Ceramides bind VDAC2 to trigger mitochondrial apoptosis

Ceramides draw wide attention as tumor suppressor lipids that act directly on mitochondria to trigger apoptotic cell death. However, molecular details of the underlying mechanism are largely unknown. Using a photoactivatable ceramide probe, we here identify the voltage-dependent anion channels VDAC1 and VDAC2 as mitochondrial ceramide binding proteins. Coarse-grain molecular dynamics simulations reveal that both channels harbor a ceramide binding site on one side of the barrel wall. This site includes a membrane-buried glutamate that mediates direct contact with the ceramide head group. Substitution or chemical modification of this residue abolishes photolabeling of both channels with the ceramide probe. Unlike VDAC1 removal, loss of VDAC2 or replacing its membrane-facing glutamate with glutamine renders human colon cancer cells largely resistant to ceramide-induced apoptosis. Collectively, our data support a role of VDAC2 as direct effector of ceramide-mediated cell death, providing a molecular framework for how ceramides exert their anti-neoplastic activity

Detection of microRNA Expression in Human Peripheral Blood Microvesicles

MicroRNAs (miRNA) are small non-coding RNAs that regulate translation of mRNA and protein. Loss or enhanced expression of miRNAs is associated with several diseases, including cancer. However, the identification of circulating miRNA in healthy donors is not well characterized. Microvesicles, also known as exosomes or microparticles, circulate in the peripheral blood and can stimulate cellular signaling. In this study, we hypothesized that under normal healthy conditions, microvesicles contain miRNAs, contributing to biological homeostasis.Microvesicles were isolated from the plasma of normal healthy individuals. RNA was isolated from both the microvesicles and matched mononuclear cells and profiled for 420 known mature miRNAs by real-time PCR. Hierarchical clustering of the data sets indicated significant differences in miRNA expression between peripheral blood mononuclear cells (PBMC) and plasma microvesicles. We observed 71 miRNAs co-expressed between microvesicles and PBMC. Notably, we found 33 and 4 significantly differentially expressed miRNAs in the plasma microvesicles and mononuclear cells, respectively. Prediction of the gene targets and associated biological pathways regulated by the detected miRNAs was performed. The majority of the miRNAs expressed in the microvesicles from the blood were predicted to regulate cellular differentiation of blood cells and metabolic pathways. Interestingly, a select few miRNAs were also predicted to be important modulators of immune function.This study is the first to identify and define miRNA expression in circulating plasma microvesicles of normal subjects. The data generated from this study provides a basis for future studies to determine the predictive role of peripheral blood miRNA signatures in human disease and will enable the definition of the biological processes regulated by these miRNA

Breed and adaptive response modulate bovine peripheral blood cells’ transcriptome

Background: Adaptive response includes a variety of physiological modifications to face changes in external or internal conditions and adapt to a new situation. The acute phase proteins (APPs) are reactants synthesized against environmental stimuli like stress, infection, inflammation. Methods: To delineate the differences in molecular constituents of adaptive response to the environment we performed the whole-blood transcriptome analysis in Italian Holstein (IH) and Italian Simmental (IS) breeds. For this, 663 IH and IS cows from six commercial farms were clustered according to the blood level of APPs. Ten extreme individuals (five APP+ and APP- variants) from each farm were selected for the RNA-seq using the Illumina sequencing technology. Differentially expressed (DE) genes were analyzed using dynamic impact approach (DIA) and DAVID annotation clustering. Milk production data were statistically elaborated to assess the association of APP+ and APP- gene expression patterns with variations in milk parameters. Results: The overall de novo assembly of cDNA sequence data generated 13,665 genes expressed in bovine blood cells. Comparative genomic analysis revealed 1,152 DE genes in the comparison of all APP+ vs. all APP- variants; 531 and 217 DE genes specific for IH and IS comparison respectively. In all comparisons overexpressed genes were more represented than underexpressed ones. DAVID analysis revealed 369 DE genes across breeds, 173 and 73 DE genes in IH and IS comparison respectively. Among the most impacted pathways for both breeds were vitamin B6 metabolism, folate biosynthesis, nitrogen metabolism and linoleic acid metabolism. Conclusions: Both DIA and DAVID approaches produced a high number of significantly impacted genes and pathways with a narrow connection to adaptive response in cows with high level of blood APPs. A similar variation in gene expression and impacted pathways between APP+ and APP- variants was found between two studied breeds. Such similarity was also confirmed by annotation clustering of the DE genes. However, IH breed showed higher and more differentiated impacts compared to IS breed and such particular features in the IH adaptive response could be explained by its higher metabolic activity. Variations of milk production data were significantly associated with APP+ and APP- gene expression patterns

Circulating microparticles: square the circle

Background: The present review summarizes current knowledge about microparticles (MPs) and provides a systematic overview of last 20 years of research on circulating MPs, with particular focus on their clinical relevance. Results: MPs are a heterogeneous population of cell-derived vesicles, with sizes ranging between 50 and 1000 nm. MPs are capable of transferring peptides, proteins, lipid components, microRNA, mRNA, and DNA from one cell to another without direct cell-to-cell contact. Growing evidence suggests that MPs present in peripheral blood and body fluids contribute to the development and progression of cancer, and are of pathophysiological relevance for autoimmune, inflammatory, infectious, cardiovascular, hematological, and other diseases. MPs have large diagnostic potential as biomarkers; however, due to current technological limitations in purification of MPs and an absence of standardized methods of MP detection, challenges remain in validating the potential of MPs as a non-invasive and early diagnostic platform. Conclusions: Improvements in the effective deciphering of MP molecular signatures will be critical not only for diagnostics, but also for the evaluation of treatment regimens and predicting disease outcomes

Understanding How Microplastics Affect Marine Biota on the Cellular Level Is Important for Assessing Ecosystem Function: A Review

Plastic has become indispensable for human life. When plastic debris is discarded into waterways, these items can interact with organisms. Of particular concern are microscopic plastic particles (microplastics) which are subject to ingestion by several taxa. This review summarizes the results of cutting-edge research about the interactions between a range of aquatic species and microplastics, including effects on biota physiology and secondary ingestion. Uptake pathways via digestive or ventilatory systems are discussed, including (1) the physical penetration of microplastic particles into cellular structures, (2) leaching of chemical additives or adsorbed persistent organic pollutants (POPs), and (3) consequences of bacterial or viral microbiota contamination associated with microplastic ingestion. Following uptake, a number of individual-level effects have been observed, including reduction of feeding activities, reduced growth and reproduction through cellular modifications, and oxidative stress. Microplastic-associated effects on marine biota have become increasingly investigated with growing concerns regarding human health through trophic transfer. We argue that research on the cellular interactions with microplastics provide an understanding of their impact to the organisms’ fitness and, therefore, its ability to sustain their functional role in the ecosystem. The review summarizes information from 236 scientific publications. Of those, only 4.6% extrapolate their research of microplastic intake on individual species to the impact on ecosystem functioning. We emphasize the need for risk evaluation from organismal effects to an ecosystem level to effectively evaluate the effect of microplastic pollution on marine environments. Further studies are encouraged to investigate sublethal effects in the context of environmentally relevant microplastic pollution conditions

2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

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Genetic Basis of Myocarditis: Myth or Reality?

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