Zinc enhances intestinal epithelial barrier function through the PI3K/AKT/mTOR signaling pathway in Caco-2 cells |
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| Affiliation: | 1. State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Yuanmingyuan West Road, Haidian District, Beijing, 100193, China;2. Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, 1207 W. Gregory Ave., Urbana, IL, 61801, USA;3. Department of Animal Sciences, University of Illinois at Urbana-Champaign, 1207 W. Gregory Ave., Urbana, IL, 61801, USA;4. Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1207 W. Gregory Ave., Urbana, IL, 61801, USA;1. Department of Oncological Radiotherapy, Affiliated Huai''an First Hospital, Nanjing Medical University, Huaian City, Jiangsu Province, PR China;2. Department of Gastrointestinal Surgery, Affiliated Huai''an First Hospital, Nanjing Medical University, Huaian City, Jiangsu Province, PR China;1. Institute of Immunological Engineering, Lyubuchany 142380, Moscow Region, Russia;2. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Ministry of Health, Moscow 117997, Russia;3. Skryabin Institute of Biochemistry and Physiology of Microorganisms, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Science”, Pushchino 142290, Moscow Region, Russia;4. Laboratory of Cell Immunity, Blokhin National Research, Center of Oncology Ministry of Health RF, Moscow 115478, Russia;5. NRC Institute of immunology FMBA of Russia, Moscow 115522, Russia;6. Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173-8610, Japan;7. Gabrichevsky Moscow Research Institute of Epidemiology and Microbiology, Federal Service for Supervision of Consumer Rights Protection and Human Welfare, Moscow 152212, Russia;8. Federal State Education Institution of Higher Professional Education Moscow State Academy of Veterinary Medicine and Biotechnology named after K.I. Skryabin, Moscow 109472, Russia;9. Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA;10. Department of Science, Engineering and Computing, Kingston University London, Kingston upon Thames KT1 2EE, UK |
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| Abstract: | Zinc plays an important role in maintaining intestinal barrier function as well as modulating cellular signaling recognition and protein kinase activities. The phosphatidylinositol 3-kinase (PI3K) cascade has been demonstrated to affect intercellular integrity and tight junction (TJ) proteins. The current study investigated the hypothesis that zinc regulates intestinal intercellular junction integrity through the PI3K/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. A transwell model of Caco-2 cell was incubated with 0, 50 and 100 μM of zinc at various time points. Transepithelial electrical resistance (TEER), paracellular permeability, TJ proteins, cell proliferation, differentiation and cell damage were measured. Compared with controls, 50 and 100 μM of zinc increased cell growth at 6, 12 and 24 h and the expression of proliferating cell nuclear antigen at 24 h. Zinc (100 μM) significantly elevated TEER at 6–24 h and reduced TJ permeability at 24 h, accompanied by the up-regulation of alkaline phosphatase (AP) activity and zonula occludens (ZO)-1 expression. In addition, zinc (100 μM) affected the PI3K/AKT/mTOR pathway by stimulating phosphorylation of AKT and the downstream target mTOR. Inhibition of PI3K signaling by LY294002 counteracted zinc promotion, as shown by a decrease in AP activity, TEER, the abundance of ZO-1 and phosphorylation of AKT and mTOR. Additionally, TJ permeability and the expression of caspase-3 and LC3II (markers of cell damage) were increased by addition of PI3K inhibitor. In conclusion, the activation of PI3K/AKT/mTOR signaling by zinc is involved in improving intestinal barrier function by enhancing cell differentiation and expression of TJ protein ZO-1. |
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