scholarly journals Calcineurin inhibitors cyclosporine A and tacrolimus induce vascular inflammation and endothelial activation through TLR4 signaling

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Raquel Rodrigues-Diez ◽  
Cristian González-Guerrero ◽  
Carlos Ocaña-Salceda ◽  
Raúl R. Rodrigues-Diez ◽  
Jesús Egido ◽  
...  
Keyword(s):  
Cyclosporine A ◽  
Vascular Inflammation ◽  
Calcineurin Inhibitors ◽  
Endothelial Activation ◽  
Tlr4 Signaling

Regulation of Endothelial Activation and Vascular Inflammation by Shear Stress

2012 ◽  
pp. 77-85 ◽  
Author(s):  
Annapurna Nayak ◽  
Carola S. König ◽  
Uday Kishore ◽  
Paul C. Evans
Keyword(s):  
Shear Stress ◽  
Vascular Inflammation ◽  
Endothelial Activation

scholarly journals Therapeutic Perspectives of Adenosine Deaminase Inhibition in Cardiovascular Diseases

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4652
Author(s):  
Barbara Kutryb-Zajac ◽  
Paulina Mierzejewska ◽  
Ewa M. Slominska ◽  
Ryszard T. Smolenski
Keyword(s):  
Adenosine Deaminase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Vascular Inflammation ◽  
Endothelial Activation ◽  
Enzymatic Function ◽  
Adenosine Uptake ◽  
Cardiovascular Pathologies ◽  
Ada Protein ◽  
Myocardial Ischemia Reperfusion

Adenosine deaminase (ADA) is an enzyme of purine metabolism that irreversibly converts adenosine to inosine or 2′deoxyadenosine to 2′deoxyinosine. ADA is active both inside the cell and on the cell surface where it was found to interact with membrane proteins, such as CD26 and adenosine receptors, forming ecto-ADA (eADA). In addition to adenosine uptake, the activity of eADA is an essential mechanism that terminates adenosine signaling. This is particularly important in cardiovascular system, where adenosine protects against endothelial dysfunction, vascular inflammation, or thrombosis. Besides enzymatic function, ADA protein mediates cell-to-cell interactions involved in lymphocyte co-stimulation or endothelial activation. Furthermore, alteration in ADA activity was demonstrated in many cardiovascular pathologies such as atherosclerosis, myocardial ischemia-reperfusion injury, hypertension, thrombosis, or diabetes. Modulation of ADA activity could be an important therapeutic target. This work provides a systematic review of ADA activity and anchoring inhibitors as well as summarizes the perspectives of their therapeutic use in cardiovascular pathologies associated with increased activity of ADA.

scholarly journals YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6

2018 ◽  
Vol 123 (1) ◽  
pp. 43-56 ◽  
Author(s):  
Yang Lv ◽  
Kyungho Kim ◽  
Yue Sheng ◽  
Jaehyung Cho ◽  
Zhijian Qian ◽  
...  
Keyword(s):  
Vascular Inflammation ◽  
Endothelial Activation

Natural alkaloid tryptanthrin exhibits novel anticryptococcal activity

2020 ◽  
Author(s):  
Chi-Jan Lin ◽  
Ya-Lin Chang ◽  
Yu-Liang Yang ◽  
Ying-Lien Chen
Keyword(s):  
Cell Cycle ◽  
Antifungal Activity ◽  
Signaling Pathways ◽  
Natural Product ◽  
Cyclosporine A ◽  
Cryptococcal Meningitis ◽  
Synergistic Effects ◽  
Calcineurin Inhibitors ◽  
Genes Encoding ◽  
Cryptococcus Species

Abstract Cryptococcal meningitis is a prevalent invasive fungal infection that causes around 180 000 deaths annually. Currently, treatment for cryptococcal meningitis is limited and new therapeutic options are needed. Historically, medicinal plants are used to treat infectious and inflammatory skin infections. Tryptanthrin is a natural product commonly found in these plants. In this study, we demonstrated that tryptanthrin had antifungal activity with minimum inhibitory concentration (MIC) of 2 μg/ml against Cryptococcus species and of 8 μg/ml against Trichophyton rubrum. Further analysis demonstrated that tryptanthrin exerted fungistatic and potent antifungal activity at elevated temperature. In addition, tryptanthrin exhibited a synergistic effect with the calcineurin inhibitors FK506 and cyclosporine A against Cryptococcus neoformans. Furthermore, our data showed that tryptanthrin induced cell cycle arrest at the G1/S phase by regulating the expression of genes encoding cyclins and the SBF/MBF complex (CLN1, MBS1, PCL1, and WHI5) in C. neoformans. Screening of a C. neoformans mutant library further revealed that tryptanthrin was associated with various transporters and signaling pathways such as the calcium transporter (Pmc1) and protein kinase A signaling pathway. In conclusion, tryptanthrin exerted novel antifungal activity against Cryptococcus species through a mechanism that interferes with the cell cycle and signaling pathways. Lay Summary The natural product tryptanthrin had antifungal activity against Cryptococcus species by interfering cell cycle and exerted synergistic effects with immunosuppressants FK506 and cyclosporine A. Our findings suggest that tryptanthrin may be a potential drug or adjuvant for the treatment of cryptococcosis.

