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"Miller, Mark R."
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Ambient air pollution and thrombosis
Air pollution is a growing public health concern of global significance. Acute and chronic exposure is known to impair cardiovascular function, exacerbate disease and increase cardiovascular mortality. Several plausible biological mechanisms have been proposed for these associations, however, at present, the pathways are incomplete. A seminal review by the American Heart Association (2010) concluded that the thrombotic effects of particulate air pollution likely contributed to their effects on cardiovascular mortality and morbidity. The aim of the current review is to appraise the newly accumulated scientific evidence (2009–2016) on contribution of haemostasis and thrombosis towards cardiovascular disease induced by exposure to both particulate and gaseous pollutants.
Seventy four publications were reviewed in-depth. The weight of evidence suggests that acute exposure to fine particulate matter (PM
2.5
) induces a shift in the haemostatic balance towards a pro-thrombotic/pro-coagulative state. Insufficient data was available to ascertain if a similar relationship exists for gaseous pollutants, and very few studies have addressed long-term exposure to ambient air pollution. Platelet activation, oxidative stress, interplay between interleukin-6 and tissue factor, all appear to be potentially important mechanisms in pollution-mediated thrombosis, together with an emerging role for circulating microvesicles and epigenetic changes.
Overall, the recent literature supports, and arguably strengthens, the contention that air pollution contributes to cardiovascular morbidity by promoting haemostasis. The volume and diversity of the evidence highlights the complexity of the pathophysiologic mechanisms by which air pollution promotes thrombosis; multiple pathways are plausible and it is most likely they act in concert. Future research should address the role gaseous pollutants play in the cardiovascular effects of air pollution mixture and direct comparison of potentially susceptible groups to healthy individuals.
Journal Article
Temperate functional niche availability not resident-invader competition shapes tropicalisation in reef fishes
Temperate reefs are at the forefront of warming-induced community alterations resulting from poleward range shifts. This tropicalisation is exemplified and amplified by tropical species’ invasions of temperate herbivory functions. However, whether other temperate ecosystem functions are similarly invaded by tropical species, and by what drivers, remains unclear. We examine tropicalisation footprints in nine reef fish functional groups using trait-based analyses and biomass of 550 fish species across tropical to temperate gradients in Japan and Australia. We discover that functional niches in transitional communities are asynchronously invaded by tropical species, but with congruent invasion schedules for functional groups across the two hemispheres. These differences in functional group tropicalisation point to habitat availability as a key determinant of multi-species range shifts, as in the majority of functional groups tropical and temperate species share functional niche space in suitable habitat. Competition among species from different thermal guilds played little part in limiting tropicalisation, rather available functional space occupied by temperate species indicates that tropical species can invade. Characterising these drivers of reef tropicalisation is pivotal to understanding, predicting, and managing marine community transformation.
This study examines how the tropicalisation of shallow reefs changes functional niches for fishes in Japan and Australia. They discover that functional niches in tropical-temperate transitional communities are asynchronously invaded by tropical species, mediated more by habitat availability than competition with resident temperate species.
Journal Article
Star destroyers : big ships blowing things up
\"In space, size matters. Boomers. Ships of the Line. Star Destroyers. The bigger the ship, the better the bang. From the dawn of history onward, commanding the most powerful ship around has been a dream of admirals, sultans, emperors, kings, generalissimos, and sea captains everywhere. For what the intimidation factor alone doesn't achieve, a massive barrage from super-weapons probably will. Thus it was, and ever shall be, even into the distant future. From the oceans of Earth, to beneath the ice of Europa, to the distant reaches of galactic empires, it is the great warships and their crews that sometimes keep civilization safe for the rest of us -- but sometimes become an extinction-level event in and of themselves\"--Back cover.
Book
Environmental modulators of vascular physiology and inflammation
Environmental factors play a crucial role in modulating vascular inflammation, contributing significantly to the development of atherosclerosis and cardiovascular disease. This review synthesizes current evidence on how various environmental exposures influence vascular function and inflammation, with a focus on pollutants such as particulate matter and chemical toxins like bisphenols and per‐ and polyfluoroalkyl substances. These environmental stressors can trigger oxidative stress, chronic inflammation and vascular dysfunction, potentially accelerating the progression of atherosclerosis. We also explore the protective effects of natural compounds and exposure to green spaces in dampening inflammation and reducing cardiovascular risk. By examining the complex interplay between traditional risk factors and environmental exposures, this work highlights the need for comprehensive public health strategies that address both individual lifestyle factors and broader environmental determinants of cardiovascular health. We underscore the importance of further research to elucidate the precise cellular and molecular mechanisms by which environmental factors influence vascular function, with the aim of developing targeted interventions to mitigate their harmful effects and promote cardiovascular well‐being. What is the topic of this review? The review examines how environmental factors, particularly pollutants and natural compounds, influence vascular physiology, inflammation, and the development of atherosclerosis and cardiovascular disease. What advances does it highlight? This review highlights advances in understanding how environmental factors, particularly pollutants and natural compounds, influence vascular physiology, inflammation and the development of atherosclerosis. We emphasize the need for comprehensive public health strategies addressing both individual lifestyle factors and broader environmental exposures to address the rise in cardiovascular morbidity and mortality.
