A systems biology analysis of brain microvascular endothelial cell lipotoxicity.

BackgroundNeurovascular inflammation is associated with a number of neurological diseases including vascular dementia and Alzheimer's disease, which are increasingly important causes of morbidity and mortality around the world. Lipotoxicity is a metabolic disorder that results from accumulation of lipids, particularly fatty acids, in non-adipose tissue leading to cellular dysfunction, lipid droplet formation, and cell death.ResultsOur studies indicate for the first time that the neurovascular circulation also can manifest lipotoxicity, which could have major effects on cognitive function. The penetration of integrative systems biology approaches is limited in this area of research, which reduces our capacity to gain an objective insight into the signal transduction and regulation dynamics at a systems level. To address this question, we treated human microvascular endothelial cells with triglyceride-rich lipoprotein (TGRL) lipolysis products and then we used genome-wide transcriptional profiling to obtain transcript abundances over four conditions. We then identified regulatory genes and their targets that have been differentially expressed through analysis of the datasets with various statistical methods. We created a functional gene network by exploiting co-expression observations through a guilt-by-association assumption. Concomitantly, we used various network inference algorithms to identify putative regulatory interactions and we integrated all predictions to construct a consensus gene regulatory network that is TGRL lipolysis product specific.ConclusionSystem biology analysis has led to the validation of putative lipid-related targets and the discovery of several genes that may be implicated in lipotoxic-related brain microvascular endothelial cell responses. Here, we report that activating transcription factors 3 (ATF3) is a principal regulator of TGRL lipolysis products-induced gene expression in human brain microvascular endothelial cell

Synthetic biology: advancing biological frontiers by building synthetic systems

Advances in synthetic biology are contributing to diverse research areas, from basic biology to biomanufacturing and disease therapy. We discuss the theoretical foundation, applications, and potential of this emerging field

Comparative transcriptome profiling of the injured zebrafish and mouse hearts identifies miRNA-dependent repair pathways.

The adult mammalian heart has poor regenerative capacity. In contrast, the zebrafish heart retains a robust capacity for regeneration into adulthood. These distinct responses are consequences of a differential utilization of evolutionary-conserved gene regulatory networks in the damaged heart. To systematically identify miRNA-dependent networks controlling cardiac repair following injury, we performed comparative gene and miRNA profiling of the cardiac transcriptome in adult mice and zebrafish. Using an integrated approach, we show that 45 miRNA-dependent networks, involved in critical biological pathways, are differentially modulated in the injured zebrafish vs. mouse hearts. We study, more particularly, the miR-26a-dependent response. Therefore, miR-26a is down-regulated in the fish heart after injury, whereas its expression remains constant in the mouse heart. Targets of miR-26a involve activators of the cell cycle and Ezh2, a component of the polycomb repressive complex 2 (PRC2). Importantly, PRC2 exerts repressive functions on negative regulators of the cell cycle. In cultured neonatal cardiomyocytes, inhibition of miR-26a stimulates, therefore, cardiomyocyte proliferation. Accordingly, miR-26a knockdown prolongs the proliferative window of cardiomyocytes in the post-natal mouse heart. This novel strategy identifies a series of miRNAs and associated pathways, in particular miR-26a, which represent attractive therapeutic targets for inducing repair in the injured heart

Species-specific differences in follicular antral sizes result from diffusion-based limitations on the thickness of the granulosa cell layer

The size of mature oocytes is similar across mammalian species, yet the size of ovarian follicles increases with species size, with some ovarian follicles reaching diameters more than 1000-fold the size of the enclosed oocyte. Here we show that the different follicular sizes can be explained with diffusion-based limitations on the thickness of the hormone-secreting granulosa layer. By analysing published data on human follicular growth and granulosa cell expansion during follicular maturation we find that the 4-fold increase of the antral follicle diameter is entirely driven by an increase in the follicular fluid volume, while the thickness of the surrounding granulosa layer remains constant at about 45+/-10 mkm. Based on the measured kinetic constants, the model reveals that the observed fall in the gonadotropin concentration from peripheral blood circulation to the follicular antrum is a result of sequestration in the granulosa. The model further shows that as a result of sequestration, an increased granulosa thickness cannot substantially increase estradiol production but rather deprives the oocyte from gonadotropins. Larger animals (with a larger blood volume) require more estradiol as produced by the ovaries to downregulate FSH-secretion in the pituitary. Larger follicle diameters result in larger follicle surface areas for constant granulosa layer thickness. The reported increase in follicular surface area in larger species indeed correlates linearly both with species mass and with the predicted increase in estradiol output. In summary, we propose a structural role for the antrum in that it determines the volume of the granulosa layer and thus the level of estrogen production.Comment: Mol Hum Repr 201

