Myeloid IκBα Deficiency Promotes Atherogenesis by Enhancing Leukocyte Recruitment to the Plaques

Activation of the transcription factor NF-κB appears to be involved in different stages of atherogenesis. In this paper we investigate the role of NF-κB inhibitor IκBα in atherosclerosis. Myeloid-specific deletion of IκBα results in larger and more advanced lesions in LDL-R-deficient mice without affecting the compositional phenotype of the plaques or systemic inflammatory markers in the plasma. We show that IκBα-deleted macrophages display enhanced adhesion to an in vitro endothelial cell layer, coinciding with an increased expression of the chemokine CCL5. Also, in vivo we found that IκBαdel mice had more leukocytes adhering to the luminal side of the endothelial cell layers that cover the atherosclerotic plaques. Moreover, we introduce ER-MP58 in this paper as a new immunohistochemical tool for quantifying newly recruited myeloid cells in the atherosclerotic lesion. This staining confirms that in IκBαdel mice more leukocytes are attracted to the plaques. In conclusion, we show that IκBα deletion in myeloid cells promotes atherogenesis, probably through an induced leukocyte recruitment to plaques

Effect of protocatechuic acid on insulin responsiveness and inflammation in visceral adipose tissue from obese individuals: possible role for PTP1B

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How has internet addiction research evolved since the advent of internet gaming disorder? An overview of cyberaddictions from a psychological perspective

During the past two decades, Internet addiction (IA) has been the most commonly used term in research into online activities and their influence on the development of behavioral addictions. The aim of this review is to assess the impact of the concept of Internet gaming disorder (IGD), proposed by the American Psychiatric Association, on the scientific literature regarding IA. It presents a bibliometric analysis of the IA literature starting from the time IGD was first proposed, with the objective of observing and comparing the topics that have arisen during this period among the different IA themes researched. The findings demonstrate a steady evolution, particularly regarding publications related to the general aspects of IA: its clinical component, its prevalence and psychometric measures, the growing interest in the contextual factors promoting this addictive behavior, scientific progress in its conceptualization based on existing theoretical models, and neuropsychological studies. Nevertheless, many of the studies (22 %) focus on specific IA behaviors and show heterogeneity among the cyberaddictions, with online gaming (related to IGD) most common, followed by cybersex and social networking. Although research on the general concept of IA continues, investigators have begun to pay attention to the diverse spectrum of specific cyberaddictions and their psychological components

Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009

Insulin resistance is a hallmark of type 2 diabetes mellitus and is associated with a metabolic and cardiovascular cluster of disorders (dyslipidaemia, hypertension, obesity [especially visceral], glucose intolerance, endothelial dysfunction), each of which is an independent risk factor for cardiovascular disease (CVD). Multiple prospective studies have documented an association between insulin resistance and accelerated CVD in patients with type 2 diabetes, as well as in non-diabetic individuals. The molecular causes of insulin resistance, i.e. impaired insulin signalling through the phosphoinositol-3 kinase pathway with intact signalling through the mitogen-activated protein kinase pathway, are responsible for the impairment in insulin-stimulated glucose metabolism and contribute to the accelerated rate of CVD in type 2 diabetes patients. The current epidemic of diabetes is being driven by the obesity epidemic, which represents a state of tissue fat overload. Accumulation of toxic lipid metabolites (fatty acyl CoA, diacylglycerol, ceramide) in muscle, liver, adipocytes, beta cells and arterial tissues contributes to insulin resistance, beta cell dysfunction and accelerated atherosclerosis, respectively, in type 2 diabetes. Treatment with thiazolidinediones mobilises fat out of tissues, leading to enhanced insulin sensitivity, improved beta cell function and decreased atherogenesis. Insulin resistance and lipotoxicity represent the missing links (beyond the classical cardiovascular risk factors) that help explain the accelerated rate of CVD in type 2 diabetic patients

Erythro-myeloid progenitors can differentiate from endothelial cells and modulate embryonic vascular remodeling

Erythro-myeloid progenitors (EMPs) were recently described to arise from the yolk sac endothelium, just prior to vascular remodeling, and are the source of adult/post-natal tissue resident macrophages. Questions remain, however, concerning whether EMPs differentiate directly from the endothelium or merely pass through. We provide the first evidence in vivo that EMPs can emerge directly from endothelial cells (ECs) and demonstrate a role for these cells in vascular development. We find that EMPs express most EC markers but late EMPs and EMP-derived cells do not take up acetylated low-density lipoprotein (AcLDL), as ECs do. When the endothelium is labelled with AcLDL before EMPs differentiate, EMPs and EMP-derived cells arise that are AcLDL+. If AcLDL is injected after the onset of EMP differentiation, however, the majority of EMP-derived cells are not double labelled. We find that cell division precedes entry of EMPs into circulation, and that blood flow facilitates the transition of EMPs from the endothelium into circulation in a nitric oxide-dependent manner. In gain-of-function studies, we inject the CSF1-Fc ligand in embryos and found that this increases the number of CSF1R+ cells, which localize to the venous plexus and significantly disrupt venous remodeling. This is the first study to definitively establish that EMPs arise from the endothelium in vivo and show a role for early myeloid cells in vascular development

