PirB Overexpression Exacerbates Neuronal Apoptosis by Inhibiting TrkB and mTOR Phosphorylation After Oxygen and Glucose Deprivation Injury.

Previous studies have proven that paired immunoglobulin-like receptor B (PirB) plays a crucial suppressant role in neurite outgrowth and neuronal plasticity after central nervous system injury. However, the role of PirB in neuronal survival after cerebral ischemic injury and its mechanisms remains unclear. In the present study, the role of PirB is investigated in the survival and apoptosis of cerebral cortical neurons in cultured primary after oxygen and glucose deprivation (OGD)-induced injury. The results have shown that rebarbative PirB exacerbates early neuron apoptosis and survival. PirB gene silencing remarkably decreases early apoptosis and promotes neuronal survival after OGD. The expression of bcl-2 markedly increased and the expression of bax significantly decreased in PirB RNAi-treated neurons, as compared with the control- and control RNAi-treated ones. Further, phosphorylated TrkB and mTOR levels are significantly downregulated in the damaged neurons. However, the PirB silencing markedly upregulates phosphorylated TrkB and mTOR levels in the neurons after the OGD. Taken together, the overexpression of PirB inhibits the neuronal survival through increased neuron apoptosis. Importantly, the inhibition of the phosphorylation of TrkB and mTOR may be one of its mechanisms.

High-continuity genome assembly of the jellyfish Chrysaora quinquecirrha.

The Atlantic sea nettle ( Chrysaora quinquecirrha) has an important evolutionary position due to its high ecological value. However, due to limited sequencing technologies and complex jellyfish genomic sequences, the current C. quinquecirrha genome assembly is highly fragmented. Here, we used the most advanced high-throughput chromosome conformation capture (Hi-C) technology to obtain high-coverage sequencing data of the C. quinquecirrha genome. We then anchored these data to the previously published contig-level assembly to improve the genome. Finally, a high-continuity genome sequence of C. quinquecirrha was successfully assembled, which contained 1 882 scaffolds with a N50 length of 3.83 Mb. The N50 length of the genome assembly was 5.23 times longer than the previously released one, and additional analysis revealed that it had a high degree of genomic continuity and accuracy. Acquisition of the high-continuity genome sequence of C. quinquecirrha not only provides a basis for the study of jellyfish evolution through comparative genomics but also provides an important resource for studies on jellyfish growth and development.

Expression and functional characterization of transient receptor potential vanilloid 4 in the dorsal root ganglion and spinal cord of diabetic rats with mechanical allodynia.

Diabetic mechanical allodynia (DMA) is a common manifestation in patients with diabetes mellitus, and currently, no effective treatment is available. Transient receptor potential vanilloid 4 (TRPV4) is involved in mechanical hypersensitivity resulting from varying aetiologies in animal, but its expression pattern during DMA and whether it contributes to this condition are still unclear. We investigated the spatial and temporal expression patterns of TRPV4 in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) by qRT-PCR, Western blotting and immunofluorescence assays. The pathophysiological role of TRPV4 in DMA was also investigated by intrathecal application of the TRPV4 selective antagonist HC-067047 or the agonist GSK1016790A. The results showed that both the mRNA and protein levels of TRPV4 were strikingly upregulated on day 14 in the rats with DMA. The increase in TRPV4 was mainly observed in the soma and central processes of calcitonin gene-related peptide (CGRP)- or neurofilament 200 kDa (NF200)-containing DRG neurons. Both single and repetitive intrathecal applications of HC-067047 (400 ng/kg) significantly alleviated mechanical allodynia in the rats with DMA, whereas a single application of GSK1016790A (200 ng/kg) aggravated mechanical allodynia. The present data suggest that TRPV4 undergoes expression changes that are associated with mechanical hypersensitivity in diabetic rats. TRPV4 may be a new molecular target for developing a clinical strategy to treat this intractable neuropathic pain.

Inhibition of PirB Activity by TAT-PEP Improves Mouse Motor Ability and Cognitive Behavior.

Paired immunoglobulin-like receptor B (PirB), a functional receptor for myelin-associated inhibitory proteins, plays an important role in axon regeneration in injured brains. However, its role in normal brain function with age has not been previously investigated. Therefore in this study, we examined the expression level of PirB in the cerebral cortex, hippocampus and cerebellum of mice at 1 month, 3 months and 18 months of age. The results showed that the expression of PirB increased with age. We further demonstrated that overexpression of PirB inhibited neurite outgrowth in PC12 cells, and this inhibitory activity of PirB could be reversed by TAT-PEP, which is a recombinant soluble PirB ectodomain fused with TAT domain for blood-brain barrier penetration. In vivo study, intraperitoneal administration of TAT-PEP was capable of enhancing motor capacity and spatial learning and memory in mice, which appeared to be mediated through regulation of brain-derived neurotrophic factor (BDNF) secretion. Our study suggests that PirB is associated with aging and TAT-PEP may be a promising therapeutic agent for modulation of age-related motor and cognitive dysfunctions.

Contradictory Relationships between Cancer and Normal Cells and Implications for Anti-cancer Therapy.

Cancer treatment remains a serious problem worldwide. Analysis of the relationship between cancer cells and normal cells reveals that these two share characteristics in contradiction, thus could be analyzed by using contradictory principles. Under the theory of contradictory principles, induction of a dormant state or reversal of cancer cells is an important treatment strategy beyond traditional cytotoxic therapy. Normal cells are also the targets and under the influence of anti-cancer treatments and should be considered during therapy. Findings based on crosstalk between these two cell types may offer opportunities for the development of new biomarkers and therapies.

M9, a novel region of amino-Nogo-A, attenuates cerebral ischemic injury by inhibiting NADPH oxidase-derived superoxide production in mice.

AIMS: In acute stroke, neurological damage is due to oxidative stress and neuronal apoptotic death. This study investigated whether Nogo-A 290-562 residues region (M9), fused to the transduction domain of the HIV trans-activator (TAT) protein, is neuroprotective against cerebral ischemia and the mechanisms. METHODS: Transient focal cerebral ischemia was induced by middle cerebral artery occlusion in male C57BL/6J mice. TAT-M9, its mutation or vehicle was applied via intraperitoneal injection at the onset of reperfusion. The neurobehavioral scores, infarction volumes, neuronal apoptosis, and the ratio of Bax/Bcl-2 were evaluated. Malondialdehyde (MDA), reactive oxygen species (ROS) levels, and NADPH oxidase activation were measured in the presence or absence of the NADPH oxidase inhibitor apocynin or activator tetrabromocinnamic acid (TBCA). RESULTS: Immunofluorescence results confirmed that TAT-M9 was transduced into brain parenchyma, and it significantly improved neurological behavior, reduced infarct volumes, protected neuronal cells from apoptosis, inhibited activation of NADPH oxidase, and decreased MDA and ROS contents. Furthermore, apocynin imitated the beneficial effects of TAT-M9, while TBCA abolished them. CONCLUSIONS: Our results demonstrate that TAT-M9 administration attenuates cerebral ischemia by inhibiting NADPH oxidase-mediated oxidative damage and neuronal apoptosis in mice. TAT-M9 may be a potential treatment for cerebrovascular disease.