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McGettigan P.,William Harvey Research Institute | Henry D.,Institute for Clinical Evaluative science | Henry D.,University of Toronto | Henry D.,University of Newcastle
PLoS Medicine | Year: 2013

Background: Certain non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., rofecoxib [Vioxx]) increase the risk of heart attack and stroke and should be avoided in patients at high risk of cardiovascular events. Rates of cardiovascular disease are high and rising in many low- and middle-income countries. We studied the extent to which evidence on cardiovascular risk with NSAIDs has translated into guidance and sales in 15 countries. Methods and Findings: Data on the relative risk (RR) of cardiovascular events with individual NSAIDs were derived from meta-analyses of randomised trials and controlled observational studies. Listing of individual NSAIDs on Essential Medicines Lists (EMLs) was obtained from the World Health Organization. NSAID sales or prescription data for 15 low-, middle-, and high-income countries were obtained from Intercontinental Medical Statistics Health (IMS Health) or national prescription pricing audit (in the case of England and Canada). Three drugs (rofecoxib, diclofenac, etoricoxib) ranked consistently highest in terms of cardiovascular risk compared with nonuse. Naproxen was associated with a low risk. Diclofenac was listed on 74 national EMLs, naproxen on just 27. Rofecoxib use was not documented in any country. Diclofenac and etoricoxib accounted for one-third of total NSAID usage across the 15 countries (median 33.2%, range 14.7-58.7%). This proportion did not vary between low- and high-income countries. Diclofenac was by far the most commonly used NSAID, with a market share close to that of the next three most popular drugs combined. Naproxen had an average market share of less than 10%. Conclusions: Listing of NSAIDs on national EMLs should take account of cardiovascular risk, with preference given to low risk drugs. Diclofenac has a risk very similar to rofecoxib, which was withdrawn from worldwide markets owing to cardiovascular toxicity. Diclofenac should be removed from EMLs. Please see later in the article for the Editors' Summary. © 2013 McGettigan, Henry.

Ye S.,Queen Mary, University of London | Ye S.,William Harvey Research Institute
Pharmacology and Therapeutics | Year: 2015

There is compelling evidence indicating that some members of the matrix metalloproteinase (MMP) family play important roles in the pathogenesis of atherosclerosis and related vascular and cardiac conditions such as atherosclerotic plaque rupture leading to myocardial infarction, heart failure after myocardial infarction, neointima formation following angioplasty, and abdominal aortic aneurysm. Studies have shown that administration of MMP inhibitors can deter some of these conditions in experimental animal models, but few pertinent human clinical trials have been reported to date. Clinical studies of broad-spectrum MMP inhibitors in cancers and arthritis, however, have reported considerable side effects that are likely to be related to the lack of selectivity of these inhibitors. Since different members of the MMP family can have divergent and even opposing functions, it is believed that selective MMP inhibitors that specifically target particular MMPs that are key in the disease pathogenesis will likely have greater efficacy and less adverse effects. In recent years there has been accumulating evidence indicating an important role of MMP8 in atherosclerosis and the associated conditions mentioned above. This article will review findings from studies examining MMP8 in relation to these conditions and discuss rationale of targeting MMP8 as a potential therapeutic strategy. © 2014 Elsevier Inc.

Yaqoob M.M.,William Harvey Research Institute
Current Opinion in Nephrology and Hypertension | Year: 2010

Purpose of review: Chronic kidney disease progressively impairs the ability of kidneys to excrete hydrogen ions owing to the reduced capacity of the kidney to synthesize ammonia resulting in metabolic acidosis. There is good experimental evidence that metabolic acidosis contributes to protein energy wasting disorder and progression of chronic kidney disease (CKD). However, there was a lack of robust clinical evidence to support these experimental observations. Recent findings: Three recent publications have confirmed the experimental evidence and the only randomized controlled study of its kind has suggested that the correction of acidosis by sodium bicarbonate in patients with advanced CKD is associated with attenuation of the rate of decline of renal function, reduction in the incidence of end stage renal disease and improvement of nutritional parameters. Summary: In light of these recent studies, it appears that this cheap and simple strategy, which is in line with current renal recommendations, has the potential of translating into significant economic, quality of life and clinical outcome benefits in an expanding pool of patients with CKD. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

