A time-course analysis of changes in cerebral metal levels following a controlled cortical impact

© 2016 The Royal Society of Chemistry. Traumatic brain injury (TBI) is complicated by a sudden and dramatic change in brain metal levels, including iron (Fe), copper (Cu) and zinc (Zn). Specific 'metallo-pathological' features of TBI include increased non-heme bound Fe and the liberation of free Zn ions, both of which may contribute to the pathogenesis of TBI. To further characterise the metal dyshomeostasis that occurs following brain trauma, we performed a quantitative time-course survey of spatial Fe, Cu and Zn distribution in mice receiving a controlled cortical impact TBI. Images of brain metal levels produced using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) in the upper quadrant of the ipsilateral hemisphere were compared to the corresponding contralateral hemisphere, together with regional areas radiating toward the center of the brain from the site of lesion. Significant regional and time point specific elevations in Fe, Zn and Cu were detected immediately and up to 28 days after TBI. The magnitude and timeframe of many of these changes suggest that TBI results in a pronounced and sustained alteration in normal metal levels within the brain. Such alterations are likely to play a role in both the short- and long-term consequences of head trauma and suggest that pharmacological modulation to normalize these metal levels may be efficacious in improving functional outcome

Destabilization of cortical dendrites and spines by BDNF

Particle-mediated gene transfer and two-photon microscopy were used to monitor the behavior of dendrites of individual cortical pyramidal neurons coexpressing green fluorescent protein (GFP) and brain-derived neurotrophic factor (BDNF). While the dendrites and spines of neurons expressing GFP alone grew modestly over 24-48 hr, coexpressing BDNF elicited dramatic sprouting of basal dendrites, accompanied by a regression of dendritic spines. Compared to GFP-transfected controls, the newly formed dendrites and spines were highly unstable. Experiments utilizing Trk receptor bodies, K252a, and overexpression of nerve growth factor (NGF) demonstrated that these effects were mediated by secreted BDNF interacting with extracellular TrkB receptors. Thus, BDNF induces structural instability in dendrites and spines, which, when restricted to particular portions of a dendritic arbor, may help translate activity patterns into specific morphological changes

Age modulates the injury-induced metallomic profile in the brain

© 2017 The Royal Society of Chemistry. The biological transition metals iron (Fe), copper (Cu) and zinc (Zn) are thought to contribute to the neuronal pathologies that occur following traumatic brain injury (TBI), and indeed our previously published work in young (3 month-old) mice clearly demonstrates a significant spatiotemporal modulation of metals following TBI. Of note, however, is the literature observation that there is both an apparent detrimental effect of aging on TBI outcomes and an alteration in metals and their various transporters with normal advancing age. Therefore, to determine whether there was an interaction between aging, metals and TBI, we have utilised laser ablation-inductively coupled plasma-mass spectrometry to examine the spatial and temporal distribution of Fe, Zn and Cu following an acute controlled cortical impact brain injury in aged (24 months) rodents. The relative abundance of metals in corresponding regions within the ipsilateral and contralateral hemispheres as well as the hippocampus was assessed. Substantial region and time point specific alterations in Fe, Zn and Cu were identified immediately and up to 28 days post-TBI. The data from this follow-up study has also been compared to our previous data from young animals, and aged mice exhibit an appreciably enhanced and persistent elevation of all metals in every region surveyed, with individual metal disparities at various time points observed post-injury. This may potentially contribute to the acceleration in the onset of cognitive decline and neurological disease that has been observed in the aged population following head trauma

Gyrate: CCM3 Dances with a Different Angiogenic Partner

A healthy vasculature is an essential component of development and is regulated by different signaling pathways. One of the most critical pathways involved is the vascular endothelial growth factor (VEGF) pathway. Components of this pathway serve as the first marker of primitive endothelial cells and are instrumental in inducing the initial differentiation of endothelial cells and later refining them into either arteries or veins. However, the regulation of VEGF signaling remains a mystery, with most studies focusing on the downstream components of this signaling cascade. New evidence shows that the protein cerebral cavernous malformation 3 (CCM3) is a key regulator of the VEGF pathway, bringing to light a previously unknown component of the VEGF signaling axis and opening the door to an exciting new era of vasculogenic research

