Pathological Conversion of Mouse Perivascular Adipose Tissue by Notch Activation.

Objective: Perivascular adipose tissue (PVAT) surrounding arteries supports healthy vascular function. During obesity, PVAT loses its vasoprotective effect. We study pathological conversion of PVAT, which involves molecular changes in protein profiles and functional changes in adipocytes.

The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction.

Coiled-coil-helix-coiled-coil-helix domain-containing 10 (CHCHD10) and CHCHD2 (MNRR1) are homologous proteins with 58% sequence identity and belong to the twin CXC family of proteins that mediate cellular stress responses. Despite the identification of several neurodegeneration-associated mutations in the gene, few studies have assessed its physiological role. Here, we investigated CHCHD10's function as a regulator of oxidative phosphorylation in the mitochondria and the nucleus.

Key proteins and pathways that regulate lifespan.

Here, we review three sets of key proteins and their corresponding downstream pathways that have been linked to extending lifespan and promoting health span in a wide range of organisms. In particular, we review the biology of the sirtuin family of proteins, the insulin/insulin-like growth factor (IGF) signaling (IIS) pathway, and the mechanistic target of rapamycin (mTOR). Using insights derived from simple model organisms, mice, and humans we discuss how these proteins and pathways may potentially alter the rate of aging.

Phosphorylation of Cytochrome c Threonine 28 Regulates Electron Transport Chain Activity in Kidney: IMPLICATIONS FOR AMP KINASE.

Mammalian cytochrome c (Cytc) plays a key role in cellular life and death decisions, functioning as an electron carrier in the electron transport chain and as a trigger of apoptosis when released from the mitochondria. However, its regulation is not well understood. We show that the major fraction of Cytc isolated from kidneys is phosphorylated on Thr, leading to a partial inhibition of respiration in the reaction with cytochrome c oxidase.

Forkhead Box O3A (FOXO3) and the Mitochondrial Disulfide Relay Carrier (CHCHD4) Regulate p53 Protein Nuclear Activity in Response to Exercise.

Although exercise is linked with improved health, the specific molecular mechanisms underlying its various benefits require further clarification. Here we report that exercise increases the nuclear localization and activity of p53 by acutely down-regulating coiled-coil-helix-coiled-coil-helix domain 4 (CHCHD4), a carrier protein that mediates p53 import into the mitochondria. This response to exercise is lost in transgenic mice with constitutive expression of CHCHD4.

MicroRNA-433 Dampens Glucocorticoid Receptor Signaling, Impacting Circadian Rhythm and Osteoblastic Gene Expression.

Serum glucocorticoids play a critical role in synchronizing circadian rhythm in peripheral tissues, and multiple mechanisms regulate tissue sensitivity to glucocorticoids. In the skeleton, circadian rhythm helps coordinate bone formation and resorption. Circadian rhythm is regulated through transcriptional and post-transcriptional feedback loops that include microRNAs.

DLL4/Notch1 and BMP9 Interdependent Signaling Induces Human Endothelial Cell Quiescence via P27KIP1 and Thrombospondin-1.

Objective: Bone morphogenetic protein-9 (BMP9)/activin-like kinase-1 and delta-like 4 (DLL4)/Notch promote endothelial quiescence, and we aim to understand mechanistic interactions between the 2 pathways. We identify new targets that contribute to endothelial quiescence and test whether loss of Dll4(+/-) in adult vasculature alters BMP signaling.

Approach And Results: Human endothelial cells respond synergistically to BMP9 and DLL4 stimulation, showing complete quiescence and induction of HEY1 and HEY2.

The ins and outs of mitochondrial calcium.

Calcium is thought to play an important role in regulating mitochondrial function. Evidence suggests that an increase in mitochondrial calcium can augment ATP production by altering the activity of calcium-sensitive mitochondrial matrix enzymes. In contrast, the entry of large amounts of mitochondrial calcium in the setting of ischemia-reperfusion injury is thought to be a critical event in triggering cellular necrosis.

The role of autophagy in vascular biology.

There is increasing interest in the role of autophagic flux in maintaining normal vessel wall biology and a growing suspicion that autophagic dysregulation may be a common pathway through which vascular aging and associated pathologies develop. Within endothelial and smooth muscle cells, diverse but important triggers that range from oxidized lipids to β-amyloid seem to stimulate autophagosome formation potently. In addition, emerging evidence links autophagy to a wide array of vascular processes ranging from angiogenesis to calcification of the vessel wall.

Association between the XRCC6 polymorphisms and cancer risks: a systematic review and meta-analysis.

A number of studies have been carried out to investigate the association of X-ray repair complementing defective repair in Chinese hamster cells 6 (XRCC6) polymorphisms and cancer risks, and the results remained inconsistent and inconclusive.To assess the effect of XRCC6 polymorphisms on cancer susceptibility, we conducted a meta-analysis, up to May 23rd 2014, 6267 cases with different types of tumor and 7536 controls from 20 published case-control studies. Summary odds ratios and corresponding 95% confidence intervals for XRCC6 polymorphism and cancer risk were estimated using fixed- or random-effects models when appropriate.

α7 Nicotinic acetylcholine receptor is expressed in human atherosclerosis and inhibits disease in mice--brief report.

Objective: Cholinergic pathways of the autonomic nervous system are known to modulate inflammation. Because atherosclerosis is a chronic inflammatory condition, we tested whether cholinergic signaling operates in this disease. We have analyzed the expression of the α7 nicotinic acetylcholine receptor (α7nAChR) in human atherosclerotic plaques and studied its effects on the development of atherosclerosis in the hypercholesterolemic Ldlr(-/-) mouse model.

Human pluripotent stem cells have a novel mismatch repair-dependent damage response.

Human pluripotent stem cells (PSCs) are presumed to have robust DNA repair pathways to ensure genome stability. PSCs likely need to protect against mutations that would otherwise be propagated throughout all tissues of the developing embryo. How these cells respond to genotoxic stress has only recently begun to be investigated.

B cells and humoral immunity in atherosclerosis.

Insights into the important contribution of inflammation and immune functions in the development and progression of atherosclerosis have greatly improved our understanding of this disease. Although the role of T cells has been extensively studied for decades, only recently has the role of B cells gained more attention. Recent studies have identified differential effects of different B-cell subsets and helped to clarify the still poorly understood mechanisms by which these act.

miR-29 promotes murine osteoclastogenesis by regulating osteoclast commitment and migration.

Osteoclast differentiation is regulated by transcriptional, post-transcriptional, and post-translational mechanisms. MicroRNAs are fundamental post-transcriptional regulators of gene expression. The function of the miR-29 (a/b/c) family in cells of the osteoclast lineage is not well understood.

A receptor-specific function for Notch2 in mediating vascular smooth muscle cell growth arrest through cyclin-dependent kinase inhibitor 1B.

Rationale: Deregulated vascular smooth muscle cell (VSMC) proliferation contributes to multiple vascular pathologies, and Notch signaling regulates VSMC phenotype.

Objective: Previous work focused on Notch1 and Notch3 in VSMC during vascular disease; however, the role of Notch2 is unknown. Because injured murine carotid arteries display increased Notch2 in VSMC as compared with uninjured arteries, we sought to understand the impact of Notch2 signaling in VSMCs.