Coronary artery disease (CAD) arising from atherosclerosis is a leading cause of death and morbidity worldwide. The underlying pathogenesis involves an imbalanced lipid metabolism and a maladaptive ...immune response entailing a chronic inflammation of the arterial wall. The disturbed equilibrium of lipid accumulation, immune responses and their clearance is shaped by leukocyte trafficking and homeostasis governed by chemokines and their receptors. New pro- and anti-inflammatory pathways linking lipid and inflammation biology have been discovered, and genetic profiling studies have unveiled variations involved in human CAD. The growing understanding of the inflammatory processes and mediators has uncovered an intriguing diversity of targetable mechanisms that can be exploited to complement lipid-lowering therapies. Here we aim to systematically survey recently identified molecular mechanisms, translational developments and clinical strategies for targeting lipid-related inflammation in atherosclerosis and CAD.
Traditionally, neutrophils have been acknowledged to be the first immune cells that are recruited to an inflamed tissue and have mainly been considered in the context of acute inflammation. By ...contrast, their importance during chronic inflammation has been studied in less depth. This Review aims to summarize our current understanding of the roles of neutrophils in chronic inflammation, with a focus on how they communicate with other immune and non-immune cells within tissues. We also scrutinize the roles of neutrophils in wound healing and the resolution of inflammation, and finally, we outline emerging therapeutic strategies that target neutrophils.
Neutrophil extracellular traps expelled from suicidal neutrophils comprise a complex structure of nuclear chromatin and proteins of nuclear, granular, and cytosolic origin. These net-like structures ...have also been detected in atherosclerotic lesions and arterial thrombi in humans and mice. Functionally, neutrophil extracellular traps have been shown to induce activation of endothelial cells, antigen-presenting cells, and platelets, resulting in a proinflammatory immune response. Overall, this suggests that they are not only present in plaques and thrombi but also they may play a causative role in triggering atherosclerotic plaque formation and arterial thrombosis. This review will focus on current findings of the involvement of neutrophil extracellular traps in atherogenesis and atherothrombosis.
Abstract
The outcomes of the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial have unequivocally proven that inflammation is a key driver of atherosclerosis and that targeting ...inflammation, in this case by using an anti-interleukin-1β antibody, improves cardiovascular disease (CVD) outcomes. This is especially true for CVD patients with a pro-inflammatory constitution. Although CANTOS has epitomized the importance of targeting inflammation in atherosclerosis, treatment with canakinumab did not improve CVD mortality, and caused an increase in infections. Therefore, the identification of novel drug targets and development of novel therapeutics that block atherosclerosis-specific inflammatory pathways and exhibit limited immune-suppressive side effects, as pursued in our collaborative research centre, are required to optimize immunotherapy for CVD. In this review, we will highlight the potential of novel immunotherapeutic targets that are currently considered to become a future treatment for CVD.
The maladaptation of endothelial cells to disturbed flow at arterial bifurcations increases permeability for lipoproteins. Additional injury by chemically modified lipoproteins disrupts the ...continuous repair of maladapted endothelial cells and triggers intimal macrophage accumulation. Macrophages remove modified lipoproteins from the extracellular space until the cholesterol overload leads to macrophage death and insufficient efferocytosis. This macrophage failure promotes the progression to advanced lesions by formation of a lipid-rich necrotic core, which may rupture and cause myocardial infarction and stroke. In this article, we summarize the fundamental roles of microRNAs (miRNAs) in the regulation of endothelial maladaptation and macrophage failure during atherosclerosis. We describe how miRNAs coordinate the mutual interaction between chronic endothelial repair and endothelial senescence and mechanistically link the regulation of macrophage cholesterol homeostasis with defective efferocytosis. Lastly, we discuss how miRNAs may challenge and extend current theories about atherosclerosis.
Chronic inflammation drives the development of atherosclerosis, and details regarding the involvement of different leukocyte subpopulations in the pathology of this disease have recently emerged. ...This Review highlights the surprising contribution of granulocyte subsets and mast cells to early atherogenesis and subsequent plaque instability, and describes the complex, double-edged role of monocyte, macrophage and dendritic-cell subsets through crosstalk with T cells and vascular progenitor cells. Improved understanding of the selective contributions of specific cell types to atherogenesis will pave the way for new targeted approaches to therapy.
Acute myocardial infarction (MI) is the leading cause of mortality worldwide. Anti-inflammatory strategies to reduce neutrophil-driven acute post-MI injury have been shown to limit acute cardiac ...tissue damage. On the other hand, whether neutrophils are required for resolving post-MI inflammation and repair is unknown.
We show that neutrophil-depleted mice subjected to MI had worsened cardiac function, increased fibrosis, and progressively developed heart failure. Flow cytometry of blood, lymphoid organs and digested hearts revealed reduced numbers of Ly6Chigh monocytes in infarcts of neutrophil-depleted mice, whereas the number of macrophages increased, which was paralleled by reduced splenic Ly6Chigh monocyte mobilization but enhanced proliferation of cardiac macrophages. Macrophage subtype analysis revealed reduced cardiac expression of M1 markers, whereas M2 markers were increased in neutrophil-depleted mice. Surprisingly, we found reduced expression of phagocytosis receptor myeloid-epithelial-reproductive tyrosine kinase, a marker of reparative M2c macrophages which mediate clearance of apoptotic cells. In agreement with this finding, neutrophil-depleted mice had increased numbers of TUNEL-positive cells within infarcts. We identified neutrophil gelatinase-associated lipocalin (NGAL) in the neutrophil secretome as a key inducer of macrophages with high capacity to engulf apoptotic cells. The cardiac macrophage phenotype in neutrophil-depleted mice was restored by administration of neutrophil secretome or NGAL.