Age-related changes in blood-brain barrier integrity in C57BL/6J mice

The blood-brain barrier (BBB) is formed by the endothelial cells of the brain microvasculature, which control the molecular traffic between the blood and brain to maintain the neural microenvironment

A bovine lymphosarcoma cell line infected with theileria annulata exhibits an irreversible reconfiguration of host cell gene expression

Theileria annulata, an intracellular parasite of bovine lymphoid cells, induces substantial phenotypic alterations to its host cell including continuous proliferation, cytoskeletal changes and resistance to apoptosis. While parasite induced modulation of host cell signal transduction pathways and NFκB activation are established, there remains considerable speculation on the complexities of the parasite directed control mechanisms that govern these radical changes to the host cell. Our objectives in this study were to provide a comprehensive analysis of the global changes to host cell gene expression with emphasis on those that result from direct intervention by the parasite. By using comparative microarray analysis of an uninfected bovine cell line and its Theileria infected counterpart, in conjunction with use of the specific parasitacidal agent, buparvaquone, we have identified a large number of host cell gene expression changes that result from parasite infection. Our results indicate that the viable parasite can irreversibly modify the transformed phenotype of a bovine cell line. Fifty percent of genes with altered expression failed to show a reversible response to parasite death, a possible contributing factor to initiation of host cell apoptosis. The genes that did show an early predicted response to loss of parasite viability highlighted a sub-group of genes that are likely to be under direct control by parasite infection. Network and pathway analysis demonstrated that this sub-group is significantly enriched for genes involved in regulation of chromatin modification and gene expression. The results provide evidence that the Theileria parasite has the regulatory capacity to generate widespread change to host cell gene expression in a complex and largely irreversible manner

Loss of ATF3 exacerbates liver damage through the activation of mTOR/p70S6K/ HIF-1α signaling pathway in liver inflammatory injury.

Activating transcription factor 3 (ATF3) is a stress-induced transcription factor that plays important roles in regulating immune and metabolic homeostasis. Activation of the mechanistic target of rapamycin (mTOR) and hypoxia-inducible factor (HIF) transcription factors are crucial for the regulation of immune cell function. Here, we investigated the mechanism by which the ATF3/mTOR/HIF-1 axis regulates immune responses in a liver ischemia/reperfusion injury (IRI) model. Deletion of ATF3 exacerbated liver damage, as evidenced by increased levels of serum ALT, intrahepatic macrophage/neutrophil trafficking, hepatocellular apoptosis, and the upregulation of pro-inflammatory mediators. ATF3 deficiency promoted mTOR and p70S6K phosphorylation, activated high mobility group box 1 (HMGB1) and TLR4, inhibited prolyl-hydroxylase 1 (PHD1), and increased HIF-1α activity, leading to Foxp3 downregulation and RORγt and IL-17A upregulation in IRI livers. Blocking mTOR or p70S6K in ATF3 knockout (KO) mice or bone marrow-derived macrophages (BMMs) downregulated HMGB1, TLR4, and HIF-1α and upregulated PHD1, increasing Foxp3 and decreasing IL-17A levels in vitro. Silencing of HIF-1α in ATF3 KO mice ameliorated IRI-induced liver damage in parallel with the downregulation of IL-17A in ATF3-deficient mice. These findings demonstrated that ATF3 deficiency activated mTOR/p70S6K/HIF-1α signaling, which was crucial for the modulation of TLR4-driven inflammatory responses and T cell development. The present study provides potential therapeutic targets for the treatment of liver IRI followed by liver transplantation

Age-related changes to lumbosacral spinal cord motoneurons that modulate bladder and bowel functions in male C57BL/6 mice

Incontinence and sexual dysfunction are often increased in the aged human population. In rats and mice the pattern of micturition and faecal clearance also changes with ageing and is suggestive of bladder and bowel dysfunction