Protective effect of furofuranone against cerebral ischemic stroke via activation of PI3k/Akt/GSK 3β signaling pathway

Purpose: To study the protective effects of furofuranone on oxygen and glucose-deprived damage to brain microvascular endothelial cells (BMECs) in vitro, and in vivo in cerebral ischemic stroke rat model. Methods: BMECs were isolated from the Sprague Dawley rats and deprived of oxygen and glucose. The effect of 10, 20, 30, 40, 50 and 100 µM furofuranone on the oxygen/glucose-deprived BMECs was studied using Transwell chamber method. A rat cerebral ischemic stroke model was established using middle cerebral arterial occlusion method. Caspase-3 and other proteins, inflammatory cytokines, and other parameters of the brain tissue were evaluated by enzyme-linked assay (ELISA), polymerase chain reaction (PCR) and Western blot as appropriate. Further studies on the brain tissues was carried out by immunochemical analysis and hematoxylin and eosin staining. Results: Furofuranone decreased caspase 3 levels in a dose-based manner in rat BMECs, and significantly reduced the release of lactate dehydrogenase (LDH) in ischemic stroke rat model (p < 0.05). It also led to marked increases in the levels of p PI3k, p Akt and p GSK3β in cerebral ischemic stroke rats. Growth-associated protein-43 (GAP-43) and microtubule-associated protein 2 (MAP-2) levels increased in the cerebral ischemic stroke rat brain tissues, in addition to marked increase in ionized calcium-binding adaptor protein (IBA-1) and glial fibrillary acidic protein (GFAP) (p < 0.05). Furofuranone treatment reduced the population of microtubule-associated protein light chain 3 (MAP1LC3A) and Beclin 1-positive cells, and significantly downregulated L selectin, leptin, monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor (TNF)-α (p < 0.05). The release of tissue inhibitor of metalloproteinases 1 (TIMP-1) was enhanced in the cerebral ischemic stroke rats by furofuranone treatment. Conclusion: Furofuranone treatment prevents cerebral ischemic stroke-induced damage in rats via phosphorylation of PI3k, Akt and GSK3β proteins, and reduction of inflammatory cytokine levels. Therefore, furofuranone may be useful as chemotherapeutic agent for cerebral ischemic stroke

High Intensity Physical Rehabilitation Later Than 24 h Post Stroke Is Beneficial in Patients: A Pilot Randomized Controlled Trial (RCT) Study in Mild to Moderate Ischemic Stroke

Objective: Very early mobilization was thought to contribute to beneficial outcomes in stroke-unit care, but the optimal intervention strategy including initiation time and intensity of mobilization are unclear. In this study, we sought to confirm the rehabilitative effects of different initiation times (24 vs. 48 h) with different mobilization intensities (routine or intensive) in ischemic stroke patients within three groups.Materials and Methods: We conducted a randomized and controlled trial with a blinded follow-up assessment. Patients with ischemic stroke, first or recurrent, admitted to stroke unit within 24 h after stroke onset were recruited. Eligible subjects were randomly assigned (1:1:1) to 3 groups: Early Routine Mobilization in which patients received < 1.5 h/d out-of-bed mobilization within 24–48 h after stroke onset, Early Intensive Mobilization in which patients initiated ≥3 h/d mobilization at 24–48 h after the stroke onset, and Very Early Intensive Mobilization in which patients received≥3 h/d mobilization within 24 h. The modified Rankin Scale score of 0–2 was used as the primary favorable outcome.Results: We analyzed 248 of the 300 patients (80 in Early Routine Mobilization, 82 in Very Early Intensive Mobilization and 86 in Early Intensive Mobilization), with 52 dropping out (20 in Early Routine Mobilization, 18 in Very Early Intensive Mobilization and 14 in Early Intensive Mobilization). Among the three groups, the Early Intensive Mobilization group had the most favorable outcomes at 3-month follow-up, followed by patients in the Early Routine Mobilization group. Patients in Very Early Intensive Mobilization received the least odds of favorable outcomes. At 3 month follow up, 53.5%, (n = 46) of patients with Early Intensive Mobilization showed a favorable outcome (modified Rankin Scale 0–2) (p = 0.041) as compared to 37.8% (n = 31) of patients in the Very Early Intensive Mobilization.Conclusions: Post-stroke rehabilitation with high intensity physical exercise at 48 h may be beneficial. Very Early Intensive Mobilization did not lead to a favorable outcome at 3 months.Clinical Trial Registration:www.chictr.org.cn, identifier ChiCTR-ICR-15005992

