The cortical NG2-glia response to traumatic brain injury.

Traumatic brain injury (TBI) is a significant worldwide cause of morbidity and mortality. A chronic neurologic disease bearing the moniker of "the silent epidemic," TBI currently has no targeted therapies to ameliorate cellular loss or enhance functional recovery. Compared with those of astrocytes, microglia, and peripheral immune cells, the functions and mechanisms of NG2-glia following TBI are far less understood, despite NG2-glia comprising the largest population of regenerative cells in the mature cortex. Here, we synthesize the results from multiple rodent models of TBI, with a focus on cortical NG2-glia proliferation and lineage potential, and propose future avenues for glia researchers to address this unique cell type in TBI. As the molecular mechanisms that regulate NG2-glia regenerative potential are uncovered, we posit that future therapeutic strategies may exploit cortical NG2-glia to augment local cellular recovery following TBI.

Hypercapnia Causes Injury of the Cerebral Cortex and Cognitive Deficits in Newborn Piglets.

In critically ill newborns, exposure to hypercapnia (HC) is common and often accepted in neonatal intensive care units to prevent severe lung injury. However, as a "safe" range of arterial partial pressure of carbon dioxide levels in neonates has not been established, the potential impact of HC on the neurodevelopmental outcomes in these newborns remains a matter of concern. Here, in a newborn Yorkshire piglet model of either sex, we show that acute exposure to HC induced persistent cortical neuronal injury, associated cognitive and learning deficits, and long-term suppression of cortical electroencephalogram frequencies. HC induced a transient energy failure in cortical neurons, a persistent dysregulation of calcium-dependent proapoptotic signaling in the cerebral cortex, and activation of the apoptotic cascade, leading to nuclear deoxyribonucleic acid fragmentation. While neither 1 h of HC nor the rapid normalization of HC was associated with changes in cortical bioenergetics, rapid resuscitation resulted in a delayed onset of synaptosomal membrane lipid peroxidation, suggesting a dissociation between energy failure and the occurrence of synaptosomal lipid peroxidation. Even short durations of HC triggered biochemical responses at the subcellular level of the cortical neurons resulting in altered cortical activity and impaired neurobehavior. The deleterious effects of HC on the developing brain should be carefully considered as crucial elements of clinical decisions in the neonatal intensive care unit.

Blockade of CCR1 induces a phenotypic shift in macrophages and triggers a favorable antilymphoma activity.

Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) play an important role in tumor growth and progression. TAMs have been involved in producing immunosuppressive TME via various factors; however, the underlying mechanisms remain unclear in B-cell lymphoma, including mantle cell lymphoma (MCL). We identified that chemokine receptor-1 (CCR1) is highly expressed on monocytes (Mo) and macrophages (MΦ), and CCR1 pharmacological inhibition or CCR1 siRNA abolished lymphoma-mediated Mo/MΦ migration in a chemotaxis assay. The deficiency of host CCR1 (CCR1 KO) was associated with decreased infiltration of peritoneal-MΦ compared with WT-CCR1. Functional studies indicated that the genetic depletion of CCR1 or treatment inhibited protumor MΦ (M2-like) phenotype by decreasing CD206 and IL-10 expression. Moreover, CCR1 depletion reprogrammed MΦ toward an MHCII+/TNFα+ immunogenic phenotype. Mechanistically, protumor MΦ driven-IL-10 provides a positive feedback loop to tumor-CCL3 by regulating the CCL3 promoter via STAT1 signaling. Therapeutic in vivo targeting of CCR1 with CCR1 antagonist BX-471 significantly reduced FC-muMCL1 mouse tumors in the syngeneic MCL model by the depletion of M2-TAMs and increased infiltration of cytotoxic CD8+ T cells. Our study established that CCR1 exerts a pivotal role in macrophage programming, thus shaping protumor TME and lymphoma progression. CCR1 inhibition through CCR1 antagonists may be a promising therapeutic strategy to reprogram macrophages in lymphoma-TME and achieve better clinical outcomes in patients.

Endogenous Circadian Clock Machinery in Cortical NG2-Glia Regulates Cellular Proliferation.

The molecular circadian clock can be found throughout the body and is essential for the synchronizing cellular physiology with the 24 h day. However, the role of the clock in regulating the regenerative potential of the brain has not been explored. We report here that murine NG2-glia, the largest population of proliferative cells in the mature central nervous system, rhythmically express circadian clock genes in a 24 h period, including the critical clock component Bmal1 RNA and BMAL1 protein. Interestingly, daily NG2-glia proliferation preferentially occurs during the time of day in which Bmal1 expression is high, while conditional knockout of Bmal1 decreases both cortical NG2-glia density and cellular proliferation. Furthermore, in a neurotrauma model, we show that pathology-induced NG2-glia proliferation is also dependent on Bmal1 expression. Because circadian rhythm disturbances are common in neurologic disorders across the life span, including in traumatic brain injury, these findings bear significant implications for cellular regeneration in brain injuries and disease.

Neuroprotective effect of Src kinase in hypoxia-ischemia: A systematic review.

Background: Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality worldwide. While the application of therapeutic hypothermia has improved neurodevelopmental outcomes for some survivors of HIE, this lone treatment option is only available to a subset of affected neonates. Src kinase, an enzyme central to the apoptotic cascade, is a potential pharmacologic target to preserve typical brain development after HIE. Here, we present evidence of the neuroprotective effects of targeting Src kinase in preclinical models of HIE. Methods: We performed a comprehensive literature search using the National Library of Medicine's MEDLINE database to compile studies examining the impact of Src kinase regulation on neurodevelopment in animal models. Each eligible study was assessed for bias. Results: Twenty studies met the inclusion criteria, and most studies had an intermediate risk for bias. Together, these studies showed that targeting Src kinase resulted in a neuroprotective effect as assessed by neuropathology, enzymatic activity, and neurobehavioral outcomes. Conclusion: Src kinase is an effective neuroprotective target in the setting of acute hypoxic injury. Src kinase inhibition triggers multiple signaling pathways of the sub-membranous focal adhesions and the nucleus, resulting in modulation of calcium signaling and prevention of cell death. Despite the significant heterogeneity of the research studies that we examined, the available evidence can serve as proof-of-concept for further studies on this promising therapeutic strategy.

Secretome profiling identifies neuron-derived neurotrophic factor as a tumor-suppressive factor in lung cancer.

Clinical and preclinical studies show tissue-specific differences in tumorigenesis. Tissue specificity is controlled by differential gene expression. We prioritized genes that encode secreted proteins according to their preferential expression in normal lungs to identify candidates associated with lung cancer. Indeed, most of the lung-enriched genes identified in our analysis have known or suspected roles in lung cancer. We focused on the gene encoding neuron-derived neurotrophic factor (NDNF), which had not yet been associated with lung cancer. We determined that NDNF was preferentially expressed in the normal adult lung and that its expression was decreased in human lung adenocarcinoma and a mouse model of this cancer. Higher expression of NDNF was associated with better clinical outcome of patients with lung adenocarcinoma. Purified NDNF inhibited proliferation of lung cancer cells, whereas silencing NDNF promoted tumor cell growth in culture and in xenograft models. We determined that NDNF is downregulated through DNA hypermethylation near CpG island shores in human lung adenocarcinoma. Furthermore, the lung cancer-related DNA hypermethylation sites corresponded to the methylation sites that occurred in tissues with low NDNF expression. Thus, by analyzing the tissue-specific secretome, we identified a tumor-suppressive factor, NDNF, which is associated with patient outcomes in lung adenocarcinoma.