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      Isogarcinol Is a New Immunosuppressant

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          Abstract

          Calcineurin (CN), a unique protein phosphatase, plays an important role in immune regulation. In this study we used CN as a target enzyme to investigate the immunosuppressive properties of a series of natural compounds from Garcinia mangostana L., and discovered an active compound, isogarcinol. Enzymatic assays showed that isogarcinol inhibited CN in a dose-dependent manner. At concentrations resulting in relatively low cytotoxicity isogarcinol significantly inhibited proliferation of murine spleen T-lymphocytes induced by concanavalin A (ConA) and the mixed lymphocyte reaction (MLR). In addition, it performed much better in acute toxicity tests and via oral administration in mice than cyclosporin A (CsA), with few adverse reactions and low toxicity in experimental animals. Oral administration of isogarcinol in mice resulted in a dose-dependent decrease in delayed type hypersensitivity (DTH) and prolonged graft survival in allogeneic skin transplantation. These findings suggest that isogarcinol could serve as a new oral immunomodulatory drug for preventing transplant rejection, and for long-term medication in autoimmune diseases.

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          Immunomodulatory and therapeutic properties of the Nigella sativa L. seed.

          Rany Salem (2005)
          A larger number of medicinal plants and their purified constituents have been shown beneficial therapeutic potentials. Seeds of Nigella sativa, a dicotyledon of the Ranunculaceae family, have been employed for thousands of years as a spice and food preservative. The oil and seed constituents, in particular thymoquinine (TQ), have shown potential medicinal properties in traditional medicine. In view of the recent literature, this article lists and discusses different immunomodulatory and immunotherapeutic potentials for the crude oil of N. sativa seeds and its active ingredients. The published findings provide clear evidence that both the oil and its active ingredients, in particular TQ, possess reproducible anti-oxidant effects through enhancing the oxidant scavenger system, which as a consequence lead to antitoxic effects induced by several insults. The oil and TQ have shown also potent anti-inflammatory effects on several inflammation-based models including experimental encephalomyelitis, colitis, peritonitis, oedama, and arthritis through suppression of the inflammatory mediators prostaglandins and leukotriens. The oil and certain active ingredients showed beneficial immunomodulatory properties, augmenting the T cell- and natural killer cell-mediated immune responses. Most importantly, both the oil and its active ingredients expressed anti-microbial and anti-tumor properties toward different microbes and cancers. Coupling these beneficial effects with its use in folk medicine, N. sativa seed is a promising source for active ingredients that would be with potential therapeutic modalities in different clinical settings. The efficacy of the active ingredients, however, should be measured by the nature of the disease. Given their potent immunomodulatory effects, further studies are urgently required to explore bystander effects of TQ on the professional antigen presenting cells, including macrophages and dendritic cells, as well as its modulatory effects upon Th1- and Th2-mediated inflammatory immune diseases. Ultimately, results emerging from such studies will substantially improve the immunotherapeutic application of TQ in clinical settings.
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            The mechanism of action of cyclosporin A and FK506.

            J Northrop, I Graef, N A Clipstone … (1996)
            The immunosuppressants cyclosporin A (CsA), FK506, and rapamycin suppress the immune response by inhibiting evolutionary conserved signal transduction pathways. CsA, FK506, and rapamycin bind to their intracellular receptors, immunophilins, creating composite surfaces that block the activity of specific targets. For CsA/cyclophilin and FK506/FKBP the target is calcineurin. Because of the large surface area of interaction of the drug-immunophilin complex with calcineurin, FK506 and CsA have a specificity for their biologic targets that is equivalent to growth factor-receptor interactions. To date, all the therapeutic as well as toxic effects of these drugs have been shown to be due to inhibition of calcineurin. Inhibition of the action of calcineurin results in a complete block in the translocation of the cytosolic component of the nuclear factor of activated T cells (NF-AT), resulting in a failure to activate the genes regulated by the NF-AT transcription factor. These genes include those required for B-cell help such as interleukin (IL-4) and CD40 ligand as well as those necessary for T-cell proliferation such as IL-2. The purpose of this article is to illustrate the means by which these drugs produce immunosuppression.
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              Specific inhibition of p300-HAT alters global gene expression and represses HIV replication.

              K. Mantelingu, B. Reddy, V. Swaminathan … (2007)
              Reversible acetylation of histone and nonhistone proteins plays pivotal role in cellular homeostasis. Dysfunction of histone acetyltransferases (HATs) leads to several diseases including cancer, neurodegenaration, asthma, diabetes, AIDS, and cardiac hypertrophy. We describe the synthesis and characterization of a set of p300-HAT-specific small-molecule inhibitors from a natural nonspecific HAT inhibitor, garcinol, which is highly toxic to cells. We show that the specific inhibitor selectively represses the p300-mediated acetylation of p53 in vivo. Furthermore, inhibition of p300-HAT down regulates several genes but significantly a few important genes are also upregulated. Remarkably, these inhibitors were found to be nontoxic to T cells, inhibit histone acetylation of HIV infected cells, and consequently inhibit the multiplication of HIV.
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                Author and article information

                Contributors
                David L. McCormick: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2013
                Publication date (Electronic): 13 June 2013
                Volume: 8
                Issue: 6
                Electronic Location Identifier: e66503
                Affiliations
                [1 ]Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology Beijing Key Laboratory, Beijing, P. R. of China
                [2 ]Province and Ministry Established Key Laboratory of Resource and Complex Prescription of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, P. R. of China
                IIT Research Institute, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JRC QW. Performed the experiments: JRC MSS YXF HLZ MQW. Analyzed the data: JRC ZYS. Contributed reagents/materials/analysis tools: MSS YFY YXF HLZ. Wrote the paper: JRC QW.

                Article
                Publisher ID: PONE-D-13-03963
                DOI: 10.1371/journal.pone.0066503
                PMC ID: 3681756
                PubMed ID: 23785505
                SO-VID: 88c70fa4-06c6-4ea8-9827-c501eb4c747c
                Copyright statement: Copyright @ 2013
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 22 January 2013
                Date accepted : 6 May 2013
                Page count
                Pages: 10
                Funding
                The work was supported by grants from the National Natural Science Foundation of China, the National Important Novel Medicine Research Project, the International Cooperation Project and the Fundamental Research Funds for the Central Universities. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Biochemistry
                Subject: Enzymes
                Subject: Enzyme Kinetics
                Subject: Drug Discovery
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Mouse
                Subject: Medicine
                Subject: Drugs and Devices
                Subject: Drug Research and Development
                Subject: Drug Discovery
                Subject: Pharmacokinetics
                Subject: Drug Metabolism

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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