8-Chloroadenosine induces apoptosis in human coronary artery endothelial cells through the activation of the unfolded protein response

© 2019 The Authors Infiltration of leukocytes within the vessel at sites of inflammation and the subsequent generation of myeloperoxidase-derived oxidants, including hypochlorous acid, are key characteristics of atherosclerosis. Hypochlorous acid is a potent oxidant that reacts readily with most biological molecules, including DNA and RNA. This results in nucleic acid modification and the formation of different chlorinated products. These products have been used as biomarkers of inflammation, owing to their presence in elevated amounts in different inflammatory fluids and diseased tissue, including atherosclerotic lesions. However, it is not clear whether these materials are simply biomarkers, or could also play a role in the development of chronic inflammatory pathologies. In this study, we examined the reactivity of different chlorinated nucleosides with human coronary artery endothelial cells (HCAEC). Evidence was obtained for the incorporation of each chlorinated nucleoside into the cellular RNA or DNA. However, only 8-chloro-adenosine (8ClA) had a significant effect on the cell viability and metabolic activity. Exposure of HCAEC to 8ClA decreased glycolysis, and resulted in a reduction in ATP, with a corresponding increase in the chlorinated analogue, 8Cl-ATP in the nucleotide pool. 8ClA also induced sustained endoplasmic reticulum stress within the HCAEC, which resulted in activation of the unfolded protein response, the altered expression of antioxidant genes and culminated in the release of calcium into the cytosol and cell death by apoptosis. Taken together, these data provide new insight into pathways by which myeloperoxidase activity and resultant hypochlorous acid generation could promote endothelial cell damage during chronic inflammation, which could be relevant to the progression of atherosclerosis

Assessing the efficacy of dietary selenomethionine supplementation in the setting of cardiac ischemia/reperfusion injury

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. article distributed under the terms and conditions of the Cr. Oxidative stress is a major hallmark of cardiac ischemia/reperfusion (I/R) injury. This partly arises from the presence of activated phagocytes releasing myeloperoxidase (MPO) and its production of hypochlorous acid (HOCl). The dietary supplement selenomethionine (SeMet) has been shown to bolster endogenous antioxidant processes as well as readily react with MPO-derived oxidants. The aim of this study was to assess whether supplementation with SeMet could modulate the extent of cellular damage observed in an in vitro cardiac myocyte model exposed to (patho)-physiological levels of HOCl and an in vivo rat model of cardiac I/R injury. Exposure of the H9c2 cardiac myoblast cell line to HOCl resulted in a dose-dependent increase in necrotic cell death, which could be prevented by SeMet supplementation and was attributed to SeMet preventing the HOCl-induced loss of mitochondrial inner trans-membrane potential, and the associated cytosolic calcium accumulation. This protection was credited primarily to the direct oxidant scavenging ability of SeMet, with a minor contribution arising from the ability of SeMet to bolster cardiac myoblast glutathione peroxidase (GPx) activity. In vivo, a significant increase in selenium levels in the plasma and heart tissue were seen in male Wistar rats fed a diet supplemented with 2 mg kg−1 SeMet compared to controls. However, SeMet-supplementation demonstrated only limited improvement in heart function and did not result in better heart remodelling following I/R injury. These data indicate that SeMet supplementation is of potential benefit within pathological settings where excessive HOCl is known to be generated but has limited efficacy as a therapeutic agent for the treatment of heart attack

A pivotal role for NF-κB in the macrophage inflammatory response to the myeloperoxidase oxidant hypothiocyanous acid

© 2018 Elsevier Inc. Atherosclerosis is characterised by the infiltration of macrophages at sites of inflammation within the vessel wall and the release of myeloperoxidase (MPO), which forms hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). HOCl is a damaging oxidant implicated in the development of atherosclerosis. Preferential formation of HOSCN occurs under conditions where thiocyanate ions are elevated, as is the case in smokers. HOSCN reacts selectively with thiols, which can result in more enzyme inactivation and damage than HOCl at susceptible sites, which may contribute to atherosclerosis in smokers. In this study, we show that exposure of macrophages to HOSCN results in a time- and dose-dependent increase in the mRNA expression and release of pro-inflammatory cytokines and chemokines, including monocyte chemotactic protein 1, tumour necrosis factor alpha, and interleukins 6, 8 and 1β. At high oxidant concentrations (>200 μM), a significant loss of cellular thiols and increased cell death is observed. HOSCN-induced cytokine/chemokine expression and cell death were decreased on pharmacological inhibition of nuclear factor kappa B. These data highlight a pathway by which HOSCN could promote inflammation and the development of atherosclerosis, in the presence of supra-physiological levels of the precursor thiocyanate, which are achievable by cigarette smoking

Comparative reactivity of the myeloperoxidase-derived oxidants HOCl and HOSCN with low-density lipoprotein (LDL): Implications for foam cell formation in atherosclerosis

© 2015 Elsevier Inc. All rights reserved. Abstract Atherosclerosis is characterised by the accumulation of lipids within macrophages in the artery wall. Low-density lipoprotein (LDL) is the source of this lipid, owing to the uptake of oxidised LDL by scavenger receptors. Myeloperoxidase (MPO) released by leukocytes during inflammation produces oxidants that are implicated in atherosclerosis. Modification of LDL by the MPO oxidant hypochlorous acid (HOCl), results in extensive lipid accumulation by macrophages. However, the reactivity of the other major MPO oxidant, hypothiocyanous acid (HOSCN) with LDL is poorly characterised, which is significant given that thiocyanate is the favoured substrate for MPO. In this study, we comprehensively compare the reactivity of HOCl and HOSCN with LDL, and show key differences in the profile of oxidative damage observed. HOSCN selectively modifies Cys residues on apolipoprotein B100, and oxidises cholesteryl esters resulting in formation of lipid hydroperoxides, 9-hydroxy-10,12-octadecadienoic acid (9-HODE) and F2-isoprostanes. The modification of LDL by HOSCN results macrophage lipid accumulation, though generally to a lesser extent than HOCl-modified LDL. This suggests that a change in the ratio of HOSCN:HOCl formation by MPO from variations in plasma thiocyanate levels, will influence the nature of LDL oxidation in vivo, and has implications for the progression of atherosclerosis

