The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Jiianghuei Jeng - One of the best experts on this subject based on the ideXlab platform.

  • Areca Nut Components Affect COX-2, Cyclin B1/cdc25C and Keratin Expression, PGE2 Production in Keratinocyte Is Related to Reactive Oxygen Species, CYP1A1, Src, EGFR and Ras Signaling
    2016
    Co-Authors: Ru-hsiu Cheng, Liang-jiunn Hahn, Jiianghuei Jeng
    Abstract:

    Aims: Chewing of betel quid (BQ) increases the risk of oral cancer and oral submucous fibrosis (OSF), possibly by BQ-induced toxicity and induction of inflammatory response in oral mucosa. Methods: Primary gingival keratinocytes (GK cells) were exposed to Areca Nut (AN) components with/without inhibitors. Cytotoxicity was measured by 3-(4,5-dimethyl- thiazol- 2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. mRNA and protein expression was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting. PGE2/ PGF2a production was measured by enzyme-linked immunosorbent assays. Results: Areca Nut extract (ANE) stimulated PGE2/PGF2a production, and upregulated the expression of cyclooxygenase-2 (COX-2), cytochrome P450 1A1 (CYP1A1) and hemeoxygenase-1 (HO-1), but inhibited expression of keratin 5/14, cyclinB1 and cdc25C in GK cells. ANE also activated epidermal growth factor receptor (EGFR), Src and Ras signaling pathways. ANE-induced COX-2, keratin 5, keratin 14 and cdc25C expression as well as PGE2 production were differentially regulated by a– naphthoflavone (a CYP 1A1/1A2 inhibitor), PD153035 (EGFR inhibitor), pp2 (Src inhibitor), and manumycin A (a Ras inhibitor). ANE-induced PGE2 production was suppressed by piper betle leaf (PBL) extract and hydroxychavicol (two major BQ components), dicoumarol (a NAD(P)H:Quinone Oxidoreductase- NQO1 inhibitor) and curcumin. ANE-induced cytotoxicity was inhibited by catalase and enhanced by dicoumarol, suggesting that AN components may contribute to th

  • Areca Nut components affect cox 2 cyclin b1 cdc25c and keratin expression pge2 production in keratinocyte is related to reactive oxygen species cyp1a1 src egfr and ras signaling
    PLOS ONE, 2014
    Co-Authors: Mei Chi Chang, Ru-hsiu Cheng, Liang-jiunn Hahn, Yijane Chen, Hsiaohua Chang, Chiupo Chan, Chienyang Yeh, Yinlin Wang, Jiianghuei Jeng
    Abstract:

    Aims Chewing of betel quid (BQ) increases the risk of oral cancer and oral submucous fibrosis (OSF), possibly by BQ-induced toxicity and induction of inflammatory response in oral mucosa. Methods Primary gingival keratinocytes (GK cells) were exposed to Areca Nut (AN) components with/without inhibitors. Cytotoxicity was measured by 3-(4,5-dimethyl- thiazol- 2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. mRNA and protein expression was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting. PGE2/PGF2α production was measured by enzyme-linked immunosorbent assays. Results Areca Nut extract (ANE) stimulated PGE2/PGF2α production, and upregulated the expression of cyclooxygenase-2 (COX-2), cytochrome P450 1A1 (CYP1A1) and hemeoxygenase-1 (HO-1), but inhibited expression of keratin 5/14, cyclinB1 and cdc25C in GK cells. ANE also activated epidermal growth factor receptor (EGFR), Src and Ras signaling pathways. ANE-induced COX-2, keratin 5, keratin 14 and cdc25C expression as well as PGE2 production were differentially regulated by α–naphthoflavone (a CYP 1A1/1A2 inhibitor), PD153035 (EGFR inhibitor), pp2 (Src inhibitor), and manumycin A (a Ras inhibitor). ANE-induced PGE2 production was suppressed by piper betle leaf (PBL) extract and hydroxychavicol (two major BQ components), dicoumarol (a NAD(P)H:Quinone Oxidoreductase - NQO1 inhibitor) and curcumin. ANE-induced cytotoxicity was inhibited by catalase and enhanced by dicoumarol, suggesting that AN components may contribute to the pathogenesis of OSF and oral cancer via induction of aberrant differentiation, cytotoxicity, COX-2 expression, and PGE2/PGF2αproduction. Conclusions CYP4501A1, reactive oxygen species (ROS), EGFR, Src and Ras signaling pathways could all play a role in ANE-induced pathogenesis of oral cancer. Addition of PBL into BQ and curcumin consumption could inhibit the ANE-induced inflammatory response.

  • role of Areca Nut in betel quid associated chemical carcinogenesis current awareness and future perspectives
    Oral Oncology, 2001
    Co-Authors: Jiianghuei Jeng, Mei Chi Chang, L J Hahn
    Abstract:

