scholarly journals The chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling

2021 ◽  
Author(s):  
Yanyan Ding ◽  
Yuzhe Li ◽  
Qiangfeng Cliff Zhang ◽  
Feng Liu
Keyword(s):  
Venous Thrombosis ◽  
Blood Clot ◽  
Underlying Mechanism ◽  
Chromatin Accessibility ◽  
Clot Formation ◽  
Erythrocyte Aggregation ◽  
Thrombin Inhibitor ◽  
Zebrafish Model ◽  
Nrf2 Signaling Pathway ◽  
Therapeutic Assessments

AbstractAlthough thrombosis has been extensively studied using various animal models, however, our understanding of the underlying mechanism remains elusive. Here, using zebrafish model, we demonstrated that smarca5-deficient red blood cells (RBCs) formed blood clots in the caudal vein plexus that mimics venous thrombosis. We further used the anti-thrombosis drugs to treat smarca5zko1049a embryos and found that a thrombin inhibitor, argatroban, partially prevented blood clot formation in smarca5zko1049a. To explore the regulatory mechanism of smarca5 in RBC homeostasis, we profiled the chromatin accessibility landscape and transcriptome features in RBCs from smarca5zko1049a and their siblings and found that both the chromatin accessibility at the keap1a promoter and expression of keap1a were decreased. Keap1 is a suppressor protein of Nrf2, which is a major regulator of oxidative responses. We further identified that the expression of hmox1a, a downstream target of Keap1-Nrf2 signaling pathway, was markedly increased upon smarca5 deletion. Importantly, overexpression of keap1a or knockdown of hmox1a partially rescued the blood clot formation, suggesting that the disrupted Keap1-Nrf2 signaling is responsible for the venous thrombosis-like phenotypes in smarca5 mutants. Together, our study using zebrafish smarca5 mutants not only characterizes a novel role for smarca5 in blood clot formation, but also provides a new venous thrombosis animal model to support drug screening and pre-clinical therapeutic assessments to treat thrombosis.

scholarly journals The chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Yanyan Ding ◽  
Yuzhe Li ◽  
Zhiqian Zhao ◽  
Qiangfeng Cliff Zhang ◽  
Feng Liu
Keyword(s):  
Blood Clot ◽  
Underlying Mechanism ◽  
Chromatin Accessibility ◽  
Clot Formation ◽  
Erythrocyte Aggregation ◽  
Thrombin Inhibitor ◽  
Zebrafish Model ◽  
Nrf2 Signaling Pathway ◽  
Rbc Aggregation ◽  
Therapeutic Assessments

Although thrombosis has been extensively studied using various animal models, our understanding of the underlying mechanism remains elusive. Here, using zebrafish model, we demonstrated that smarca5-deficient red blood cells (RBCs) formed blood clots in the caudal vein plexus. We further used the anti-thrombosis drugs to treat smarca5zko1049a embryos and found that a thrombin inhibitor, argatroban, partially prevented blood clot formation in smarca5zko1049a. To explore the regulatory mechanism of smarca5 in RBC homeostasis, we profiled the chromatin accessibility landscape and transcriptome features in RBCs from smarca5zko1049a and their siblings and found that both the chromatin accessibility at the keap1a promoter and expression of keap1a were decreased. Keap1 is a suppressor protein of Nrf2, which is a major regulator of oxidative responses. We further identified that the expression of hmox1a, a downstream target of Keap1-Nrf2 signaling pathway, was markedly increased upon smarca5 deletion. Importantly, overexpression of keap1a or knockdown of hmox1a partially rescued the blood clot formation, suggesting that the disrupted Keap1-Nrf2 signaling is responsible for the RBC aggregation in smarca5 mutants. Together, our study using zebrafish smarca5 mutants characterizes a novel role for smarca5 in RBC aggregation, which may provide a new venous thrombosis animal model to support drug screening and pre-clinical therapeutic assessments to treat thrombosis.

Effect of Progesterone and Synthetic Progestins on Whole Blood Clot Formation and Erythrocyte Structure

2017 ◽  
Vol 23 (3) ◽  
pp. 607-617 ◽  
Author(s):  
Albe C. Swanepoel ◽  
Odette Emmerson ◽  
Etheresia Pretorius
Keyword(s):  
Whole Blood ◽  
Blood Clot ◽  
Thrombotic Event ◽  
Clot Formation ◽  
Erythrocyte Aggregation ◽  
Erythrocyte Morphology ◽  
Increased Risk ◽  
Blood Clots ◽  
Membrane Ultrastructure

AbstractCombined oral contraceptive (COC) use is a risk factor for venous thrombosis (VT) and related to the specific type of progestin used. VT is accompanied by inflammation and pathophysiological clot formation, that includes aberrant erythrocytes and fibrin(ogen) interactions. In this paper, we aim to determine the influence of progesterone and different synthetic progestins found in COCs on the viscoelasticity of whole blood clots, as well as erythrocyte morphology and membrane ultrastructure, in an in vitro laboratory study. Thromboelastography (TEG), light microscopy, and scanning electron microscopy were our chosen methods. Our results point out that progestins influence the rate of whole blood clot formation. Alterations to erythrocyte morphology and membrane ultrastructure suggest the presence of eryptosis. We also note increased rouleaux formation, erythrocyte aggregation, and spontaneous fibrin formation in whole blood which may explain the increased risk of VT associated with COC use. Although not all COC users will experience a thrombotic event, individuals with a thrombotic predisposition, due to inflammatory or hematological illness, should be closely monitored to prevent pathological thrombosis.

