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      Effects of resveratrol on Th17 cell-related immune responses under tacrolimus-based immunosuppression

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          Abstract

          Background

          We previously reported that tacrolimus (Tac) does not decrease T helper 17 cells (Th17) response in kidney transplantation. In this study, we evaluated whether Resveratrol (Resv) has immunosuppressive effects by decreasing Th17 responses in Tac-based immunosuppression.

          Methods

          We investigated the effects of Resv under Tac-treatment conditions, on CD4 + T cell differentiation to Th17 cells in peripheral blood mononuclear cells (PBMCs), and proliferation of CD4 + T cells co-cultured with human renal proximal tubular epithelial cells (HRPTEpiCs). The effects of Resv on Th17 cells were tested in the murine skin transplant model.

          Results

          In PBMCs, Tac did not but combination of Tac and Resv further suppressed Th17 immune response. In the co-culture study, combination of Resv to Tac significantly decreased HRPTEpiC-induced T cell proliferation compared to Tac alone. Resv treatment in the Jurkat cell induced the expression of AMP-activated protein kinase and suppressed the expression of mammalian target of rapamycin (mTOR), suggesting blocking Th17 pathway by Resv. In the murine skin transplant model, combination of Resv to Tac significantly prolonged skin graft survival accompanied by the suppression of Th17 cells, compared to either the Tac-alone or control groups.

          Conclusion

          The results of our study suggest that Resv provides additional immunosuppressive effects to Tac by suppressing effector CD4 + T cells, especially Th17 cells, in the transplantation setting .

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          Most cited references42

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          Immunosuppressive drugs for kidney transplantation.

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            Plant foods and herbal sources of resveratrol.

            Stilbenes, in particular trans-resveratrol and its glucoside, are widely reported to be beneficial to health, having been shown to possess antioxidative, anticarcinogenic, and antitumor properties. Major dietary sources include grapes, wine, peanuts, and soy; however, they can also be introduced into the diet through Itadori tea, which has long been used in Japan and China as a traditional herbal remedy for heart disease and strokes. Analysis of grapes, peanuts, and Itadori tea shows that they contain mainly trans-resveratrol glucoside. In contrast, red wines are primarily a source of the aglycones cis- and trans-resveratrol. While peanuts and grapes contain low levels of the stilbenes, Itadori tea and red wine both supply relatively high concentrations of resveratrol. For people who do not consume alcohol, Itadori tea may be a suitable substitute for red wine. However, further study on the potential biological effects of other endogenous compounds in Itadori tea is required and there is also a need for more information on the absorption and in vivo biomedical actions of free and conjugated resveratrol.
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              AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism.

              Alzheimer disease is an age-related neurodegenerative disorder characterized by amyloid-beta (Abeta) peptide deposition into cerebral amyloid plaques. The natural polyphenol resveratrol promotes anti-aging pathways via the activation of several metabolic sensors, including the AMP-activated protein kinase (AMPK). Resveratrol also lowers Abeta levels in cell lines; however, the underlying mechanism responsible for this effect is largely unknown. Moreover, the bioavailability of resveratrol in the brain remains uncertain. Here we show that AMPK signaling controls Abeta metabolism and mediates the anti-amyloidogenic effect of resveratrol in non-neuronal and neuronal cells, including in mouse primary neurons. Resveratrol increased cytosolic calcium levels and promoted AMPK activation by the calcium/calmodulin-dependent protein kinase kinase-beta. Direct pharmacological and genetic activation of AMPK lowered extracellular Abeta accumulation, whereas AMPK inhibition reduced the effect of resveratrol on Abeta levels. Furthermore, resveratrol inhibited the AMPK target mTOR (mammalian target of rapamycin) to trigger autophagy and lysosomal degradation of Abeta. Finally, orally administered resveratrol in mice was detected in the brain where it activated AMPK and reduced cerebral Abeta levels and deposition in the cortex. These data suggest that resveratrol and pharmacological activation of AMPK have therapeutic potential against Alzheimer disease.
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                Author and article information

                Contributors
                kchan87@catholic.ac.kr
                bbom87@catholic.ac.kr
                woon1212@catholic.ac.kr
                Chungbh@catholic.ac.kr
                +82-2-2258-6037 , yangch@catholic.ac.kr
                Journal
                BMC Complement Altern Med
                BMC Complement Altern Med
                BMC Complementary and Alternative Medicine
                BioMed Central (London )
                1472-6882
                4 March 2019
                4 March 2019
                2019
                : 19
                : 54
                Affiliations
                [1 ]ISNI 0000 0004 0470 4224, GRID grid.411947.e, Convergent Research Consortium for Immunologic disease, , St. Mary’s Hospital, The Catholic University of Korea, ; Seoul, South Korea
                [2 ]ISNI 0000 0004 0470 4224, GRID grid.411947.e, Transplant research center, , St. Mary’s Hospital, The Catholic University of Korea, ; Seoul, South Korea
                [3 ]ISNI 0000 0004 0470 4224, GRID grid.411947.e, Department of Internal Medicine, College of Medicine, , Seoul St. Mary’s Hospital, The Catholic University of Korea, ; Seoul, South Korea
                Author information
                http://orcid.org/0000-0001-9796-636X
                Article
                2464
                10.1186/s12906-019-2464-1
                6399827
                30832648
                cf1531ba-ac29-48e6-9446-b2367436adb5
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 31 August 2017
                : 25 February 2019
                Funding
                Funded by: the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea
                Award ID: HI13C1232
                Award Recipient :
                Funded by: the Korean Health Technology R&D Project, Ministry for Health & Welfare, Republic of Korea
                Award ID: HI14C3417
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                Complementary & Alternative medicine
                th17 cells,resveratrol,tacrolimus,ampk,mtor,organ transplantation
                Complementary & Alternative medicine
                th17 cells, resveratrol, tacrolimus, ampk, mtor, organ transplantation

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