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.

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.

Development of Strategies for Glycopeptide Synthesis: An Overview on the Glycosidic Linkage

2020 ◽  
Vol 24 (21) ◽  
pp. 2475-2497
Author(s):  
Andrea Verónica Rodríguez-Mayor ◽  
German Jesid Peralta-Camacho ◽  
Karen Johanna Cárdenas-Martínez ◽  
Javier Eduardo García-Castañeda
Keyword(s):  
Chemical Synthesis ◽  
Solid Phase ◽  
Building Blocks ◽  
Heterogeneous Environments ◽  
Phase Synthesis ◽  
Low Concentrations ◽  
Biological Sources ◽  
Synthetic Routes ◽  
The Impact ◽  
Potential Use

Glycoproteins and glycopeptides are an interesting focus of research, because of their potential use as therapeutic agents, since they are related to carbohydrate-carbohydrate, carbohydrate-protein, and carbohydrate-lipid interactions, which are commonly involved in biological processes. It has been established that natural glycoconjugates could be an important source of templates for the design and development of molecules with therapeutic applications. However, isolating large quantities of glycoconjugates from biological sources with the required purity is extremely complex, because these molecules are found in heterogeneous environments and in very low concentrations. As an alternative to solving this problem, the chemical synthesis of glycoconjugates has been developed. In this context, several methods for the synthesis of glycopeptides in solution and/or solid-phase have been reported. In most of these methods, glycosylated amino acid derivatives are used as building blocks for both solution and solid-phase synthesis. The synthetic viability of glycoconjugates is a critical parameter for allowing their use as drugs to mitigate the impact of microbial resistance and/or cancer. However, the chemical synthesis of glycoconjugates is a challenge, because these molecules possess multiple reaction sites and have a very specific stereochemistry. Therefore, it is necessary to design and implement synthetic routes, which may involve various protection schemes but can be stereoselective, environmentally friendly, and high-yielding. This review focuses on glycopeptide synthesis by recapitulating the progress made over the last 15 years.

Value assessment of antimicrobials and the implications for development, access, and funding of effective treatments: Australian stakeholder perspective

2020 ◽  
pp. 1-7
Author(s):  
Nadine T. Hillock ◽  
Tracy L. Merlin ◽  
Jonathan Karnon ◽  
John Turnidge ◽  
Jaklin Eliott
Keyword(s):  
Cost Effectiveness ◽  
Healthcare Resource ◽  
Economic Evaluations ◽  
Value Assessment ◽  
Antimicrobial Drugs ◽  
Policy Makers ◽  
Stakeholder Perspective ◽  
Definition Of ◽  
The Impact ◽  
Potential Use

Abstract Background The frameworks used by Health Technology Assessment (HTA) agencies for value assessment of medicines aim to optimize healthcare resource allocation. However, they may not be effective at capturing the value of antimicrobial drugs. Objectives To analyze stakeholder perceptions regarding how antimicrobials are assessed for value for reimbursement purposes and how the Australian HTA framework accommodates the unique attributes of antimicrobials in cost-effectiveness evaluation. Methods Eighteen individuals representing the pharmaceutical industry or policy-makers were interviewed. Interviews were transcribed verbatim, coded, and thematically analyzed. Results Key emergent themes were that reimbursement decision-making should consider the antibiotic spectrum when assessing value, risk of shortages, the impact of procurement processes on low-priced comparators, and the need for methodological transparency when antimicrobials are incorporated into the economic evaluation of other treatments. Conclusions Participants agreed that the current HTA framework for antimicrobial value assessment is inadequate to properly inform funding decisions, as the contemporary definition of cost-effectiveness fails to explicitly incorporate the risk of future resistance. Policy-makers were uncertain about how to incorporate future resistance into economic evaluations without a systematic method to capture costs avoided due to good stewardship. Lacking financial reward for the benefits of narrower-spectrum antimicrobials, companies will likely focus on developing broad-spectrum agents with wider potential use. The perceived risks of shortages have influenced the funding of generic antimicrobials in Australia, with policy-makers suggesting a willingness to pay more for assured supply. Although antibiotics often underpin the effectiveness of other medicines, it is unclear how this is incorporated into economic models.

scholarly journals Neurotrophins as Key Regulators of Cell Metabolism: Implications for Cholesterol Homeostasis

2021 ◽  
Vol 22 (11) ◽  
pp. 5692
Author(s):  
Mayra Colardo ◽  
Noemi Martella ◽  
Daniele Pensabene ◽  
Silvia Siteni ◽  
Sabrina Di Bartolomeo ◽  
...  
Keyword(s):  
Growth Factors ◽  
Cholesterol Metabolism ◽  
System Development ◽  
Cell Metabolism ◽  
Redox Balance ◽  
Nervous System Development ◽  
Cholesterol Homeostasis ◽  
Signaling Cascades ◽  
Target Cells ◽  
The Impact