DWright R.,William Harvey Research Institute | Cooper D.,William Harvey Research Institute
Glycobiology | Year: 2014

To fulfill their potential, leukocytes must be able to exit the vasculature and reach the site of inflammation within the tissue. This process of leukocyte extravasation is a tightly regulated sequence of events that is governed by a host of cell adhesion molecules, cytokines, chemokines and lipid mediators. Of major importance to this process and the function of many of the proteins and lipids involved is the posttranslational modification of these moieties by glycosylation. The glycosylation process is coordinated by multiple enzymes that add and remove saccharides to/from glycan structures on proteins and lipids, resulting in a unique molecular signature that affords specificity to the molecules involved in leukocyte recruitment. This review will discuss how glycosylation impacts the function of these key molecules involved in the recruitment of leukocytes during inflammation and the function of specific lectins (carbohydratebinding proteins) that have a role in leukocyte trafficking. © The Author 2014. Published by Oxford University Press. All rights reserved.

Accumulating evidence indicates that stem/progenitor cells (SPCs) represent an important source of cells in atheromas and contribute to lesion formation and progression. We investigated whether matrix metalloproteinase-8 (MMP8) played a role in SPC migration and their recruitment into atheromas. We found that SPCs in atheromas expressed MMP8 and that MMP8 knockout significantly reduced SPC numbers in atherosclerotic lesions in apolipoprotein E (ApoE)-deficient mice fed a Western diet. Further in vivo experiments showed that ApoE(-/-)/MMP8(-/-) mice injected with stem cells isolated from bone marrows of ApoE(-/-)/MMP8(-/-) mice had fewer SPCs in atheromas and smaller lesions than ApoE(-/-)/MMP8(-/-) mice injected with stem cells isolated from bone marrows of ApoE(-/-)/MMP8(+/+) mice. Ex vivo experiments showed that MMP8 deficiency inhibited the ability of SPCs to migrate from the arterial lumen and the adventitia into atherosclerotic lesions. In vitro assays indicated that MMP8 facilitated SPC migration across endothelial cells and through Matrigel or collagen I. We also found that MMP8 cleaved a-disintegrin-and-metalloproteinase-domain-10 and that MMP8 deficiency reduced mature a-disintegrin-and-metalloproteinase-domain-10 on SPCs. Knockdown of MMP8 or incubation with the a-disintegrin-and-metalloproteinase-domain-10 inhibitor GI254023X decreased E-cadherin shedding on SPCs. The decrease in migratory ability of SPCs with MMP8 knockdown was reduced by incubation of such cells with culture supernatant from SPCs without MMP8 knockdown, and this compensatory effect was abolished by an antibody against soluble E-cadherin. MMP8 plays an important role in SPC migration and their recruitment into atherosclerotic lesions.

Solito E.,William Harvey Research Institute | Sastre M.,Imperial College London
Frontiers in Pharmacology | Year: 2012

Contrary to early views, we now know that systemic inflammatory/immune responses transmit to the brain. The microglia, the resident "macrophages" of the brain's innate immune system, are most responsive, and increasing evidence suggests that they enter a hyper-reactive state in neurodegenerative conditions and aging. As sustained over-production of microglial pro-inflammatory mediators is neurotoxic, this raises great concern that systemic inflammation (that also escalates with aging) exacerbates or possibly trig-gers, neurological diseases (Alzheimer's, prion, motoneuron disease). It is known that inflammation has an essential role in the progression of Alzheimer's disease (AD), since amyloid-β (Aβ) is able to activate microglia, initiating an inflammatory response, which could have different consequences for neuronal survival. On one hand, microglia may delay the progression of AD by contributing to the clearance of Aβ, since they phagocyte Aβ and release enzymes responsible for Aβ degradation. Microglia also secrete growth factors and anti-inflammatory cytokines, which are neuroprotective. In addition, microglia removal of damaged cells is a very important step in the restoration of the normal brain environ-ment, as if left such cells can become potent inflammatory stimuli, resulting in yet further tissue damage. On the other hand, as we age microglia become steadily less efficient at these processes, tending to become over-activated in response to stimulation and instigat-ing too potent a reaction, which may cause neuronal damage in its own right. Therefore, it is critical to understand the state of activation of microglia in different AD stages to be able to determine the effect of potential anti-inflammatory therapies. We discuss here recent evidence supporting both the beneficial or detrimental performance of microglia in AD, and the attempt to find molecules/biomarkers for early diagnosis or therapeutic interventions. © 2012 Solito and Sastre.