    Betel quid (BQ)-chewing is a popular oral habit with potential links to the occurrence of oral cancer. Many of the literature-based studies reveal that Areca Nut (AN) extract may demonstrate mutagenic and genotoxic effects, in addition to inducing preneoplastic as well as neoplastic lesions in experimental animals. Areca Nut should, thus, be highly suspected as a human carcinogen. Toxicity studies relating to AN-contained polyphenols and tannins are not conclusive, with both carcinogenic and anti-carcinogenic effects being reported. The mutagenicity and genotoxicity of Areca alkaloids has been detected by many short-term assays. However, their genotoxicity to oral fibroblasts and keratinocytes, the target cells of BQ, has not been identified. It would thus appear that AN toxicity is not completely due to its polyphenol, tannin and alkaloid content. The single agent which is responsible for AN carcinogenicity awaits further clarification. Reactive oxygen species produced during auto-oxidation of AN polyphenols in the BQ-chewer's saliva, are crucial in the initiation and promotion of oral cancer. Nitrosation of Areca alkaloids also produces AN-specific nitrosamines, that have been demonstrated to be mutagenic, genotoxic and are capable of inducing tumors in experimental animals. Arecaidine and AN extract are further suggested to be tumor promoters. Antioxidants such as glutathione and N-acetyl-L-cysteine can potentially prevent such AN-elicited cytotoxicity. Further studies are needed to delineate the metabolism of AN ingredient and their roles in the multi-step chemical carcinogenesis, in order to enhance the success of the future chemoprevention of oral cancer and oral submucous fibrosis.

  • Areca Nut extract and arecoline induced the cell cycle arrest but not apoptosis of cultured oral kb epithelial cells association of glutathione reactive oxygen species and mitochondrial membrane potential
    Carcinogenesis, 2001
    Co-Authors: Mei Chi Chang, Liang-jiunn Hahn, Chiupo Chan, Yuan Soon Ho, P H Lee, Jangjaer Lee, Ying Jen Wang, Jiianghuei Jeng
    Abstract:

    There are 600 million betel quid (BQ) chewers in the world. BQ chewing is a major etiologic factor of oral cancer. Areca Nut (AN) and arecoline may inhibit the growth of oral mucosal fibroblasts (OMF) and keratinocytes. In this study, AN extract (100-800 μg/ml) and arecoline (20-120 μM) inhibited the growth of oral KB cells by 36-90 and 15-75%, respectively. Exposure to arecoline (>0.2 mM) for 24 h induced G 2 /M cell cycle arrest of OMF and KB cells. Areca Nut extract (>400 μg/ml) also induced G 2 /M arrest of KB cells, being preceded by S-phase arrest at 7-h of exposure. No evident sub-G 0 /G 1 peak was noted. Marked retraction and intracellular vacuoles formation of OMF and KB cells were observed. Glutathione (GSH) level, mitochondrial membrane potential (Δβm) and H 2 O 2 production of KB cells were measured by flow cytometry. GSH level [indicated by 5-chloromethyl-fluorescein (CMF) fluorescence] was depleted by 24-h exposure of KB cells to arecoline (0.4-1.2 mM) and AN extract (800-1200 μg/ml), with increasing the percentage of cells in low CMF fluorescence. By contrast, arecoline (0.1-1.2 mM) and AN extract (800-1200 μg/ml) induced decreasing and increasing H 2 O 2 production (by 2',7'-dichlorofluorescein fluorescence), respectively. Hyperpolarization of Δβm (increasing of rhodamine uptake) was noted by 24-h exposure of KB cells to arecoline (0.4-1.2 mM) and AN extract (800-1200 μg/ml). AN extract (100-1200 μg/ml) and arecoline (0.1-1.2 mM) induced little DNA fragmentation on KB cells within 24 h. These results indicate that AN ingredients are crucial in the pathogenesis of oral submucous fibrosis (OSF) and oral cancer by differentially inducing the dysregulation of cell cycle control, Δβm, GSH level and intracellular H 2 O 2 production, these events being not coupled with cellular apoptosis.

  • Areca Nut extract and arecoline induced the cell cycle arrest but not apoptosis of cultured oral kb epithelial cells association of glutathione reactive oxygen species and mitochondrial membrane potential
    Carcinogenesis, 2001
    Co-Authors: Mei Chi Chang, Liang-jiunn Hahn, Chiupo Chan, P H Lee, Jangjaer Lee, Ying Jen Wang, Jiianghuei Jeng
    Abstract:

    There are 600 million betel quid (BQ) chewers in the world. BQ chewing is a major etiologic factor of oral cancer. Areca Nut (AN) and arecoline may inhibit the growth of oral mucosal fibroblasts (OMF) and keratinocytes. In this study, AN extract (100-800 microg/ml) and arecoline (20-120 microM) inhibited the growth of oral KB cells by 36-90 and 15-75%, respectively. Exposure to arecoline (> 0.2 mM) for 24 h induced G(2)/M cell cycle arrest of OMF and KB cells. Areca Nut extract (> 400 microg/ml) also induced G(2)/M arrest of KB cells, being preceded by S-phase arrest at 7-h of exposure. No evident sub-G(0)/G(1) peak was noted. Marked retraction and intracellular vacuoles formation of OMF and KB cells were observed. Glutathione (GSH) level, mitochondrial membrane potential (Deltabetam) and H(2)O(2) production of KB cells were measured by flow cytometry. GSH level [indicated by 5-chloromethyl-fluorescein (CMF) fluorescence] was depleted by 24-h exposure of KB cells to arecoline (0.4-1.2 mM) and AN extract (800-1200 microg/ml), with increasing the percentage of cells in low CMF fluorescence. By contrast, arecoline (0.1-1.2 mM) and AN extract (800-1200 microg/ml) induced decreasing and increasing H(2)O(2) production (by 2',7'-dichloro- fluorescein fluorescence), respectively. Hyperpolarization of Deltabetam (increasing of rhodamine uptake) was noted by 24-h exposure of KB cells to arecoline (0.4-1.2 mM) and AN extract (800-1200 microg/ml). AN extract (100- 1200 microg/ml) and arecoline (0.1-1.2 mM) induced little DNA fragmentation on KB cells within 24 h. These results indicate that AN ingredients are crucial in the pathogenesis of oral submucous fibrosis (OSF) and oral cancer by differentially inducing the dysregulation of cell cycle control, Deltabetam, GSH level and intracellular H(2)O(2) production, these events being not coupled with cellular apoptosis.