scholarly journals IL-20R Activation via rIL-19 Enhances Hematoma Resolution through the IL-20R1/ERK/Nrf2 Pathway in an Experimental GMH Rat Pup Model

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Shengpeng Liu ◽  
Jerry J. Flores ◽  
Bo Li ◽  
Shuixiang Deng ◽  
Gang Zuo ◽  
...  
Keyword(s):  
Blood Clot ◽  
Scavenger Receptor ◽  
Underlying Mechanism ◽  
Neurological Deficits ◽  
Long Term Results ◽  
Primary Role ◽  
Sprague Dawley ◽  
Rat Pups ◽  
Cd163 Expression ◽  
Nrf2 Signaling Pathway

Aims. Blood clots play the primary role in neurological deficits after germinal matrix hemorrhage (GMH). Previous studies have shown a beneficial effect in blood clot clearance after hemorrhagic stroke. The purpose of this study is to investigate interleukin-19’s role in hematoma clearance after GMH and its underlying mechanism of IL-20R1/ERK/Nrf2 signaling pathway. Methods. A total of 240 Sprague-Dawley P7 rat pups were used. GMH was induced by intraparenchymal injection of bacterial collagenase. rIL-19 was administered intranasally 1 hour post-GMH. IL-20R1 CRISPR was administered intracerebroventricularly, or Nrf2 antagonist ML385 was administered intraperitoneally 48 hours and 1 hour before GMH induction, respectively. Neurobehavior, Western blot, immunohistochemistry, histology, and hemoglobin assay were used to evaluate treatment regiments in the short- and long-term. Results. Endogenous IL-19, IL-20R1, IL-20R2, and scavenger receptor CD163 were increased after GMH. rIL-19 treatment improved neurological deficits, reduced hematoma volume and hemoglobin content, reduced ventriculomegaly, and attenuated cortical thickness loss. Additionally, treatment increased ERK, Nrf2, and CD163 expression, whereas IL-20R1 CRISPR-knockdown plasmid and ML385 inhibited the effects of rIL-19 on CD163 expression. Conclusion. rIL-19 treatment improved hematoma clearance and attenuated neurological deficits induced by GMH, which was mediated through the upregulation of the IL-20R1/ERK/Nrf2 pathways. rIL-19 treatment may provide a promising therapeutic strategy for the GMH patient population.

scholarly journals Inner Ear and Muscle Developmental Defects in Smpx-Deficient Zebrafish Embryos

2021 ◽  
Vol 22 (12) ◽  
pp. 6497
Author(s):  
Anna Ghilardi ◽  
Alberto Diana ◽  
Renato Bacchetta ◽  
Nadia Santo ◽  
Miriam Ascagni ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Inner Ear ◽  
Hair Cells ◽  
Muscle Fibers ◽  
Underlying Mechanism ◽  
Loss Of Function ◽  
Zebrafish Model ◽  
Developmental Defects ◽  
Inner Ear Development ◽  
Syndromic Hearing Loss

The last decade has witnessed the identification of several families affected by hereditary non-syndromic hearing loss (NSHL) caused by mutations in the SMPX gene and the loss of function has been suggested as the underlying mechanism. In the attempt to confirm this hypothesis we generated an Smpx-deficient zebrafish model, pointing out its crucial role in proper inner ear development. Indeed, a marked decrease in the number of kinocilia together with structural alterations of the stereocilia and the kinocilium itself in the hair cells of the inner ear were observed. We also report the impairment of the mechanotransduction by the hair cells, making SMPX a potential key player in the construction of the machinery necessary for sound detection. This wealth of evidence provides the first possible explanation for hearing loss in SMPX-mutated patients. Additionally, we observed a clear muscular phenotype consisting of the defective organization and functioning of muscle fibers, strongly suggesting a potential role for the protein in the development of muscle fibers. This piece of evidence highlights the need for more in-depth analyses in search for possible correlations between SMPX mutations and muscular disorders in humans, thus potentially turning this non-syndromic hearing loss-associated gene into the genetic cause of dysfunctions characterized by more than one symptom, making SMPX a novel syndromic gene.

