Insights into the molecular basis and mechanism of heme‐triggered TLR4 signalling: The role of heme‐binding motifs in TLR4 and MD2 DOI Creative Commons
Marie-Thérèse Hopp,

Janine Holze,

Felicitas Lauber

et al.

Immunology, Journal Year: 2023, Volume and Issue: 171(2), P. 181 - 197

Published: Oct. 26, 2023

Abstract Haemolytic disorders, such as sickle cell disease, are accompanied by the release of high amounts labile heme into intravascular compartment resulting in induction proinflammatory and prothrombotic complications affected patients. In addition to relevance heme‐regulated proteins from complement blood coagulation systems, activation TLR4 signalling pathway was ascribed a crucial role progression these pathological processes. Heme binding TLR4‐MD2 complex has been proposed recently, however, essential mechanistic information processes at molecular level, heme‐binding kinetics, capacity respective sites (HBMs) is still missing. We report interaction TLR4, MD2 with consequences thereof employing biochemical, spectroscopic, bioinformatic physiologically relevant approaches. occurs transiently through up four HBMs two least their complex. Functional studies highlight that mutations individual preserve full receptor heme, suggesting interacts different independently MD2. Furthermore, we confirm extend major for heme‐mediated cytokine responses human immune cells.

Language: Английский

Red blood cells as oxygen carrier during normothermic machine perfusion of kidney grafts: Friend or foe? DOI Creative Commons
Asel S. Arykbaeva, Lente J. S. Lerink, J. Vos

et al.

American Journal of Transplantation, Journal Year: 2024, Volume and Issue: 24(7), P. 1172 - 1179

Published: Jan. 11, 2024

Renal ex vivo normothermic machine perfusion (NMP) is under development as an assessment tool for high-risk kidney grafts and a means of achieving more physiologically accurate organ preservation. On-going hemolysis has been reported during NMP, this technique relies on red blood cells oxygen delivery. In study, we confirm the occurrence progressive 6-hour NMP. NMP-associated erythrostasis in glomeruli peri-glomerular vascular networks points to interaction between graft. Continuous resulted prooxidative changes perfusate, which could be quenched by addition fresh frozen plasma. cell-based system, induced redox stress exhibited toxic effects at high concentrations. These findings highlight need refined carrier context renal

Language: Английский

Citations

6
Nonlinear optical and spectroscopic properties, thermal analysis, and hemolytic capacity evaluation of quinoline-1,3-benzodioxole chalcone DOI Creative Commons
Efraín Polo-Cuadrado, Edison Osorio,

Karen Acosta-Quiroga

et al.

RSC Advances, Journal Year: 2024, Volume and Issue: 14(15), P. 10199 - 10208

Published: Jan. 1, 2024

This article details the synthesis, full characterization, optical properties, theoretical analysis, evaluation of nonlinear properties (NLO), and determination hemolytic capacity quinoline-1,3-benzodioxole chalcone(5).

Language: Английский

Citations

6
Ferroptosis as an emerging target in sickle cell disease DOI Creative Commons
Vitor Fortuna, Jaqueline Costa Lima,

Gabriel F. Oliveira

et al.

Current Research in Toxicology, Journal Year: 2024, Volume and Issue: 7, P. 100181 - 100181

Published: Jan. 1, 2024

Sickle cell disease (SCD) is an inherited hemoglobin disorder marked by red blood sickling, resulting in severe anemia, painful episodes, extensive organ damage, and shortened life expectancy. In SCD, increased iron levels can trigger ferroptosis, a specific type of death characterized reactive oxygen species (ROS) lipid peroxide accumulation, leading to damage impairments. The intricate interplay between iron, inflammation, oxidative stress SCD underscores the necessity thoroughly understanding these processes for development innovative therapeutic strategies. This review highlights importance balancing complex interactions among various factors exploitation knowledge developing novel therapeutics this devastating disease.

Language: Английский

Citations

6
An oral carbon monoxide–releasing molecule protects against acute hyperhemolysis in sickle cell disease DOI
Kim Nguyen, Alessandro Mattè, Roberta Foresti

et al.

