Abstract 29: Chronic Stress Predisposes to Thrombosis by Abnormal Megakaryopiesis: Protective Effect of Apocynin

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Leonardo Sandrini ◽  
Alessandro Ieraci ◽  
Elisa Turra ◽  
Patrizia Amadio ◽  
Maurizio Popoli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nadph Oxidase ◽  
Chronic Stress ◽  
Redox Balance ◽  
Antioxidant Systems ◽  
Ros Generation ◽  
Reticulated Platelets ◽  
Stress Studies ◽  
Coronary Syndromes ◽  
Maturation State

Introduction: Psychological stress (e.g. anxiety and depression) has been identified as an important trigger of acute coronary syndromes (ACS), as a consequence of enhanced coagulation and of hyper-reactive platelets. Changes in redox balance, alteration of genes regulating antioxidant systems, including NADPH oxidase, and increased production of reactive oxygen species (ROS) have been measured in both chronic stress and ACS. However, the mechanisms by which chronic stress affects platelet activation and predisposes to thrombosis are not well known. Hypothesis: We hypothesized that Apocynin, an inhibitor of NADPH oxidase influences the alteration of megakaryopoiesis and activation of platelets induced by chronic stress in mice. Methods and Results: We show the NADPH/NADP + ratio in bone marrow (BM) of mice exposed to forced swimming for 4 days (5 min twice/day) is markedly reduced compared to control mice, and that Apocynin treatment (2.4 mg/ml in drinking water for 4 days) prevents this alteration. Chronic stress leads to an abnormal megakaryopoiesis increasing the number of BM megakaryocytes (MKs) and affecting circulating platelets. MKs of stressed mice show an advanced maturation state (e.g. nuclear/cytoplasmic ratios and expression of CD42d), and an enhanced ability to produce ROS. Interestingly, a higher number of large and reticulated platelets with marked functional activation (e.g. integrin α IIb β3 and P-selectin expression, and platelet/leukocyte aggregates) is detected after chronic stress. In addition, Apocynin prevents ROS MKs generation and decreases the total number of MKs without affecting the percentage of CD42d + cells. Finally, the inhibitor of NADPH oxidase activity reduces the hyper-activation of platelets and the enhanced susceptibility to FeCl3-induced arterial thrombosis in stressed mice. Conclusion: Apocynin treatment, reducing ROS generation in MKs, restores the physiological bone marrow megakaryopoiesis and platelet behaviour, and it prevents the detrimental effect of chronic stress on atherothrombosis. These data suggest a potential use of NADPH oxidase inhibitors in the occurrence of thrombosis associated with chronic stress. Studies in human will verify the clinical impact of these findings.

scholarly journals Apocynin Prevents Abnormal Megakaryopoiesis and Platelet Activation Induced by Chronic Stress

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Leonardo Sandrini ◽  
Alessandro Ieraci ◽  
Patrizia Amadio ◽  
Maurizio Popoli ◽  
Elena Tremoli ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Platelet Activation ◽  
Redox Balance ◽  
Reticulated Platelets ◽  
Swimming Stress ◽  
Coronary Syndromes ◽  
Maturation State ◽  
The Impact ◽  
Potential Use ◽  
Plasma Malondialdehyde

Environmental chronic stress (ECS) has been identified as a trigger of acute coronary syndromes (ACS). Changes in redox balance, enhanced reactive oxygen species (ROS) production, and platelet hyperreactivity were detected in both ECS and ACS. However, the mechanisms by which ECS predisposes to thrombosis are not fully understood. Here, we investigated the impact of ECS on platelet activation and megakaryopoiesis in mice and the effect of Apocynin in this experimental setting. ECS induced by 4 days of forced swimming stress (FSS) treatment predisposed to arterial thrombosis and increased oxidative stress (e.g., plasma malondialdehyde levels). Interestingly, Apocynin treatment prevented these alterations. In addition, FSS induced abnormal megakaryopoiesis increasing the number and the maturation state of bone marrow megakaryocytes (MKs) and affecting circulating platelets. In particular, a higher number of large and reticulated platelets with marked functional activation were detected after FSS. Apocynin decreased the total MK number and prevented their ability to generate ROS without affecting the percentage of CD42d+ cells, and it reduced the platelet hyperactivation in stressed mice. In conclusion, Apocynin restores the physiological megakaryopoiesis and platelet behavior, preventing the detrimental effect of chronic stress on thrombosis, suggesting its potential use in the occurrence of thrombosis associated with ECS.

