Pathological Comparisons of the Hippocampal Changes in the Transient and Permanent Middle Cerebral Artery Occlusion Rat Models

© Copyright © 2019 Shah, Li, Kury, Zeb, Khatoon, Liu, Yang, Liu, Yao, Khan, Koh, Jiang and Li. Ischemic strokes are categorized by permanent or transient obstruction of blood flow, which impedes delivery of oxygen and essential nutrients to brain. In the last decade, the therapeutic window for tPA has increased from 3 to 5–6 h, and a new technique, involving the mechanical removal of the clot (endovascular thrombectomy) to allow reperfusion of the injured area, is being used more often. This last therapeutic approach can be done until 24 h after stroke onset. Due to this fact, more acute ischemic stroke patients are now being recanalized, and so tMCAO is probably the “best” model to address these patients that have a potential good outcome in terms of survival and functional recovery. However, permanent occlusion patients are also important, not only to increase survival rate but also to improve functional outcomes, although these are more difficult to achieve. So, both models are important, and which target different stroke patients in the clinical scenario. Hippocampus has a vital role in memory and cognition, is prone to ischemic induced neurodegeneration. This study was designed to delineate the molecular, pathological, and neurological changes in rat models of t-MCAO, permanent MCAO (pMCAO), and pMCAO with diabetic conditions in hippocampal tissue. Our results showed that these three models showed distinct discrepancies at numerous pathological process, including key signaling molecules involved in neuronal apoptosis, glutamate induced excitotoxicity, neuroinflammation, oxidative stress, and neurotrophic changes. Our result suggests that the two commonly used MCAO models exhibited tremendous differences in terms of neuronal cell loss, glutamate excitotoxic related signaling, synaptic transmission markers, neuron inflammatory and oxidative stress molecules. These differences may reflect the variations in different models, which may provide valuable information for mechanistic and therapeutic inconsistences as experienced in both preclinical models and clinical trials

The effect of socioeconomic status on three-year mortality after first-ever ischemic stroke in Nanjing, China

BACKGROUND: Low socioeconomic status (SES) is associated with increased mortality after stroke in developed countries. This study was performed to determine whether a similar association also exists in China. METHODS: A total of 806 patients with first-ever ischemic stroke were enrolled in our study. From August 1999 to August 2005, the three-year all-cause mortality following the stroke was determined. Level of education, occupation, taxable income and housing space were used as indicators for SES. Stepwise univariate and multivariate COX proportional hazards models were used to study the association between the SES measures and the three-year mortality. RESULTS: Our analyses confirmed that occupation, taxable income and housing space were significantly associated with three-year mortality after first-ever stroke. Manual workers had a significant hazard ratio of 5.44 (95% CI 2.75 to 10.77) for death within three years when compared with non-manual workers. Those in the zero income group had a significant hazard ratio of 5.35 (95% CI 2.95 to 9.70) and those in the intermediate income group 2.10 (95% CI 1.24 to 3.58) when compared with those in the highest income group. Those in two of the three groups with the smallest housing space also had significant hazard ratios of 2.06 (95% CI 1.16 to 3.65) and 1.68 (95% CI 1.12 to 2.52) when compared with those in group with the largest housing space. These hazard ratios remained largely unchanged after multivariate adjustment for age, gender, baseline cardiovascular disease risk factors, and stroke severity. The analyses did not confirm an association with educational level. CONCLUSION: Lower SES has a negative impact on the outcome of first-ever stroke in Nanjing, China. This confirms the need to improve preventive and secondary care for stroke among low SES groups

Melatonin Protects MCAO-Induced Neuronal Loss via NR2A Mediated Prosurvival Pathways

Stroke is the significant cause of human mortality and sufferings depending upon race and demographic location. Melatonin is a potent antioxidant that exerts protective effects in differential experimental stroke models. Several mechanisms have been previously suggested for the neuroprotective effects of melatonin in ischemic brain injury. The aim of this study is to investigate whether melatonin treatment affects the glutamate N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor signaling in cerebral cortex and striatum 24 h after permanent middle cerebral artery occlusion (MCAO). Melatonin (5 mg/kg) attenuated ischemia-induced down regulation of NMDA receptor 2 (NR2a), postsynaptic density-95 (PSD95) and increases NR2a/PSD95 complex association, which further activates the pro-survival PI3K/Akt/GSK3β pathway with mitigated collapsin response mediator protein 2 (CRMP2) phosphorylation. Furthermore, melatonin increases the expression of γ-enolase, a neurotrophic factor in ischemic cortex and striatum, and preserve the expression of presynaptic (synaptophysin and SNAP25) and postsynaptic (p-GluR1845) protein. Our study demonstrated a novel neuroprotective mechanism for melatonin in ischemic brain injury which could be a promising neuroprotective agent for the treatment of ischemic stroke

Aprotic phosphonium-based ionic liquid as electrolyte for high CO2 electroreduction to oxalate