Brothers and Sisters: Molecular Insights Into Arterial-Venous Heterogeneity

The molecular differences between arteries and veins are genetically predetermined and are evident even before the first embryonic heart beat. Although ephrinB2 and EphB4 are expressed in cells that will ultimately differentiate into arteries and veins respectively, many other genes have been shown to play a significant role in cell fate determination. The expression patterns of ephrinB2 and EphB4 are restricted to arterial-venous boundaries, and Eph/ephrin signaling provides repulsive cues at arterial-venous boundaries that are thought to prevent intermixing of arterial- and venous-fated cells. However, the maintenance of arterial-venous fate is susceptible to some degree of plasticity. Thus, in response to signals from the ambient microenvironment and shear stress, there is flow-mediated intercalation of the arteries and veins that ultimately leads to the formation of a functional, closed-loop circulation. In addition, cells in the blood vessels of each organ undergo epigenetic, morphologic and functional adaptive changes that are specific to the proximate function of their cognate organ(s). These adaptive changes result in an inter-organ and intra-organ vessel heterogeneity that manifest clinically in a disparate response of different organs to identical risk factors and injury in the same animal. In this review, we will focus on the molecular and physiologic factors influencing arterial-venous heterogeneity between and within different organ(s). We will explore arterial-venous differences in selected organs as well as their respective endothelial cell architectural organization that results in their inter- and intra-organ heterogeneity

Tear Me Down: Role of Calpain in the Development of Cardiac Ventricular Hypertrophy

Cardiac hypertrophy develops most commonly in response to hypertension and is an independent risk factor for the development of heart failure. The mechanisms by which cardiac hypertrophy may be reversed to reduce this risk have not been fully determined to the point where mechanism-specific therapies have been developed. Recently, proteases in the calpain family have been implicated in regulating the development of cardiac hypertrophy in preclinical animal models. In this review, we summarize the molecular mechanisms by which calpain inhibition has been shown to modulate the development of cardiac (specifically ventricular) hypertrophy. The context within which calpain inhibition might be developed for therapeutic intervention of cardiac hypertrophy is then discussed

SDF-1 stimulates JNK3 activity via eNOS-dependent nitrosylation of MKP7 to enhance endothelial migration

The chemokine stromal cell-derived factor-1α (SDF-1α) is a pivotal player in angiogenesis. It is capable of influencing such cellular processes as tubulogenesis and endothelial cell migration, yet very little is known about the actual signaling events that mediate SDF-1α-induced endothelial cell function. In this report, we describe the identification of an intricate SDF-1α-induced signaling cascade that involves endothelial nitric oxide synthase (eNOS), JNK3, and MAPK phosphatase 7 (MKP7). We demonstrate that the SDF-1α-induced activation of JNK3, critical for endothelial cell migration, depends on the prior activation of eNOS. Specifically, activation of eNOS leads to production of NO and subsequent nitrosylation of MKP7, rendering the phosphatase inactive and unable to inhibit the activation of JNK3. These observations reinforce the importance of nitric oxide and S-nitrosylation in angiogenesis and provide a mechanistic pathway for SDF-1α-induced endothelial cell migration. In addition, the discovery of this interactive network of pathways provides novel and unexpected therapeutic targets for angiogenesis-dependent diseases

Back to your heart: Ubiquitin proteasome system-regulated signal transduction

Awareness of the regulation of cell signaling by post-translational ubiquitination has emerged over the past 2 decades. Like phosphorylation, post-translational modification of proteins with ubiquitin can result in the regulation of numerous cellular functions, for example, the DNA damage response, apoptosis, cell growth, and the innate immune response. In this review, we discuss recently published mechanisms by which the ubiquitin proteasome system regulates key signal transduction pathways in the heart, including MAPK JNK, calcineurin, FOXO, p53, and estrogen receptors α and β. We then explore how ubiquitin proteasome system-specific regulation of these signal transduction pathways plays a role in the pathophysiology of common cardiac diseases, such as cardiac hypertrophy, heart failure, ischemia reperfusion injury, and diabetes

NADPH Oxidase-Generated Reactive Oxygen Species Are Required for Stromal Cell-Derived Factor-1 -Stimulated Angiogenesis

Reactive oxygen species (ROS) act as signaling molecules during angiogenesis, however, the mechanisms used for such signaling events remain unclear. Stromal cell-derived factor-1α (SDF-1α) is one of the most potent angiogenic chemokines. Here we examined the role of ROS in the regulation of SDF-1α-dependent angiogenesis