Paturu Kondaiah - One of the best experts on this subject based on the ideXlab platform.

  • molecular pathways regulated by Areca Nut in the etiopathogenesis of oral submucous fibrosis
    Periodontology 2000, 2019
    Co-Authors: Paturu Kondaiah, Ila Pant, Imran Khan
    Abstract:

    Many oral mucosal lesions are due to substance abuse, such as tobacco and Areca Nut, amongst others. There is considerable evidence that oral lesions/disorders such as some leukoplakias, most erythroplakias, and submucous fibrosis have malignant potential, with a conversion rate of 5%-10% over a 10-year period. There have been several reports on possible biomarkers that predict malignant conversion of the oral lesions associated with these disorders. Management of these is mostly surgical removal of the lesion followed by observation, and in some cases treatment by antioxidants and anti-inflammatory agents. Oral submucous fibrosis is due to excessive deposition of extracellular matrix in the connective tissue plus, particularly, collagens. The deposition of collagen leads to stiffness of the affected regions and results in difficulty in mouth opening. Areca Nut chewing is proposed as the most probable etiological factor in the manifestation of oral submucous fibrosis. Several studies suggest involvement of proinflammatory cytokines, dysregulated by Areca Nut, in the development of the disease. Amongst these, transforming growth factor-β is in the forefront, which is also shown to be involved in fibrosis of other organs. This review addresses the molecular mechanisms involved in oral submucous fibrosis development and provides a model for the regulation of transforming growth factor-β by Areca Nut. It provides an exemplar of the role of modern molecular techniques in the study of oral disease.

  • role of Areca Nut induced jnk atf2 jun axis in the activation of tgf β pathway in precancerous oral submucous fibrosis
    Scientific Reports, 2016
    Co-Authors: Ila Pant, Girish S Rao, Paturu Kondaiah
    Abstract:

    Oral submucous fibrosis (OSF) is potentially premalignant with progressive and irreversible extracellular matrix deposition accompanied by epithelial atrophy and like other fibrotic disorders, is primarily a TGF-β driven disease. OSF is caused by prolonged chewing of Areca Nut. Our previous studies reported a pivotal role for TGF-β activation and its effects contributing to OSF. However, the mechanism for activation of TGF-β signaling in OSF is still unknown. In this study we demonstrate activation of TGF-β signaling with sub-cytotoxic dose of Areca Nut in epithelial cells and discovered a key role for pJNK in this process. In good correlation; pJNK was detected in OSF tissues but not in normal tissues. Moreover, activation of JNK was found to be dependent on muscarinic acid receptor induced Ca2+/CAMKII as well as ROS. JNK dependent phosphorylation of ATF2/c-Jun transcription factors resulted in TGF-β transcription and its signaling. pATF2/p-c-Jun were enriched on TGF-β promoter and co-localized in nuclei of epithelial cells upon Areca Nut treatment. In corroboration, OSF tissue sections also had nuclear pATF2 and p-c-Jun. Our results provide comprehensive mechanistic details of TGF-β signaling induced by etiological agent Areca Nut in the manifestation of fibrosis which can lead to new therapeutic modalities for OSF.

  • Activation of TGF-b Pathway by Areca Nut Constituents: A Possible Cause of Oral Submucous Fibrosis
    2016
    Co-Authors: Imran Khan, Neeraj Kumar, Ila Pant, Sivakrishna Narra, Paturu Kondaiah
    Abstract:

    Oral submucous fibrosis (OSF) is a chronic inflammatory disease characterized by the accumulation of excess collagen, and Areca Nut chewing has been proposed as an important etiological factor for disease manifestation. Activation of transforming growth factor-b signaling has been postulated as the main causative event for increased collagen production in OSF. Oral epithelium plays important roles in OSF, and arecoline has been shown to induce TGF-b in epithelial cells. In an attempt to understand the role of Areca Nut constituents in the manifestation of OSF, we studied the global gene expression profile in epithelial cells (HaCaT) following treatment with Areca Nut water extract or TGF-b. Interestingly, 64 % of the differentially regulated genes by Areca Nut water extract matches with the TGF-b induced gene expression profile. Out of these, expression of 57 % of genes was compromised in the presence of ALK5 (TbRI) inhibitor and 7 % were independently induced by Areca Nut, highlighting the importance of TGF-b in Areca Nut actions. Areca Nut water extract treatment induced p-SMAD2 and TGF-b downstream targets in HaCaT cells but not in human gingival fibroblast cells (hGF), suggesting epithelial cells could be the source of TGF-b in promoting OSF. Water extract of Areca Nut consists of polyphenols and alkaloids. Both polyphenol and alkaloid fractions of Areca Nut were able to induce TGF-b signaling and its downstream targets. Also, SMAD-2 was phosphorylated following treatment of HaCaT cells by Catechin, Tannin and alkaloids namely Arecoline, Arecaidine and Guvacine. Moreover, both polyphenols and alkaloids induced TGF-b2 and THBS1 (activator o