Journal Article
Silica nanoparticles trigger the vascular endothelial dysfunction and prethrombotic state via miR-451 directly regulating the IL6R signaling pathway
Background
Safety evaluation is a prerequisite for nanomaterials in a wide range of fields, including chemical industries, medicine or food sciences. Previously, we had demonstrated that SiNPs could trigger the thrombotic effects in vivo, but the underlying mechanisms remain unknown. This study was aimed to explore and verify the role of miR-451a on SiNPs-induced vascular endothelial dysfunction and pre-thrombotic state.
Results
The color doppler ultrasound results showed that SiNPs had the inhibitory effects on aorta velocity and cardiac output. The histological and ultrastructural analysis manifested that SiNPs could induce the vascular endothelial damage. In addition, the expression level of MDA was elevated while the activity of SOD and GSH-Px were decreased in aortic arch triggered by SiNPs, accompanied with the release of iNOS and decline of eNOS in blood serum. The immunohistochemistry results showed that the positive staining of TF and PECAM-1 were elevated in a dose-dependent manner induced by SiNPs. The activation of coagulation function occurred via shortened TT, PT and APTT while the FIB was elevated markedly induced by SiNPs. Coagulant factors (TF, FXa and vWF) and PLT numbers were increased whereas the levels of anticoagulant factors (ATIII, TFPI and t-PA) were decreased. Microarray analysis showed that the down-regulated miR-451a could target the gene expression of
IL6R
, which further activated the JAK/STAT signaling pathway triggered by SiNPs. Dual-luciferase reporter gene assay confirmed the directly target relationship between miR-451a and IL6R. Additionally, the chemical mimics of miR-451a led to attenuate the expression of IL6R/STAT/TF signaling pathway in vitro and in vivo induced by SiNPs, while the inhibitor of miR-451a enhanced the activation of IL6R/STAT/TF signaling pathway.
Conclusions
In summary, SiNPs could accelerate the vascular endothelial dysfunction and prethrombotic state via miR-451a negative regulating the IL6R/STAT/TF signaling pathway.
Journal Article
A biomimetic approach for enhancing the in vivo half-life of peptides
Linking a peptide with a small-molecule ligand for the serum protein transthyretin ensures half-life extension without diminishing potency through protection against proteases and decreasing glomerular filtration.
The tremendous therapeutic potential of peptides has not yet been realized, mainly owing to their short
in vivo
half-life. Although conjugation to macromolecules has been a mainstay approach for enhancing protein half-life, the steric hindrance of macromolecules often harms the binding of peptides to target receptors, compromising the
in vivo
efficacy. Here we report a new strategy for enhancing the
in vivo
half-life of peptides without compromising their potency. Our approach involves endowing peptides with a small molecule that binds reversibly to the serum protein transthyretin. Although there are a few molecules that bind albumin reversibly, we are unaware of designed small molecules that reversibly bind other serum proteins and are used for half-life extension
in vivo
. We show here that our strategy was effective in enhancing the half-life of an agonist for GnRH receptor while maintaining its binding affinity, which was translated into superior
in vivo
efficacy.
Journal Article
From particles to patients: oxidative stress and the cardiovascular effects of air pollution
Air pollution, especially airborne particulate matter (PM), is associated with an increase in both morbidity and mortality from cardiovascular disease, although the underlying mechanisms remain incompletely established. The one consistent observation that links the pulmonary and cardiovascular effects of inhaled PM is oxidative stress. This article examines the evidence for the role of oxidative stress in the cardiovascular effects of air pollution, beginning with observations from epidemiological and controlled exposure studies and then exploring potential mechanistic pathways involving free radical generation from PM itself, to effects of PM on cell cultures, isolated organs, healthy animals and animal models of disease. Particular emphasis is placed on the vascular and atherosclerotic effects of urban air pollution and diesel exhaust emissions as rich sources of environmental ultrafine particles.
Journal Article
The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis
VEGF-A activity is tightly regulated by ligand and receptor availability. Here we investigate the physiological function of heterodimers between VEGF receptor-1 (VEGFR-1; Flt-1) and VEGFR-2 (KDR; Flk-1) (VEGFR
1−2
) in endothelial cells with a synthetic ligand that binds specifically to VEGFR
1−2
. The dimeric ligand comprises one VEGFR-2-specific monomer (VEGF-E) and a VEGFR-1-specific monomer (PlGF-1). Here we show that VEGFR
1−2
activation mediates VEGFR phosphorylation, endothelial cell migration, sustained
in vitro
tube formation and vasorelaxation via the nitric oxide pathway. VEGFR
1−2
activation does not mediate proliferation or elicit endothelial tissue factor production, confirming that these functions are controlled by VEGFR-2 homodimers. We further demonstrate that activation of VEGFR
1−2
inhibits VEGF-A-induced prostacyclin release, phosphorylation of ERK1/2 MAP kinase and mobilization of intracellular calcium from primary endothelial cells. These findings indicate that VEGFR-1 subunits modulate VEGF activity predominantly by forming heterodimer receptors with VEGFR-2 subunits and such heterodimers regulate endothelial cell homeostasis.
Vascular endothelial growth factor receptors (VEGFRs) assemble in dimers, the composition of which is thought to influence their function. Here, Cudmore
et al
. create a synthetic ligand that specifically activates VEGFR-1:VEGFR-2 heterodimers and explore their role in regulating endothelial cell function.
Journal Article