Neutrophils are crucially involved in cardiac repair after MI by polarizing macrophages towards a reparative phenotype. Therapeutic strategies to reduce acute neutrophil-driven inflammation after MI should be carefully balanced as they might interfere with the healing response and cardiac remodelling.
Display omitted
•A robust three-phase numerical simulation model of a fixed-bed gasifier is developed.•The generated regression models have a high degree of accuracy.•High temperature favors CO and ...H2 production, H2 yield, LHVSyngas, CGE, and PCG.•Optimal performance is achieved at temperatures of 820–1090 °C and ER of 0.06–0.10.•An optimum H2 yield of 46.39 g/kg and PCG of 75.93% is observed.
Biomass gasification is recognized as a viable avenue to accelerate the sustainable production of hydrogen. In this work, a numerical simulation model of air gasification of rice husks is developed using the Aspen Plus to investigate the feasibility of producing hydrogen-rich syngas. The model is experimentally validated with rice husk gasification results and other published studies. The influence of temperature and equivalence ratio on the syngas composition, H2 yield, LHVSyngas, H2/CO ratio, CGE, and PCG was studied. Furthermore, the synchronized effects of temperature and ER are studied using RSM to determine the operational point of maximizing H2 yield and PCG. The RSM analysis results show optimum performance at temperatures between 820 °C and 1090 °C and ER in the range of 0.06–0.10. The findings show that optimal operating conditions of the gasification system can be achieved at a more refined precision through simulations coupled with advanced optimization techniques.
Irritable bowel syndrome and gut microbiota Canakis, Andrew; Haroon, Mustafa; Weber, H Christian
Current opinion in endocrinology, diabetes, and obesity,
02/2020, Letnik:
27, Številka:
1
Journal Article
Recenzirano
To provide an overview of recent studies exploring the gut microbiota in pathogenesis and treatment of irritable bowel syndrome (IBS).
Primary bacterial gut disturbances have been linked to the ...development and severity of IBS. Dysbiosis, or alteration in the normal intestinal flora, modulates intestinal permeability, inflammation, gut motility and likely quality of life. These biomechanical changes are associated with enteric and central nervous system processing as well. When compared to healthy controls, IBS patients display poor quality of life measures and are at increased risk of depression and anxiety. The severity of psychological and gastrointestinal symptoms in IBS has been linked with a distinct intestinal microbiota signature. Efforts to modulate intestinal dysbiosis in IBS have shown little improvement in large systematic reviews. The low FODMAP diet reduces bacteria, such as Bifidobacterum and Actinobacteria. Although rifaximin improves symptoms, it may only stimulate a transient effect on the gut microbiota. Fecal microbiota transplant does not provide prolonged symptom relief in IBS.
This review elucidates recent advances in IBS and the gut microbiota. Microbiota changes are one underlying factor in perpetuating global IBS symptoms. The opportunity to exploit this disturbance through treatment modalities requires further investigation.
•Gasification process is optimized using multi-objective response surface methodology.•High gasification temperatures and low moisture contents yield high.LHVSyngas.•Gasification temperature and ...equivalence ratio are the most effective parameters.•The generated regression models are found to have a high degree of accuracy.•Optimal settings in the optimization model yield favorable results in all responses.
Efficient utilization of biomass as an alternative energy resource to fossil fuel has been considered the most promising clean energy option. Gasification technology is at the forefront of biomass conversion amidst other technologies due to its high flexibility in utilizing various kinds of biomass feedstocks. In this study, a thermodynamic model of gasification of sugarcane bagasse with air as the gasifying agent is developed to predict the composition of syngas in a downdraft gasifier using Aspen Plus software at various operating conditions. The model is validated with published experimental results from previous studies. A sensitivity analysis is performed to study the influence of the main operating parameters, namely; gasification temperature, moisture content (MC), and equivalence ratio (ER) on the syngas composition, syngas yield (Qyield), lower heating value of syngas (LHVSyngas), cold gas efficiency (CGE), and carbon conversion efficiency (CCE). Furthermore, response surface methodology is applied to study the combined effects of the main operating parameters and thus determine the optimized zone of the operating condition for maximumLHVSyngas, CGE, hydrogen production, and minimum carbon dioxide production. The regression models for lower heating value, cold gas efficiency, and the concentration of syngas (CO2, and H2) generated from the ANOVA tool are found to have a high degree of accuracy. The optimal operating condition of the gasification temperature, equivalence ratio, and moisture content for maximumLHVSyngas, CGE,H2concentration and minimum carbon dioxide concentration is found to be 877.27 °C, 0.08, and 10%, respectively with the corresponding optimal product values of 7.92 MJ/Nm3, 74.22 %, 31.24%, and 3.91%. The findings of this study show that a blend of simulation with advanced optimization tools can indeed achieve optimal operating conditions of a gasification system at a more refined precision.