  • epithelial atrophy in oral submucous fibrosis is mediated by copper ii and arecoline of Areca Nut
    Journal of Cellular and Molecular Medicine, 2015
    Co-Authors: Imran Khan, Ila Pant, Sivakrishna Narra, Somanahalli Girish Rao, Rekha Radhesh, K Ranganathan, Paturu Kondaiah
    Abstract:

    Exposure of oral cavity to Areca Nut is associated with several pathological conditions including oral submucous fibrosis (OSF). Histopathologically OSF is characterized by epithelial atrophy, chronic inflammation, juxtaepithelial hyalinization, leading to fibrosis of submucosal tissue and affects 0.5% of the population in the Indian subcontinent. As the molecular mechanisms leading to atrophied epithelium and fibrosis are poorly understood, we studied Areca Nut actions on human keratinocyte and gingival fibroblast cells. Areca Nut water extract (ANW) was cytotoxic to epithelial cells and had a pro-proliferative effect on fibroblasts. This opposite effect of ANW on epithelial and fibroblast cells was intriguing but reflects the OSF histopathology such as epithelial atrophy and proliferation of fibroblasts. We demonstrate that the pro-proliferative effects of ANW on fibroblasts are dependent on insulin-like growth factor signalling while the cytotoxic effects on keratinocytes are dependent on the generation of reactive oxygen species. Treatment of keratinocytes with arecoline which is a component of ANW along with copper resulted in enhanced cytotoxicity which becomes comparable to IC50 of ANW. Furthermore, studies using cyclic voltammetry, mass spectrometry and plasmid cleavage assay suggested that the presence of arecoline increases oxidation reduction potential of copper leading to enhanced cleavage of DNA which could generate an apoptotic response. Terminal deoxynucleotidyl transferase dUTP Nick End Labeling assay and Ki-67 index of OSF tissue sections suggested epithelial apoptosis, which could be responsible for the atrophy of OSF epithelium.

  • role of Areca Nut induced tgf β and epithelial mesenchymal interaction in the pathogenesis of oral submucous fibrosis
    PLOS ONE, 2015
    Co-Authors: Ila Pant, Imran Khan, Neeraj Kumar, Somanahalli Girish Rao, Paturu Kondaiah
    Abstract:

    Areca Nut consumption has been implicated in the progression of Oral Submucous fibrosis (OSF); an inflammatory precancerous fibrotic condition. Our previous studies have demonstrated the activation of TGF-β signaling in epithelial cells by Areca Nut components and also propose a role for epithelial expressed TGF-β in the pathogenesis of OSF. Although the importance of epithelial cells in the manifestation of OSF has been proposed, the actual effectors are fibroblast cells. However, the role of Areca Nut and TGF-β in the context of fibroblast response has not been elucidated. Therefore, to understand their role in the context of fibroblast response in OSF pathogenesis, human gingival fibroblasts (hGF) were treated with Areca Nut and/or TGF-β followed by transcriptome profiling. The gene expression profile obtained was compared with the previously published transcriptome profiles of OSF tissues and Areca Nut treated epithelial cells. The analysis revealed regulation of 4666 and 1214 genes by Areca Nut and TGF-β treatment respectively. The expression of 413 genes in hGF cells was potentiated by Areca Nut and TGF-β together. Further, the differentially expressed genes of OSF tissues compared to normal tissues overlapped significantly with Areca Nut and TGF-β induced genes in epithelial and hGF cells. Several positively enriched pathways were found to be common between OSF tissues and Areca Nut +TGF-β treated hGF cells. In concordance, Areca Nut along with TGF-β enhanced fibroblast activation as demonstrated by potentiation of αSMA, γSMA and collagen gel contraction by hGF cells. Furthermore, TGF-β secreted by Areca Nut treated epithelial cells influenced fibroblast activation and other genes implicated in fibrosis. These data establish a role for Areca Nut influenced epithelial cells in OSF progression by activation of fibroblasts and emphasizes the importance of epithelial-mesenchymal interaction in OSF.

Mei Chi Chang - One of the best experts on this subject based on the ideXlab platform.

  • Areca Nut components affect cox 2 cyclin b1 cdc25c and keratin expression pge2 production in keratinocyte is related to reactive oxygen species cyp1a1 src egfr and ras signaling
    PLOS ONE, 2014
    Co-Authors: Mei Chi Chang, Ru-hsiu Cheng, Liang-jiunn Hahn, Yijane Chen, Hsiaohua Chang, Chiupo Chan, Chienyang Yeh, Yinlin Wang, Jiianghuei Jeng
    Abstract:

    Aims Chewing of betel quid (BQ) increases the risk of oral cancer and oral submucous fibrosis (OSF), possibly by BQ-induced toxicity and induction of inflammatory response in oral mucosa. Methods Primary gingival keratinocytes (GK cells) were exposed to Areca Nut (AN) components with/without inhibitors. Cytotoxicity was measured by 3-(4,5-dimethyl- thiazol- 2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. mRNA and protein expression was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting. PGE2/PGF2α production was measured by enzyme-linked immunosorbent assays. Results Areca Nut extract (ANE) stimulated PGE2/PGF2α production, and upregulated the expression of cyclooxygenase-2 (COX-2), cytochrome P450 1A1 (CYP1A1) and hemeoxygenase-1 (HO-1), but inhibited expression of keratin 5/14, cyclinB1 and cdc25C in GK cells. ANE also activated epidermal growth factor receptor (EGFR), Src and Ras signaling pathways. ANE-induced COX-2, keratin 5, keratin 14 and cdc25C expression as well as PGE2 production were differentially regulated by α–naphthoflavone (a CYP 1A1/1A2 inhibitor), PD153035 (EGFR inhibitor), pp2 (Src inhibitor), and manumycin A (a Ras inhibitor). ANE-induced PGE2 production was suppressed by piper betle leaf (PBL) extract and hydroxychavicol (two major BQ components), dicoumarol (a NAD(P)H:Quinone Oxidoreductase - NQO1 inhibitor) and curcumin. ANE-induced cytotoxicity was inhibited by catalase and enhanced by dicoumarol, suggesting that AN components may contribute to the pathogenesis of OSF and oral cancer via induction of aberrant differentiation, cytotoxicity, COX-2 expression, and PGE2/PGF2αproduction. Conclusions CYP4501A1, reactive oxygen species (ROS), EGFR, Src and Ras signaling pathways could all play a role in ANE-induced pathogenesis of oral cancer. Addition of PBL into BQ and curcumin consumption could inhibit the ANE-induced inflammatory response.