IL-35 Suppresses Lipopolysaccharide-Induced Endothelial Cell Activation Through Downregulation of MAPK Signaling-Mediated Upregulation of Adhesion Molecule VCAM-1

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3310-3310
Author(s):  
Xiaojin Sha ◽  
Shu Meng ◽  
Xinyuan Li ◽  
Jahaira Lopez Pastrana ◽  
Hong Wang ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Adhesion Molecule ◽  
Cell Activation ◽  
Conflicts Of Interest ◽  
Vascular Inflammation ◽  
Endothelial Activation ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 12 ◽  
Endothelial Cell Activation

Abstract Abstract 3310 Our previous reports showed that survival/apoptosis of CD4+CD25+Foxp3+ regulatory T cells (Tregs) modulates vascular inflammation even though the mode of Tregs inhibition was unknown. Interleukin-35 (IL-35), consisting of two subunits Epstein-Barr virus–induced gene 3 (EBI3) and p35, is a novel anti-inflammatory cytokine, which is a member of the interleukin-12 (IL-12) cytokine family. IL-35 is produced by Tregs. It has been shown that IL-35 suppresses chronic inflammatory diseases such as asthma and inflammatory bowel diseases. However, an important question of whether IL-35 can carry out Tregs suppression and inhibit endothelial cell (EC) activation in acute inflammation remained unknown. Here we found that IL-35 significantly inhibits lung neutrophil infiltration into the surrounding areas of bronchioles and alveolar space when induced by intraperitoneal injection of lipopolysaccharide (LPS) in wild type mice and EBI3-deficient mice. Furthermore, cremaster microvasculature study using intravital microscopy showed IL-35 significantly suppresses leukocyte adhesion to the vascular wall as well, suggesting IL-35 inhibition of endothelial activation. Mechanistically, IL-35 inhibited LPS-induced upregulation of adhesion molecules on human aortic endothelial cells, a marker of endothelial activation, including vascular cell adhesion molecule 1 (VCAM-1). IL-35 acted through new IL-35 dimeric receptors gp130 and IL-12Rβ2, and inhibited VCAM-1 promoter transcription in mitogen-activated protein kinase (MAPK)-mediated pathway. These results provide a novel insight on Tregs and IL-35 inhibition of vascular inflammation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Soluble thrombomodulin reduces inflammation and prevents microalbuminuria induced by chronic endothelial activation in transgenic mice

2012 ◽  
Vol 302 (6) ◽  
pp. F703-F712 ◽  
Author(s):  
Gangaraju Rajashekhar ◽  
Akanksha Gupta ◽  
Abby Marin ◽  
Jessica Friedrich ◽  
Antje Willuweit ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Cell Activation ◽  
Vascular Inflammation ◽  
Kidney Injury ◽  
Endothelial Activation ◽  
Endothelial Cell Activation ◽  
Soluble Thrombomodulin ◽  
Inflammatory Chemokines

Chronic kidney disease pathogenesis involves both tubular and vascular injuries. Despite abundant investigations to identify the risk factors, the involvement of chronic endothelial dysfunction in developing nephropathies is insufficiently explored. Previously, soluble thrombomodulin (sTM), a cofactor in the activation of protein C, has been shown to protect endothelial function in models of acute kidney injury. In this study, the role for sTM in treating chronic kidney disease was explored by employing a mouse model of chronic vascular activation using endothelial-specific TNF-α-expressing (tie2-TNF) mice. Analysis of kidneys from these mice after 3 mo showed no apparent phenotype, whereas 6-mo-old mice demonstrated infiltration of CD45-positive leukocytes accompanied by upregulated gene expression of inflammatory chemokines, markers of kidney injury, and albuminuria. Intervention with murine sTM with biweekly subcutaneous injections during this window of disease development between months 3 and 6 prevented the development of kidney pathology. To better understand the mechanisms of these findings, we determined whether sTM could also prevent chronic endothelial cell activation in vitro. Indeed, treatment with sTM normalized increased chemokines, adhesion molecule expression, and reduced transmigration of monocytes in continuously activated TNF-expressing endothelial cells. Our results suggest that vascular inflammation associated with vulnerable endothelium can contribute to loss in renal function as suggested by the tie2-TNF mice, a unique model for studying the role of vascular activation and inflammation in chronic kidney disease. Furthermore, the ability to restore the endothelial balance by exogenous administration of sTM via downregulation of specific adhesion molecules and chemokines suggests a potential for therapeutic intervention in kidney disease associated with chronic inflammation.

