Mitochondrial oxidative stress and nitrate tolerance – comparison of nitroglycerin and pentaerithrityl tetranitrate in Mn-SOD(+/- )mice

BACKGROUND: Chronic therapy with nitroglycerin (GTN) results in a rapid development of nitrate tolerance which is associated with an increased production of reactive oxygen species (ROS). According to recent studies, mitochondrial ROS formation and oxidative inactivation of the organic nitrate bioactivating enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) play an important role for the development of nitrate and cross-tolerance. METHODS: Tolerance was induced by infusion of wild type (WT) and heterozygous manganese superoxide dismutase mice (Mn-SOD(+/-)) with ethanolic solution of GTN (12.5 μg/min/kg for 4 d). For comparison, the tolerance-free pentaerithrityl tetranitrate (PETN, 17.5 μg/min/kg for 4 d) was infused in DMSO. Vascular reactivity was measured by isometric tension studies of isolated aortic rings. ROS formation and aldehyde dehydrogenase (ALDH-2) activity was measured in isolated heart mitochondria. RESULTS: Chronic GTN infusion lead to impaired vascular responses to GTN and acetylcholine (ACh), increased the ROS formation in mitochondria and decreased ALDH-2 activity in Mn-SOD(+/- )mice. In contrast, PETN infusion did not increase mitochondrial ROS formation, did not decrease ALDH-2 activity and accordingly did not lead to tolerance and cross-tolerance in Mn-SOD(+/- )mice. PETN but not GTN increased heme oxygenase-1 mRNA in EA.hy 926 cells and bilirubin efficiently scavenged GTN-derived ROS. CONCLUSION: Chronic GTN infusion stimulates mitochondrial ROS production which is an important mechanism leading to tolerance and cross-tolerance. The tetranitrate PETN is devoid of mitochondrial oxidative stress induction and according to the present animal study as well as numerous previous clinical studies can be used without limitations due to tolerance and cross-tolerance

Acute exposure to nocturnal train noise induces endothelial dysfunction and pro-thromboinflammatory changes of the plasma proteome in healthy subjects

Nocturnal train noise exposure has been associated with hypertension and myocardial infarction. It remains unclear whether acute nighttime train exposure may induce subclinical atherosclerosis, such as endothelial dysfunction and other functional and/or biochemical changes. Thus, we aimed to expose healthy subjects to nocturnal train noise and to assess endothelial function, changes in plasma protein levels and clinical parameters. In a randomized crossover study, we exposed 70 healthy volunteers to either background or two different simulated train noise scenarios in their homes during three nights. After each night, participants visited the study center for measurement of vascular function and assessment of other biomedical and biochemical parameters. The three nighttime noise scenarios were exposure to either background noise (control), 30 or 60 train noise events (Noise30 or Noise60), with average sound pressure levels of 33, 52 and 54 dB(A), respectively. Flow-mediated dilation (FMD) of the brachial artery was 11.23 ± 4.68% for control, compared to 8.71 ± 3.83% for Noise30 and 8.47 ± 3.73% for Noise60 (p < 0.001 vs. control). Sleep quality was impaired after both Noise30 and Noise60 nights (p < 0.001 vs. control). Targeted proteomic analysis showed substantial changes of plasma proteins after the Noise60 night, mainly centered on redox, pro-thrombotic and proinflammatory pathways. Exposure to simulated nocturnal train noise impaired endothelial function. The proteomic changes point toward a proinflammatory and pro-thrombotic phenotype in response to nocturnal train noise and provide a molecular basis to explain the increased cardiovascular risk observed in epidemiological noise studies

Noise annoyance and risk of prevalent and incident atrial fibrillation–A sex-specific analysis

BackgroundWhile chronic exposure to high levels of noise was demonstrated to increase the risk of various cardiovascular diseases, the association between noise annoyance and risk of cardiovascular disease remains still inconsistent. Recently, we showed that noise annoyance is associated with prevalent atrial fibrillation in the general population. However, the association between noise annoyance and risk of incident atrial fibrillation as well as potential sex-differences remain still elusive.Methods and results15,010 subjects from a German population-based cohort were examined at baseline (2007 to 2012) and follow-up five years later (2012 to 2017) to investigative the association between noise annoyance due to multiple sources and prevalent and incident atrial fibrillation. After multivariable adjustment, the results from logistic regression analyses revealed overall consistent and positive associations between noise annoyance and prevalent and incident atrial fibrillation in men, whereas this association was weaker in women, in particular with respect to incident atrial fibrillation. For instance, industrial noise annoyance was associated with 21% (95% confidence interval (CI) 9–34%) and 18% (8–29%) higher odds of prevalent atrial fibrillation in men and women, respectively. In prospective analysis, this association remained stable in men (odds ratio (OR) 1.25, 1.07–1.44), while in women no association was observed (OR 1.03, 0.89–1.18).ConclusionsThe findings suggest that noise annoyance can increase the risk of incident atrial fibrillation in a large population-based cohort and that men may be more sensitive to the adverse effects of noise annoyance with regard to the risk of atrial fibrillation

