Calcium phosphate particles stimulate interleukin-1β release from human vascular smooth muscle cells: A role for spleen tyrosine kinase and exosome release

Aims: Calcium phosphate (CaP) particle deposits are found in several inflammatory diseases including atherosclerosis and osteoarthritis. CaP, and other forms of crystals and particles, can promote inflammasome formation in macrophages leading to caspase-1 activation and secretion of mature interleukin-1β (IL-1β). Given the close association of small CaP particles with vascular smooth muscle cells (VSMCs) in atherosclerotic fibrous caps, we aimed to determine if CaP particles affected pro-inflammatory signalling in human VSMCs. Methods and results: Using ELISA to measure IL-1β release from VSMCs, we demonstrated that CaP particles stimulated IL-1β release from proliferating and senescent human VSMCs, but with substantially greater IL-1β release from senescent cells; this required caspase-1 activity but not LPS-priming of cells. Potential inflammasome agonists including ATP, nigericin and monosodium urate crystals did not stimulate IL-1β release from VSMCs. Western blot analysis demonstrated that CaP particles induced rapid activation of spleen tyrosine kinase (SYK) (increased phospho-Y525/526). The SYK inhibitor R406 reduced IL-1β release and caspase-1 activation in CaP particle-treated VSMCs, indicating that SYK activation occurs upstream of and is required for caspase-1 activation. In addition, IL-1β and caspase-1 colocalised in intracellular endosome-like vesicles and we detected IL-1β in exosomes isolated from VSMC media. Furthermore, CaP particle treatment stimulated exosome secretion by VSMCs in a SYK-dependent manner, while the exosome-release inhibitor spiroepoxide reduced IL-1β release. Conclusions: CaP particles stimulate SYK and caspase-1 activation in VSMCs, leading to the release of IL-1β, at least in part via exosomes. These novel findings in human VSMCs highlight the pro-inflammatory and procalcific potential of microcalcification

Global Levels of Histone Modifications in Peripheral Blood Mononuclear Cells of Subjects with Exposure to Nickel

Background: Occupational exposure to nickel (Ni) is associated with an increased risk for lung and nasal cancers. Ni compounds exhibit weak mutagenic activity, cause gene amplification, and disrupt cellular epigenetic homeostasis. However, the Ni-induced changes in global histone modification levels have only been tested in vitro

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Human matrix metalloproteinases (MMPs) belong to the M10 family of the MA clan of endopeptidases. They are ubiquitarian enzymes, structurally characterized by an active site where a Zn(2+) atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid as a general base. Various MMPs display different domain composition, which is very important for macromolecular substrates recognition. Substrate specificity is very different among MMPs, being often associated to their cellular compartmentalization and/or cellular type where they are expressed. An extensive review of the different MMPs structural and functional features is integrated with their pathological role in several types of diseases, spanning from cancer to cardiovascular diseases and to neurodegeneration. It emerges a very complex and crucial role played by these enzymes in many physiological and pathological processes

Preparation and Properties of PP/PAN/Cotton Fibers Composite Membrane as Lithium-Ion Battery Separator with Thermal Shut-Off Function

The lithium-ion battery separator plays roles of separating the positive and negative electrodes and providing ion channels, and at the same time, it can play a more important role in the safety of the lithium-ion battery. In this work, a modified PP (polypropylene)/PAN (polyacrylonitrile)/cotton fibers composite membrane with a thermal shut-off function was prepared by a wet-laid process. The results are as follows: When the fibers’ mass fraction was 50%, the composite membrane had the best combination properties, with a tensile strength of 1.644 KN·m−1, the porosity was 63%, and it had good wettability with an aspiration height of 39 mm and a liquid absorption rate of 269%. The thermal shrinkage of the composite membrane was less than 4% after thermal treatment under 160 °C. More importantly, the DSC curve showed that the modified PP/PAN/cotton fibers composite membrane had a thermal shut-off function with the temperature between 110 °C and 160 °C. After thermal treatment under 160 °C for 1 h, the ionic conductivity of the fiber membrane decreased to 0.32 mS·cm−1 from 1.99 mS·cm−1. Electrochemical performance tests showed that the button battery using the fiber composite membrane had a slightly better initial discharge, capacity retention and cycle performance at different rates than the button battery equipped with the PP membrane. The results show that the modified PP/PAN/cotton fibers composite membrane improves the safety and electrochemical performance of lithium-ion battery