The Haemocompatibility of Biomaterials In Vitro: Investigations on the Mechanism of the Whole-blood Clot Formation Test

1992 ◽  
Vol 20 (3) ◽  
pp. 390-395 ◽  
Author(s):  
Thomas Groth ◽  
Katrin Derdau ◽  
Frank Strietzel ◽  
Frank Foerster ◽  
Hartmut Wolf
Keyword(s):  
Whole Blood ◽  
Blood Clotting ◽  
Blood Clot ◽  
Formation Rate ◽  
Clot Formation ◽  
Coagulation Cascade ◽  
Contact Activation ◽  
Human Fibrinogen ◽  
Static Conditions

Twenty years ago Imai & Nose introduced a whole-blood clotting test for the estimation of haemocompatibility of biomaterials in vitro In our paper a modification of this assay is described and the mechanism of clot formation further elucidated. It was found that neither the inhibition of platelet function nor the removal of platelets from blood significantly changed the clot formation rate on glass and polyvinyl chloride in comparison to the rate tor whole blood. Scanning electron microscopy demonstrated that platelets were not involved in clot formation near the blood/biomaterial interface. Thus, it was concluded that the system of contact activation of the coagulation cascade dominates during clot formation under static conditions. The latter conclusion was supported by the fact that preadsorption of human serum albumin or human fibrinogen onto the glass plates used, decreased the clot formation rate in the same manner.

Clinical Outcomes in Atrial Fibrillation Patients With a History of Cancer Treated With Non-Vitamin K Antagonist Oral Anticoagulants: A Nationwide Cohort Study

Stroke ◽  
2021 ◽  
Author(s):  
Yi-Hsin Chan ◽  
Tze-Fan Chao ◽  
Hsin-Fu Lee ◽  
Shao-Wei Chen ◽  
Pei-Ru Li ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Cohort Study ◽  
Propensity Score ◽  
Venous Thrombosis ◽  
Clinical Outcomes ◽  
Lower Risk ◽  
Hazard Ratio ◽  
Thrombin Inhibitor ◽  
Major Adverse Cardiovascular Events ◽  
Research Database

Background and Purpose: Data on clinical outcomes for nonvitamin K antagonist oral anticoagulant (NOACs) and warfarin in patients with atrial fibrillation and cancer are limited, and patients with active cancer were excluded from randomized trials. We investigated the effectiveness and safety for NOACs versus warfarin among patients with atrial fibrillation with cancer. Methods: In this nationwide retrospective cohort study from Taiwan National Health Insurance Research Database, we identified a total of 6274 and 1681 consecutive patients with atrial fibrillation with cancer taking NOACs and warfarin from June 1, 2012, to December 31, 2017, respectively. Propensity score stabilized weighting was used to balance covariates across study groups. Results: There were 1031, 1758, 411, and 3074 patients treated with apixaban, dabigatran, edoxaban, and rivaroxaban, respectively. After propensity score stabilized weighting, NOAC was associated with a lower risk of major adverse cardiovascular events (hazard ratio, 0.63 [95% CI, 0.50–0.80]; P =0.0001), major adverse limb events (hazard ratio, 0.41 [95% CI, 0.24–0.70]; P =0.0010), venous thrombosis (hazard ratio, 0.37 [95% CI, 0.23–0.61]; P <0.0001), and major bleeding (hazard ratio, 0.73 [95% CI, 0.56–0.94]; P =0.0171) compared with warfarin. The outcomes were consistent with either direct thrombin inhibitor (dabigatran) or factor Xa inhibitor (apixaban, edoxaban, and rivaroxaban) use, among patients with stroke history, and among patients with different type of cancer and local, regional, or metastatic stage of cancer ( P interaction >0.05). When compared with warfarin, NOAC was associated with lower risk of major adverse cardiovascular event, and venous thrombosis in patients aged <75 but not in those aged ≥75 years ( P interaction <0.05). Conclusions: Thromboprophylaxis with NOACs rather than warfarin should be considered for the majority of the atrial fibrillation population with cancer.

scholarly journals Anticoagulant Polyethylene Terephthalate Surface by Plasma-Mediated Fucoidan Immobilization

Polymers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 750 ◽  
Author(s):  
Kadir Ozaltin ◽  
Marian Lehocky ◽  
Petr Humpolicek ◽  
Jana Pelkova ◽  
Antonio Di Martino ◽  
...  
Keyword(s):  
Polyethylene Terephthalate ◽  
Photoelectron Spectroscopy ◽  
Anticoagulant Activity ◽  
Blood Clot ◽  
Clot Formation ◽  
Thrombin Time ◽  
Air Plasma ◽  
Water Contact ◽  
Polymeric Biomaterials ◽  
Performance Surface

Biomaterial-based blood clot formation is one of the biggest drawbacks of blood-contacting devices. To avoid blood clot formation, their surface must be tailored to increase hemocompatibility. Most synthetic polymeric biomaterials are inert and lack bonding sites for chemical agents to bond or tailor to the surface. In this study, polyethylene terephthalate was subjected to direct current air plasma treatment to enhance its surface energy and to bring oxidative functional binding sites. Marine-sourced anticoagulant sulphated polysaccharide fucoidan from Fucus vesiculosus was then immobilized onto the treated polyethylene terephthalate (PET) surface at different pH values to optimize chemical bonding behavior and therefore anticoagulant performance. Surface properties of samples were monitored using the water contact angle; chemical analyses were performed by FTIR and X-ray photoelectron spectroscopy (XPS) and their anticoagulant activity was tested by means of prothrombin time, activated partial thromboplastin time and thrombin time. On each of the fucoidan-immobilized surfaces, anticoagulation activity was performed by extending the thrombin time threshold and their pH 5 counterpart performed the best result compared to others.

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