scholarly journals Potentiation of complement regulator factor H protects human endothelial cells from complement attack in aHUS sera

2019 ◽  
Vol 3 (4) ◽  
pp. 621-632 ◽  
Author(s):  
Richard B. Pouw ◽  
Mieke C. Brouwer ◽  
Marlon de Gast ◽  
Anna E. van Beek ◽  
Lambertus P. van den Heuvel ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Complement Activation ◽  
Protective Role ◽  
Human Cells ◽  
Factor H ◽  
Human Endothelial Cells ◽  
Complement Regulation ◽  
Wide Range ◽  
Complement Regulator

Abstract Mutations in the gene encoding for complement regulator factor H (FH) severely disrupt its normal function to protect human cells from unwanted complement activation, resulting in diseases such as atypical hemolytic uremic syndrome (aHUS). aHUS presents with severe hemolytic anemia, thrombocytopenia, and renal disease, leading to end-stage renal failure. Treatment of severe complement-mediated disease, such as aHUS, by inhibiting the terminal complement pathway, has proven to be successful but at the same time fails to preserve the protective role of complement against pathogens. To improve complement regulation on human cells without interfering with antimicrobial activity, we identified an anti-FH monoclonal antibody (mAb) that induced increased FH-mediated protection of primary human endothelial cells from complement, while preserving the complement-mediated killing of bacteria. Moreover, this FH-activating mAb restored complement regulation in sera from aHUS patients carrying various heterozygous mutations in FH known to impair FH function and dysregulate complement activation. Our data suggest that FH normally circulates in a less active conformation and can become more active, allowing enhanced complement regulation on human cells. Antibody-mediated potentiation of FH may serve as a highly effective approach to inhibit unwanted complement activation on human cells in a wide range of hematological diseases while preserving the protective role of complement against pathogens.

scholarly journals Albizia chinensis bark extract ameliorates the genotoxic effect of cyclophosphamide

2020 ◽  
Vol 44 (1) ◽  
Author(s):  
Marian Nabil ◽  
Entesar E. Hassan ◽  
Neven S. Ghaly ◽  
Fawzia A. Aly ◽  
Farouk R. Melek ◽  
...  
Keyword(s):  
Folk Medicine ◽  
Inhibitory Effect ◽  
Protective Role ◽  
Bark Extract ◽  
Repeated Treatment ◽  
Mouse Bone Marrow ◽  
Sperm Abnormalities ◽  
Wide Range ◽  
Different Doses

Abstract Background The genus Albizia (Leguminoseae) is used in folk medicine for the treatment of a wide range of ailments. Recently, saponins from plant origin have attracted much attention. Saponins are recorded to have a broad range of biological and pharmacological activities. This study was performed to evaluate the protective role of Albizia chinensis bark methanolic extract (MEAC) against the genotoxicity induced by cyclophosphamide (CP) using different mutagenic parameters. Results The results showed that MEAC induced an inhibitory effect against chromosomal aberrations of CP in mouse bone marrow and spermatocytes. Such effect was found to be significant (p < 0.01) with a dose of 100 mg/kg treated once for 24 h and also after repeated treatment at a dose of 25 mg/kg for 7 days. In sperm abnormalities, the protective effect of Albizia extract showed a dose-related relationship. Different doses of MEAC (25, 50, and 100 mg/kg) significantly (p < 0.01) ameliorated sperm abnormalities induced by CP dose-dependently. The percentage of sperm abnormalities was decreased to 5.14 ± 0.72 in the group of animals treated with CP plus MEAC (100 mg/kg) indicating an inhibitory effect of about 50%. Conclusion MEAC at the doses examined was non-genotoxic compared to control (negative) and exhibited a protective role against CP genotoxicity.

Carboxiterminal pro-endothelin-1 as an endothelial cell biomarker in thrombotic thrombocytopenic purpura

2016 ◽  
Vol 115 (05) ◽  
pp. 1034-1043 ◽  
Author(s):  
György Sinkovits ◽  
Péter Farkas ◽  
Dorottya Csuka ◽  
Katalin Rázsó ◽  
Marienn Réti ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Acute Phase ◽  
Complement Activation ◽  
Endothelial Activation ◽  
Factor H ◽  
Healthy Controls ◽  
Activation Markers ◽  
Thrombocytopenic Purpura ◽  
Endothelin 1