Blood, Journal Year: 2024, Volume and Issue: 143(24), P. 2544 - 2558

Published: March 22, 2024

Language: Английский

Citations

5
Impacts of oxidative stress and anti-oxidants on the development, pathogenesis, and therapy of sickle cell disease: A comprehensive review DOI Open Access

E. Pavitra,

Rakesh Kumar Acharya, Vivek Kumar Gupta

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 176, P. 116849 - 116849

Published: June 1, 2024

Sickle cell disease (SCD) is the most severe monogenic hemoglobinopathy caused by a single genetic mutation that leads to repeated polymerization and depolymerization of hemoglobin resulting in intravascular hemolysis, adhesion, vascular occlusion, ischemia–reperfusion injury. Hemolysis causes oxidative damage indirectly generating reactive oxygen species through various pathophysiological mechanisms, which include autoxidation, endothelial nitric oxide synthase uncoupling, reduced bioavailability, elevated levels asymmetric dimethylarginine. Red blood cells have built-in anti-oxidant system includes enzymes like sodium dismutase, catalase, glutathione peroxidase, along with free radical scavenging molecules, such as vitamin C, E, glutathione, help them fight damage. However, these anti-oxidants may not be sufficient prevent effects stress SCD patients. Therefore, line recent FDA request focus placed on development innovative therapies for address root cause disease, there need target restore redox balance This review summarizes current state knowledge regarding role potential benefits therapies. It also discusses challenges limitations suggests future directions research development.

Language: Английский

Citations

5
Aortic Valve Stenosis Causes Accumulation of Extracellular Hemoglobin and Systemic Endothelial Dysfunction DOI Open Access
Christine Quast, Florian Bönner, Amin Polzin

et al.

Circulation, Journal Year: 2024, Volume and Issue: 150(12), P. 952 - 965

Published: June 5, 2024

BACKGROUND: Whether aortic valve stenosis (AS) can adversely affect systemic endothelial function independently of standard modifiable cardiovascular risk factors is unknown. METHODS: We therefore investigated and cardiac in an experimental model AS mice devoid human cohorts with scheduled for transcatheter replacement. Endothelial was determined by flow-mediated dilation using ultrasound. Extracellular hemoglobin (eHb) concentrations nitric oxide (NO) consumption were blood plasma humans ELISA chemiluminescence. This complemented measurements flow 4-dimensional acquisition magnetic resonance imaging computational fluid dynamics simulations. The effects red cell (RBC) suspensions on vascular transfer experiments a murine vasorelaxation bioassay system. RESULTS: In mice, the induction caused dysfunction. presence normal systolic left ventricular mild hypertrophy, increase transvalvular gradient associated elevated eryptosis, increased eHb, NO consumption; eHb sequestration haptoglobin restored function. Because orifice area patients decreased, postvalvular mechanical stress central ascending aorta increased. circulating RBC-derived microvesicles, eryptotic cells, lower levels without clinically relevant anemia, consecutive Transfer demonstrated that reduction treatment or elimination dynamic replacement subclinical RBC fragmentation, remaining RBCs before after exhibited intact membrane function, deformability, resistance to osmotic hypoxic stress. CONCLUSIONS: increases swirling aorta, triggering fragmentation accumulation plasma. blood, thereby limiting bioavailability. Thus, itself promotes dysfunction independent other established factors. Transcatheter capable scavenging rescuing realigning near physiological patterns. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT05603520 NCT01805739.

Language: Английский

Citations

5
Heme Drives Susceptibility of Glomerular Endothelium to Complement Overactivation Due to Inefficient Upregulation of Heme Oxygenase-1 DOI Creative Commons
Olivia May, Nicolas S. Merle,

Anne Grünenwald

et al.

