabolismo , Queratinócitos/metabolismo , beta-Galactosidase/metabolismo
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