Lipid accumulation and dendritic cell dysfunction in cancer

Professional antigen presenting cells, dendritic cells (DC) are responsible for initiation and maintenance of immune responses. Here, we report that a substantial proportion of DCs in tumor-bearing mice and cancer patients have increased levels of triglycerides. Lipid accumulation in DCs was caused by increased uptake of extracellular lipids due to up-regulation of scavenger receptor A. DCs with high lipid content were not able to effectively stimulate allogeneic T cells or present tumor-associated antigens. DCs with high and normal lipid levels did not differ in expression of MHC and co-stimulatory molecules. However, lipid-laden DCs had reduced capacity to process antigens. Pharmacological normalization of lipid levels in DCs with an inhibitor of acetyl-CoA carboxylase restored the functional activity of DCs and substantially enhanced the effects of a cancer vaccine. These findings support the regulation of immune responses in cancer by manipulation of lipid levels in DCs

Relative contributions of crust and mantle to generation of Campanian high-K calc-alkaline I-type granitoids in a subduction setting, with special reference to the Harsit Pluton, Eastern Turkey

We present elemental and Sr-Nd-Pb isotopic data for the magmatic suite (similar to 79 Ma) of the Harsit pluton, from the Eastern Pontides (NE Turkey), with the aim of determining its magma source and geodynamic evolution. The pluton comprises granite, granodiorite, tonalite and minor diorite (SiO(2) = 59.43-76.95 wt%), with only minor gabbroic diorite mafic microgranular enclaves in composition (SiO(2) = 54.95-56.32 wt%), and exhibits low Mg# (<46). All samples show a high-K calc-alkaline differentiation trend and I-type features. The chondrite-normalized REE patterns are fractionated [(La/Yb)(n) = 2.40-12.44] and display weak Eu anomalies (Eu/Eu* = 0.30-0.76). The rocks are characterized by enrichment of LILE and depletion of HFSE. The Harsit host rocks have weak concave-upward REE patterns, suggesting that amphibole and garnet played a significant role in their generation during magma segregation. The host rocks and their enclaves are isotopically indistinguishable. Sr-Nd isotopic data for all of the samples display I(Sr) = 0.70676-0.70708, epsilon(Nd)(79 Ma) = -4.4 to -3.3, with T(DM) = 1.09-1.36 Ga. The lead isotopic ratios are ((206)Pb/(204)pb) = 18.79-18.87, ((207)Pb/(204)Pb) = 15.59-15.61 and ((208)Pb/(204)Pb) = 38.71-38.83. These geochemical data rule out pure crustal-derived magma genesis in a post-collision extensional stage and suggest mixed-origin magma generation in a subduction setting. The melting that generated these high-K granitoidic rocks may have resulted from the upper Cretaceous subduction of the Izmir-Ankara-Erzincan oceanic slab beneath the Eurasian block in the region. The back-arc extensional events would have caused melting of the enriched subcontinental lithospheric mantle and formed mafic magma. The underplating of the lower crust by mafic magmas would have played a significant role in the generation of high-K magma. Thus, a thermal anomaly induced by underplated basic magma into a hot crust would have caused partial melting in the lower part of the crust. In this scenario, the lithospheric mantle-derived basaltic melt first mixed with granitic magma of crustal origin at depth. Then, the melts, which subsequently underwent a fractional crystallization and crustal assimilation processes, could ascend to shallower crustal levels to generate a variety of rock types ranging from diorite to granite. Sr-Nd isotope modeling shows that the generation of these magmas involved similar to 65-75% of the lower crustal-derived melt and similar to 25-35% of subcontinental lithospheric mantle. Further, geochemical data and the Ar-Ar plateau age on hornblende, combined with regional studies, imply that the Harsit pluton formed in a subduction setting and that the back-arc extensional period started by least similar to 79 Ma in the Eastern Pontides.Geochemistry & GeophysicsMineralogySCI(E)33ARTICLE4467-48716

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Macrophage secretory phospholipase A2 group X enhances anti-inflammatory responses, promotes lipid accumulation, and contributes to aberrant lung pathology.

Secreted phospholipase A2 group X (sPLA(2)-X) is one of the most potent enzymes of the phospholipase A(2) lipolytic enzyme superfamily. Its high catalytic activity toward phosphatidylcholine (PC), the major phospholipid of cell membranes and low-density lipoproteins (LDL), has implicated sPLA(2)-X in chronic inflammatory conditions such as atherogenesis. We studied the role of sPLA(2)-X enzyme activity in vitro and in vivo, by generating sPLA(2)-X-overexpressing macrophages and transgenic macrophage-specific sPLA(2)-X mice. Our results show that sPLA(2)-X expression inhibits macrophage activation and inflammatory responses upon stimulation, characterized by reduced cell adhesion and nitric oxide production, a decrease in tumor necrosis factor (TNF), and an increase in interleukin (IL)-10. These effects were mediated by an increase in IL-6, and enhanced production of prostaglandin E(2) (PGE(2)) and 15-deoxy-Delta12,14-prostaglandin J(2) (PGJ(2)). Moreover, we found that overexpression of active sPLA(2)-X in macrophages strongly increases foam cell formation upon incubation with native LDL but also oxidized LDL (oxLDL), which is mediated by enhanced expression of scavenger receptor CD36. Transgenic sPLA(2)-X mice died neonatally because of severe lung pathology characterized by interstitial pneumonia with massive granulocyte and surfactant-laden macrophage infiltration. We conclude that overexpression of the active sPLA(2)-X enzyme results in enhanced foam cell formation but reduced activation and inflammatory responses in macrophages in vitro. Interestingly, enhanced sPLA(2)-X activity in macrophages in vivo leads to fatal pulmonary defects, suggesting a crucial role for sPLA(2)-X in inflammatory lung disease