Frontiers in Immunology, Journal Year: 2018, Volume and Issue: 9

Published: Dec. 19, 2018

Atypical hemolytic uremic syndrome (aHUS) is a severe disease characterized by microvascular endothelial cells (EC) lesions leading to thrombi formation, mechanical hemolysis and organ failure, predominantly renal. Complement system overactivation hallmark of aHUS. To investigate this selective susceptibility the renal endothelium complement attack thrombotic microangiopathic lesions, we compared cyto-protection markers on EC, from different vascular beds, in vitro vivo models as well patients. No difference was observed for deposits or expression coagulation regulators between macrovascular either at resting state after inflammatory challenge. After prolonged exposure hemolysis-derived heme, higher C3 were found glomerular vivo, with other EC culture mice organs (liver, skin, brain, lungs heart). This could be explained reduced regulation capacity due weaker binding Factor H inefficient upregulation thrombomodulin (TM). Microvascular also failed upregulate cytoprotective heme-degrading enzyme heme-oxygenase 1 (HO-1), normally induced products. Only HUVEC (Human Umbilical Vein EC) developed adaptation which lost inhibition HO-1 activity. Interestingly, KLF2 KLF4 – known transcription factors TM, described possible modulators HO-1, micro- than under conditions. Our results show that especially fail adapt stress imposed acquire pro-coagulant complement-activating phenotype. Together, these findings indicate vulnerability key factor aHUS, amplifying lesions.

Language: Английский

Citations

40
Linking Labile Heme with Thrombosis DOI Open Access
Marie-Thérèse Hopp, Diana Imhof

Journal of Clinical Medicine, Journal Year: 2021, Volume and Issue: 10(3), P. 427 - 427

Published: Jan. 22, 2021

Thrombosis is one of the leading causes death worldwide. As such, it also occurs as major complications in hemolytic diseases, like uremic syndrome, hemorrhage and sickle cell disease. Under these conditions, red blood lysis finally leads to release large amounts labile heme into vascular compartment. This, turn, can trigger oxidative stress proinflammatory reactions. Moreover, heme-induced activation coagulation system was suggested a mechanism for initiation thrombotic events under conditions. Studies infusion subsequent reactions support this assumption. Furthermore, several direct effects on different cellular protein components were reported. However, are controversially discussed or not yet fully understood. This review summarizes existing reports its interference processes, emphasizing relevance considering context treatment thrombosis patients with disorders.

Language: Английский

Citations

32
Heme Oxygenase 1: A Defensive Mediator in Kidney Diseases DOI Open Access

Anne Grünenwald,

Lubka T. Roumenina, Marie Frimat

et al.

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(4), P. 2009 - 2009

Published: Feb. 18, 2021

The incidence of kidney disease is rising, constituting a significant burden on the healthcare system and making identification new therapeutic targets increasingly urgent. heme oxygenase (HO) performs an important function in regulation oxidative stress inflammation and, via these mechanisms, thought to play role prevention non-specific injuries following acute renal failure or resulting from chronic disease. expression HO-1 strongly inducible by wide range stimuli kidney, consequent kidney’s filtration which means exposed endogenous exogenous molecules, it has been shown be protective variety nephropathological animal models. Interestingly, positive effect occurs both hemolysis- rhabdomyolysis-dominated diseases, where extensively (a major inducer), as well non-heme-dependent diseases such hypertension, diabetic nephropathy progression end-stage This highlights complexity HO-1’s functions, also illustrated fact that, despite abundance preclinical data, no drug targeting so far translated into clinical use. objective this review assess current knowledge relating its potential interest nephroprotection agent. openings will presented, particular through trials enzyme products.

Language: Английский

Citations

32
Case Report: Adult Post-COVID-19 Multisystem Inflammatory Syndrome and Thrombotic Microangiopathy DOI Creative Commons
Idris Boudhabhay, Marion Rabant, Lubka T. Roumenina

et al.

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: June 23, 2021

Background The coronavirus disease 2019 (COVID-19) pandemic has affected millions of people worldwide. A clinical series Kawasaki-like multisystem inflammatory syndrome (MIS), occurring after SARS-CoV-2 infection, have been described in children (MIS-C) and adults (MIS-A), but the pathophysiology remains unknown. Case Presentation We describe a case post-COVID-19 MIS-A 46-year-old man with biopsy-proven renal thrombotic microangiopathy (TMA). Specific complement inhibition eculizumab was initiated promptly led to dramatic improvement function. Conclusion Our suggests that TMA could play central role MIS-A, making blockers an interesting therapeutic option.

Language: Английский

Citations

28