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      Cynarin attenuates LPS-induced endothelial inflammation via upregulation of the negative regulator MKP-3


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          Clinical observations have revealed that non-resolving low-grade inflammation is linked to the pathogenesis of chronic inflammatory diseases, for example arthritis, atherosclerosis, Alzheimer’s disease, diabetes, and chronic kidney disease. Interestingly, low levels of circulating lipopolysaccharides (LPS) derived from the outer membrane of gram-negative bacteria appear to be one of the primary causes of persistent low-grade inflammation. The inner surface of the blood vessels is lined with endothelial cells; therefore, even low levels of circulating LPS can directly activate these cells and elicit specific cellular responses, such as an increase in the expression levels of cell adhesion molecules and proinflammatory mediators. In endothelial cells, LPS exposure results in an inflammatory response through activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases. Cynarin, a phytochemical found in artichokes, has several pharmacological properties against endothelial inflammation. In the present study, we discovered that cynarin suppressed the LPS-induced increase in the expression levels of vascular cell adhesion molecule-1 and proinflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), and interleukin-1β in EA.hy926 cells. Further, cynarin inhibited the activation of p38 and NF-κB pathways by inducing the negative regulator mitogen-activated protein kinase phosphatase 3 (MKP-3) in LPS-stimulated EA.hy926 cells. In conclusion, cynarin alleviates inflammation by upregulating MKP-3, a negative regulator of p38 and NF-κB, and it may be a therapeutic option for treating endothelial inflammation-related diseases.

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          Most cited references58

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          Low-grade inflammation, diet composition and health: current research evidence and its translation

          The importance of chronic low-grade inflammation in the pathology of numerous age-related chronic conditions is now clear. An unresolved inflammatory response is likely to be involved from the early stages of disease development. The present position paper is the most recent in a series produced by the International Life Sciences Institute's European Branch (ILSI Europe). It is co-authored by the speakers from a 2013 workshop led by the Obesity and Diabetes Task Force entitled ‘Low-grade inflammation, a high-grade challenge: biomarkers and modulation by dietary strategies’. The latest research in the areas of acute and chronic inflammation and cardiometabolic, gut and cognitive health is presented along with the cellular and molecular mechanisms underlying inflammation–health/disease associations. The evidence relating diet composition and early-life nutrition to inflammatory status is reviewed. Human epidemiological and intervention data are thus far heavily reliant on the measurement of inflammatory markers in the circulation, and in particular cytokines in the fasting state, which are recognised as an insensitive and highly variable index of tissue inflammation. Potential novel kinetic and integrated approaches to capture inflammatory status in humans are discussed. Such approaches are likely to provide a more discriminating means of quantifying inflammation–health/disease associations, and the ability of diet to positively modulate inflammation and provide the much needed evidence to develop research portfolios that will inform new product development and associated health claims.
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            Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity.

            NF-kappaB (nuclear factor-kappaB) is a collective name for inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif. NF-kappaB is found in essentially all cell types and is involved in activation of an exceptionally large number of genes in response to infections, inflammation, and other stressful situations requiring rapid reprogramming of gene expression. NF-kappaB is normally sequestered in the cytoplasm of nonstimulated cells and consequently must be translocated into the nucleus to function. The subcellular location of NF-kappaB is controlled by a family of inhibitory proteins, IkappaBs, which bind NF-kappaB and mask its nuclear localization signal, thereby preventing nuclear uptake. Exposure of cells to a variety of extracellular stimuli leads to the rapid phosphorylation, ubiquitination, and ultimately proteolytic degradation of IkappaB, which frees NF-kappaB to translocate to the nucleus where it regulates gene transcription. NF-kappaB activation represents a paradigm for controlling the function of a regulatory protein via ubiquitination-dependent proteolysis, as an integral part of a phosphorylationbased signaling cascade. Recently, considerable progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1. The multisubunit IkappaB kinase (IKK) responsible for inducible IkappaB phosphorylation is the point of convergence for most NF-kappaB-activating stimuli. IKK contains two catalytic subunits, IKKalpha and IKKbeta, both of which are able to correctly phosphorylate IkappaB. Gene knockout studies have shed light on the very different physiological functions of IKKalpha and IKKbeta. After phosphorylation, the IKK phosphoacceptor sites on IkappaB serve as an essential part of a specific recognition site for E3RS(IkappaB/beta-TrCP), an SCF-type E3 ubiquitin ligase, thereby explaining how IKK controls IkappaB ubiquitination and degradation. A variety of other signaling events, including phosphorylation of NF-kappaB, hyperphosphorylation of IKK, induction of IkappaB synthesis, and the processing of NF-kappaB precursors, provide additional mechanisms that modulate the level and duration of NF-kappaB activity.
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              Endotoxemia and gut barrier dysfunction in alcoholic liver disease.

              R K Rao (2009)

                Author and article information

                Anim Cells Syst (Seoul)
                Anim Cells Syst (Seoul)
                Animal Cells and Systems
                Taylor & Francis
                20 May 2022
                20 May 2022
                : 26
                : 3
                : 119-128
                [a ]Department of Molecular Medicine, College of Medicine, Inha University , Incheon, Republic of Korea
                [b ]Program in Biomedical Science and Engineering, College of Medicine, Inha University , Incheon, Republic of Korea
                [c ]Yongsan International School of Seoul, Seoul, Republic of Korea
                [d ]Department of Biomedical Sciences, College of Medicine, Inha University , Incheon, Republic of Korea
                Author notes
                [CONTACT ] Seung-Woo Kim swkim1@ 123456inha.ac.kr Department of Biomedical Sciences, College of Medicine, Inha University , Incheon 22212, Republic of Korea
                Hong Seok Kim kimhs0622@ 123456inha.ac.kr Department of Molecular Medicine, College of Medicine, Inha University , Incheon 22212, Republic of Korea

                Da Bin Kim and Banzragchgarav Unenkhuu contributed equally to this work.

                © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 6, Tables: 1, Equations: 0, References: 58, Pages: 10
                Signaling & Biomolecules
                Research Article

                cynarin,endotoxin,endothelial inflammation,mkp-3
                cynarin, endotoxin, endothelial inflammation, mkp-3


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