  • role of Areca Nut in betel quid associated chemical carcinogenesis current awareness and future perspectives
    Oral Oncology, 2001
    Co-Authors: Jiianghuei Jeng, Mei Chi Chang, L J Hahn
    Abstract:

    Betel quid (BQ)-chewing is a popular oral habit with potential links to the occurrence of oral cancer. Many of the literature-based studies reveal that Areca Nut (AN) extract may demonstrate mutagenic and genotoxic effects, in addition to inducing preneoplastic as well as neoplastic lesions in experimental animals. Areca Nut should, thus, be highly suspected as a human carcinogen. Toxicity studies relating to AN-contained polyphenols and tannins are not conclusive, with both carcinogenic and anti-carcinogenic effects being reported. The mutagenicity and genotoxicity of Areca alkaloids has been detected by many short-term assays. However, their genotoxicity to oral fibroblasts and keratinocytes, the target cells of BQ, has not been identified. It would thus appear that AN toxicity is not completely due to its polyphenol, tannin and alkaloid content. The single agent which is responsible for AN carcinogenicity awaits further clarification. Reactive oxygen species produced during auto-oxidation of AN polyphenols in the BQ-chewer's saliva, are crucial in the initiation and promotion of oral cancer. Nitrosation of Areca alkaloids also produces AN-specific nitrosamines, that have been demonstrated to be mutagenic, genotoxic and are capable of inducing tumors in experimental animals. Arecaidine and AN extract are further suggested to be tumor promoters. Antioxidants such as glutathione and N-acetyl-L-cysteine can potentially prevent such AN-elicited cytotoxicity. Further studies are needed to delineate the metabolism of AN ingredient and their roles in the multi-step chemical carcinogenesis, in order to enhance the success of the future chemoprevention of oral cancer and oral submucous fibrosis.

  • Areca Nut extract and arecoline induced the cell cycle arrest but not apoptosis of cultured oral kb epithelial cells association of glutathione reactive oxygen species and mitochondrial membrane potential
    Carcinogenesis, 2001
    Co-Authors: Mei Chi Chang, Liang-jiunn Hahn, Chiupo Chan, Yuan Soon Ho, P H Lee, Jangjaer Lee, Ying Jen Wang, Jiianghuei Jeng
    Abstract:

    There are 600 million betel quid (BQ) chewers in the world. BQ chewing is a major etiologic factor of oral cancer. Areca Nut (AN) and arecoline may inhibit the growth of oral mucosal fibroblasts (OMF) and keratinocytes. In this study, AN extract (100-800 μg/ml) and arecoline (20-120 μM) inhibited the growth of oral KB cells by 36-90 and 15-75%, respectively. Exposure to arecoline (>0.2 mM) for 24 h induced G 2 /M cell cycle arrest of OMF and KB cells. Areca Nut extract (>400 μg/ml) also induced G 2 /M arrest of KB cells, being preceded by S-phase arrest at 7-h of exposure. No evident sub-G 0 /G 1 peak was noted. Marked retraction and intracellular vacuoles formation of OMF and KB cells were observed. Glutathione (GSH) level, mitochondrial membrane potential (Δβm) and H 2 O 2 production of KB cells were measured by flow cytometry. GSH level [indicated by 5-chloromethyl-fluorescein (CMF) fluorescence] was depleted by 24-h exposure of KB cells to arecoline (0.4-1.2 mM) and AN extract (800-1200 μg/ml), with increasing the percentage of cells in low CMF fluorescence. By contrast, arecoline (0.1-1.2 mM) and AN extract (800-1200 μg/ml) induced decreasing and increasing H 2 O 2 production (by 2',7'-dichlorofluorescein fluorescence), respectively. Hyperpolarization of Δβm (increasing of rhodamine uptake) was noted by 24-h exposure of KB cells to arecoline (0.4-1.2 mM) and AN extract (800-1200 μg/ml). AN extract (100-1200 μg/ml) and arecoline (0.1-1.2 mM) induced little DNA fragmentation on KB cells within 24 h. These results indicate that AN ingredients are crucial in the pathogenesis of oral submucous fibrosis (OSF) and oral cancer by differentially inducing the dysregulation of cell cycle control, Δβm, GSH level and intracellular H 2 O 2 production, these events being not coupled with cellular apoptosis.

