Brain injuries such as trauma and stroke lead to glial scar formation by reactive astrocytes which produce and secret axonal outgrowth inhibitors. Chondroitin sulfate proteoglycans (CSPG) constitute a well-known class of extracellular matrix molecules produced at the glial scar and cause growth cone collapse. The CSPG glycosaminoglycan side chains composed of chondroitin sulfate (CS) are responsible for its inhibitory activity on neurite outgrowth and are dependent on RhoA activation. Here, we hypothesize that CSPG also impairs neural stem cell migration inhibiting their penetration into an injury site. We show that DCX+ neuroblasts do not penetrate a CSPG-rich injured area probably due to Nogo receptor activation and RhoA/ROCK signaling pathway as we demonstrate in vitro with neural stem cells cultured as neurospheres and pull-down for RhoA. Furthermore, CS-impaired cell migration in vitro induced the formation of large mature adhesions and altered cell protrusion dynamics. ROCK inhibition restored migration in vitro as well as decreased adhesion size.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-017-0565-8) contains supplementary material, which is available to authorized users.

The role of innate immunity in COVID-19 is not completely understood. Therefore, this study explored the impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection on the expression of Pattern Recognition Receptors (PRRs) in peripheral blood cells and their correlated cytokines. Seventy-nine patients with severe COVID-19 on admission, according to World Health Organization (WHO) classification, were divided into two groups: patients who needed mechanical ventilation and/or deceased (SEVERE, n = 50) and patients who used supplementary oxygen but not mechanical ventilation and survived (MILD, n = 29); a control group (CONTROL, n = 17) was also enrolled. In the peripheral blood, gene expression (mRNA) of Toll-like receptors (TLRs) 3, 4, 7, 8, and 9, retinoic-acid inducible gene I (RIGI), NOD-like receptor family pyrin domain containing 3 (NLRP3), interferon alpha (IFN-α), interferon beta (IFN-β), interferon gamma (IFN-γ), interferon lambda (IFN-λ), pro-interleukin(IL)-1β (pro-IL-1β), and IL-18 was determined on admission, between 5–9 days, and between 10–15 days. Circulating cytokines in plasma were also measured. When compared to the COVID-19 MILD group, the COVID-19 SEVERE group had lower expression of TLR3 and overexpression of TLR4.

Traumatic brain injury is an important cause of mortality and morbidity all over the world. After the initial injury there is a cascade of cellular and molecular events that ultimately lead to cell death. Therapies aim not only to counteract these mechanisms but also to replenish the lost cell population in order to achieve a better recovery. The adult mammal brain in not as plastic as the postnatal, but it has at least two neurogenic regions that maintains physiological functions in the brain; the subgranular zone of the dentate gyrus of the hippocampus, which produces neurons that integrate locally, and the subventricular zone (SVZ) of the lateral ventricles, that produces neuroblasts that migrate through the rostral migratory stream (RMS) to the olfactory bulbs.Brain injuries, as well as neurodegenerative diseases, induce the SVZ to respond by increasing cell proliferation and migration to the injured areas.Here we report that SVZ cells migrate to the injured cortex after traumatic brain injury in mice, and that the physiological RMS migration is not impaired.We also show that Prokineticin 2 (PROK2), a chemokine important for the olfactory bulb neurogenesis by promoting the directional migration of neuroblasts, is induced in the injured cortex. Using PROK2 receptor antagonist and recombinant PROK2 we show for the first time that PROK2 can directionally attract SVZ cells in vitro and in vivo. The data we present here links one more element of the inflammatory process, PROK2 secreted by microglia, to the attempt to regenerate an acutely injured mammalian cortex.

Traumatic brain injury is an important cause of mortality and morbidity all over the world. After the initial injury there is a cascade of cellular and molecular events that ultimately lead to cell death. Therapies aim not only to counteract these mechanisms but also to replenish the lost cell population in order to achieve a better recovery. The adult mammal brain in not as plastic as the postnatal, but it has at least two neurogenic regions that maintains physiological functions in the brain; the subgranular zone of the dentate gyrus of the hippocampus, which produces neurons that integrate locally, and the subventricular zone (SVZ) of the lateral ventricles, that produces neuroblasts that migrate through the rostral migratory stream (RMS) to the olfactory bulbs.Brain injuries, as well as neurodegenerative diseases, induce the SVZ to respond by increasing cell proliferation and migration to the injured areas.Here we report that SVZ cells migrate to the injured cortex after traumatic brain injury in mice, and that the physiological RMS migration is not impaired.We also show that Prokineticin 2 (PROK2), a chemokine important for the olfactory bulb neurogenesis by promoting the directional migration of neuroblasts, is induced in the injured cortex. Using PROK2 receptor antagonist and recombinant PROK2 we show for the first time that PROK2 can directionally attract SVZ cells in vitro and in vivo. The data we present here links one more element of the inflammatory process, PROK2 secreted by microglia, to the attempt to regenerate an acutely injured mammalian cortex.

Systemic inflammatory response, as observed in sepsis and severe COVID-19, may lead to endothelial damage. Therefore, we aim to compare the extent of endothelial injury and its relationship to inflammation in both diseases. We included patients diagnosed with sepsis (SEPSIS group, n = 21), mild COVID-19 (MILD group, n = 31), and severe COVID-19 (SEVERE group, n = 24). Clinical and routine laboratory data were obtained, circulating cytokines (INF-γ, TNF-α, and IL-10) and endothelial injury markers (E-Selectin, Tissue Factor (TF) and von Willebrand factor (vWF)) were measured. Compared to the SEPSIS group, patients with severe COVID-19 present similar clinical and laboratory data, except for lower circulating IL-10 and E-Selectin levels. Compared to the MILD group, patients in the SEVERE group showed higher levels of TNF-α, IL-10, and TF. There was no clear relationship between cytokines and endothelial injury markers among the three studied groups; however, in SEVERE COVID-19 patients, there is a positive relationship between INF-γ with TF and a negative relationship between IL-10 and vWF. In conclusion, COVID-19 and septic patients have a similar pattern of cytokines and endothelial dysfunction markers. These findings highlight the importance of endothelium dysfunction in COVID-19 and suggest that endothelium should be better evaluated as a therapeutic target for the disease.