Glucosamine Protects Rat Bone Marrow Cells Against Cisplatin-induced Genotoxicity and Cytotoxicity

2019 ◽  
Vol 19 (14) ◽  
pp. 1695-1702 ◽  
Author(s):  
Mohsen Cheki ◽  
Salman Jafari ◽  
Masoud Najafi ◽  
Aziz Mahmoudzadeh
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Micronucleus Assay ◽  
Ros Generation ◽  
Polychromatic Erythrocytes ◽  
Hematological Analysis ◽  
Antagonistic Potential ◽  
Harmful Effects ◽  
Rat Bone ◽  
Marrow Cells

Background and Objective: Glucosamine is a widely prescribed dietary supplement used in the treatment of osteoarthritis. In the present study, the chemoprotectant ability of glucosamine was evaluated against cisplatin-induced genotoxicity and cytotoxicity in rat bone marrow cells. Methods: Glucosamine was orally administrated to rats at doses of 75 and 150 mg/kg body weight for seven consecutive days. On the seventh day, the rats were treated with a single injection of cisplatin (5 mg/kg, i.p.) at 1h after the last oral administration. The cisplatin antagonistic potential of glucosamine was assessed by micronucleus assay, Reactive Oxygen Species (ROS) level analysis, hematological analysis, and flow cytometry. Results: Glucosamine administration to cisplatin-treated rats significantly decreased the frequencies of Micronucleated Polychromatic Erythrocytes (MnPCEs) and Micronucleated Normchromatic Erythrocytes (MnNCEs), and also increased PCE/(PCE+NCE) ratio in bone marrow cells. Furthermore, treatment of rats with glucosamine before cisplatin significantly inhibited apoptosis, necrosis and ROS generation in bone marrow cells, and also increased red blood cells count in peripheral blood. Conclusion: This study shows glucosamine to be a new effective chemoprotector against cisplatin-induced DNA damage and apoptosis in rat bone marrow cells. The results of this study may be helpful in reducing the harmful effects of cisplatin-based chemotherapy in the future.

scholarly journals Physical Activity and Redox Balance in the Elderly: Signal Transduction Mechanisms

2021 ◽  
Vol 11 (5) ◽  
pp. 2228
Author(s):  
Daniela Galli ◽  
Cecilia Carubbi ◽  
Elena Masselli ◽  
Mauro Vaccarezza ◽  
Valentina Presta ◽  
...  
Keyword(s):  
Physical Activity ◽  
Molecular Mechanisms ◽  
Vascular Tissue ◽  
The Elderly ◽  
Redox Balance ◽  
Antioxidant Systems ◽  
Targeted Prevention ◽  
Individual Subject ◽  
Aged People ◽  
The Individual

Reactive Oxygen Species (ROS) are molecules naturally produced by cells. If their levels are too high, the cellular antioxidant machinery intervenes to bring back their quantity to physiological conditions. Since aging often induces malfunctioning in this machinery, ROS are considered an effective cause of age-associated diseases. Exercise stimulates ROS production on one side, and the antioxidant systems on the other side. The effects of exercise on oxidative stress markers have been shown in blood, vascular tissue, brain, cardiac and skeletal muscle, both in young and aged people. However, the intensity and volume of exercise and the individual subject characteristics are important to envisage future strategies to adequately personalize the balance of the oxidant/antioxidant environment. Here, we reviewed the literature that deals with the effects of physical activity on redox balance in young and aged people, with insights into the molecular mechanisms involved. Although many molecular pathways are involved, we are still far from a comprehensive view of the mechanisms that stand behind the effects of physical activity during aging. Although we believe that future precision medicine will be able to transform exercise administration from wellness to targeted prevention, as yet we admit that the topic is still in its infancy.