  • Areca Nut extract and arecoline induced the cell cycle arrest but not apoptosis of cultured oral kb epithelial cells association of glutathione reactive oxygen species and mitochondrial membrane potential
    Carcinogenesis, 2001
    Co-Authors: Mei Chi Chang, Liang-jiunn Hahn, Chiupo Chan, P H Lee, Jangjaer Lee, Ying Jen Wang, Jiianghuei Jeng
    Abstract:

    There are 600 million betel quid (BQ) chewers in the world. BQ chewing is a major etiologic factor of oral cancer. Areca Nut (AN) and arecoline may inhibit the growth of oral mucosal fibroblasts (OMF) and keratinocytes. In this study, AN extract (100-800 microg/ml) and arecoline (20-120 microM) inhibited the growth of oral KB cells by 36-90 and 15-75%, respectively. Exposure to arecoline (> 0.2 mM) for 24 h induced G(2)/M cell cycle arrest of OMF and KB cells. Areca Nut extract (> 400 microg/ml) also induced G(2)/M arrest of KB cells, being preceded by S-phase arrest at 7-h of exposure. No evident sub-G(0)/G(1) peak was noted. Marked retraction and intracellular vacuoles formation of OMF and KB cells were observed. Glutathione (GSH) level, mitochondrial membrane potential (Deltabetam) and H(2)O(2) production of KB cells were measured by flow cytometry. GSH level [indicated by 5-chloromethyl-fluorescein (CMF) fluorescence] was depleted by 24-h exposure of KB cells to arecoline (0.4-1.2 mM) and AN extract (800-1200 microg/ml), with increasing the percentage of cells in low CMF fluorescence. By contrast, arecoline (0.1-1.2 mM) and AN extract (800-1200 microg/ml) induced decreasing and increasing H(2)O(2) production (by 2',7'-dichloro- fluorescein fluorescence), respectively. Hyperpolarization of Deltabetam (increasing of rhodamine uptake) was noted by 24-h exposure of KB cells to arecoline (0.4-1.2 mM) and AN extract (800-1200 microg/ml). AN extract (100- 1200 microg/ml) and arecoline (0.1-1.2 mM) induced little DNA fragmentation on KB cells within 24 h. These results indicate that AN ingredients are crucial in the pathogenesis of oral submucous fibrosis (OSF) and oral cancer by differentially inducing the dysregulation of cell cycle control, Deltabetam, GSH level and intracellular H(2)O(2) production, these events being not coupled with cellular apoptosis.

Saman Warnakulasuriya - One of the best experts on this subject based on the ideXlab platform.

  • defining a global research and policy agenda for betel quid and Areca Nut
    Lancet Oncology, 2017
    Co-Authors: Hedieh Mehrtash, Mark Parascandola, Prakash C Gupta, Kalina Duncan, Annette M David, Ellen R Gritz, Ravi Mehrotra, Amer Siddiq Amer Nordin, Paul C Pearlman, Saman Warnakulasuriya
    Abstract:

    Betel quid and Areca Nut are known risk factors for many oral and oesophageal cancers, and their use is highly prevalent in the Asia-Pacific region. Additionally, betel quid and Areca Nut are associated with health effects on the cardiovascular, nervous, gastrointestinal, metabolic, respiratory, and reproductive systems. Unlike tobacco, for which the WHO Framework Convention on Tobacco Control provides evidence-based policies for reducing tobacco use, no global policy exists for the control of betel quid and Areca Nut use. Multidisciplinary research is needed to address this neglected global public health emergency and to mobilise efforts to control betel quid and Areca Nut use. In addition, future research is needed to advance our understanding of the basic biology, mechanisms, and epidemiology of betel quid and Areca Nut use, to advance possible prevention and cessation programmes for betel quid and Areca Nut users, and to design evidence-based screening and early diagnosis programmes to address the growing burden of cancers that are associated with use.

  • oral lichenoid contact lesions induced by Areca Nut and betel quid chewing a mini review
    Journal of Investigative and Clinical Dentistry, 2012
    Co-Authors: Peter A Reichart, Saman Warnakulasuriya
    Abstract:

    Betel quid (BQ) and Areca Nut chewing is widely prevalent in many parts of Asia and Asian-migrant communities throughout the world. Global reports estimate 600 million users. Sufficient evidence of carcinogenicity has been found for BQ and its main ingredient, Areca Nut. BQ Areca Nut users have an increased risk of potentially malignant disorders. Among chewers, BQ remains in contact with the oral mucosa for prolonged periods. This review examines the clinical and pathological aspects of lichenoid lesions caused by Areca Nut and BQ, a condition that has received little attention in the published literature.

  • Areca Nut chewing habit is a significant risk factor for metabolic syndrome a systematic review
    Journal of Nutrition Health & Aging, 2012
    Co-Authors: Fawad Javed, Khalid Alhezaimi, Saman Warnakulasuriya
    Abstract:

    Background Areca-Nut (AN) chewing habit has been associated with oral diseases including oral cancer, oral submucous fibrosis and periodontal disease; however, some authors have reported that the ANchewing abuse may also jeopardize the systemic health among its users.