154 DIFFERENTIAL EFFECT OF CALCINEURIN INHIBITORS, TACROLIMUS AND CYCLOSPORINE A, ON INTERFERON INDUCED ANTI-VIRAL PROTEIN IN HUMAN HEPATOCYTE CELL

2008 ◽  
Vol 48 ◽  
pp. S67-S68
Author(s):  
T. Ichikawa ◽  
K. Nakao ◽  
H. Miyaaki ◽  
H. Shibata ◽  
S. Takashita ◽  
...  
Keyword(s):  
Cyclosporine A ◽  
Viral Protein ◽  
Differential Effect ◽  
Calcineurin Inhibitors ◽  
Human Hepatocyte

scholarly journals The Transcription Factor Erg Controls Endothelial Cell Quiescence by Repressing Activity of Nuclear Factor (NF)-κB p65

2012 ◽  
Vol 287 (15) ◽  
pp. 12331-12342 ◽  
Author(s):  
Nicola H. Dryden ◽  
Andrea Sperone ◽  
Silvia Martin-Almedina ◽  
Rebecca L. Hannah ◽  
Graeme M. Birdsey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Dna Sequences ◽  
Vascular Inflammation ◽  
Enrichment Analysis ◽  
Endothelial Activation ◽  
Organ Damage ◽  
Gene Set Enrichment Analysis ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1

The interaction of transcription factors with specific DNA sequences is critical for activation of gene expression programs. In endothelial cells (EC), the transcription factor NF-κB is important in the switch from quiescence to activation, and is tightly controlled to avoid excessive inflammation and organ damage. Here we describe a novel mechanism that controls the activation of NF-κB in EC. The transcription factor Erg, the most highly expressed ETS member in resting EC, controls quiescence by repressing proinflammatory gene expression. Focusing on intercellular adhesion molecule 1(ICAM)-1 as a model, we identify two ETS binding sites (EBS −118 and −181) within the ICAM-1 promoter required for Erg-mediated repression. We show that Erg binds to both EBS −118 and EBS −181, the latter located within the NF-κB binding site. Interestingly, inhibition of Erg expression in quiescent EC results in increased NF-κB-dependent ICAM-1 expression, indicating that Erg represses basal NF-κB activity. Erg prevents NF-κB p65 from binding to the ICAM-1 promoter, suggesting a direct mechanism of interference. Gene set enrichment analysis of transcriptome profiles of Erg and NF-κB-dependent genes, together with chromatin immunoprecipitation (ChIP) studies, reveals that this mechanism is common to other proinflammatory genes, including cIAP-2 and IL-8. These results identify a role for Erg as a gatekeeper controlling vascular inflammation, thus providing an important barrier to protect against inappropriate endothelial activation.

scholarly journals Cyclosporine A inhibits MRTF-SRF signalling through Na+/K+ ATPase inhibition & Actin remodelling

2018 ◽  
Author(s):  
Bastien Burat ◽  
Quentin Faucher ◽  
Petra Čechová ◽  
Hélène Arnion ◽  
Florent Di Meo ◽  
...  
Keyword(s):  
Cyclosporine A ◽  
Phosphorylation Site ◽  
Specific Inhibitor ◽  
Calcineurin Inhibitors ◽  
Actin Binding ◽  
Specific Expression ◽  
Actin Organization ◽  
Proteomic Approach ◽  
Renal Proximal Tubular Cells ◽  
Actin Remodelling

AbstractCalcineurin Inhibitors (CNI) are the pillars of immunosuppression in transplantation. However, they display a potent nephrotoxicity whose mechanisms remained widely unsolved. We used an untargeted quantitative proteomic approach (iTRAQ technology) to highlight new targets of CNI in renal proximal tubular cells (RPTCs). CNI-treated RPTCs proteome displayed an over-representation of Actin-binding proteins with a CNI-specific expression profile. Cyclosporine A (CsA) induced F-Actin remodelling and depolymerisation, decreased F-Actin-stabilizing, polymerization-promoting Cofilin (CFL) oligomers and inhibited the G-Actin-regulated serum responsive factor (SRF) pathway. Inhibition of CFL canonical phosphorylation pathway reproduced CsA effects; however, Ser3, an analogue of the phosphorylation site of CFL prevented the effects of CsA which suggests that CsA acted independently from the canonical CFL regulation. CFL is known to be regulated by the Na+/K+-ATPase. Molecular docking calculations evidenced 2 inhibiting sites of CsA on Na+/K+-ATPase and a 23% decrease in Na+/K+-ATPase activity of RPTCs was observed with CsA. Ouabain, a specific inhibitor of Na+/K+-ATPase also reproduced CsA effects on Actin organization and SRF activity. Altogether, these results described a new original pathway explaining CsA nephrotoxicity.

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