Expression regulation of MAO isoforms in monocytic cells in response to Th2 cytokines

Background: Th2-cytokines, such as interleukins-4 and –13 (IL-4, IL-13), have been identified as alternative stimuli of monocytes/macrophages. We have recently profiled the gene-expression pattern of IL-4-teated human peripheral monocytes and found that 15-lipoxygenase-1 (15-LOX1) and monoamine oxidase A (MAO-A) are among the five most strongly upregulated gene products in IL-4-treated cells. Transfection of monocytic cells (U937) with 15-LOX1 also induced MAO-A expression. These data suggested that 15-LOX1 products might play a role in the IL4-induced signaling cascade leading to expression of MAO-A in human monocytes. Material/Methods: To test this hypothesis we incubated wild-type and 15-LOX1-transfected U937 cells with different concentrations of either IL-4 or 15-LOX-products [13S-H(p)ODE, 15S-H(p)ETE] and quantified the expression of 15-LOX1, MAO-A, and MAO-B by activity assays and real-time RT-PCR. Results: Wild-type U937 cells express neither MAO-A nor MAO-B, but after three days of IL4 treatment, MAO-A mRNA was detected. A similar isoform-specific expression of MAO-A mRNA was observed when U937 cells were transfected with 15-LOX1 or when the cells were incubated with primary 15-LOX1 products (hydroperoxy fatty acids) or H2O2. In contrast, the corresponding hydroxy fatty acids were ineffective. Conclusions: These data indicate that increased intracellular peroxide concentrations (oxidative stress) induce MAO-A expression in monocytes/macrophages, which normally do not express the enzyme. Our findings also suggest that IL-4-induced upregulation of MAO-A expression in human peripheral monocytes may proceed via 15-LOX1-dependent and 15-LOX1-independent pathways. The biological role of MAO-A expression for monocyte function is discussed

Adhesion to carbon nanotube conductive scaffolds forces action-potential appearance in immature rat spinal neurons

In the last decade, carbon nanotube growth substrates have been used to investigate neurons and neuronal networks formation in vitro when guided by artificial nano-scaled cues. Besides, nanotube-based interfaces are being developed, such as prosthesis for monitoring brain activity. We recently described how carbon nanotube substrates alter the electrophysiological and synaptic responses of hippocampal neurons in culture. This observation highlighted the exceptional ability of this material in interfering with nerve tissue growth. Here we test the hypothesis that carbon nanotube scaffolds promote the development of immature neurons isolated from the neonatal rat spinal cord, and maintained in vitro. To address this issue we performed electrophysiological studies associated to gene expression analysis. Our results indicate that spinal neurons plated on electro-conductive carbon nanotubes show a facilitated development. Spinal neurons anticipate the expression of functional markers of maturation, such as the generation of voltage dependent currents or action potentials. These changes are accompanied by a selective modulation of gene expression, involving neuronal and non-neuronal components. Our microarray experiments suggest that carbon nanotube platforms trigger reparative activities involving microglia, in the absence of reactive gliosis. Hence, future tissue scaffolds blended with conductive nanotubes may be exploited to promote cell differentiation and reparative pathways in neural regeneration strategies

Altered Activation of Innate Immunity Associates with White Matter Volume and Diffusion in First-Episode Psychosis

First-episode psychosis (FEP) is associated with inflammatory and brain structural changes, but few studies have investigated whether systemic inflammation associates with brain structural changes in FEP. Thirty-seven FEP patients (median 27 days on antipsychotic medication), and 19 matched controls were recruited. Serum levels of 38 chemokines and cytokines, and cardiovascular risk markers were measured at baseline and 2 months later. We collected T1-and diffusion-weighted MRIs with a 3 T scanner from the patients at baseline. We analyzed the association of psychosis-related inflammatory markers with gray and white matter (WM) volume using voxel-based morphometry and WM diffusion using tract-based spatial statistics with whole-brain and region-of-interest (ROI) analyses. FEP patients had higher CCL22 and lower TGFa, CXCL1, CCL7, IFN-alpha 2 and ApoA-I than controls. CCL22 decreased significantly between baseline and 2 months in patients but was still higher than in controls. The association between inflammatory markers and FEP remained significant after adjusting for age, sex, smoking and BMI. We did not observe a correlation of inflammatory markers with any symptoms or duration of antipsychotic treatment. Baseline CCL22 levels correlated negatively with WM volume and positively with mean diffusivity and radial diffusivity bilaterally in the frontal lobes in ROI analyses. Decreased serum lan association between circulating chemokine levels and WM in FEP patients. Interestingly, CCL22 has been previously implicated in autoimmune diseases associated with WM pathology. The results suggest that an altered activation of innate immunity may contribute to WM damage in psychotic disorders.evel of ApoA-I was associated with smaller volume of the medial temporal WM. In whole-brain analyses, CCL22 correlated positively with mean diffusivity and radial diffusivity, and CXCL1 associated negatively with fractional anisotropy and positively with mean diffusivity and radial diffusivity in several brain regions. This is the first report to demonstratePeer reviewe

