Fatty Acid and Peptide Profiles in Plasma Membrane and Membrane Rafts of PUFA Supplemented RAW264.7 Macrophages

The eukaryotic cell membrane possesses numerous complex functions, which are essential for life. At this, the composition and the structure of the lipid bilayer are of particular importance. Polyunsaturated fatty acids may modulate the physical properties of biological membranes via alteration of membrane lipid composition affecting numerous physiological processes, e.g. in the immune system. In this systematic study we present fatty acid and peptide profiles of cell membrane and membrane rafts of murine macrophages that have been supplemented with saturated fatty acids as well as PUFAs from the n-3, the n-6 and the n-9 family. Using fatty acid composition analysis and mass spectrometry-based peptidome profiling we found that PUFAs from both the n-3 and the n-6 family have an impact on lipid and protein composition of plasma membrane and membrane rafts in a similar manner. In addition, we found a relation between the number of bis-allyl-methylene positions of the PUFA added and the unsaturation index of plasma membrane as well as membrane rafts of supplemented cells. With regard to the proposed significance of lipid microdomains for disease development and treatment our study will help to achieve a targeted dietary modulation of immune cell lipid bilayers

Европейское соглашение по применению ферментной заместительной терапии у взрослых пациентов с болезнью Помпе: 10-летний опыт

.Реферативный перевод из: van der Ploeg A. T., Kruijshaar M. E., Toscano A. et al. European consensus for starting and stopping enzyme replacement therapy in adult patients with Pompe disease: a 10-year experience. Eur J Neurol 2017;4(6):768-e31. DOI: 10.1200/JCO.2016.71.6472.Перевод: Сергей Сергеевич Никитин Введение. Болезнь Помпе – редкое наследственное мышечное заболевание, для лечения которого с 2006 г. применяют ферментную заместительную терапию. В документе представлены последние рекомендации по началу и прекращению ферментной заместительной терапии у взрослых пациентов. Методы. В ходе Европейского консорциума по болезни Помпе эксперты из 11 европейских стран обсудили данные литературы об эффективности ферментной заместительной терапии у взрослых пациентов на основании оценки показателей прогноза клинического течения и качества жизни больных. В данной статье представлены результаты обсуждений 3 согласительных совещаний во время консорциума. Результаты. Специалисты пришли к соглашению относительно подтверждения диагноза болезни Помпе, сроков начала ферментной заместительной терапии, показаний и условий ее прекращения и применения во время беременности. Общее соглашение по перечисленным вопросам принято на основании мнения экспертов и подтверждено данными литературы. При проведении исследований в группах были получены данные о положительном эффекте ферментной заместительной терапии. Анализ проводили при оценке 586 взрослых пациентов из 1 клинического испытания и 43 наблюдательных исследований. Обратили внимание на индивидуальные различия в эффективности лечения, обнаруженные в отдельных сообщениях. В 11 наблюдательных исследованиях, включающих пациентов с тяжелой степенью поражения, также была доказана эффективность ферментной заместительной терапии. Исследования эффектов лечения у больных на доклинической стадии заболевания отсутствуют. Выводы. В ходе 1-го Европейского консорциума на основании международного экспертного мнения составлены рекомендации по началу и прекращению ферментной заместительной терапии у взрослых пациентов с болезнью Помпе

Mechanisms of leukocyte lipid body formation and function in inflammation

An area of increasingly interest for the understanding of cell signaling are the spatio-temporal aspects of the different enzymes involved in lipid mediator generation (eicosanoid-forming enzymes, phospholipases and their regulatory kinases and phosphatases) and pools of lipid precursors. The compartmentalization of signaling components within discrete and dynamic sites in the cell is critical for specificity and efficiency of enzymatic reactions of phosphorilation, enzyme activation and function. We hypothesized that lipid bodies - inducible non-membrane bound cytoplasmic lipid domains - function as specialized intracellular sites of compartmentalization of signaling with major roles in lipid mediator formation within leukocytes engaged in inflammatory process. Over the past years substantial progresses have been made demonstrating that all enzymes involved in eicosanoid synthesis localize at lipid bodies and lipid bodies are distinct sites for eicosanoid generation. Here we will review our current knowledge on the mechanisms of formation and functions of lipid bodies pertinent to inflammation

Modulation of 11β-hydroxysteroid dehydrogenase as a strategy to reduce vascular inflammation

Atherosclerosis is a chronic inflammatory disease in which initial vascular damage leads to extensive macrophage and lymphocyte infiltration. Although acutely glucocorticoids suppress inflammation, chronic glucocorticoid excess worsens atherosclerosis, possibly by exacerbating systemic cardiovascular risk factors. However, glucocorticoid action within the lesion may reduce neointimal proliferation and inflammation. Glucocorticoid levels within cells do not necessarily reflect circulating levels due to pre-receptor metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSDs). 11β-HSD2 converts active glucocorticoids into inert 11-keto forms. 11β-HSD1 catalyses the reverse reaction, regenerating active glucocorticoids. 11β-HSD2-deficiency/ inhibition causes hypertension, whereas deficiency/ inhibition of 11β-HSD1 generates a cardioprotective lipid profile and improves glycemic control. Importantly, 11β-HSD1-deficiency/ inhibition is atheroprotective, whereas 11β-HSD2-deficiency accelerates atherosclerosis. These effects are largely independent of systemic risk factors, reflecting modulation of glucocorticoid action and inflammation within the vasculature. Here, we consider whether evidence linking the 11β-HSDs to vascular inflammation suggests these isozymes are potential therapeutic targets in vascular injury and atherosclerosis

Particle-induced pulmonary acute phase response correlates with neutrophil influx linking inhaled particles and cardiovascular risk

BACKGROUND: Particulate air pollution is associated with cardiovascular disease. Acute phase response is causally linked to cardiovascular disease. Here, we propose that particle-induced pulmonary acute phase response provides an underlying mechanism for particle-induced cardiovascular risk. METHODS: We analysed the mRNA expression of Serum Amyloid A (Saa3) in lung tissue from female C57BL/6J mice exposed to different particles including nanomaterials (carbon black and titanium dioxide nanoparticles, multi- and single walled carbon nanotubes), diesel exhaust particles and airborne dust collected at a biofuel plant. Mice were exposed to single or multiple doses of particles by inhalation or intratracheal instillation and pulmonary mRNA expression of Saa3 was determined at different time points of up to 4 weeks after exposure. Also hepatic mRNA expression of Saa3, SAA3 protein levels in broncheoalveolar lavage fluid and in plasma and high density lipoprotein levels in plasma were determined in mice exposed to multiwalled carbon nanotubes. RESULTS: Pulmonary exposure to particles strongly increased Saa3 mRNA levels in lung tissue and elevated SAA3 protein levels in broncheoalveolar lavage fluid and plasma, whereas hepatic Saa3 levels were much less affected. Pulmonary Saa3 expression correlated with the number of neutrophils in BAL across different dosing regimens, doses and time points. CONCLUSIONS: Pulmonary acute phase response may constitute a direct link between particle inhalation and risk of cardiovascular disease. We propose that the particle-induced pulmonary acute phase response may predict risk for cardiovascular disease