G protein-coupled receptor 158 modulates sensitivity to the sedative-hypnotic effect of ethanol in male mice.

BACKGROUND: Sensitivity to ethanol provides an index of the predisposition to recover from unconsciousness induced by a dose of ethanol. The role of the G protein-coupled receptor 158 (GPR158) in modulating sensitivity to the sedative-hypnotic effect of ethanol has not been investigated. METHODS: Loss of righting reflex (LORR) is a behavioral indicator of hypnosis in rodents. In this study, Gpr158-/- mice and wild-type (WT) littermates (n = 8/genotype) were tested using LORR induced by a dose of 3.5 g/kg ethanol, an open-field test (OFT), and a measure of blood ethanol concentration. The OFT was used to examine the role of GPR158 in the ethanol effect on motor activity in Gpr158-/- mice (n = 6/genotype). We also tested CamK2A-Cre;Gpr158fl/fl (n = 9) and Vgat-Cre;Gpr158fl/fl mice (n = 10) using the LORR test and OFT to compare with controls (n = 9 and 8, respectively). RESULTS: Gpr158 deficiency prolonged the LORR duration by 110.6%, t(14) = -5.241, p = 0.0001, without altering spontaneous activity, t(14) = -0.718, p = 0.485, or ethanol metabolism, F(1, 8) = 0.259, p = 0.625. Gpr158 knockout did not change the ethanol effect on locomotion, F(1, 10) = 0.262, p = 0.62. The LORR duration increased by 69% in the conditional knockouts of Gpr158 within calcium/calmodulin-dependent protein kinase II alpha-positive (CamK2A+ ) neurons, t(16) = -2.914, p = 0.01, and by 92% in the vesicular GABA transporter-positive (Vgat+ ) neurons, t(9.802) = -2.519, p = 0.023. Locomotion was not altered in Camk2A-Cre;Gpr158fl/fl , t(16) = 0.49, p = 0.631 or Vgat-Cre;Gpr158fl/fl mice, t(16) = 0.035, p = 0.972. CONCLUSIONS: This study reveals the key role of neuronal GPR158 in shaping sensitivity to the sedative-hypnotic effect of ethanol. These findings contribute to our understanding of the neurobiology of ethanol intoxication.

Combination Therapy with LXW7 and Ceria Nanoparticles Protects against Acute Cerebral Ischemia/Reperfusion Injury in Rats.

Ischemia/reperfusion is known to greatly increase oxidative stress in the penumbra, which results in brain damage. Integrin αvß3 is selectively up-regulated with ischemic injury to the brain and remains elevated throughout reperfusion. We determined whether or not a new compound biotinylated-LXW7-ceria nanoparticle (CeNP) (bLXW7-CeNP) plays a role in brain protection in the rat model of middle cerebral artery occlusion/reperfusion and shows better effects than CeNPs alone in improving the outcomes of focal oxidative stress and apoptosis more effectively. Male Sprague-Dawley rats were subjected to focal cerebral ischemia for 2 h followed by a 24-h reperfusion. Drug treatment was intravenously administered via the caudal vein 1 h after occlusion. Rats were randomly divided into the following 4 groups: bLXW7-CeNP treatment group (0.5 mg/kg); CeNP treatment group (0.5 mg/kg); control saline group; and sham group. Brains were harvested 24 h after reperfusion, and the neurologic deficit scores, infarction volume, blood-brain barrier (BBB) disruption, and the level of oxidative stress and apoptosis were determined. Results showed that the bLXW7-CeNP and CeNP treatments could improve neurologic deficit scores, infarction volume, BBB disruption, and the level of oxidative stress and apoptosis. Compound bLXW7-CeNP treatment exhibited better effects than CeNp treatment and showed remarkable statistical differences in the infarction volume, the degree of BBB breakdown, the apoptosis and oxidative stress, apart from neurologic deficit scores. Thus, we concluded that bLXW7-CeNP protects against acute cerebral ischemia/reperfusion injury. BLXW7, as a ligand of integrin αvß3, may be able to effectively localize the anti-oxidant CeNPs to the ischemic penumbra region, which may provide more adequate opportunities for CeNPs to exert anti-oxidative stress effects and subsequently reduce apoptosis in acute cerebral ischemia/reperfusion.

Prognostic Value of Albumin/Globulin Ratio in Survival and Lymph Node Metastasis in Patients with Cancer: A Systematic Review and Meta-analysis.

The impact of albumin to globulin ratio (AGR) on the prognosis of various human cancers has not been well established. Here, a systemic review and meta-analysis has been performed to comprehensively assess the relationships between AGR and lymph node metastasis (LNM) or overall survival (OS). Systematical search through six electronic databases has been carried out to identify reports involving the role of AGR on OS and LNM in human cancers. Hazard ratio (HR), odd ratio (OR) and their 95% confidence intervals (95% CI) were evaluated through meta-analysis according to standard steps. Of 403 studies retrieved, 14 eligible studies with 4136 patients were included in this study. The analysis based on random-effect model demonstrated that low AGR was significantly associated with poor OS in various cancers (HR=1.87, 95% CI 1.50-2.34; P < 0.001). Subsequent results showed a significant increase in the risk of LNM in the low AGR group when compared with high AGR group (HR=2.24; 95% CI=1.49-3.36; P<0.001). To conclusion, this study suggested that AGR was associated with OS and LNM in cancer patients and AGR may be a potential marker to assess prognosis of cancer patients. However, a large scale of samples and prospective studies are needed in the future to validate the role of AGR in practice.

Integrated Analysis and Identification of Novel Biomarkers in Parkinson's Disease.

