The critical role of ERK in death resistance and invasiveness of hypoxia-selected glioblastoma cells

<p>Abstract</p> <p>Background</p> <p>The rapid growth of tumor parenchyma leads to chronic hypoxia that can result in the selection of cancer cells with a more aggressive behavior and death-resistant potential to survive and proliferate. Thus, identifying the key molecules and molecular mechanisms responsible for the phenotypic changes associated with chronic hypoxia has valuable implications for the development of a therapeutic modality. The aim of this study was to identify the molecular basis of the phenotypic changes triggered by chronic repeated hypoxia.</p> <p>Methods</p> <p>Hypoxia-resistant T98G (HRT98G) cells were selected by repeated exposure to hypoxia and reoxygenation. Cell death rate was determined by the trypan blue exclusion method and protein expression levels were examined by western blot analysis. The invasive phenotype of the tumor cells was determined by the Matrigel invasion assay. Immunohistochemistry was performed to analyze the expression of proteins in the brain tumor samples. The Student T-test and Pearson Chi-Square test was used for statistical analyses.</p> <p>Results</p> <p>We demonstrate that chronic repeated hypoxic exposures cause T98G cells to survive low oxygen tension. As compared with parent cells, hypoxia-selected T98G cells not only express higher levels of anti-apoptotic proteins such as Bcl-2, Bcl-X_L, and phosphorylated ERK, but they also have a more invasive potential in Matrigel invasion chambers. Activation or suppression of ERK pathways with a specific activator or inhibitor, respectively, indicates that ERK is a key molecule responsible for death resistance under hypoxic conditions and a more invasive phenotype. Finally, we show that the activation of ERK is more prominent in malignant glioblastomas exposed to hypoxia than in low grade astrocytic glial tumors.</p> <p>Conclusion</p> <p>Our study suggests that activation of ERK plays a pivotal role in death resistance under chronic hypoxia and phenotypic changes related to the invasive phenotype of HRT98G cells compared to parent cells.</p

Lipoic acid plays a role in scleroderma: insights obtained from scleroderma dermal fibroblasts

Abstract Introduction Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis of the skin and organs. Increase in oxidative stress and platelet-derived growth factor receptor (PDGFR) activation promote type I collagen (Col I) production, leading to fibrosis in SSc. Lipoic acid (LA) and its active metabolite dihydrolipoic acid (DHLA) are naturally occurring thiols that act as cofactors and antioxidants and are produced by lipoic acid synthetase (LIAS). Our goals in this study were to examine whether LA and LIAS were deficient in SSc patients and to determine the effect of DHLA on the phenotype of SSc dermal fibroblasts. N-acetylcysteine (NAC), a commonly used thiol antioxidant, was included as a comparison. Methods Dermal fibroblasts were isolated from healthy subjects and patients with diffuse cutaneous SSc. Matrix metalloproteinase (MMPs), tissue inhibitors of MMPs (TIMP), plasminogen activator inhibitor 1 (PAI-1) and LIAS were measured by enzyme-linked immunosorbent assay. The expression of Col I was measured by immunofluorescence, hydroxyproline assay and quantitative PCR. PDGFR phosphorylation and α-smooth muscle actin (αSMA) were measured by Western blotting. Student’s t-tests were performed for statistical analysis, and P-values less than 0.05 with two-tailed analysis were considered statistically significant. Results The expression of LA and LIAS in SSc dermal fibroblasts was lower than normal fibroblasts; however, LIAS was significantly higher in SSc plasma and appeared to be released from monocytes. DHLA lowered cellular oxidative stress and decreased PDGFR phosphorylation, Col I, PAI-1 and αSMA expression in SSc dermal fibroblasts. It also restored the activities of phosphatases that inactivated the PDGFR. SSc fibroblasts produced lower levels of MMP-1 and MMP-3, and DHLA increased them. In contrast, TIMP-1 levels were higher in SSc, but DHLA had a minimal effect. Both DHLA and NAC increased MMP-1 activity when SSc cells were stimulated with PDGF. In general, DHLA showed better efficacy than NAC in most cases. Conclusions DHLA acts not only as an antioxidant but also as an antifibrotic because it has the ability to reverse the profibrotic phenotype of SSc dermal fibroblasts. Our study suggests that thiol antioxidants, including NAC, LA, or DHLA, could be beneficial for patients with SSc.http://deepblue.lib.umich.edu/bitstream/2027.42/112060/1/13075_2014_Article_411.pd

