Structural Basis for Certain Naturally Occurring Bioflavonoids to Function as Reducing Co-Substrates of Cyclooxygenase I and II

Recent studies showed that some of the dietary bioflavonoids can strongly stimulate the catalytic activity of cyclooxygenase (COX) I and II in vitro and in vivo, presumably by facilitating enzyme re-activation. In this study, we sought to understand the structural basis of COX activation by these dietary compounds.A combination of molecular modeling studies, biochemical analysis and site-directed mutagenesis assay was used as research tools. Three-dimensional quantitative structure-activity relationship analysis (QSAR/CoMFA) predicted that the ability of bioflavonoids to activate COX I and II depends heavily on their B-ring structure, a moiety known to be associated with strong antioxidant ability. Using the homology modeling and docking approaches, we identified the peroxidase active site of COX I and II as the binding site for bioflavonoids. Upon binding to this site, bioflavonoid can directly interact with hematin of the COX enzyme and facilitate the electron transfer from bioflavonoid to hematin. The docking results were verified by biochemical analysis, which reveals that when the cyclooxygenase activity of COXs is inhibited by covalent modification, myricetin can still stimulate the conversion of PGG(2) to PGE(2), a reaction selectively catalyzed by the peroxidase activity. Using the site-directed mutagenesis analysis, we confirmed that Q189 at the peroxidase site of COX II is essential for bioflavonoids to bind and re-activate its catalytic activity.These findings provide the structural basis for bioflavonoids to function as high-affinity reducing co-substrates of COXs through binding to the peroxidase active site, facilitating electron transfer and enzyme re-activation

Magnetic resonance imaging of brain angiogenesis after stroke

Stroke is a major cause of mortality and long-term disability worldwide. The initial changes in local perfusion and tissue status underlying loss of brain function are increasingly investigated with noninvasive imaging methods. In addition, there is a growing interest in imaging of processes that contribute to post-stroke recovery. In this review, we discuss the application of magnetic resonance imaging (MRI) to assess the formation of new vessels by angiogenesis, which is hypothesized to participate in brain plasticity and functional recovery after stroke. The excellent soft tissue contrast, high spatial and temporal resolution, and versatility render MRI particularly suitable to monitor the dynamic processes involved in vascular remodeling after stroke. Here we review recent advances in the field of MR imaging that are aimed at assessment of tissue perfusion and microvascular characteristics, including cerebral blood flow and volume, vascular density, size and integrity. The potential of MRI to noninvasively monitor the evolution of post-ischemic angiogenic processes is demonstrated from a variety of in vivo studies in experimental stroke models. Finally, we discuss some pitfalls and limitations that may critically affect the accuracy and interpretation of MRI-based measures of (neo)vascularization after stroke

Different strokes for different folks: the rich diversity of animal models of focal cerebral ischemia

No single animal model is able to encompass all of the variables known to affect human ischemic stroke. This review highlights the major strengths and weaknesses of the most commonly used animal models of acute ischemic stroke in the context of matching model and experimental aim. Particular emphasis is placed on the relationships between outcome and underlying vascular variability, physiologic control, and use of models of comorbidity. The aim is to provide, for novice and expert alike, an overview of the key controllable determinants of experimental stroke outcome to help ensure the most effective application of animal models to translational research

VIP in construction: systematic development and evaluation of a multifaceted health programme aiming to improve physical activity levels and dietary patterns among construction workers

<p>Abstract</p> <p>Background</p> <p>The prevalence of both overweight and musculoskeletal disorders (MSD) in the construction industry is high. Many interventions in the occupational setting aim at the prevention and reduction of these health problems, but it is still unclear how these programmes should be designed. To determine the effectiveness of interventions on these health outcomes randomised controlled trials (RCTs) are needed. The aim of this study is to systematically develop a tailored intervention for prevention and reduction of overweight and MSD among construction workers and to describe the evaluation study regarding its (cost-)effectiveness.</p> <p>Methods/Design</p> <p>The Intervention Mapping (IM) protocol was applied to develop and implement a tailored programme aimed at the prevention and reduction of overweight and MSD. The (cost-) effectiveness of the intervention programme will be evaluated using an RCT. Furthermore, a process evaluation will be conducted. The research population will consist of blue collar workers of a large construction company in the Netherlands.</p> <p>Intervention</p> <p>The intervention programme will be aimed at improving (vigorous) physical activity levels and healthy dietary behaviour and will consist of tailored information, face-to-face and telephone counselling, training instruction (a fitness "card" to be used for exercises), and materials designed for the intervention (overview of the company health promoting facilities, waist circumference measuring tape, pedometer, BMI card, calorie guide, recipes, and knowledge test).</p> <p>Main study parameters/endpoints</p> <p>The intervention effect on body weight and waist circumference (primary outcome measures), as well as on lifestyle behaviour, MSD, fitness, CVD risk indicators, and work-related outcomes (i.e. productivity, sick leave) (secondary outcome measures) will be assessed.</p> <p>Discussion</p> <p>The development of the VIP in construction intervention led to a health programme tailored to the needs of construction workers. This programme, if proven effective, can be directly implemented.</p> <p>Trial registration</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2095">NTR2095</a></p

Dutch Oncology COVID-19 consortium:Outcome of COVID-19 in patients with cancer in a nationwide cohort study

Aim of the study: Patients with cancer might have an increased risk for severe outcome of coronavirus disease 2019 (COVID-19). To identify risk factors associated with a worse outcome of COVID-19, a nationwide registry was developed for patients with cancer and COVID-19. Methods: This observational cohort study has been designed as a quality of care registry and is executed by the Dutch Oncology COVID-19 Consortium (DOCC), a nationwide collaboration of oncology physicians in the Netherlands. A questionnaire has been developed to collect pseudonymised patient data on patients' characteristics, cancer diagnosis and treatment. All patients with COVID-19 and a cancer diagnosis or treatment in the past 5 years are eligible. Results: Between March 27th and May 4th, 442 patients were registered. For this first analysis, 351 patients were included of whom 114 patients died. In multivariable analyses, age ≥65 years (p < 0.001), male gender (p = 0.035), prior or other malignancy (p = 0.045) and active diagnosis of haematological malignancy (p = 0.046) or lung cancer (p = 0.003) were independent risk factors for a fatal outcome of COVID-19. In a subgroup analysis of patients with active malignancy, the risk for a fatal outcome was mainly determined by tumour type (haematological malignancy or lung cancer) and age (≥65 years). Conclusion: The findings in this registry indicate that patients with a haematological malignancy or lung cancer have an increased risk of a worse outcome of COVID-19. During the ongoing COVID-19 pandemic, these vulnerable patients should avoid exposure to severe acute respiratory syndrome coronavirus 2, whereas treatment adjustments and prioritising vaccination, when available, should also be considered