Parkinson's disease (PD) is a quite common neurodegenerative disorder with a prevalence of approximately 1:800-1,000 in subjects over 60 years old. The aim of our study was to determine the candidate target genes in PD through meta-analysis of multiple gene expression arrays datasets and to further combine mRNA and miRNA expression analyses to identify more convincing biological targets and their regulatory factors. Six included datasets were obtained from the Gene Expression Omnibus database by systematical search, including five mRNA datasets (150 substantia nigra samples in total) and one miRNA dataset containing 32 peripheral blood samples. A chip meta-analysis of five microarray data was conducted by using the metaDE package and 94 differentially expressed (DE) mRNAs were comprehensively obtained. And 19 deregulated DE miRNAs were obtained through the analysis of one miRNAs dataset by Qlucore Omics Explorer software. An interaction network formed by DE mRNAs, DE miRNAs, and important pathways was discovered after we analyzed the functional enrichment, protein-protein interactions, and miRNA targetome prediction analysis. In conclusion, this study suggested that five significantly downregulated mRNAs (MAPK8, CDC42, NDUFS1, COX4I1, and SDHC) and three significantly downregulated miRNAs (miR-126-5p, miR-19-3p, and miR-29a-3p) were potentially useful diagnostic markers in clinic, and lipid metabolism (especially non-alcoholic fatty liver disease pathway) and mitochondrial dysregulation may be the keys to biochemically detectable molecular defects. However, the role of these new biomarkers and molecular mechanisms in PD requires further experiments in vivo and in vitro and further clinical evidence.

Neuroprotective Effect of CeO2@PAA-LXW7 Against H2O2-Induced Cytotoxicity in NGF-Differentiated PC12 Cells.

CeO2 nanoparticles (nanoceria) have been used in many studies as a powerful free radical scavenger, and LXW7, a small-molecule peptide, can specifically target the integrin αvß3, whose neuroprotective effects have also been demonstrated. The objective of this study is to observe the neuroprotective effect and potential mechanism of CeO2@PAA-LXW7, a new compound that couples CeO2@PAA (nanoceria modified with the functional group of polyacrylic acid) with LXW7 via a series of chemical reactions, in H2O2-induced NGF-differentiated PC12 cells. We examined the effects of LXW7, CeO2@PAA, and CeO2@PAA-LXW7 on the viability of primary hippocampal neurons and found that there was no significant difference under control conditions, but increased cellular viability was observed in the case of H2O2-induced injury. We used H2O2-induced NGF-differentiated PC12 cells as the classical injury model to investigate the neuroprotective effect of CeO2@PAA-LXW7. In this study, LXW7, CeO2@PAA, and CeO2@PAA-LXW7 inhibit H2O2-induced oxidative stress by reducing the production of reactive oxygen species (ROS) and regulating Bax/Bcl-2, cleaved caspase-3 and mitochondrial cytochrome C (cyto C) in the apoptotic signaling pathways. We found that the levels of phosphorylation of focal adhesion kinase (FAK) and of signal transducer and activator of transcription 3 (STAT3) increased significantly in H2O2-induced NGF-differentiated PC12 cells, whereas LXW7, CeO2@PAA, and CeO2@PAA-LXW7 suppressed the increase to different degrees. Among the abovementioned changes, the inhibitory effect of CeO2@PAA-LXW7 on H2O2-induced changes, including the increases in the levels of p-FAK and p-STAT3, is more obvious than that of LXW7 or CeO2@PAA alone. In summary, these results suggest that integrin signaling participates in the regulation of apoptosis via the regulation of ROS and of the apoptosis pathway in H2O2-induced NGF-differentiated PC12 cells. LXW7, CeO2@PAA, and CeO2@PAA-LXW7 can play neuroprotective roles by counteracting the oxidative stress and apoptosis induced by H2O2 in NGF-differentiated PC12 cells. CeO2@PAA-LXW7 exerting a more powerful synergistic effect via the conjunction of LXW7 and CeO2@PAA.

Long non-coding RNA ANRIL in gene regulation and its duality in atherosclerosis.

The antisense transcript long non-coding RNA (lncRNA) (antisense non-coding RNA in the INK4 locus, ANRIL) is an antisense of the cyclin-dependent kinase inhibitor 2B (CDKN2B) gene on chromosome 9p21 that contains an overlapping 299-bp region and shares a bidirectional promoter with alternate open reading frame (ARF). In the context of gene regulation, ANRIL is responsible for directly recruiting polycomb group (PcG) proteins, including polycomb repressive complex-1 (PRC-1) and polycomb repressive complex-2 (PRC-2), to modify the epigenetic chromatin state and subsequently inhibit gene expression in cis-regulation. On the other hand, previous reports have indicated that ANRIL is capable of binding to a specific site or sequence, including the Alu element, E2F transcription factor 1 (E2F1), and CCCTC-binding factor (CTCF), to achieve trans-regulation functions. In addition to its function in cell proliferation, adhesion and apoptosis, ANRIL is very closely associated with atherosclerosis- related diseases. The different transcripts and the SNPs that are related to atherosclerotic vascular diseases (ASVD-SNPs) are inextricably linked to the development and progression of atherosclerosis. Linear transcripts have been shown to be a risk factor for atherosclerosis, whereas circular transcripts are protective against atherosclerosis. Furthermore, ANRIL also acts as a component of the inflammatory pathway involved in the regulation of inflammation, which is considered to be one of the causes of atherosclerosis. Collectively, ANRIL plays an important role in the formation of atherosclerosis, and the artificial modification of ANRIL transcripts should be considered following the development of this disease.