336 research outputs found
Lymphocytic tumor necrosis factor receptor superfamily co-stimulatory molecules in the pathogenesis of atherosclerosis
Purpose of reviewThe role of lymphocytes in the chronic inflammatory disease atherosclerosis has emerged over the past decade. Co-stimulatory molecules of the heterogeneous tumor necrosis factor receptor superfamily play a pivotal role in lymphocyte activation, proliferation and differentiation. Here we describe the immune modulatory properties and mechanisms of four tumor necrosis factor receptor superfamily members in atherosclerosis.Recent findingsCD40/CD40L, OX40L/OX40, CD70/CD27 and CD137/CD137L are present in human atherosclerotic plaques and have shown strong immune modulatory functions in atherosclerosis, resulting in either atherogenic or atheroprotective effects in mouse models of atherosclerosis.SummaryInsight into the immune modulatory mechanisms of co-stimulatory interactions in atherosclerosis can contribute to clinical exploitation of these interactions in the treatment of cardiovascular disease
2016 Jeffrey M. Hoeg Award Lecture: Immune Checkpoints in Atherosclerosis: Toward Immunotherapy for Atheroprotection
Innate and adaptive immune effector mechanisms, in conjunction with hyperlipidemia, are important drivers of atherosclerosis. The interaction between the different immune cells and the secretion of cytokines and chemokines determine the progression of atherosclerosis. The activation or dampening of the immune response is tightly controlled by immune checkpoints. Costimulatory and coinhibitory immune checkpoints represent potential targets for immune modulatory therapies for atherosclerosis. This review will discuss the current knowledge on immune checkpoints in atherosclerosis and the clinical potential of immune checkpoint targeted therapy for atherosclerosis
CD40-CD40L: Linking pancreatic, adipose tissue and vascular inflammation in type 2 diabetes and its complications
Numerous epidemiological studies have consistently demonstrated the strong association between type 2 diabetes mellitus (T2DM) and an increased risk to develop cardiovascular disease. The pathogenesis of T2DM and its complications are characterized by pancreatic, adipose tissue and vascular inflammation. CD40 and CD40L, members of the tumour necrosis factor (receptor) TNF(R) family, are well known for their role in immunity and inflammation. Here we give an overview on the role of CD40-CD40L interactions in the pathogenesis of T2DM with a special focus on pancreatic, adipose tissue and vascular inflammation. In addition, we explore the role of soluble CD40L (sCD40L) as a potential biomarker for the development of cardiovascular disease in T2DM subjects. Finally, the therapeutic potential of CD40-CD40L inhibition in T2DM is highlighted
Lymphocytic tumor necrosis factor receptor superfamily co-stimulatory molecules in the pathogenesis of atherosclerosis
