| 1. |
- Anagnostopoulos, George, et al.
(författare)
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Strain Engineering in Highly Wrinkled CVD Graphene/Epoxy Systems
- 2018
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Ingår i: ACS Applied Materials & Interfaces. - : American Chemical Society (ACS). - 1944-8252 .- 1944-8244. ; 10:49, s. 43192-43202
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Tidskriftsartikel (refereegranskat)abstract
- Chemical vapor deposition (CVD) is regarded as a promising fabrication method for the automated, large-scale, production of graphene and other two-dimensional materials. However, its full commercial exploitation is limited by the presence of structural imperfections such as folds, wrinkles, and even cracks that downgrade its physical and mechanical properties. For example, as shown here by means of Raman spectroscopy, the stress transfer from an epoxy matrix to CVD graphene is on average 30% of that of exfoliated monolayer graphene of over 10 μm in dimensions. However, in terms of electrical response, the situation is reversed; the resistance has been found here to decrease by the imposition of mechanical deformation possibly due to the opening up of the structure and the associated increase of electron mobility. This finding paves the way for employing CVD graphene/epoxy composites or coatings as conductive "networks" or bridges in cases for which the conductivity needs to be increased or at least retained when the system is under deformation. The tuning/control of such systems and their operative limitations are discussed here.
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| 2. |
- Forteza, Maria J., et al.
(författare)
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Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk
- 2023
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Ingår i: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 119:7, s. 1524-1536
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies have revealed a close connection between cellular metabolism and the chronic inflammatory process of atherosclerosis. While the link between systemic metabolism and atherosclerosis is well established, the implications of altered metabolism in the artery wall are less understood. Pyruvate dehydrogenase kinase (PDK)-dependent inhibition of pyruvate dehydrogenase (PDH) has been identified as a major metabolic step regulating inflammation. Whether the PDK/PDH axis plays a role in vascular inflammation and atherosclerotic cardiovascular disease remains unclear. Methods and results Gene profiling of human atherosclerotic plaques revealed a strong correlation between PDK1 and PDK4 transcript levels and the expression of pro-inflammatory and destabilizing genes. Remarkably, the PDK1 and PDK4 expression correlated with a more vulnerable plaque phenotype, and PDK1 expression was found to predict future major adverse cardiovascular events. Using the small-molecule PDK inhibitor dichloroacetate (DCA) that restores arterial PDH activity, we demonstrated that the PDK/PDH axis is a major immunometabolic pathway, regulating immune cell polarization, plaque development, and fibrous cap formation in Apoe−/− mice. Surprisingly, we discovered that DCA regulates succinate release and mitigates its GPR91-dependent signals promoting NLRP3 inflammasome activation and IL-1β secretion by macrophages in the plaque. Conclusions We have demonstrated for the first time that the PDK/PDH axis is associated with vascular inflammation in humans and particularly that the PDK1 isozyme is associated with more severe disease and could predict secondary cardiovascular events. Moreover, we demonstrate that targeting the PDK/PDH axis with DCA skews the immune system, inhibits vascular inflammation and atherogenesis, and promotes plaque stability features in Apoe−/− mice. These results point toward a promising treatment to combat atherosclerosis.
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| 3. |
- Polyzos, Konstantinos A
(författare)
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The interplay between lipoproteins, immunity and tryptophan metabolism in atherosclerosis
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atherosclerotic cardiovascular disease (CVD) is the leading cause of mortality worldwide. Atherosclerosis is initiated by the infiltration and accumulation of low-density lipoprotein (LDL) cholesterol in the vascular wall, which activates the innate and adaptive arm of immunity, thereby causing chronic vascular inflammation. The LDL particle is immunogenic, as it not only activates lesional macrophages but is also recognized by T cells, and it elicits B cell-mediated antibody responses. Animal immunization studies suggest that anti-LDL antibodies inhibit atherosclerosis, but concerns exist about the potential proinflammatory role of lesional LDL-reactive T cells. In addition to lipoproteins, amino acids and their metabolites can shape immune cell responses, which has been the subject of intense research in the emerging field of immunometabolism. Current clinical practice guidelines on the prevention of CVD focus on controlling traditional risk factors, such as hypercholesterolemia, which indirectly influence inflammation in the vascular wall. Despite optimal management, however, residual inflammatory risk persists and underscores the need for novel therapeutics that directly target vascular inflammation. In Paper I, we generated mouse strains bearing T cell receptor (TCR) transgenic T cells that react to human LDL. Adoptive transfer of these autoreactive T cells or the intercross of TCR transgenic mice with animals expressing human apolipoprotein B-100 (apoB100) on the LDL receptor−/− (LDLR−/−) background led to reduced vascular inflammation and atherosclerosis. Interestingly, a significant proportion of LDL-reactive T cells differentiated into T follicular helper cells, which helped B cells produce anti-LDL antibodies that formed immune complexes with circulating LDL, thereby reducing plasma cholesterol. In Paper II, we employed dendritic cell (DC) based immunotherapy in an attempt to induce apoB100-specific regulatory T (Treg) cells that can exert anti-inflammatory functions in developing plaques. The vaccine was prepared using bone marrow-derived DCs, which were loaded with apoB100 in the presence of the anti-inflammatory cytokine transforming growth factor beta 2 (TGF-β2). Immunotherapy with these DCs promoted an immune response to apoB100 that favoured the accumulation of Treg cells in atherosclerotic plaques, increased vascular expression of the immunomodulatory enzyme indoleamine 2,3-dioxygenase 1 (IDO1), and ameliorated atherosclerosis. In vitro experiments suggested that the Treg molecule cytotoxic T- lymphocyte–associated antigen-4 (CTLA-4) regulates IDO1 expression in macrophages and vascular cells. In Paper III, we studied the role of IDO1-mediated tryptophan metabolism in atherosclerosis using an inhibitor of IDO1 enzyme, 1-methyl-tryptophan. In vivo and in vitro data indicated that IDO1 regulates vascular inflammation, particularly in smooth muscle cells, and inhibits atherosclerosis possibly via the generation of the metabolite 3-hydroxyanthranilic acid (3- HAA). In Paper IV, we investigated the effects of increased endogenous 3-HAA levels on plasma lipids and atherosclerosis using an inhibitor of the enzyme 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO). Our data suggested that 3-HAA can lower plasma lipids via inhibition of the sterol regulatory element binding protein-2 (SREBP-2) pathway in hepatocytes and suppress inflammation via inhibition of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in macrophages. The studies included in the present thesis illustrate the intricate interplay between metabolism and immunity in atherosclerosis. It is my belief that our findings will contribute to the development of effective immunomodulatory strategies directly targeting vascular inflammation and addressing the residual inflammatory cardiovascular risk.
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