Carotid Revascularization in Older Adults: A Systematic Review and Meta-Analysis

Background: Results from studies comparing carotid artery endarterectomy (CEA) with carotid artery stenting (CAS) in the elderly population are variable in the literature. The objective of this study was to investigate whether CEA or CAS is associated with a better safety profile in older adults (>80 years of age) for treatment of symptomatic and asymptomatic stenosis. Methods: A random-effects meta-analysis was performed, and the I2 statistic was used to assess heterogeneity according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Subgroup analyses were performed as needed. Results: Nine studies comprising 5955 patients were included in this meta-analysis. No differences were identified in terms of 30-day stroke (CEA: 5.8% [n = 257/4415]; CAS: 10.5% [n = 81/767]; odds ratio [OR], 0.57; 95% confidence interval [CI], 0.30–1.08; I2 = 26.1%), myocardial infarction (MI) (CEA: 1.1% [n = 4/357]; CAS: 0.5% [n = 2/355]; OR, 1.67; 95% CI, 0.37–7.46; I2 = 0%), transient ischemic attack (TIA) (CEA: 0% [n = 0/98]; CAS: 4.2% [n = 7/166]; OR, 0.28; 95% CI, 0.03–2.52; I2 = 0%), death (CEA: 1.5% [n = 8/523]; CAS: 0.9% [n = 4/431]; OR, 1.41; 95% CI, 0.43–4.58; I2 = 0%), and cranial nerve injury (CEA: 5.8% [n = 3/51]; CAS: 0% [n = 0/51]; OR, 4.74; 95% CI, 0.5–44.98; I2 =0%). A subgroup comparing CEA with transfemoral protected CAS showed that patients in the CEA group had a statistically significant lower risk of 30-day stroke (OR, 0.31; 95% CI, 0.17–0.57; I2 = 30.8%). Conclusions: This study shows that CEA is associated with a statistically significant lower risk of 30-day stroke in the elderly population compared with transfemoral CAS with distal or proximal protection. No differences were noted in the rates of periprocedural TIA, MI, death, and cranial nerve injury between CEA and CAS in the original pooled analysis. © 2019 Elsevier Inc

Synchronous Carotid Endarterectomy and Coronary Artery Bypass Graft versus Staged Carotid Artery Stenting and Coronary Artery Bypass Graft for Patients with Concomitant Severe Coronary and Carotid Stenosis: A Systematic Review and Meta-analysis

Background: Owing to the systemic nature of atherosclerosis, medium and large arteries at different sites are commonly simultaneously affected. As a result, severe coronary artery disease (CAD) requiring coronary artery bypass graft (CABG) frequently coexists with significant carotid stenosis that warrants revascularization. The aim of this study was to compare synchronous carotid endarterectomy (CEA) and CABG vs. staged carotid artery stenting (CAS) and CABG for patients with concomitant CAD and carotid artery stenosis in terms of perioperative (30-day) outcomes. Methods: This study was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Eligible studies were identified through a search of PubMed, Scopus, and Cochrane until July 2018. A meta-analysis was conducted with the use of a random-effects model. The I-square statistic was used to assess heterogeneity. Results: Five studies comprising 16,712 patients were included in this meta-analysis. Perioperative stroke (odds ratio [OR]: 0.84; 95% confidence interval [CI]: 0.43–1.64; I2 = 39.1%), transient ischemic attack (TIA; OR: 0.32; 95% CI: 0.04–2.67; I2 = 27.6%), and myocardial infarction (MI) rates (OR: 0.56; 95% CI: 0.08–3.85; I2 = 68.9%) were similar between the two groups. However, patients who underwent simultaneous CEA and CABG were at a statistically significant higher risk for perioperative mortality (OR: 1.80; 95% CI: 1.05–3.06; I2 = 0.0%). Conclusions: The current meta-analysis did not detect statistically significant differences in the rates of perioperative stroke, TIA, and MI between the groups. However, patients in the simultaneous CEA and CABG group had a significantly higher risk of 30-day mortality. Future randomized trials or prospective cohorts are needed to validate our results. © 2019 Elsevier Inc

Regulation of monoamine oxidase A (MAO-A) expression, activity, and function in IL-13–stimulated monocytes and A549 lung carcinoma cells

Monoamine oxidase A (MAO-A) is a mitochondrial flavoen-zyme implicated in the pathogenesis of atherosclerosis and inflammation and also in many neurological disorders. MAO-A also has been reported as a potential therapeutic target in prostate cancer. However, the regulatory mechanisms controlling cytokine-induced MAO-A expression in immune or cancer cells remain to be identified. Here, we show that MAO-A expression is co-induced with 15-lipoxygenase (15-LO) in interleukin 13 (IL-13)-activated primary human monocytes and A549 nonsmall cell lung carcinoma cells. We present evidence that MAO-A gene expression and activity are regulated by signal transducer and activator of transcription 1, 3, and 6 (STAT1, STAT3, and STAT6), early growth response 1 (EGR1), and cAMP-responsive element– binding protein (CREB), the same transcription factors that control IL-13– dependent 15-LO expression. We further established that in both primary monocytes and in A549 cells, IL-13–stimulated MAO-A expression, activity, and function are directly governed by 15-LO. In contrast, IL-13– driven expression and activity of MAO-A was 15-LO–independent in U937 promonocytic cells. Furthermore, we demonstrate that the 15-LO– dependent transcriptional regulation of MAO-A in response to IL-13 stimulation in monocytes and in A549 cells is mediated by peroxisome proliferator–activated receptor (PPAR) and that signal transducer and activator of transcription 6 (STAT6) plays a crucial role in facilitating the transcriptional activity of PPAR. We further report that the IL-13–STAT6 – 15-LO–PPAR axis is critical for MAO-A expression, activity, and function, including migration and reactive oxygen species generation. Altogether, these results have major implications for the resolution of inflammation and indicat