In this study, a new CO2 electroreduction electrolyte system consisting of tetrabutylphosphonium 4-(methoxycarbonyl) phenol ([P-4444][4-MF-PhO]) ionic liquid (IL) and acetonitrile (AcN) was designed to produce oxalate, and the electroreduction mechanism was studied. The results show that using the new IL-based electrolyte, the electroreduction system exhibits 93.8% Faradaic efficiency and 12.6 mA cm(-2) partial current density of oxalate at -2.6 V. The formation rate of oxalate is 234.4 mu mol cm(-2) h(-1), which is better than those reported in the literature. The mechanism study using density functional theory (DFT) calculations reveals that [P-4444][4-MF-PhO] can effectively activate CO2 molecule through ester and phenoxy double active sites. In addition, in the phosphonium-based ionic environment, the potential barriers of the key intermediates *CO2- and *C2O42- are reduced by the induced electric field, which greatly facilitates the activation and conversion of CO2 molecule to oxalate

Aprotic phosphonium-based ionic liquid as electrolyte for high CO2 electroreduction to oxalate

In this study, a new CO2 electroreduction electrolyte system consisting of tetrabutylphosphonium 4-(methoxycarbonyl) phenol ([P-4444][4-MF-PhO]) ionic liquid (IL) and acetonitrile (AcN) was designed to produce oxalate, and the electroreduction mechanism was studied. The results show that using the new IL-based electrolyte, the electroreduction system exhibits 93.8% Faradaic efficiency and 12.6 mA cm(-2) partial current density of oxalate at -2.6 V. The formation rate of oxalate is 234.4 mu mol cm(-2) h(-1), which is better than those reported in the literature. The mechanism study using density functional theory (DFT) calculations reveals that [P-4444][4-MF-PhO] can effectively activate CO2 molecule through ester and phenoxy double active sites. In addition, in the phosphonium-based ionic environment, the potential barriers of the key intermediates *CO2- and *C2O42- are reduced by the induced electric field, which greatly facilitates the activation and conversion of CO2 molecule to oxalate

Melatonin protects MCAO-induced neuronal loss via NR2A mediated prosurvival pathways

© 2019 Shah, Liu, Al Kury, Zeb, Abbas, Li, Yang, Liu, Jiang and Li. Stroke is the significant cause of human mortality and sufferings depending upon race and demographic location. Melatonin is a potent antioxidant that exerts protective effects in differential experimental stroke models. Several mechanisms have been previously suggested for the neuroprotective effects of melatonin in ischemic brain injury. The aim of this study is to investigate whether melatonin treatment affects the glutamate N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor signaling in cerebral cortex and striatum 24 h after permanent middle cerebral artery occlusion (MCAO). Melatonin (5 mg/kg) attenuated ischemia-induced down regulation of NMDA receptor 2 (NR2a), postsynaptic density-95 (PSD95) and increases NR2a/PSD95 complex association, which further activates the pro-survival PI3K/Akt/GSK3β pathway with mitigated collapsin response mediator protein 2 (CRMP2) phosphorylation. Furthermore, melatonin increases the expression of γ-enolase, a neurotrophic factor in ischemic cortex and striatum, and preserve the expression of presynaptic (synaptophysin and SNAP25) and postsynaptic (p-GluR1845) protein. Our study demonstrated a novel neuroprotective mechanism for melatonin in ischemic brain injury which could be a promising neuroprotective agent for the treatment of ischemic stroke

Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma

Abstract Background Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and lethal hepatobiliary tumor with few therapeutic strategies. The metabolic reprogramming of tumor cells plays an essential role in the development of tumors, while the metabolic molecular classification of iCCA is largely unknown. Here, we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients, hoping to provide a novel perspective to understand and treat iCCA. Methods We performed integrated multiomics analysis in 116 iCCA samples, including whole‐exome sequencing, bulk RNA‐sequencing and proteome analysis. Based on the non‐negative matrix factorization method and the protein abundance of metabolic genes in human genome‐scale metabolic models, the metabolic subtype of iCCA was determined. Survival and prognostic gene analyses were used to compare overall survival (OS) differences between metabolic subtypes. Cell proliferation analysis, 5‐ethynyl‐2'‐deoxyuridine (EdU) assay, colony formation assay, RNA‐sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinase α (DGKA) in iCCA cells. Results Three metabolic subtypes (S1‐S3) with subtype‐specific biomarkers of iCCA were identified. These metabolic subtypes presented with distinct prognoses, metabolic features, immune microenvironments, and genetic alterations. The S2 subtype with the worst survival showed the activation of some special metabolic processes, immune‐suppressed microenvironment and Kirsten rat sarcoma viral oncogene homolog (KRAS)/AT‐rich interactive domain 1A (ARID1A) mutations. Among the S2 subtype‐specific upregulated proteins, DGKA was further identified as a potential drug target for iCCA, which promoted cell proliferation by enhancing phosphatidic acid (PA) metabolism and activating mitogen‐activated protein kinase (MAPK) signaling. Conclusion Via multiomics analyses, we identified three metabolic subtypes of iCCA, revealing that the S2 subtype exhibited the poorest survival outcomes. We further identified DGKA as a potential target for the S2 subtype