Sonic hedgehog signaling: Alternative splicing and pathogenic role in medulloblastoma

Alternative splicing (AS) produces the different mRNA splicing bodies, which are then translated into multiple protein isoforms and participate in various biological functions. With a deeper understanding of alternative splicing through the study of transcriptomes using high-throughput sequencing-based methods, the correlation between aberrant AS and diseases triggered a great concern, especially abnormal AS and cancer. Medulloblastoma (MB) is an intracranial tumor in children. Sonic hedgehog MB (SHH-MB) accounted for approximately 30% of MB, which is associated with the activation of SHH signaling. Growing evidence shows that aberrant AS is closely related to the tumorigenesis of MB. Here, we briefly introduced the AS and its mechanism. Next, we described canonical/noncanonical hedgehog signaling and its correlation with MB. The main description focused on AS of various regulators in canonical hedgehog signaling in MB. In addition, we also described AS of various regulators in noncanonical hedgehog signaling. Meanwhile, activated hedgehog signaling also induces AS in MB. Then, we pointed out that aberrant AS of hedgehog signaling is associated with different MB subgroups. Finally, we summarized the therapeutic applications of targeted AS in cancer treatment. In summary, further understanding of AS in SHH-MB could develop therapeutic targets for splicing factors which may be a novel therapeutic strategy

Prioritizing Disease Candidate Proteins in Cardiomyopathy-Specific Protein-Protein Interaction Networks Based on “Guilt by Association” Analysis

<div><p>The cardiomyopathies are a group of heart muscle diseases which can be inherited (familial). Identifying potential disease-related proteins is important to understand mechanisms of cardiomyopathies. Experimental identification of cardiomyophthies is costly and labour-intensive. In contrast, bioinformatics approach has a competitive advantage over experimental method. Based on “guilt by association” analysis, we prioritized candidate proteins involving in human cardiomyopathies. We first built weighted human cardiomyopathy-specific protein-protein interaction networks for three subtypes of cardiomyopathies using the known disease proteins from Online Mendelian Inheritance in Man as seeds. We then developed a method in prioritizing disease candidate proteins to rank candidate proteins in the network based on “guilt by association” analysis. It was found that most candidate proteins with high scores shared disease-related pathways with disease seed proteins. These top ranked candidate proteins were related with the corresponding disease subtypes, and were potential disease-related proteins. Cross-validation and comparison with other methods indicated that our approach could be used for the identification of potentially novel disease proteins, which may provide insights into cardiomyopathy-related mechanisms in a more comprehensive and integrated way.</p></div

AUC for three subtypes of cardiomyopathies obtained using GeneMANIA and ToppGenet.

<p>AUC for three subtypes of cardiomyopathies obtained using GeneMANIA and ToppGenet.</p

The workflow of our method in prioritizing disease candidate proteins.

<p>First, cardiomyopathy (DCM, HCM or ARVC)-specific PPINs were constructed, which were composed of seed proteins and their direct neighbors (candidate proteins) from human PPIN. Secondly, two weights (interaction confidence scores and functional similarities) were used to measure each protein interaction. The disease relevance score of each protein was measured by using these weights. Finally, the proteins ranked at top of each candidate list in descending order of disease relevance score were taken as potential disease-related proteins.</p

DCM pathway.

<p>DCM seed proteins are colored in cyan. Red nodes are proteins which were verified to be DCM-related proteins, and yellow nodes represent proteins which are potential DCM-related proteins.</p