Antiplatelet drugs in patients with enhanced platelet turnover: biomarkers versus platelet function testing

2015 ◽  
Vol 114 (09) ◽  
pp. 459-468 ◽  
Author(s):  
Susanne Gruber ◽  
Erik Grove ◽  
Thomas Weiss ◽  
Johann Wojta ◽  
Kurt Huber ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Platelet Reactivity ◽  
Platelet Inhibition ◽  
Antiplatelet Drugs ◽  
P2y12 Inhibitors ◽  
Reticulated Platelets ◽  
Increased Risk ◽  
Key Factor ◽  
Coronary Syndromes ◽  
Function Testing

SummaryPlatelets are key players in atherothrombosis. Antiplatelet therapy comprising aspirin alone or with P2Y12-inhibitors are effective for prevention of atherothrombotic complications. However, there is interindividual variability in the response to antiplatelet drugs, leaving some patients at increased risk of recurrent atherothrombotic events. Several risk factors associated with high on-treatment platelet reactivity (HTPR), including elevated platelet turnover, have been identified. Platelet turnover is adequately estimated from the fraction of reticulated platelets. Reticulated platelets are young platelets, characterised by residual messenger RNA. They are larger, haemostatically more active and there is evidence that platelet turnover is a causal and prognostic factor in atherothrombotic disease. Whether platelet turnover per se represents a key factor in pathogenesis, progression and prognosis of atherothrombotic diseases (with focus on acute coronary syndromes) or whether it merely facilitates insufficient platelet inhibition will be discussed in this state-of-the art review.

Abstract 107: Apocynin Attenuates Isoproterenol-induced Myocardial Injury: Implications For Targeting Nadph Oxidase In Myocardial Fibrogenesis

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Yu Chen ◽  
Jingang Cui ◽  
Qinbo Yang ◽  
Chenglin Jia ◽  
Minqi Xiong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Myocardial Fibrosis ◽  
Myocardial Injury ◽  
Oxidase Inhibitor ◽  
Ros Generation ◽  
Dependent Manner ◽  
Expression Of Genes ◽  
Therapeutic Development ◽  
Myocardial Injuries

Myocardial fibrosis results from cardiac injuries caused by various pathophysiological mechanisms including myocardial infarction, leading to destruction of myocardial architecture and progressive cardiac dysfunction. Oxidative stress is likely involved in myocardial ischemic injury and the subsequent tissue remodeling mediated by myocardial fibrogenesis. Our current study aimed to evaluate the implication of NADPH oxidase in overproduction of reactive oxygen species and its contribution to the pathogenesis of myocardial fibrogenesis after ischemic injuries. The effects of Apocynin, a selective NADPH oxidase inhibitor, were evaluated in the mouse model of isoproterenol-induced myocardial injury by histopathological approaches and whole-genome gene expression profiling. The results demonstrated that Apocynin was able to inhibit the development of ISO-induced myocardial necrotic lesions and fibrogenesis in a dose-dependent manner. Moreover, the preventive effects of Apocynin on myocardial injuries were associated with suppressed expression of genes implicated in inflammation responses and extracellular matrix, which were remarkably upregulated by isoproterenol administration. In summary, o ur study provides proof-of-concept for the involvement of NADPH oxidase-mediated ROS generation in myocardial ischemic injuries and fibrogenesis, which will benefit the mechanism-based therapeutic development targeting NADPH oxidase and oxidative stress in treating myocardial fibrosis and related disorders.

Abstract 177: Promotion Of Nitroso-redox Balance By Beta 3 Adrenoceptor Agonism: Therapeutic Implications For Cardiovascular Complications Of Diabetes

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Keyvan Karimi Galougahi ◽  
Chia-chi Liu ◽  
Alvaro Garcia ◽  
Natasha A Fry ◽  
Clare L Hawkins ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Cardiac Myocytes ◽  
Vascular Dysfunction ◽  
Pump Current ◽  
Redox Balance ◽  
Cardiovascular Complications ◽  
Oxidative Modification ◽  
Oxidation Products ◽  
Therapeutic Implications ◽  
Endothelial Nitric Oxide