Handedness and White Matter Networks

The development and persistence of laterality is a key feature of human motor behavior, with the asymmetry of hand use being the most prominent. The idea that asymmetrical functions of the hands reflect asymmetries in terms of structural and functional brain organization has been tested many times. However, despite advances in laterality research and increased understanding of this population-level bias, the neural basis of handedness remains elusive. Recent developments in diffusion magnetic resonance imaging enabled the exploration of lateralized motor behavior also in terms of white matter and connectional neuroanatomy. Despite incomplete and partly inconsistent evidence, structural connectivity of both intrahemispheric and interhemispheric white matter seems to differ between left and right-handers. Handedness was related to asymmetry of intrahemispheric pathways important for visuomotor and visuospatial processing (superior longitudinal fasciculus), but not to projection tracts supporting motor execution (corticospinal tract). Moreover, the interindividual variability of the main commissural pathway corpus callosum seems to be associated with handedness. The review highlights the importance of exploring new avenues for the study of handedness and presents the latest state of knowledge that can be used to guide future neuroscientific and genetic research

Corticospinal excitability and conductivity are related to the anatomy of the corticospinal tract

Probing the brain structure–function relationship is at the heart of modern neuroscientific explorations, enabled by recent advances in brain mapping techniques. This study aimed to explore the anatomical blueprint of corticospinal excitability and shed light on the structure–function relationship within the human motor system. Using diffusion magnetic resonance imaging tractography, based on the spherical deconvolution approach, and transcranial magnetic stimulation (TMS), we show that anatomical inter-individual variability of the corticospinal tract (CST) modulates the corticospinal excitability and conductivity. Our findings show for the first time the relationship between increased corticospinal excitability and conductivity in individuals with a bigger CST (i.e., number of streamlines), as well as increased corticospinal microstructural organization (i.e., fractional anisotropy). These findings can have important implications for the understanding of the neuroanatomical basis of TMS as well as the study of the human motor system in both health and disease

Neuroanatomical correlates of binge\u2010eating behavior: At the roots of unstoppable eating

Binge\u2010eating refers to episodes of uncontrolled eating accompanied by a perceived loss of control, which can be common in the general population. Given the profound negative consequences of persistent binge\u2010eating such as weight and eating disorders, it is vital to determine what makes someone more vulnerable than others to engage in such a conduct. A total of 42 normal-weight individuals (21 with binge\u2010eating episodes and 21 without binge\u2010eating episodes) underwent a structural magnetic resonance imaging measurement and Voxel\u2010based morphometry (VBM) was used to assess between\u2010group differences in terms of gray matter volume (GMV), together with self\u2010report impulsivity and binge\u2010eating measures. The results showed binge\u2010eating individuals as characterized by higher trait impulsivity and greater regional GMV in the left middle frontal gyrus: however, the GMV in this region appeared to be positively correlated only with measures of binge\u2010eating but not with trait impulsivity measures. These findings provide novel insights on the neurobiological roots of BE in normal\u2010weight individuals and highlight how this behavior can be associated with brain morphometric changes within prefrontal regions also in a non\u2010clinical population. Overall, this study provides a further characterization of the neural correlates of binge\u2010eating and novel insights into the treatment of its more severe pathological forms

Exploring the ventral white matter language network in bimodal and unimodal bilinguals

We used diffusion magnetic resonance imaging tractography to investigate the effect of language modality on the anatomy of the ventral white matter language network by comparing unimodal (Italian/English) and bimodal bilinguals (Italian/Italian Sign Language). We extracted the diffusion tractography measures of the Inferior Longitudinal fasciculus (ILF), Uncinate fasciculus (UF) and Inferior Fronto-Occipital fasciculus (IFOF) and we correlated them with the degree of bilingualism and the individual performance in fluency tasks. For both groups of bilinguals, the microstructural properties of the right ILF were correlated with individual level of proficiency in L2, confirming the involvement of this tract in bilingualism. In addition, we found that the degree of left lateralization of the ILF predicted the performance in semantic fluency in L1. The microstructural properties of the right UF correlated with performance in phonological fluency in L1, only for bimodal bilinguals. Overall, the pattern shows both similarities and differences between the two groups of bilinguals

Corticospinal excitability and conductivity are related to the anatomy of the corticospinal tract

Probing the brain structure–function relationship is at the heart of modern neuroscientific explorations, enabled by recent advances in brain mapping techniques. This study aimed to explore the anatomical blueprint of corticospinal excitability and shed light on the structure–function relationship within the human motor system. Using diffusion magnetic resonance imaging tractography, based on the spherical deconvolution approach, and transcranial magnetic stimulation (TMS), we show that anatomical inter-individual variability of the corticospinal tract (CST) modulates the corticospinal excitability and conductivity. Our findings show for the first time the relationship between increased corticospinal excitability and conductivity in individuals with a bigger CST (i.e., number of streamlines), as well as increased corticospinal microstructural organization (i.e., fractional anisotropy). These findings can have important implications for the understanding of the neuroanatomical basis of TMS as well as the study of the human motor system in both health and disease