Metabolic flexibility as a major predictor of spatial distribution in microbial communities

A better understand the ecology of microbes and their role in the global ecosystem could be achieved if traditional ecological theories can be applied to microbes. In ecology organisms are defined as specialists or generalists according to the breadth of their niche. Spatial distribution is often used as a proxy measure of niche breadth; generalists have broad niches and a wide spatial distribution and specialists a narrow niche and spatial distribution. Previous studies suggest that microbial distribution patterns are contrary to this idea; a microbial generalist genus (Desulfobulbus) has a limited spatial distribution while a specialist genus (Methanosaeta) has a cosmopolitan distribution. Therefore, we hypothesise that this counter-intuitive distribution within generalist and specialist microbial genera is a common microbial characteristic. Using molecular fingerprinting the distribution of four microbial genera, two generalists, Desulfobulbus and the methanogenic archaea Methanosarcina, and two specialists, Methanosaeta and the sulfate-reducing bacteria Desulfobacter were analysed in sediment samples from along a UK estuary. Detected genotypes of both generalist genera showed a distinct spatial distribution, significantly correlated with geographic distance between sites. Genotypes of both specialist genera showed no significant differential spatial distribution. These data support the hypothesis that the spatial distribution of specialist and generalist microbes does not match that seen with specialist and generalist large organisms. It may be that generalist microbes, while having a wider potential niche, are constrained, possibly by intrageneric competition, to exploit only a small part of that potential niche while specialists, with far fewer constraints to their niche, are more capable of filling their potential niche more effectively, perhaps by avoiding intrageneric competition. We suggest that these counter-intuitive distribution patterns may be a common feature of microbes in general and represent a distinct microbial principle in ecology, which is a real challenge if we are to develop a truly inclusive ecology

Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research

Building social capital through breastfeeding peer support: Insights from an evaluation of a voluntary breastfeeding peer support service in North-West England

Background: Peer support is reported to be a key method to help build social capital in communities. To date there are no studies that describe how this can be achieved through a breastfeeding peer support service. In this paper we present findings from an evaluation of a voluntary model of breastfeeding peer support in North-West England to describe how the service was operationalized and embedded into the community. This study was undertaken from May, 2012 to May, 2013. Methods: Interviews (group or individual) were held with 87 participants: 24 breastfeeding women, 13 peer supporters and 50 health and community professionals. The data contained within 23 monthly monitoring reports (January, 2011 to February 2013) compiled by the voluntary peer support service were also extracted and analysed. Results: Thematic analysis was undertaken using social capital concepts as a theoretical lens. Key findings were identified to resonate with ’bonding’, ‘bridging’ and ‘linking’ forms of social capital. These insights illuminate how the peer support service facilitates ‘bonds’ with its members, and within and between women who access the service; how the service ‘bridges’ with individuals from different interests and backgrounds, and how ‘links’ were forged with those in authority to gain access and reach to women and to promote a breastfeeding culture. Some of the tensions highlighted within the social capital literature were also identified. Conclusions: Horizontal and vertical relationships forged between the peer support service and community members enabled peer support to be embedded into care pathways, helped to promote positive attitudes to breastfeeding and to disseminate knowledge and maximise reach for breastfeeding support across the community. Further effort to engage with those of different ethnic backgrounds and to resolve tensions between peer supporters and health professionals is warranted

Vision-based real-time position control of a semi-automated system for robot-assisted joint fracture surgery

Purpose: Joint fracture surgery quality can be improved by robotic system with high-accuracy and high-repeatability fracture fragment manipulation. A new real-time vision-based system for fragment manipulation during robot-assisted fracture surgery was developed and tested. Methods: The control strategy was accomplished by merging fast open-loop control with vision-based control. This two-phase process is designed to eliminate the open-loop positioning errors by closing the control loop using visual feedback provided by an optical tracking system. Evaluation of the control system accuracy was performed using robot positioning trials, and fracture reduction accuracy was tested in trials on ex vivo porcine model.Results: The system resulted in high fracture reduction reliability with a reduction accuracy of 0.09mm (translations) and of (Formula presented.) (rotations), maximum observed errors in the order of 0.12mm (translations) and of (Formula presented.) (rotations), and a reduction repeatability of 0.02mm and (Formula presented.). Conclusions: The proposed vision-based system was shown to be effective and suitable for real joint fracture surgical procedures, contributing a potential improvement of their quality

Glucose Monitoring During Pregnancy

Self-monitoring of blood glucose in women with mild gestational diabetes has recently been proven to be useful in reducing the rates of fetal overgrowth and gestational weight gain. However, uncertainty remains with respect to the optimal frequency and timing of self-monitoring. A continuous glucose monitoring system may have utility in pregnant women with insulin-treated diabetes, especially for those women with blood sugars that are difficult to control or who experience nocturnal hypoglycemia; however, continuous glucose monitoring systems need additional study as part of larger, randomized trials