Neurotrophins constitute a family of growth factors initially characterized as predominant mediators of nervous system development, neuronal survival, regeneration and plasticity. Their biological activity is promoted by the binding of two different types of receptors, leading to the generation of multiple and variegated signaling cascades in the target cells. Increasing evidence indicates that neurotrophins are also emerging as crucial regulators of metabolic processes in both neuronal and non-neuronal cells. In this context, it has been reported that neurotrophins affect redox balance, autophagy, glucose homeostasis and energy expenditure. Additionally, the trophic support provided by these secreted factors may involve the regulation of cholesterol metabolism. In this review, we examine the neurotrophins’ signaling pathways and their effects on metabolism by critically discussing the most up-to-date information. In particular, we gather experimental evidence demonstrating the impact of these growth factors on cholesterol metabolism.

scholarly journals Impact of COVID-19 pandemic on stroke admissions in Qatar

2021 ◽  
Vol 3 (1) ◽  
pp. e000084
Author(s):  
Naveed Akhtar ◽  
Salman Al Jerdi ◽  
Ziyad Mahfoud ◽  
Yahia Imam ◽  
Saadat Kamran ◽  
...  
Keyword(s):  
Hospital Admissions ◽  
Small Vessel Disease ◽  
Tertiary Care ◽  
Relative Increase ◽  
Large Vessel ◽  
Tertiary Care Centre ◽  
Transient Ischaemic Attacks ◽  
Stroke Mimics ◽  
Coronary Syndromes ◽  
The Impact

IntroductionThe COVID-19 pandemic has resulted in a dramatic unexplained decline in hospital admissions due to acute coronary syndromes and stroke. Several theories have emerged aiming to explain this decline, mostly revolving around the fear of contracting the disease and thus avoiding hospital visits.AimsIn this study, we aim to examine the impact of the COVID-19 pandemic on stroke admissions to a tertiary care centre in Qatar.MethodsThe Hamad General Hospital stroke database was interrogated for stroke admissions between September 2019 and May 2020. The number of stroke admissions, stroke subtypes and short-term outcomes was compared between the ‘pre-COVID-19’ period (September 2019 to February 2020) and the COVID-19 pandemic period (March to May 2020).ResultsWe observed a significant decline in monthly admissions in March (157), April (128) and May (135) compared with the pre-COVID-19 6-month average (229) (p=0.024). The reduction in admissions was most evident in functional stroke mimics. The average admissions decreased from 87 to 34 per month (p=0.0001). Although there were no significant differences in admissions due to ischaemic stroke (IS), intracranial haemorrhage or transient ischaemic attacks between the two periods, we noted a relative decrease in IS due to small vessel disease and an increase in those due to large vessel atherosclerosis in March to May 2020.ConclusionsThe decline in overall stroke admissions during the COVID-19 pandemic is most likely related to concerns of contracting the infection, evidenced mainly by a decline in admissions of stroke mimics. However, a relative increase in large vessel occlusions raises suspicion of pathophysiological effects of the virus, and requires further investigation.

scholarly journals The Impact of “Manipulated News” on Student Attitudes and Perceptions and Their Participation in the Umbrella Movement in Hong Kong

2021 ◽  
Vol 7 (2) ◽  
pp. 205630512110197
Author(s):  
Chesca Ka Po Wong ◽  
Runping Zhu ◽  
Richard Krever ◽  
Alfred Siu Choi
Keyword(s):  
Social Media ◽  
Content Analysis ◽  
Hong Kong ◽  
Survey Research ◽  
Student Attitudes ◽  
Qualitative Content Analysis ◽  
Fake News ◽  
Attitudes And Perceptions ◽  
The Impact ◽  
Potential Use

While the impact of fake news on viewers, particularly marginalized media users, has been a cause of growing concern, there has been little attention paid to the phenomenon of deliberately “manipulated” news published on social media by mainstream news publishers. Using qualitative content analysis and quantitative survey research, this study showed that consciously biased animated news videos released in the midst of the Umbrella Movement protests in Hong Kong impacted on both the attitudes of students and their participation in the protests. The findings raise concerns over potential use of the format by media owners to promote their preferred ideologies.

Canadian Ice Wine Production: A Case for the Use of Weather Derivatives

2007 ◽  
Vol 2 (2) ◽  
pp. 145-167 ◽  
Author(s):  
Don Cyr ◽  
Martin Kusy
Keyword(s):  
Jel Classification ◽  
Seasonal Temperature ◽  
Weather Derivatives ◽  
Wine Production ◽  
Option Values ◽  
Temperature Variable ◽  
Ice Wine ◽  
The Impact ◽  
Potential Use ◽  
Underlying Variable

AbstractWeather derivatives are a relatively new form of financial security that can provide firms with the ability to hedge against the impact of weather related risks to their activities. Participants in the energy industry have employed standardized weather contracts trading on organized exchanges since 1999 and the interest in non-standardized contracts for specialized weather related risks is growing at an increasing rate. The purpose of this paper is to examine the potential use of weather derivatives to hedge against temperature related risks in Canadian ice wine production. Specifically we examine historical data for the Niagara region of the province of Ontario, Canada, the largest icewine producing region of the world, to determine an appropriate underlying variable for the design of an option contact that could be employed by icewine producers. Employing monte carlo simulation we derive a range of benchmark option values based upon varying assumptions regarding the stochastic process for an underlying temperature variable. The results show that such option contracts can provide valuable hedging opportunities for producers, given the historical seasonal temperature variations in the region. (JEL Classification: G13, G32, Q14, Q51, Q54)

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.