Rationale: Disrupted balance between NO and O2.- is central in pathobiology of diabetes-induced cardiomyopathy and vascular dysfunction. We examined if stimulation of β3 adrenergic receptors (β3 ARs), coupled to endothelial nitric oxide synthase (eNOS) activation, would re-establish NO/O2.- balance, relieve oxidative inhibition of key caveolar proteins and protect against diabetes-induced cardiovascular dysfunction. Methods/Results: A hyperglycemic, hyperinsulinemic state was established in male White New Zealand rabbits by infusion of the insulin receptor antagonist S961 (12 μg/kg/h). Diabetes induced NADPH oxidase-dependent glutathionylation (GSS-) of the caveolar proteins Na+-K+ pump’s β1 subunit and eNOS in cardiac myocytes and aorta, an oxidative modification that inhibits the pump and uncouples eNOS. Consistent with this, diabetes was associated with reduced electrogenic Na+-K+ pump current in voltage-clamped cardiac myocytes and impaired endothelium-dependent vasorelaxation. Selective β3 AR agonist CL316243 (CL, 40 μg/kg/h) restored NO levels analysed by spin-trapping of NO-Fe(DETC)2 complexes; decreased diabetes-induced elevation in O2.- measured by HPLC analysis of dihydroethidium oxidation products, improved endothelium-dependent vasorelaxation, and restored the Na+-K+ pump function in cardiac myocytes. These effects were mediated by CL abolishing diabetes-induced increase in eNOS-GSS and β1-GSS through a decrease in forward reaction rate for glutathionylation by suppressing diabetes-induced NADPH oxidase activation, which was further amplified by promotion of de-glutathionylation via enhancement in association of glutaredoxine-1, the enzyme catalysing de-glutathionylation, with eNOS and Na+-K+ pump. Conclusion: β3 AR activation re-established nitroso-redox balance and relieved oxidative inhibition of key caveolar proteins in diabetes. β3 AR agonists are promising in treatment of diabetes-induced cardiovascular complications.

scholarly journals NADPH Oxidase Inhibitor Apocynin Attenuates PCB153-Induced Thyroid Injury in Rats

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Ablikim Abliz ◽  
Chen Chen ◽  
Wenhong Deng ◽  
Weixing Wang ◽  
Rongze Sun
Keyword(s):  
Thyroid Hormone ◽  
Nadph Oxidase ◽  
Inflammatory Cytokines ◽  
Thyroid Dysfunction ◽  
Thyroid Tissue ◽  
Oxidase Inhibitor ◽  
Control Group ◽  
Ros Generation ◽  
Sprague Dawley ◽  
Serum Thyroid Hormone

PCBs, widespread endocrine disruptors, cause the disturbance of thyroid hormone (TH) homeostasis in humans and animals. However, the exact mechanism of thyroid dysfunction caused by PCBs is still unknown. In order to clarify the hypotheses that NADPH oxidase (NOX) and subsequent NF-κB pathway may play roles in thyroid dysfunction, sixty Sprague-Dawley rats were randomly divided into four groups: control group, PCB153 treated (PCB) group, received apocynin with PCB153 treatment (APO + PCB) group, and drug control (APO) group. Serum thyroid hormone levels were evaluated. The morphological change of thyroid tissue was analyzed under the light and transmission electron microscopy. NOX2, 8-OHdG, and NF-κB expression in the thyroid tissue was evaluated by immune-histochemical staining. Oxidative stress and inflammatory cytokines were detected. The following results were reduced after apocynin treatment: (1) serum thyroid hormone, (2) thyroid pathological injuries, (3) thyroid MDA, (4) thyroid ultrastructural change, (5) serum inflammatory cytokines, and (6) thyroid expression of NOX2, 8-OHdG, and NF-κB. These results suggested that NOX inhibition attenuates thyroid dysfunction induced by PCB in rats, presumably because of its role in preventing ROS generation and inhibiting the activation of NF-κB pathway. Our findings may provide new therapeutic targets for PCBs induced thyroid dysfunction.

scholarly journals Nox2 Activity Is Required in Obesity-Mediated Alteration of Bone Remodeling

2018 ◽  
Vol 2018 ◽  
pp. 1-10
Author(s):  
Md Mizanur Rahman ◽  
Amina El Jamali ◽  
Ganesh V. Halade ◽  
Allal Ouhtit ◽  
Haissam Abou-Saleh ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Marrow ◽  
Bone Remodeling ◽  
Bone Mineral ◽  
Bone Marrow Cells ◽  
Bone Marrow Microenvironment ◽  
Ros Generation ◽  
Chow Diet ◽  
Mineral Density ◽  
Marrow Cells

