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      Piperlongumine Acts as an Immunosuppressant by Exerting Prooxidative Effects in Human T Cells Resulting in Diminished T H17 but Enhanced T reg Differentiation

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          Abstract

          Piperlongumine (PL), a natural small molecule derived from the Piper longum Linn plant, has received growing interest as a prooxidative drug with promising anticancer properties. Yet, the influence of PL on primary human T cells remained elusive. Knowledge of this is of crucial importance, however, since T cells in particular play a critical role in tumor control. Therefore, we investigated the effects of PL on the survival and function of primary human peripheral blood T cells (PBTs). While PL was not cytotoxic to PBTs, it interfered with several stages of T cell activation as it inhibited T cell/APC immune synapse formation, co-stimulation-induced upregulation of CD69 and CD25, T cell proliferation and the secretion of proinflammatory cytokines. PL-induced immune suppression was prevented in the presence of thiol-containing antioxidants. In line with this finding, PL increased the levels of intracellular reactive oxygen species and decreased glutathione in PBTs. Diminished intracellular glutathione was accompanied by a decrease in S-glutathionylation on actin suggesting a global alteration of the antioxidant response. Gene expression analysis demonstrated that T H17-related genes were predominantly inhibited by PL. Consistently, the polarization of primary human naïve CD4 + T cells into T H17 subsets was significantly diminished while differentiation into T reg cells was substantially increased upon PL treatment. This opposed consequence for T H17 and T reg cells was again abolished by thiol-containing antioxidants. Taken together, PL may act as a promising agent for therapeutic immunosuppression by exerting prooxidative effects in human T cells resulting in a diminished T H17 but enhanced T reg cell differentiation.

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          Most cited references52

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          Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation.

          Activation of CD4+ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4+ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4+ T cell populations in murine models and determined that inflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and require mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed that pyruvate dehydrogenase (PDH) is a key bifurcation point between T cell glycolytic and oxidative metabolism. PDH function is inhibited by PDH kinases (PDHKs). PDHK1 was expressed in Th17 cells, but not Th1 cells, and at low levels in Tregs, and inhibition or knockdown of PDHK1 selectively suppressed Th17 cells and increased Tregs. This alteration in the CD4+ T cell populations was mediated in part through ROS, as N-acetyl cysteine (NAC) treatment restored Th17 cell generation. Moreover, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis, decreasing Th17 cells and increasing Tregs. Together, these data show that CD4+ subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases.
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            Platform-independent and Label-free Quantitation of Proteomic Data Using MS1 Extracted Ion Chromatograms in Skyline

            Despite advances in metabolic and postmetabolic labeling methods for quantitative proteomics, there remains a need for improved label-free approaches. This need is particularly pressing for workflows that incorporate affinity enrichment at the peptide level, where isobaric chemical labels such as isobaric tags for relative and absolute quantitation and tandem mass tags may prove problematic or where stable isotope labeling with amino acids in cell culture labeling cannot be readily applied. Skyline is a freely available, open source software tool for quantitative data processing and proteomic analysis. We expanded the capabilities of Skyline to process ion intensity chromatograms of peptide analytes from full scan mass spectral data (MS1) acquired during HPLC MS/MS proteomic experiments. Moreover, unlike existing programs, Skyline MS1 filtering can be used with mass spectrometers from four major vendors, which allows results to be compared directly across laboratories. The new quantitative and graphical tools now available in Skyline specifically support interrogation of multiple acquisitions for MS1 filtering, including visual inspection of peak picking and both automated and manual integration, key features often lacking in existing software. In addition, Skyline MS1 filtering displays retention time indicators from underlying MS/MS data contained within the spectral library to ensure proper peak selection. The modular structure of Skyline also provides well defined, customizable data reports and thus allows users to directly connect to existing statistical programs for post hoc data analysis. To demonstrate the utility of the MS1 filtering approach, we have carried out experiments on several MS platforms and have specifically examined the performance of this method to quantify two important post-translational modifications: acetylation and phosphorylation, in peptide-centric affinity workflows of increasing complexity using mouse and human models.
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              Molecular mechanisms of N-acetylcysteine actions.

              Oxidative stress generated by an imbalance between reactive oxygen species (ROS) and antioxidants contributes to the pathogenesis of arthritis, cancer, cardiovascular, liver and respiratory diseases. Proinflammatory cytokines and growth factors stimulate ROS production as signaling mediators. Antioxidants such as N-acetylcysteine (NAC) have been used as tools for investigating the role of ROS in numerous biological and pathological processes. NAC inhibits activation of c-Jun N-terminal kinase, p38 MAP kinase and redox-sensitive activating protein-1 and nuclear factor kappa B transcription factor activities regulating expression of numerous genes. NAC can also prevent apoptosis and promote cell survival by activating extracellular signal-regulated kinase pathway, a concept useful for treating certain degenerative diseases. NAC directly modifies the activity of several proteins by its reducing activity. Despite its nonspecificity, ability to modify DNA and multiple molecular modes of action, NAC has therapeutic value for reducing endothelial dysfunction, inflammation, fibrosis, invasion, cartilage erosion, acetaminophen detoxification and transplant prolongation.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                12 June 2020
                2020
                : 11
                : 1172
                Affiliations
                [1] 1Section Molecular Immunology, Institute of Immunology, Heidelberg University , Heidelberg, Germany
                [2] 2Mass Spectrometry Core Facility, Center for Molecular Biology (ZMBH), Heidelberg University , Heidelberg, Germany
                [3] 3Division of Rheumatology, Department of Internal Medicine V, Heidelberg University , Heidelberg, Germany
                [4] 4Department of Human Molecular Genetics, Heidelberg University , Heidelberg, Germany
                [5] 5nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University , Heidelberg, Germany
                Author notes

                Edited by: Thomas Herrmann, Julius Maximilian University of Würzburg, Germany

                Reviewed by: Xin Chen, University of Macau, China; Bhalchandra Mirlekar, UNC School of Medicine, United States

                *Correspondence: Yvonne Samstag yvonne.samstag@ 123456urz.uni-heidelberg.de

                †Present address: Jie Liang, Department of Immunology, Medical College of Qingdao University, Qingdao, China

                This article was submitted to T Cell Biology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2020.01172
                7303365
                32595640
                c53ec39b-bcfe-4e67-94e9-4e75fa153f89
                Copyright © 2020 Liang, Ziegler, Jahraus, Orlik, Blatnik, Blank, Niesler, Wabnitz, Ruppert, Hübner, Balta and Samstag.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 18 January 2020
                : 12 May 2020
                Page count
                Figures: 7, Tables: 0, Equations: 0, References: 64, Pages: 18, Words: 12457
                Funding
                Funded by: Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg 10.13039/501100003542
                Funded by: China Scholarship Council 10.13039/501100004543
                Categories
                Immunology
                Original Research

                Immunology
                piperlongumine,primary human t cells,reactive oxygen species,glutathione,th17 cells,treg cells

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