Purpose of reviewThe role of lymphocytes in the chronic inflammatory disease atherosclerosis has emerged over the past decade. Co-stimulatory molecules of the heterogeneous tumor necrosis factor receptor superfamily play a pivotal role in lymphocyte activation, proliferation and differentiation. Here we describe the immune modulatory properties and mechanisms of four tumor necrosis factor receptor superfamily members in atherosclerosis.Recent findingsCD40/CD40L, OX40L/OX40, CD70/CD27 and CD137/CD137L are present in human atherosclerotic plaques and have shown strong immune modulatory functions in atherosclerosis, resulting in either atherogenic or atheroprotective effects in mouse models of atherosclerosis.SummaryInsight into the immune modulatory mechanisms of co-stimulatory interactions in atherosclerosis can contribute to clinical exploitation of these interactions in the treatment of cardiovascular disease
Fibroblast growth factor 2 endocytosis in endothelial cells proceed via syndecan-4-dependent activation of Rac1 and a Cdc42-dependent macropinocytic pathway
Full activity of fibroblast growth factors (FGFs) requires their internalization in addition to the interaction with cell surface receptors. Recent studies have suggested that the transmembrane proteoglycan syndecan-4 functions as a FGF2 receptor. In this study we investigated the molecular basis of syndecan endocytosis and its role in FGF2 internalization in endothelial cells. We found that syndecan-4 uptake, induced either by treatment with FGF2 or by antibody clustering, requires the integrity of plasma membrane lipid rafts for its initiation, occurs in a non-clathrin-, non-dynamin-dependent manner and involves Rac1, which is activated by syndecan-4 clustering. FGF2 was internalized in a complex with syndecan-4 in 70 kDa dextran-containing endocytic vesicles. FGF2 and syndecan-4 but not dextran endocytosis were blocked by the dominant negative Rac1 while amiloride and the dominant-negative Cdc42 blocked internalization of dextran in addition to FGF2 and syndecan-4. Taken together, these results demonstrate that FGF2 endocytosis requires syndecan-4 clustering-dependent activation of Rac1 and the intact CDC42-dependent macropinocytic pathway
E3 Ubiquitin Ligases as Immunotherapeutic Target in Atherosclerotic Cardiovascular Disease
Chronic low-grade inflammation drives atherosclerosis and despite optimal pharmacological treatment of classical cardiovascular risk factors, one third of the patients with atherosclerotic cardiovascular disease has elevated inflammatory biomarkers. Additional anti-inflammatory strategies to target this residual inflammatory cardiovascular risk are therefore required. T-cells are a dominant cell type in human atherosclerotic lesions. Modulation of T-cell activation is therefore a potential strategy to target inflammation in atherosclerosis. Ubiquitination is an important regulatory mechanism of T-cell activation and several E3 ubiquitin ligases, including casitas B-lineage lymphoma proto-oncogene B (Cbl-B), itchy homolog (Itch), and gene related to anergy in lymphocytes (GRAIL), function as a natural brake on T-cell activation. In this review we discuss recent insights on the role of Cbl-B, Itch, and GRAIL in atherosclerosis and explore the therapeutic potential of these E3 ubiquitin ligases in cardiovascular medicine
ΠΠΏΡΠΈΠΌΠΈΠ·Π°ΡΠΈΡ Π·Π°ΡΡΠ°Ρ Π½Π΅ΡΡΠ΅Π³Π°Π·ΠΎΠ²ΠΎΠΉ ΠΎΡΡΠ°ΡΠ»ΠΈ Π½Π° ΠΏΡΠΈΠΌΠ΅ΡΠ΅ ΠΏΡΠ΅Π΄ΠΏΡΠΈΡΡΠΈΡ ΠΠ Β«Π’ΠΎΠΌΡΠΊΠ½Π΅ΡΡΡΒ» ΠΠΠ