  • oral mucosal lesions associated with betel quid Areca Nut and tobacco chewing habits consensus from a workshop held in kuala lumpur malaysia november 25 27 1996
    Journal of Oral Pathology & Medicine, 2007
    Co-Authors: Rosnah Binti Zain, Prakash C Gupta, Saman Warnakulasuriya, Noriaki Ikeda, C W Van Wyk, Prashanta Shrestha, Tony Axell
    Abstract:

    A variety of betel/Areca Nut/tobacco habits have been reviewed and categorized because of their possible causal association with oral cancer and various oral precancerous lesions and conditions, and on account of their widespread occurrence in different parts of the world. At a recent workshop in Kuala Lumpur it was recommended that "quid" be defined as "a substance, or mixture of substances, placed in the mouth or chewed and remaining in contact with the mucosa, usually containing one or both of the two basic ingredients, tobacco and/or Areca Nut, in raw or any manufactured or processed form." Clear delineations on contents of the quid (Areca Nut quid, tobacco quid, and tobacco and Areca Nut quid) are recommended as absolute criteria with finer subdivisions to be added if necessary. The betel quid refers to any quid wrapped in betel leaf and is therefore a specific variety of quid. The workshop proposed that quid-related lesions should be categorized conceptually into two categories: first, those that are diffusely outlined and second, those localized at the site where a quid is regularly placed. Additional or expanded criteria and guidelines were proposed to define, describe or identify lesions such as chewer's mucosa, Areca Nut chewer's lesion, oral submucous fibrosis and other quid-related lesions. A new clinical entity, betel-quid lichenoid lesion, was also proposed to describe an oral lichen planus-like lesion associated with the betel quid habit.

  • Areca Nut use an independent risk factor for oral cancer
    BMJ, 2002
    Co-Authors: Saman Warnakulasuriya, Chetan Trivedy, T J Peters
    Abstract:

    Areca Nut is the seed of the fruit of the oriental palm, Areca catechu . It is the basic ingredient of a variety of widely used chewed products. Thin slices of the Nut, either natural or processed, may be mixed with a variety of substances including slaked lime (calcium hydroxide) and spices such as cardamom, cocoNut, and saffron. Most significantly, they may be mixed with tobacco products or wrapped in the leaf of the piper betel plant. Hence the more common name betel Nut. Areca Nut is used by an estimated 200-400 million people, mainly IndoAsians and Chinese.1 It is used by men and women—in some societies the latter predominate. All age groups and social classes use the product. Areca Nut has a long history of use and is deeply ingrained in many sociocultural and religious activities.2 Of particular interest in the United Kingdom, and perhaps other developed countries, is that use of Areca Nut continues and is often enhanced following migration. Thus British Asians have brought the use of Areca from India (some via East Africa), Pakistan, Bangladesh, and other countries in the region …

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  • molecular pathways regulated by Areca Nut in the etiopathogenesis of oral submucous fibrosis
    Periodontology 2000, 2019
    Co-Authors: Paturu Kondaiah, Ila Pant, Imran Khan
    Abstract:

    Many oral mucosal lesions are due to substance abuse, such as tobacco and Areca Nut, amongst others. There is considerable evidence that oral lesions/disorders such as some leukoplakias, most erythroplakias, and submucous fibrosis have malignant potential, with a conversion rate of 5%-10% over a 10-year period. There have been several reports on possible biomarkers that predict malignant conversion of the oral lesions associated with these disorders. Management of these is mostly surgical removal of the lesion followed by observation, and in some cases treatment by antioxidants and anti-inflammatory agents. Oral submucous fibrosis is due to excessive deposition of extracellular matrix in the connective tissue plus, particularly, collagens. The deposition of collagen leads to stiffness of the affected regions and results in difficulty in mouth opening. Areca Nut chewing is proposed as the most probable etiological factor in the manifestation of oral submucous fibrosis. Several studies suggest involvement of proinflammatory cytokines, dysregulated by Areca Nut, in the development of the disease. Amongst these, transforming growth factor-β is in the forefront, which is also shown to be involved in fibrosis of other organs. This review addresses the molecular mechanisms involved in oral submucous fibrosis development and provides a model for the regulation of transforming growth factor-β by Areca Nut. It provides an exemplar of the role of modern molecular techniques in the study of oral disease.

  • role of Areca Nut induced jnk atf2 jun axis in the activation of tgf β pathway in precancerous oral submucous fibrosis
    Scientific Reports, 2016
    Co-Authors: Ila Pant, Girish S Rao, Paturu Kondaiah
    Abstract:

    Oral submucous fibrosis (OSF) is potentially premalignant with progressive and irreversible extracellular matrix deposition accompanied by epithelial atrophy and like other fibrotic disorders, is primarily a TGF-β driven disease. OSF is caused by prolonged chewing of Areca Nut. Our previous studies reported a pivotal role for TGF-β activation and its effects contributing to OSF. However, the mechanism for activation of TGF-β signaling in OSF is still unknown. In this study we demonstrate activation of TGF-β signaling with sub-cytotoxic dose of Areca Nut in epithelial cells and discovered a key role for pJNK in this process. In good correlation; pJNK was detected in OSF tissues but not in normal tissues. Moreover, activation of JNK was found to be dependent on muscarinic acid receptor induced Ca2+/CAMKII as well as ROS. JNK dependent phosphorylation of ATF2/c-Jun transcription factors resulted in TGF-β transcription and its signaling. pATF2/p-c-Jun were enriched on TGF-β promoter and co-localized in nuclei of epithelial cells upon Areca Nut treatment. In corroboration, OSF tissue sections also had nuclear pATF2 and p-c-Jun. Our results provide comprehensive mechanistic details of TGF-β signaling induced by etiological agent Areca Nut in the manifestation of fibrosis which can lead to new therapeutic modalities for OSF.

