Xin Chang

Depression has become one of the severe mental disorders threatening global human health. In this study, we first used the proteomics approach to obtain the differentially expressed proteins in the liver between naive control and chronic social defeat stress (CSDS) induced depressed mice. We have identified the upregulation of iron binding protein transferrin (TF) in the liver, the peripheral blood, and the brain in CSDS-exposed mice. Furthermore, bioinformatics analysis of the Gene Expression Omnibus (GEO) database from various mouse models of depression revealed the significantly upregulated transcripts of TF and its receptor TfR1 in multiple brain regions in depressed mice. We also used the recombinant TF administration via the tail vein to detect its permeability through the blood-brain barrier (BBB). We demonstrated the permeability of peripheral TF into the brain through the BBB. Together, these results identified the elevated expression of TF and its receptor TfR1 in both peripheral liver and the central brain in CSDS-induced depressed mice, and peripheral administration of TF can be transported into the brain through the BBB. Therefore, our data provide a compelling information for understanding the potential role and mechanisms of the cross-talk between the liver and the brain in stress-induced depression.

Sonic hedgehog (Shh) signaling plays a critical role in regulating cerebellum development by maintaining the physiological proliferation of granule neuron precursors (GNPs), and its dysregulation leads to the oncogenesis of medulloblastoma. O-GlcNAcylation (O-GlcNAc) of proteins is an emerging regulator of brain function that maintains normal development and neuronal circuitry. Here, we demonstrate that O-GlcNAc transferase (OGT) in GNPs mediate the cerebellum development, and the progression of the Shh subgroup of medulloblastoma. Specifically, OGT regulates the neurogenesis of GNPs by activating the Shh signaling pathway via O-GlcNAcylation at S355 of GLI family zinc finger 2 (Gli2), which in turn promotes its deacetylation and transcriptional activity via dissociation from p300, a histone acetyltransferases. Inhibition of OGT via genetic ablation or chemical inhibition improves survival in a medulloblastoma mouse model. These data uncover a critical role for O-GlcNAc signaling in cerebellar development, and pinpoint a potential therapeutic target for Shh-associated medulloblastoma.

Ischemic stroke is a common cause of permanent disability worldwide. Magnoflorine has been discovered to have good antioxidation, immune regulation, and cardiovascular system protection functions. However, whether magnoflorine treatment protects against cerebral ischemic stroke and the mechanism of such protection remains unknown. Here, we investigated the effect of magnoflorine on the development of ischemic stroke disorder in rats. A middle cerebral artery occlusion (MCAO) model followed by 24 h reperfusion after 90 min ischemia was used. The rats were treated with magnoflorine (10 mg/kg or 20 mg/kg) for 15 consecutive days. The neurological deficit scores, cerebral infarct volume, and brain water content were measured. The neuronal density was determined using Nissl and NeuN staining. The oxidative stress levels were determined using commercial kits. Immunofluorescence staining of LC3 and western blot assay for LC3 and p62 were used to assess autophagy. Magnoflorine treatment significantly reduced the cerebral infarct volume and brain water content and improved the neurological deficit scores in the rat MCAO model. In addition, magnoflorine ameliorated neuronal injury and neuron density in the cortex of rats. Magnoflorine also prevented oxidative damage following ischemia, reflected by the decrement of nitric oxide and malondialdehyde and the increase of glutathione (GSH) and GSH peroxidase. Moreover, the fluorescence intensity of LC3 and the ratio of LC3-II to LC3-I were remarkably downregulated in ischemic rat administration of magnoflorine. Finally, the expression levels of p62, sirtuin 1 (Sirt1), and phosphorylated-adenosine monophosphate-activated protein kinase (AMPK) were upregulated with magnoflorine. Magnoflorine attenuated the cerebral ischemia-induced neuronal damage, which was possibly associated with antioxidative stress, suppression of autophagy, and activation of the Sirt1/AMPK pathway in the rats.