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      High Glucose Level Disturbs the Resveratrol-Evoked Curtailment of CX3CL1/CX3CR1 Signaling in Human Placental Circulation

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          Abstract

          Hyperglycemia-induced hyperactivity of chemokine CX3CL1 (fractalkine) occurs in the human placenta. Anti-inflammatory/antioxidant activities of resveratrol (3,5,4′-trihydroxy- trans-stilbene) are related to the modulation of chemokine CX3CL1 and its receptor, CX3CR1, signaling pathways. We examined the influence of high glucose (25 mmol/L glucose; HG group; N = 36) on resveratrol-mediated effects on CX3CL1 and TNF- α production by the placental lobule, CX3CR1 expression and contents of CX3CR1, TNF- α receptor 1 (TNFR1), and NF- κB proteins in placental tissue. The placental lobules perfused under normoglycemic conditions formed the control NG group ( N = 36). Resveratrol (50 and 100  μM; subgroups B and C) administered into the perfusion fluid lowered the production of both CX3CL1 and TNF- α. The reductions in CX3CL1 levels were more evident in the NG group. CX3CR1 expression was significantly higher in the NG subgroups B and C compared to the HG subgroups B and C (385.2 and 426.5% versus 199.3 and 282.4%, resp.). An increase in CX3CR1 protein content in placental lysates was observed in the NG subgroups B and C. Also, resveratrol significantly decreased NF- κBp65 protein content only in the NG group, not affecting hyperglycemia-elicited TNFR1 upregulation. In conclusion, euglycemia assures optimal effects of resveratrol pertaining to CX3CL1/CX3CR1 signaling in the placenta. Future studies on resveratrol are needed, especially those including maternal-fetal risk assessments.

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          The complexity of NF-κB signaling in inflammation and cancer

          The NF-κB family of transcription factors has an essential role in inflammation and innate immunity. Furthermore, NF-κB is increasingly recognized as a crucial player in many steps of cancer initiation and progression. During these latter processes NF-κB cooperates with multiple other signaling molecules and pathways. Prominent nodes of crosstalk are mediated by other transcription factors such as STAT3 and p53 or the ETS related gene ERG. These transcription factors either directly interact with NF-κB subunits or affect NF-κB target genes. Crosstalk can also occur through different kinases, such as GSK3-β, p38, or PI3K, which modulate NF-κB transcriptional activity or affect upstream signaling pathways. Other classes of molecules that act as nodes of crosstalk are reactive oxygen species and miRNAs. In this review, we provide an overview of the most relevant modes of crosstalk and cooperativity between NF-κB and other signaling molecules during inflammation and cancer.
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            Signaling via the NFκB system.

            The nuclear factor kappa B (NFκB) family of transcription factors is a key regulator of immune development, immune responses, inflammation, and cancer. The NFκB signaling system (defined by the interactions between NFκB dimers, IκB regulators, and IKK complexes) is responsive to a number of stimuli, and upon ligand-receptor engagement, distinct cellular outcomes, appropriate to the specific signal received, are set into motion. After almost three decades of study, many signaling mechanisms are well understood, rendering them amenable to mathematical modeling, which can reveal deeper insights about the regulatory design principles. While other reviews have focused on upstream, receptor proximal signaling (Hayden MS, Ghosh S. Signaling to NF-κB. Genes Dev 2004, 18:2195-2224; Verstrepen L, Bekaert T, Chau TL, Tavernier J, Chariot A, Beyaert R. TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme. Cell Mol Life Sci 2008, 65:2964-2978), and advances through computational modeling (Basak S, Behar M, Hoffmann A. Lessons from mathematically modeling the NF-κB pathway. Immunol Rev 2012, 246:221-238; Williams R, Timmis J, Qwarnstrom E. Computational models of the NF-KB signalling pathway. Computation 2014, 2:131), in this review we aim to summarize the current understanding of the NFκB signaling system itself, the molecular mechanisms, and systems properties that are key to its diverse biological functions, and we discuss remaining questions in the field. WIREs Syst Biol Med 2016, 8:227-241. doi: 10.1002/wsbm.1331 For further resources related to this article, please visit the WIREs website.
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              Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases.

              Diabetes mellitus is associated to an increased risk of cardiovascular diseases. Hyperglycemia is an important factor in cardiovascular damage, working through different mechanisms such as activation of protein kinase C, polyol and hexosamine pathways, advanced glycation end products production. All of these pathways, in association to hyperglycemia-induced mitochondrial dysfunction and endoplasmic reticulum stress, promote reactive oxygen species (ROS) accumulation that, in turn, promote cellular damage and contribute to the diabetic complications development and progression. ROS can directly damage lipids, proteins or DNA and modulate intracellular signaling pathways, such as mitogen activated protein kinases and redox sensitive transcription factors causing changes in protein expression and, therefore, irreversible oxidative modifications. Hyperglycemia-induced oxidative stress induces endothelial dysfunction that plays a central role in the pathogenesis of micro- and macro-vascular diseases. It may also increase pro-inflammatory and pro-coagulant factors expression, induce apoptosis and impair nitric oxide release. Oxidative stress induces several phenotypic alterations also in vascular smooth-muscle cell (VSMC). ROS is one of the factors that can promote both VSMC proliferation/migration in atherosclerotic lesions and VSMC apoptosis, which is potentially involved in atherosclerotic plaque instability and rupture. Currently, there are contrasting clinical evidences on the benefits of antioxidant therapies in the prevention/treatment of diabetic cardiovascular complications. Appropriate glycemic control, in which both hypoglycemic and hyperglycemic episodes are reduced, in association to the treatment of dyslipidemia, hypertension, kidney dysfunction and obesity, conditions which are also associated to ROS overproduction, can counteract oxidative stress and, therefore, both microvascular and macrovascular complications of diabetes mellitus.
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                Author and article information

                Journal
                Mediators Inflamm
                Mediators Inflamm
                MI
                Mediators of Inflammation
                Hindawi
                0962-9351
                1466-1861
                2017
                1 June 2017
                : 2017
                : 9853108
                Affiliations
                1Department of General & Experimental Pathology with Centre for Preclinical Research and Technology (CEPT), Second Faculty of Medicine, Medical University of Warsaw, ul. Pawinskiego 3C, 02-106 Warsaw, Poland
                2Department of Obstetrics & Gynecology, Second Faculty of Medicine, Medical University of Warsaw, ul. Kondratowicza 8, 03-242 Warsaw, Poland
                3Department of Cardiology, Hypertension, and Internal Medicine, Second Faculty of Medicine, Medical University of Warsaw, ul. Kondratowicza 8, 03-242 Warsaw, Poland
                4Department of Pathology, Professor Witold Orlowski Public Clinical Hospital, Medical Center for Postgraduate Education, ul. Czerniakowska 231, 00-416 Warsaw, Poland
                Author notes

                Academic Editor: Julio Galvez

                Author information
                http://orcid.org/0000-0002-0124-060X
                http://orcid.org/0000-0003-4143-2777
                http://orcid.org/0000-0001-9601-990X
                http://orcid.org/0000-0003-0659-7322
                Article
                10.1155/2017/9853108
                5471565
                28655972
                f2bc6d14-9dfd-444e-b67b-eac54ac50578
                Copyright © 2017 Dariusz Szukiewicz et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 1 February 2017
                : 1 April 2017
                : 26 April 2017
                Funding
                Funded by: Medical University of Warsaw
                Award ID: 2M2/N1/15
                Award ID: 2M2/W1/14
                Categories
                Research Article

                Immunology
                Immunology

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