Visual ecology of aphids – a critical review on the role of colours in host finding

We review the rich literature on behavioural responses of aphids (Hemiptera: Aphididae) to stimuli of different colours. Only in one species there are adequate physiological data on spectral sensitivity to explain behaviour crisply in mechanistic terms. Because of the great interest in aphid responses to coloured targets from an evolutionary, ecological and applied perspective, there is a substantial need to expand these studies to more species of aphids, and to quantify spectral properties of stimuli rigorously. We show that aphid responses to colours, at least for some species, are likely based on a specific colour opponency mechanism, with positive input from the green domain of the spectrum and negative input from the blue and/or UV region. We further demonstrate that the usual yellow preference of aphids encountered in field experiments is not a true colour preference but involves additional brightness effects. We discuss the implications for agriculture and sensory ecology, with special respect to the recent debate on autumn leaf colouration. We illustrate that recent evolutionary theories concerning aphid–tree interactions imply far-reaching assumptions on aphid responses to colours that are not likely to hold. Finally we also discuss the implications for developing and optimising strategies of aphid control and monitoring

NECAB2 is an endosomal protein important for striatal function

Synaptic signaling depends on ATP generated by mitochondria. Dysfunctional mitochondria shift the redox balance towards a more oxidative environment. Due to extensive connectivity, the striatum is especially vulnerable to mitochondrial dysfunction. We found that neuronal calcium-binding protein 2 (NECAB2) plays a role in striatal function and mitochondrial homeostasis. NECAB2 is a predominantly endosomal striatal protein which partially colocalizes with mitochondria. This colocalization is enhanced by mild oxidative stress. Global knockout of Necab2 in the mouse results in increased superoxide levels, increased DNA oxidation and reduced levels of the antioxidant glutathione which correlates with an altered mitochondrial shape and function. Striatal mitochondria from Necab2 knockout mice are more abundant and smaller and characterized by a reduced spare capacity suggestive of intrinsic uncoupling respectively mitochondrial dysfunction. In line with this, we also found an altered stress-induced interaction of endosomes with mitochondria in Necab2 knockout striatal cultures. The predominance of dysfunctional mitochondria and the pro-oxidative redox milieu correlates with a loss of striatal synapses and behavioral changes characteristic of striatal dysfunction like reduced motivation and altered sensory gating. Together this suggests an involvement of NECAB2 in an endosomal pathway of mitochondrial stress response important for striatal functio

Expert consensus document: A 'diamond' approach to personalized treatment of angina.

In clinical guidelines, drugs for symptomatic angina are classified as being first choice (β-blockers, calcium-channel blockers, short-acting nitrates) or second choice (ivabradine, nicorandil, ranolazine, trimetazidine), with the recommendation to reserve second-choice medications for patients who have contraindications to first-choice agents, do not tolerate them, or remain symptomatic. No direct comparisons between first-choice and second-choice treatments have demonstrated the superiority of one group of drugs over the other. Meta-analyses show that all antianginal drugs have similar efficacy in reducing symptoms, but provide no evidence for improvement in survival. The newer, second-choice drugs have more evidence-based clinical data that are more contemporary than is available for traditional first-choice drugs. Considering some drugs, but not others, to be first choice is, therefore, difficult. Moreover, double or triple therapy is often needed to control angina. Patients with angina can have several comorbidities, and symptoms can result from various underlying pathophysiologies. Some agents, in addition to having antianginal effects, have properties that could be useful depending on the comorbidities present and the mechanisms of angina, but the guidelines do not provide recommendations on the optimal combinations of drugs. In this Consensus Statement, we propose an individualized approach to angina treatment, which takes into consideration the patient, their comorbidities, and the underlying mechanism of disease

