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Research Article

Activation of PI3K/Akt/NF-kB Signaling Mediates Swedish Snus Induced Proliferation and Apoptosis Evasion in the Rat Forestomach: Modulation by Blueberry

[ Vol. 20 , Issue. 1 ]

Author(s):

Singaraj Ranjani, Jaganathan Kowshik, Josephraj Sophia, Ramesh Nivetha, Abdul B. Baba, Veeran Veeravarmal, Gordana Joksić, Lars E. Rutqvist, Robert Nilsson and Siddavaram Nagini*   Pages 59 - 69 ( 11 )

Abstract:


Background and Objectives: The present study was undertaken to ascertain whether the modulatory effects of blueberries on cell proliferation induced by Swedish snus in the rat forestomach epithelium is mediated via abrogation of the PI3K/Akt/NFκB signaling axis that regulates cell fate decision.

Methods: The transcript and protein expression of genes involved in cell cycle progression and apoptosis, as well as canonical PI3K/Akt/NF-κB signaling pathways, were analyzed by qRT-PCR, immunoblotting and ELISA. Expression profiling of noncoding RNAs (ncRNAs) that influence PI3K/Akt/NF-κB signaling was undertaken. TUNEL assay was performed using flow cytometry.

Results: Administration of snus induced basal cell hyperplasia in the rat forestomach with increased cell proliferation and inhibition of apoptosis. This was associated with the activation of PI3K/Akt/NFκB signaling. Coadministration of blueberries significantly suppressed snus-induced hyperplasia. Analysis of the molecular mechanisms revealed that blueberries suppress the phosphorylation of Akt, NF-κB and IKKβ, prevent nuclear translocation of NF-κB and modulate the expression of microRNAs that influence PI3K/Akt/NF-κB signaling.

Conclusion: Taken together, the results of the current study provide compelling evidence that blueberries exert significant protective effects against snus-induced soft tissue changes in the rat forestomach epithelium mediated by inhibiting key molecular players in the PI3K/Akt/NF-κB signaling axis. Long-term studies on the impact of snus exposure on various cellular processes, signaling pathways, and the interplay between genetic and epigenetic mechanisms are however warranted. The results of this investigation may contribute to the development of protection against soft tissue changes induced by smokeless tobacco in the human oral cavity.

Keywords:

Apoptosis, blueberry, cell proliferation, forestomach, noncoding RNA, PI3K/Akt/NF-κB signalling, snus.

Affiliation:

Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, Division of Oral and Maxillofacial Pathology, Rajah Muthiah Dental College and Hospital, Annamalai University, Annamalainagar-608 002, Tamil Nadu, Vinca Institute of Nuclear Sciences, Laboratory for Physical Chemistry, University of Belgrade, Mike PetrovicaAlasa 12-14, Belgrade 11001, Swedish Match AB, Sveavägen 44, SE-11885, Stockholm, Vinca Institute of Nuclear Sciences, Laboratory for Physical Chemistry, University of Belgrade, Mike PetrovicaAlasa 12-14, Belgrade 11001, Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu

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