Despite increasing evidence suggesting a role for NADPH oxidases (Nox) in bone pathophysiology, whether Nox enzymes contribute to obesity-mediated bone remodeling remains to be clearly elucidated. Nox2 is one of the predominant Nox enzymes expressed in the bone marrow microenvironment and is a major source of ROS generation during inflammatory processes. It is also well recognized that a high-fat diet (HFD) induces obesity, which negatively impacts bone remodeling. In this work, we investigated the effect of Nox2 loss of function on obesity-mediated alteration of bone remodeling using wild-type (WT) and Nox2-knockout (KO) mice fed with a standard lab chow diet (SD) as a control or a HFD as an obesity model. Bone mineral density (BMD) of mice was assessed at the beginning and after 3 months of feeding with SD or HFD. Our results show that HFD increased bone mineral density to a greater extent in KO mice than in WT mice without affecting the total body weight and fat mass. HFD also significantly increased the number of adipocytes in the bone marrow microenvironment of WT mice as compared to KO mice. The bone levels of proinflammatory cytokines and proosteoclastogenic factors were also significantly elevated in WT-HFD mice as compared to KO-HFD mice. Furthermore, the in vitro differentiation of bone marrow cells into osteoclasts was significantly increased when using bone marrow cells from WT-HFD mice as compared to KO-HFD mice. Our data collectively suggest that Nox2 is implicated in HFD-induced deleterious bone remodeling by enhancing bone marrow adipogenesis and osteoclastogenesis.

scholarly journals Subplasmalemmal hydrogen peroxide triggers calcium influx in gonadotropes

2018 ◽  
Vol 293 (41) ◽  
pp. 16028-16042 ◽  
Author(s):  
An K. Dang ◽  
Nathan L. Chaplin ◽  
Dilyara A. Murtazina ◽  
Ulrich Boehm ◽  
Colin M. Clay ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Calcium Channels ◽  
Nadph Oxidase ◽  
Calcium Channel ◽  
Anterior Pituitary ◽  
Calcium Influx ◽  
Ros Generation ◽  
Primary Mouse ◽  
The Impact ◽  
Stimulation Of

Gonadotropin-releasing hormone (GnRH) stimulation of its eponymous receptor on the surface of endocrine anterior pituitary gonadotrope cells (gonadotropes) initiates multiple signaling cascades that culminate in the secretion of luteinizing and follicle-stimulating hormones, which have critical roles in fertility and reproduction. Enhanced luteinizing hormone biosynthesis, a necessary event for ovulation, requires a signaling pathway characterized by calcium influx through L-type calcium channels and subsequent activation of the mitogen-activated protein kinase extracellular signal-regulated kinase (ERK). We previously reported that highly localized subplasmalemmal calcium microdomains produced by L-type calcium channels (calcium sparklets) play an essential part in GnRH-dependent ERK activation. Similar to calcium, reactive oxygen species (ROS) are ubiquitous intracellular signaling molecules whose subcellular localization determines their specificity. To investigate the potential influence of oxidant signaling in gonadotropes, here we examined the impact of ROS generation on L-type calcium channel function. Total internal reflection fluorescence (TIRF) microscopy revealed that GnRH induces spatially restricted sites of ROS generation in gonadotrope-derived αT3-1 cells. Furthermore, GnRH-dependent stimulation of L-type calcium channels required intracellular hydrogen peroxide signaling in these cells and in primary mouse gonadotropes. NADPH oxidase and mitochondrial ROS generation were each necessary for GnRH-mediated stimulation of L-type calcium channels. Congruently, GnRH increased oxidation within subplasmalemmal mitochondria, and L-type calcium channel activity correlated strongly with the presence of adjacent mitochondria. Collectively, our results provide compelling evidence that NADPH oxidase activity and mitochondria-derived hydrogen peroxide signaling play a fundamental role in GnRH-dependent stimulation of L-type calcium channels in anterior pituitary gonadotropes.

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