  • Activation of TGF-b Pathway by Areca Nut Constituents: A Possible Cause of Oral Submucous Fibrosis
    2016
    Co-Authors: Imran Khan, Neeraj Kumar, Ila Pant, Sivakrishna Narra, Paturu Kondaiah
    Abstract:

    Oral submucous fibrosis (OSF) is a chronic inflammatory disease characterized by the accumulation of excess collagen, and Areca Nut chewing has been proposed as an important etiological factor for disease manifestation. Activation of transforming growth factor-b signaling has been postulated as the main causative event for increased collagen production in OSF. Oral epithelium plays important roles in OSF, and arecoline has been shown to induce TGF-b in epithelial cells. In an attempt to understand the role of Areca Nut constituents in the manifestation of OSF, we studied the global gene expression profile in epithelial cells (HaCaT) following treatment with Areca Nut water extract or TGF-b. Interestingly, 64 % of the differentially regulated genes by Areca Nut water extract matches with the TGF-b induced gene expression profile. Out of these, expression of 57 % of genes was compromised in the presence of ALK5 (TbRI) inhibitor and 7 % were independently induced by Areca Nut, highlighting the importance of TGF-b in Areca Nut actions. Areca Nut water extract treatment induced p-SMAD2 and TGF-b downstream targets in HaCaT cells but not in human gingival fibroblast cells (hGF), suggesting epithelial cells could be the source of TGF-b in promoting OSF. Water extract of Areca Nut consists of polyphenols and alkaloids. Both polyphenol and alkaloid fractions of Areca Nut were able to induce TGF-b signaling and its downstream targets. Also, SMAD-2 was phosphorylated following treatment of HaCaT cells by Catechin, Tannin and alkaloids namely Arecoline, Arecaidine and Guvacine. Moreover, both polyphenols and alkaloids induced TGF-b2 and THBS1 (activator o

  • epithelial atrophy in oral submucous fibrosis is mediated by copper ii and arecoline of Areca Nut
    Journal of Cellular and Molecular Medicine, 2015
    Co-Authors: Imran Khan, Ila Pant, Sivakrishna Narra, Somanahalli Girish Rao, Rekha Radhesh, K Ranganathan, Paturu Kondaiah
    Abstract:

    Exposure of oral cavity to Areca Nut is associated with several pathological conditions including oral submucous fibrosis (OSF). Histopathologically OSF is characterized by epithelial atrophy, chronic inflammation, juxtaepithelial hyalinization, leading to fibrosis of submucosal tissue and affects 0.5% of the population in the Indian subcontinent. As the molecular mechanisms leading to atrophied epithelium and fibrosis are poorly understood, we studied Areca Nut actions on human keratinocyte and gingival fibroblast cells. Areca Nut water extract (ANW) was cytotoxic to epithelial cells and had a pro-proliferative effect on fibroblasts. This opposite effect of ANW on epithelial and fibroblast cells was intriguing but reflects the OSF histopathology such as epithelial atrophy and proliferation of fibroblasts. We demonstrate that the pro-proliferative effects of ANW on fibroblasts are dependent on insulin-like growth factor signalling while the cytotoxic effects on keratinocytes are dependent on the generation of reactive oxygen species. Treatment of keratinocytes with arecoline which is a component of ANW along with copper resulted in enhanced cytotoxicity which becomes comparable to IC50 of ANW. Furthermore, studies using cyclic voltammetry, mass spectrometry and plasmid cleavage assay suggested that the presence of arecoline increases oxidation reduction potential of copper leading to enhanced cleavage of DNA which could generate an apoptotic response. Terminal deoxynucleotidyl transferase dUTP Nick End Labeling assay and Ki-67 index of OSF tissue sections suggested epithelial apoptosis, which could be responsible for the atrophy of OSF epithelium.

  • role of Areca Nut induced tgf β and epithelial mesenchymal interaction in the pathogenesis of oral submucous fibrosis
    PLOS ONE, 2015
    Co-Authors: Ila Pant, Imran Khan, Neeraj Kumar, Somanahalli Girish Rao, Paturu Kondaiah
    Abstract:

    Areca Nut consumption has been implicated in the progression of Oral Submucous fibrosis (OSF); an inflammatory precancerous fibrotic condition. Our previous studies have demonstrated the activation of TGF-β signaling in epithelial cells by Areca Nut components and also propose a role for epithelial expressed TGF-β in the pathogenesis of OSF. Although the importance of epithelial cells in the manifestation of OSF has been proposed, the actual effectors are fibroblast cells. However, the role of Areca Nut and TGF-β in the context of fibroblast response has not been elucidated. Therefore, to understand their role in the context of fibroblast response in OSF pathogenesis, human gingival fibroblasts (hGF) were treated with Areca Nut and/or TGF-β followed by transcriptome profiling. The gene expression profile obtained was compared with the previously published transcriptome profiles of OSF tissues and Areca Nut treated epithelial cells. The analysis revealed regulation of 4666 and 1214 genes by Areca Nut and TGF-β treatment respectively. The expression of 413 genes in hGF cells was potentiated by Areca Nut and TGF-β together. Further, the differentially expressed genes of OSF tissues compared to normal tissues overlapped significantly with Areca Nut and TGF-β induced genes in epithelial and hGF cells. Several positively enriched pathways were found to be common between OSF tissues and Areca Nut +TGF-β treated hGF cells. In concordance, Areca Nut along with TGF-β enhanced fibroblast activation as demonstrated by potentiation of αSMA, γSMA and collagen gel contraction by hGF cells. Furthermore, TGF-β secreted by Areca Nut treated epithelial cells influenced fibroblast activation and other genes implicated in fibrosis. These data establish a role for Areca Nut influenced epithelial cells in OSF progression by activation of fibroblasts and emphasizes the importance of epithelial-mesenchymal interaction in OSF.