SummaryThrombotic thrombocytopenic purpura (TTP) is characterised by the deficiency of the von Willebrand factor (VWF) cleaving protease (ADAMTS-13). Although several observations indicate an important role of endothelial activation in the pathogenesis of TTP, no reliable endothelial activation markers are available in the clinical management of TTP. Our aim was to investigate the presence of endothelial activation in TTP and to determine its connections with disease activity, therapy and complement activation. We enrolled 54 patients (median age 40.5; 44 females) and 57 healthy controls (median age 34; 30 females),VWF antigen, carboxiterminal-pro-endothelin-1 (CT-proET-1), complement Factor H and complement activation products (C3bBbP and SC5b-9) were measured. In both the acute and remission phase of TTP we found increased CT-proET-1 and VWF levels, while Factor H levels decreased compared with healthy controls. In remission, however, the elevated CT-proET-1 levels showed 22 % decrease when compared with the acute phase in paired samples (p=0.0031), whereas no changes for VWF and Factor H levels were observed. We also found positive correlations between CT-proET-1 levels and alternative pathway activation markers (C3bBbP; p=0.0360; r=0.4299). The data we present here demonstrate a role of endothelium activation in patients with acute TTP. The finding that CT-proET-1 levels decreased in remission compared with the acute phase further supports endothelial involvement. In addition, we show that endothelial activation also correlated with the activation of the alternative complement pathway. The data suggest that complement and endothelium activation jointly contribute to the development of TTP episodes in patients with predisposition to TTP.Supplementary Material to this article is available online at www.thrombosis-online.com.

Mechanism of complement regulator Factor H mediated pneumococcal uptake by human cells

2010 ◽  
Vol 47 (13) ◽  
pp. 2242-2242
Author(s):  
Vaibhav Agarwal ◽  
Tauseef Asmat ◽  
Shanshan Luo ◽  
Peter F. Zipfel ◽  
Sven Hammerschmidt
Keyword(s):  
Human Cells ◽  
Factor H ◽  
Complement Regulator

scholarly journals Cytoprotection of human endothelial cells from oxidative stress by polyphenols: the role of gene expression versus direct antioxidant effect

2010 ◽  
Vol 24 (S1) ◽  
Author(s):  
Xinyu Wang ◽  
James Bynum ◽  
Salomon Stavchansky ◽  
Michael Dubick ◽  
Robert Hackman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Endothelial Cells ◽  
Antioxidant Effect ◽  
Human Endothelial Cells

Protective role of HSP27 against UVC-induced cell death in human cells

2004 ◽  
Vol 298 (2) ◽  
pp. 584-592 ◽  
Author(s):  
Chieko Wano ◽  
Kazuko Kita ◽  
Shunji Takahashi ◽  
Shigeru Sugaya ◽  
Mizuki Hino ◽  
...  
Keyword(s):  
Cell Death ◽  
Protective Role ◽  
Human Cells

scholarly journals MicroRNA as Crucial Regulators of Gene Expression in Estradiol-Treated Human Endothelial Cells

2018 ◽  
Vol 45 (5) ◽  
pp. 1878-1892 ◽  
Author(s):  
Xavier Vidal-Gómez ◽  
Daniel Pérez-Cremades ◽  
Ana Mompeón ◽  
Ana Paula Dantas ◽  
Susana Novella ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Function ◽  
Pathway Analysis ◽  
Mirna Expression ◽  
Umbilical Vein ◽  
Mirna Gene ◽  
Mirna Profile ◽  
Human Endothelial Cells ◽  
Estrogen Regulation

Background/Aims: Estrogen signalling plays an important role in vascular biology as it modulates vasoactive and metabolic pathways in endothelial cells. Growing evidence has also established microRNA (miRNA) as key regulators of endothelial function. Nonetheless, the role of estrogen regulation on miRNA profile in endothelial cells is poorly understood. In this study, we aimed to determine how estrogen modulates miRNA profile in human endothelial cells and to explore the role of the different estrogen receptors (ERα, ERβ and GPER) in the regulation of miRNA expression by estrogen. Methods: We used miRNA microarrays to determine global miRNA expression in human umbilical vein endothelial cells (HUVEC) exposed to a physiological concentration of estradiol (E2; 1 nmol/L) for 24 hours. miRNA-gene interactions were computationally predicted using Ingenuity Pathway Analysis and changes in miRNA levels were validated by qRT-PCR. Role of ER in the E2-induced miRNA was additionally confirmed by using specific ER agonists and antagonists. Results: miRNA array revealed that expression of 114 miRNA were significantly modified after E2 exposition. Further biological pathway analysis revealed cell death and survival, lipid metabolism, reproductive system function, as the top functions regulated by E2. We validated changes in the most significantly increased (miR-30b-5p, miR-487a-5p, miR-4710, miR-501-3p) and decreased (miR-378h and miR-1244) miRNA and the role of ER in these E2-induced miRNA was determined. Results showed that both classical, ERα and ERβ, and membrane-bound ER, GPER, differentially regulated specific miRNA. In silico analysis of validated miRNA promoters identified specific ER binding sites. Conclusion: Our findings identify differentially expressed miRNA pathways linked to E2 in human endothelial cells through ER, and provide new insights by which estrogen can modulate endothelial function.

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