Mammalian Target of Rapamycin 2 (MTOR2) and C-MYC Modulate Glucosamine-6-Phosphate Synthesis in Glioblastoma (GBM) Cells Through Glutamine: Fructose-6-Phosphate Aminotransferase 1 (GFAT1) The original version of this article unfortunately contained an error in author group. The authors Yi-Xiang See, Xin Chen, Zi-Kai Chen and Ze-Bin Huang were inadvertently included in the article.

Expression of Concern

In Memoriam: Horst Grobecker (1934–2019)

MicroRNAs are Necessary for BMP-7-induced Dendritic Growth in Cultured Rat Sympathetic Neurons Abstract Neuronal connectivity is dependent on size and shape of the dendritic arbor. However, mechanisms controlling dendritic arborization, especially in the peripheral nervous system, are not completely understood. Previous studies have shown that bone morphogenetic proteins (BMPs) are important initiators of dendritic growth in peripheral neurons. In this study, we examined the hypothesis that post-transcriptional regulation mediated by microRNAs (miRNAs) is necessary for BMP-7-induced dendritic growth in these neurons. To examine the role of miRNAs in BMP-7-induced dendritic growth, microarray analyses was used to profile miRNA expression in cultured sympathetic neurons from the superior cervical ganglia of embryonic day 21 rat pups at 6 and 24 h after treatment with BMP-7 (50 ng/mL). Our data showed that BMP-7 significantly regulated the expression of 43 of the 762 miRNAs. Of the 43 miRNAs, 22 showed robust gene expression; 14 were upregulated by BMP-7 and 8 were downregulated by BMP-7. The expression profile for miR-335, miR-664-1*, miR-21, and miR-23b was confirmed using qPCR analyses. Functional studies using morphometric analyses of dendritic growth in cultured sympathetic neurons transfected with miRNA mimics and inhibitors indicated that miR-664-1*, miR-23b, and miR-21 regulated early stages of BMP-7-induced dendritic growth. In summary, our data provide evidence for miRNA-mediated post-transcriptional regulation as important downstream component of BMP-7 signaling during early stages of dendritic growth in sympathetic neurons.

The Effects of Maternal Atrazine Exposure and Swimming Training on Spatial Learning Memory and Hippocampal Morphology in Offspring Male Rats via PSD95/NR2B Signaling Pathway Abstract Atrazine (ATR), a widely used herbicide, has been previously shown to damage spatial memory capability and the hippocampus of male rats during the development. It has also been indicated that physical exercise can improve learning and memory in both humans and animals, as a neuroprotective method. Our aim here was to investigate the effect of maternal ATR exposure during gestation and lactation on spatial learning and memory function and hippocampal morphology in offspring and to further evaluate the neuroprotective effect of swimming training and identify possible related learning and memory signaling pathways. Using Sprague-Dawley rats, we examined behavioral and molecular biology effects associated with maternal ATR exposure, as well as the effects of 8 or 28 days swimming training. Maternal exposure to ATR was found to impair spatial learning and memory by behavioral test, damage the hippocampal morphology, and reduce related genes and proteins expression of learning and memory in the hippocampus. The extended, 28 days, period of swimming training produced a greater amelioration of the adverse effects of ATR exposure than the shorter, 8 days, training period. Our results suggest that maternal ATR exposure may damage the spatial learning and memory of offspring male rats via PSD95/NR2B signaling pathway. The negative effect of ATR could be at least partially reversed by swimming training, pointing to a potential neuroprotective role of physical exercise in nervous system diseases accompanying by learning and memory deficit.

Effect of Inhibiting p38 on HuR Involving in β-AChR Post-transcriptional Mechanisms in Denervated Skeletal Muscle Abstract Previous studies reported that RNA-binding protein human antigen R (HuR) mediates changes in the stability of AChR β-subunit mRNA after skeletal muscle denervation; also, p38 pathway regulated the stability of AChR β-subunit mRNA in C2C12 myotubes. However, the relationship between HuR and p38 in regulating the stability of AChR β-subunit mRNA have not been clarified. In this study, we wanted to examine the effect of inhibiting p38 on HuR in denervated skeletal muscle. Denervation model was built and 10% DMSO or SB203580 were administered respectively follow denervation. Tibialis muscles were collected in 10% DMSO-administered contralateral (undenervated) leg, 10% DMSO-administered denervated leg, SB203580-administered contralateral (undenervated) leg, and SB203580-administered denervated leg, respectively. P38 protein, β-AChR mRNA and protein, HuR protein, β-AChR mRNA stability, and HuR binding with AChR β-subunit mRNAs were measured. Results demonstrated that the administration of SB203580 can inhibit the increase of β-AChR protein expression and mRNA expression and stability, and RNA-binding protein human antigen R (HuR) expression, in cytoplasmic and nuclear fractions in skeletal muscle cells following denervation. Importantly, we observed that SB203580 also inhibited the increased level of binding activity between HuR and AChR β-subunit mRNAs following denervation. Collectively, these results suggested that inhibition of p38 can post-transcriptionally inhibit β-AChR upregulation via HuR in denervated skeletal muscle.