Partially desulfated heparin modulates the interaction between anti-protamine/heparin antibodies and platelets

2016 ◽  
Vol 115 (02) ◽  
pp. 324-332 ◽  
Author(s):  
Rabie Jouni ◽  
Heike Zöllner ◽  
Ahmad Khadour ◽  
Jan Wesche ◽  
Anne Grotevendt ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Platelet Factor ◽  
Standard Drug ◽  
Platelet Surface ◽  
Minimal Impact ◽  
Platelet Survival ◽  
Heparin Complexes ◽  
The Impact

SummaryProtamine (PRT) is the standard drug to neutralise heparin. PRT/heparin complexes induce an immune response similar to that observed in heparin-induced thrombocytopenia (HIT). Partially desulfated heparin (ODSH) was shown to interfere with anti-platelet factor 4/heparin antibodies (Abs), which are responsible for HIT. In this study, we analyse the impact of ODSH on the interaction between anti-PRT/heparin Abs and platelets. The ability of ODSH to prevent anti-PRT/heparin Ab-induced platelet destruction in vivo was investigated using the NOD/ SCID mouse model. ODSH improved platelet survival in the presence of PRT, heparin and anti-PRT/heparin Abs (median platelet survival after 300 minutes (min) with 20 μg/ml ODSH: 75 %, range 70–81 % vs without ODSH: 49%, range 44–59%, p=0.006). Furthermore, when ODSH was applied 60 min after Ab injection platelet survival was improved (median platelet survival after 300 min with ODSH: 83 %, range 77–93 % vs without ODSH: 59 %, range 29–61 %, p=0.02). In in vitro experiments ODSH inhibited platelet activation at concentrations > 16 μg/mL (p< 0.001), as well as PRT/heparin complex binding to platelets (mean fluorescence intensity [MFI] without ODSH: 85 ± 14 vs with ODSH: 15 ± 0.6, p=0.013). ODSH also displaced pre-bound complexes from the platelet surface (MFI without ODSH: 324 ± 43 vs with 32 μg/ml ODSH: 53 ± 9, p< 0.001). While interfering with platelet activation by anti-PRT/heparin Abs, up to a concentration of 16 μg/ml, ODSH had only minimal impact on neutralisation of heparin by PRT. In conclusion, our study shows that ODSH is able to inhibit platelet activation and destruction suggesting a potential clinical use to reduce anti-PRT/heparin Ab-mediated adverse effects.

scholarly journals Computational Analysis of the Impact of Chronic Stress on Intrinsic and Synaptic Excitability in the Hippocampus

2010 ◽  
Vol 103 (6) ◽  
pp. 3070-3083 ◽  
Author(s):  
Rishikesh Narayanan ◽  
Sumantra Chattarji
Keyword(s):  
Chronic Stress ◽  
Pyramidal Neurons ◽  
Three Dimensional ◽  
Input Resistance ◽  
Synaptic Potentiation ◽  
Synaptic Inputs ◽  
Hippocampal Ca3 ◽  
Ca3 Pyramidal Neurons ◽  
Dendritic Atrophy ◽  
The Impact

Dendritic atrophy and impaired long-term synaptic potentiation (LTP) are hallmarks of chronic stress-induced plasticity in the hippocampus. It has been hypothesized that these disparate structural and physiological correlates of stress lead to hippocampal dysfunction by reducing postsynaptic dendritic surface, thereby adversely affecting the availability of synaptic inputs and suppressing LTP. Here we examine the validity of this framework using biophysical models of hippocampal CA3 pyramidal neurons. To statistically match with the experimentally observed region specificity of stress-induced atrophy, we use an algorithm to systematically prune three-dimensional reconstructions of CA3 pyramidal neurons. Using this algorithm, we build a biophysically realistic computational model to analyze the effects of stress on intrinsic and synaptic excitability. We find that stress-induced atrophy of CA3 dendrites leads to an increase in input resistance, which depends exponentially on the percentage of neuronal atrophy. This increase translates directly into higher spiking frequencies in response to both somatic current injections and synaptic inputs at various locations along the dendritic arbor. Remarkably, we also find that the dendritic regions that manifest atrophy-induced synaptic hyperexcitability are governed by the region specificity of the underlying dendritic atrophy. Coupled with experimentally observed modulation of N-methyl-d-aspartate receptor currents, such hyperexcitability could tilt the balance of plasticity mechanisms in favor of synaptic potentiation over depression. Thus paradoxically, our results suggest that stress may impair hippocampal learning and memory, not by directly inhibiting LTP, but because of stress-induced facilitation of intrinsic and synaptic excitability and the consequent imbalance in bidirectional synaptic plasticity.

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