Smyth D.G.,William Harvey Research Institute
Journal of Molecular Endocrinology | Year: 2016

Many important fields of research had a humble origin. In the distant past, A J P Martin’s discovery that amino acids could be separated by paper chromatography and Moore and Stein’s use of columns for quantitative amino acid analysis provided the first steps towards the determination of structure in complex biologically active molecules. They opened the door to reveal the essential relationship that exists between structure and function. In molecular endocrinology, for example, striking advances have been made by chemists with their expertise in the identification of structure working with biologists who contributed valuable knowledge and experience. Advantage was gained from the convergence of different background, and it is notable that the whole is greater than the sum. In the determination of structure, it may be recalled that four of the world’s great pioneers (Archibald Martin, Rodney Porter, Fred Sanger and Vincent du Vigneaud) were acknowledged for their fundamental contributions when individually they were awarded the Nobel Prize. They foresaw that the identification of structure would prove of outstanding importance in the future. Indeed, study of the structures of β-endorphin and enkephalin and the different forms of opiate activity they engender has led to a transformation in our understanding of chemical transmission in the brain. © 2016 Society for Endocrinology Published by Bioscientifica Ltd.

Dell'accio F.,William Harvey Research Institute
European cells & materials | Year: 2010

Joint surface defects (JSD) involving the articular cartilage and the subchondral bone are a common clinical problem in rheumatology and orthopaedics. The recent availability of accurate imaging for diagnosis and efficacious therapeutic options has stirred new interest in their natural history and biology. The evidence that some of these lesions can heal spontaneously whereas others precipitate osteoarthritis has raised important questions as to which lesions should be treated, when, and how. Evidence of repair of some of these lesions has also stimulated research into which factors contribute to successful healing and which ones determine chronic evolution and development of osteoarthritis (OA). Older anatomical observations, together with novel molecular tools and experimental models, have revealed a complex cellular and molecular response of cartilage to focal defects, which could explain differences in healing responses between individuals, and may provide clues to stimulating intrinsic tissue repair. In the first part of this review we will discuss clinical aspects of these lesions in the patient, with particular emphasis on their biology and natural history. In the second part we will summarize the data coming from in vitro and in vivo models of cartilage injury and regeneration, focussing on the molecular control of cartilage homeostasis after creation of cartilage surface defects.

Norling L.V.,William Harvey Research Institute | Perretti M.,William Harvey Research Institute
Journal of Innate Immunity | Year: 2013

Following tissue injury or microbial invasion, neutrophils are robustly recruited to inflammatory loci, which is a hallmark of the host inflammatory response. This event initiates a series of processes required to activate resolution, including recruitment of monocytes, clearance of microbes, cellular debris and apoptotic neutrophils, the egress of phagocytes and, ultimately, regain of tissue homeostasis. Substantial evidence now signifies that resolution of inflammation is a highly coordinated, active process dictated by the spatial-temporal generation of proresolving mediators that act on specific receptors to modulate cell and tissue reactivity. This review will focus on the mediators, targets and pathways initiated to orchestrate resolution. Importantly, disruption of the key processes involved in inflammatory resolution could result in delayed restoration of tissue homeostasis, leading to fibrosis and/or persistent inflammation. Copyright © 2013 S. Karger AG, Basel.

Ortega-Gomez A.,Institute for Cardiovascular Prevention | Perretti M.,William Harvey Research Institute | Soehnlein O.,Institute for Cardiovascular Prevention
EMBO Molecular Medicine | Year: 2013

Resolution of inflammation is a coordinated and active process aimed at restoration of tissue integrity and function. This review integrates the key molecular and cellular mechanisms of resolution. We describe how abrogation of chemokine signalling blocks continued neutrophil tissue infiltration and how apoptotic neutrophils attract monocytes and macrophages to induce their clearance. Uptake of apoptotic neutrophils by macrophages reprograms macrophages towards a resolving phenotype, a key event to restore tissue homeostasis. Finally, we highlight the therapeutic potential that derives from understanding the mechanisms of resolution. © 2013.

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