Translating the oxidative stress hypothesis into the clinic: NOX versus NOS

Cardiovascular diseases remain the leading cause of death in industrialised nations. Since the pathomechanisms of most cardiovascular diseases are not understood, the majority of therapeutic approaches are symptom-orientated. Knowing the molecular mechanism of disease would enable more targeted therapies. One postulated underlying mechanism of cardiovascular diseases is oxidative stress, i.e. the increased occurrence of reactive oxygen species such as superoxide. Oxidative stress leads to a dysfunction of vascular endothelium-dependent protective mechanisms. There is growing evidence that this scenario also involves impaired nitric oxide (NO)-cyclic GMP signalling. Out of a number of enzyme families that can produce reactive oxygen species, NADPH oxidases stand out, as they are the only enzymes whose sole purpose is to produce reactive oxygen species. This review focuses on the clinically validated targets of oxidative stress, NO synthase (NOS) and the NO receptor, soluble guanylate cyclase as well as the source of ROS, e.g. NADPH oxidases. We place recent knowledge in the function and regulation of these enzyme families into clinical perspective. For a comprehensive overview of the biology and pharmacology of oxidative stress and possible other sources and targets, we refer to other literature overviews

Therapeutic effects of the mitochondrial ROS-redox modulator KH176 in a mammalian model of Leigh Disease

Leigh Disease is a progressive neurometabolic disorder for which a clinical effective treatment is currently still lacking. Here, we report on the therapeutic efficacy of KH176, a new chemical entity derivative of Trolox, in Ndufs4 (-/-) mice, a mammalian model for Leigh Disease. Using in vivo brain diffusion tensor imaging, we show a loss of brain microstructural coherence in Ndufs4 (-/-) mice in the cerebral cortex, external capsule and cerebral peduncle. These findings are in line with the white matter diffusivity changes described in mitochondrial disease patients. Long-term KH176 treatment retained brain microstructural coherence in the external capsule in Ndufs4 (-/-) mice and normalized the increased lipid peroxidation in this area and the cerebral cortex. Furthermore, KH176 treatment was able to significantly improve rotarod and gait performance and reduced the degeneration of retinal ganglion cells in Ndufs4 (-/-) mice. These in vivo findings show that further development of KH176 as a potential treatment for mitochondrial disorders is worthwhile to pursue. Clinical trial studies to explore the potency, safety and efficacy of KH176 are ongoing

The humanistic roots of Islamic administration and leadership for education : philosophical foundations for cross-cultural and transcultural teaching

For a number of decades, a humanistic approach has been a minor but persistent one in the Western field of administrative and leadership studies, and only recently has been broadening to include other humanist traditions (Dierksmeier et al., 2011) and has yet to be fully explored in educational administration and its pedagogy and curriculum although some foundational work has been done (e.g., Samier, 2005). The focus in this chapter is on the Islamic humanist tradition as it relates to the teaching of educational administration and leadership in a Muslim context, with implications for cross-cultural and transcultural use. The second purpose of the chapter is to show the correspondences that exist between the Islamic and Western humanist traditions in terms of human values, knowledge and educational ideal, which in this chapter are argued to be close to the Western Idealist tradition and the German Bildung conception of education as well as the strong interpretive and hermeneutic foundations that originated in the Islamic tradition and which influenced the foundations of many relevant European schools of thought, particularly in the Enlightenment.The initial section of the chapter is a comparative examination of the central principles of the Islamic humanist tradition from the classical through to contemporary times with the Western humanist tradition as they relate to conceptions of the good, ethics, the construction of meaning and a set of higher order values predicated upon human dignity, integrity, empathy, well-being, and the public good (Goodman, 2003) covering a number of important scholars like Al Farabi, al Isfanhani, and Edward Said (e.g., Kraemer, 1986). In both, professions are viewed as meaningful work that allow for large measures of decision making, and are grounded in human qualities and needs including autonomy, freedom and emancipation balanced with responsibilities, obligations and duties to society. These are compared with the corresponding principles of knowledge in Western humanism which includes a strong constructivist view of reality (Makdisi, 1990). Secondly, the chapter examines the principles of good or ideal leadership and administration that humanism aims at in its preparation of officials, including those in the educational sector in both the classical Islamic tradition (Hassi, 2012) and Western approaches to humanistic administration and leadership (Czarniawska-Joerges & Guillet de Monthoux, 1994; Gagliardi & Czarniawska, 2006; Leoussi, 2000). The third section focusses on close correspondences that exist between the Islamic (Afsaruddin, 2016; al-Attas, 1980; Yasin & Jani, 2013) and Western (Aloni, 2007; Veugelers, 2011) humanist education traditions in terms of educational ideal as well as the kind of teaching practices that distinguish these traditions (Daiber, 2013; Dossett, 2014) as they apply to educational administration and leadership (Greenfield & Ribbins, 1993). The chapter concludes with a discussion of how the Islamic humanist tradition can contribute to cross-cultural and transcultural graduate teaching in international educational administration (Khan & Amann, 2013)