High-Mobility Group Box 1 Neutralization Prevents Chronic Cerebral Hypoperfusion-Induced Optic Tract Injuries in the White Matter Associated with Down-regulation of Inflammatory Responses Abstract Chronic cerebral hypoperfusion (CCH)-induced white matter lesions (WMLs) are region-specific with the optic tract (OT) displaying the most severe damages and leading to visual-based behavioral impairment. Previously we have demonstrated that anti-high-mobility group box 1 (HMGB1) neutralizing antibody (Ab) prevents CCH-induced hippocampal damages via inhibition of neuroinflammation. Here we tested the protective role of the Ab on CCH-induced OT injuries. Rats were treated with permanent occlusion of common carotid arteries (2-VO) or a sham surgery, and then administered with PBS, anti-HMGB1 Ab, or paired control Ab. Pupillary light reflex examination, visual water maze, and tapered beam-walking were performed 28 days post-surgery to investigate the behavioral deficits. Meanwhile, WMLs were measured by Klüver-Barrera (KB) and H&E staining, and glial activation was further assessed to evaluate inflammatory responses in OT. Results revealed that anti-HMGB1 Ab ameliorated the morphological damages (grade scores, vacuoles, and thickness) in OT area and preserved visual abilities. Additionally, the increased levels of inflammatory responses and expressions of TLR4 and NF-κB p65 and phosphorylated NF-κB p65 (p-p65) in OT area were partly down-regulated after anti-HMGB1 treatment. Taken together, these findings suggested that HMGB1 neutralization could ease OT injuries and visual-guided behavioral deficits via suppressing inflammatory responses.

CA1 LTP Attenuated by Corticosterone is Canceled by Effusol via Rescuing Intracellular Zn 2+ Dysregulation Abstract Exposure to corticosterone attenuates hippocampal CA1 long-term potentiation (LTP) via intracellular Zn2+ dysregulation. Here we report that effusol, a phenanthrene isolated from Chinese medicine Juncus effusus, rescues CA1 LTP attenuated by corticosterone. In vivo microdialysis experiment indicated that both increases in extracellular glutamate induced under perfusion with corticosterone and high K+ are suppressed in the hippocampus by co-perfusion with effusol. Because corticosterone and high K+ also increase extracellular Zn2+ level, followed by intracellular Zn2+ dysregulation, the effect of effusol on both the increases was examined in brain slice experiments. Effusol did not suppress increase in extracellular Zn2+ in the hippocampal CA1 of brain slices bathed in corticosterone, but suppressed increase in intracellular Zn2+, which may be linked with suppressing the increase in extracellular glutamate in vivo. In vivo CA1 LTP was attenuated under perfusion with corticosterone prior to LTP induction, while the attenuation was rescued by co-perfusion with effusol, suggesting that the rescuing effect of effusol is due to suppressing the increase in intracellular Zn2+ in CA1 pyramidal cells. The present study indicates that CA1 LTP attenuated by corticosterone is canceled by effusol, which rescues intracellular Zn2+ dysregulation via suppressing extracellular glutamate accumulation. It is likely that effusol defends the hippocampal function against stress-induced cognitive decline.

Heterogeneity of GRIM-19 Expression in the Adult Mouse Brain Abstract Gene associated with retinoid-interferon-induced mortality-19 (GRIM-19) is a subunit of the mitochondrial respiratory chain complex I that has a significant effect on ATP production. The brain is particularly susceptible to ATP deficiency due to its limited energy storage capability and its high rate of oxygen consumption. Thus, GRIM-19 might be involved in regulating ATP level in the brain or cell death caused by several neurological disorders. To understand the physiological and pathophysiological roles of GRIM-19 in the brain, a thorough investigation of the neuroanatomic distribution of GRIM-19 in the normal brain is necessary. Therefore, the present study examined the distribution patterns of GRIM-19 in the adult C57BL/6 mouse brain using immunohistochemistry and identified cell types expressing GRIM-19 using double immunofluorescence staining. We found that GRIM-19 was ubiquitously but not homogenously expressed throughout the brain. GRIM-19 immunoreactivity was predominantly observed in neurons, but not in astrocytes, microglia, or oligodendrocytes under normal physiological conditions. Following transient global cerebral ischemia, GRIM-19-positive immunoreactivity was, however, observed in neurons as well as glial cells including astrocytes in the hippocampus. Furthermore, GRIM-19 was weakly expressed in the hippocampal subgranular zone, in which neural stem and progenitor cells are abundant, but highly expressed in the immature and mature neuronal cells in the granular cell layer of the normal brain, suggesting an inverse correlation between expression of GRIM-19 and stemness activity. Collectively, our study demonstrating widespread and differential distribution of GRIM-19 in the adult mouse brain contributes to investigating the functional and pathophysiological roles of this protein.

Enhancing the Astrocytic Clearance of Extracellular α-Synuclein Aggregates by Ginkgolides Attenuates Neural Cell Injury Abstract The accumulation of aggregated forms of the α-Synuclein (α-Syn) is associated with the pathogenesis of Parkinson’s disease (PD), and the efficient clearance of aggregated α-Syn represents a potential approach in PD therapy. Astrocytes are the most numerous glia cells in the brain and play an essential role in supporting brain functions in PD state. In the present study, we demonstrated that cultured primary astrocytes engulfed and degraded extracellular aggregated recombinant human α-Syn. Meanwhile, we observed that the clearance of α-Syn by astrocytes was abolished by proteasome inhibitor MG132 and autophagy inhibitor 3-methyladenine (3MA). We further showed that intracellular α-Syn was reduced after ginkgolide B (GB) and bilobalide (BB) treatment, and the decrease was reversed by MG132 and 3MA. More importantly, GB and BB reduced indirect neurotoxicity to neurons induced by α-Syn-stimulated astrocytic conditioned medium. Together, we firstly find that astrocytes can engulf and degrade α-Syn aggregates via the proteasome and autophagy pathways, and further show that GB and BB enhance astrocytic clearance of α-Syn, which gives us an insight into the novel therapy for PD in future.