Π ΡΠ°Π±ΠΎΡΠ΅ Π±ΡΠ»ΠΈ ΡΠ°ΡΡΠΌΠΎΡΡΠ΅Π½Ρ ΡΠ»Π΅Π΄ΡΡΡΠΈΠ΅ Π²ΠΎΠΏΡΠΎΡΡ: ΡΡΡΠ½ΠΎΡΡΡ Π·Π°ΡΡΠ°Ρ, ΡΠΎΡΠΌΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ ΡΠ΅Π±Π΅ΡΡΠΎΠΈΠΌΠΎΡΡΠΈ ΠΏΡΠΎΠ΄ΡΠΊΡΠΈΠΈ, ΠΌΠ΅ΡΠΎΠ΄Ρ ΡΡΠ΅ΡΠ° ΠΈ ΠΊΠ°Π»ΡΠΊΡΠ»ΡΡΠΈΡ Π·Π°ΡΡΠ°Ρ, ΠΎΡΠΎΠ±Π΅Π½Π½ΠΎΡΡΠΈ ΡΡΠ΅ΡΠ° Π·Π°ΡΡΠ°Ρ Π² Π½Π΅ΡΡΠ΅Π³Π°Π·ΠΎΠ²ΠΎΠΉ ΠΎΡΡΠ°ΡΠ»ΠΈ, ΠΏΡΡΠΈ ΡΠ½ΠΈΠΆΠ΅Π½ΠΈΡ Π·Π°ΡΡΠ°Ρ., ΠΊΡΠ°ΡΠΊΠ°Ρ Ρ
Π°ΡΠ°ΠΊΡΠ΅ΡΠΈΡΡΠΈΠΊΠ° ΠΈΡΡΠ»Π΅Π΄ΡΠ΅ΠΌΠΎΠ³ΠΎ ΠΎΠ±ΡΠ΅ΠΊΡΠ°, ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½ Π°Π½Π°Π»ΠΈΠ· ΡΠ΅Π±Π΅ΡΡΠΎΠΈΠΌΠΎΡΡΠΈ ΠΏΡΠΎΠ΄ΡΠΊΡΠΈΠΈ.V rabote byli rassmotreny sleduyushchiye voprosy: sushchnost' zatrat, formirovaniye sebestoimosti produktsii, metody ucheta i kal'kulyatsii zatrat, osobennosti ucheta zatrat v neftegazovoy otrasli, puti snizheniya zatrat., Kratkaya kharakteristika issleduyemogo ob"yekta, proveden analiz sebestoimosti produktsii
Π‘ΠΈΡΡΠ΅ΠΌΠ° ΡΠΏΡΠ°Π²Π»Π΅Π½ΠΈΡ ΡΠΊΡΡΡΡΠ·ΠΈΠΎΠ½Π½ΠΎΠΉ ΡΡΡΠ°Π½ΠΎΠ²ΠΊΠΎΠΉ ΠΏΠΎ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄ΡΡΠ²Ρ ΠΏΠΎΠ»ΠΈΠΌΠ΅ΡΠ½ΠΎΠΉ Π½ΠΈΡΠΈ
Π Π°Π±ΠΎΡΠ° Π½Π°ΠΏΡΠ°Π²Π»Π΅Π½Π° Π½Π° ΡΠ°Π·ΡΠ°Π±ΠΎΡΠΊΡ ΠΈ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠ΅ ΠΏΡΠΈΠΌΠ΅Π½Π΅Π½ΠΈΡ Π°ΠΊΡΠΈΠ²Π½ΠΎΠ³ΠΎ ΡΠΏΡΠ°Π²Π»Π΅Π½ΠΈΡ ΡΠ΅Ρ
Π½ΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΈΠΌΠΈ ΠΏΠ°ΡΠ°ΠΌΠ΅ΡΡΠ°ΠΌΠΈ Π² ΠΏΡΠΎΡΠ΅ΡΡΠ΅ ΠΈΠ·Π³ΠΎΡΠΎΠ²Π»Π΅Π½ΠΈΡ ΠΌΠ΅ΡΠΎΠ΄ΠΎΠΌ ΡΠΊΡΡΡΡΠ·ΠΈΠΈ ΡΠ²Π΅ΡΠΎΠΏΡΠΎΠ²ΠΎΠ΄ΡΡΠ΅ΠΉ ΠΏΠΎΠ»ΠΈΠΌΠ΅ΡΠ½ΠΎΠΉ Π½ΠΈΡΠΈ.The work is aimed at researching and developing the use of active control of technological process parameters in manufacturing with extrusion of a light-guiding polymer filament
Depletion of CD40 on CD11c(+) cells worsens the metabolic syndrome and ameliorates hepatic inflammation during NASH
The co-stimulatory CD40-CD40L dyad plays a central role in fine-tuning immune reactions, including obesity-induced inflammation. Genetic ablation of CD40L reduced adipose tissue inflammation, while absence of CD40 resulted in aggravated metabolic dysfunction in mice. During obesity, CD40 expressing CD11c(+) dendritic cells (DC) and macrophages accumulate in adipose tissue and liver. We investigated the role of CD40(+)CD11c(+) cells in the metabolic syndrome and nonalcoholic steatohepatitis (NASH). DC-CD40-ko mice (CD40(fl/fl)CD11c(cre)) mice were subjected to obesity or NASH. Obesity and insulin resistance were induced by feeding mice a 54% high fat diet (HFD). NASH was induced by feeding mice a diet containing 40% fat, 20% fructose and 2% cholesterol. CD40(fl/fl)CD11c(cre )mice fed a HFD displayed increased weight gain, increased adipocyte size, and worsened insulin resistance. Moreover, CD40(fl/fl)CD11c(cre )mice had higher plasma and hepatic cholesterol levels and developed profound liver steatosis. Overall, regulatory T cell numbers were decreased in these mice. In NASH, absence of CD40 on CD11c(+) cells slightly decreased liver inflammation but did not affect liver lipid accumulation. Our experiments suggest that CD40 expressing CD11c(+) cells can act as a double-edged sword: CD40 expressing CD11c(+) cells contribute to liver inflammation during NASH but are protective against the metabolic syndrome via induction of regulatory T cells
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