A functional variant alters binding of activating protein 1 regulating expression of FGF7 gene associated with chronic obstructive pulmonary disease

Abstract Background Genome-wide association studies (GWASs) of a large cohort of subjects with chronic obstructive pulmonary disease (COPD) have successfully identified multiple risk genes, including fibroblast growth factor 7 (FGF7). However, the underlying molecular mechanism influencing function of FGF7 and risk of COPD remains further study. Methods In this study, we replicated the genetic association of variants near the FGF7 gene in 258 Chinese Han patients with COPD and 311 healthy controls. Additionally, we functionally evaluated a candidate causal variant upstream of the FGF7 gene. Results The most significant association was observed at rs12905203 (P = 5.9 × 10− 3, odd ratio, OR = 1.516) that explains associations of previously reported variants at the FGF7 locus. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) assays showed that the risk allele of the variant was bound to activator protein 1 transcription factors (c-Fos and c-Jun) with a significantly reduced affinity and associated with decreased mRNA expression of FGF7 in fibroblast cells at both resting and PMA/Ionomycin-stimulated conditions. Overexpression of c-Fos and c-Jun proteins or stimulation with PMA/Ionomycin significantly increases mRNA expression of FGF7 in fibroblast cells. Bioinformatic analysis showed that the variant overlaps with multiple genetic regulatory marks, suggesting the regulatory DNA element might function as an enhancer for the FGF7 gene. Luciferase enhancer activity assays demonstrated that the DNA sequences carrying the variant produce enhancer activity while the risk allele of the variant reduces its activity. Conclusions In this study, we demonstrated a consistent association of the FGF7 gene with COPD and mechanistically characterized a candidate functional variant upstream of the FGF7 gene. These data highlighted the important role of the risk variant and the FGF7 gene in influencing risk for COPD

Intelligent augmented keyword search on spatial entities in real-life internet of vehicles

Internet of Vehicles (IoV) has attracted wide attention from both academia and industry. Due to the popularity of the geographical devices deployed on the vehicles, a tremendous amount of spatial entities which include spatial information, unstructured information and structured information, are generated every second. This development calls for intelligent augmented spatial keyword queries (ASKQ), which intelligently takes into account the locations, unstructured information (in the form of keyword sets), structured information (in the form of boolean expressions) of 182MinzuAvespatial entities. In this paper, we take the first step to address the issue of processing ASKQ in real traffic networks of IoV environments (ASKQIV) and focus on Top-k ASKQIV queries. To support network distance pruning, keyword pruning, and boolean expression pruning intelligently and simultaneously, a novel hybrid index structure called ASKTI is proposed. Note in the real-life traffic networks of IoV environments, travel cost is not only decided by the network distance, but also decided by some additional travel factors. By considering these additional factors, a combined factor Cftc of each road (edge) in the traffic network of IoV environments is calculated, and weighted network distance is calculated and adopted. Based on ASKTI, an efficient algorithm for Top-k ASKQIV query processing is proposed. Our method can also be extended to handle boolean range ASKQIV Queries and ranking ASKQIV Queries. Finally, simulation experiments on one real traffic network of IoV environments and two synthetic spatial entity sets are conducted. The results show that our ASKTI based method is superior to its competitors.University of Derb

ICT1 Promotes Osteosarcoma Cell Proliferation and Inhibits Apoptosis via STAT3/BCL-2 Pathway

Osteosarcoma (OS) is a familiar malignant bone tumor that occurs mainly in adolescents. Immature colon carcinoma transcript-1 (ICT1) is an important member of the large mitoribosomal subunit in mitochondrial ribosomes, which has been shown to be closely related to tumorigenesis. Its expression and function in OS, however, remained unclear. Here, we showed that ICT1 was significantly upregulated in OS and promoted the growth of OS cells. Mechanistically, ICT1 acted as an oncogene in OS and promoted proliferation and inhibited apoptosis of OS cells through the STAT3/BCL-2 axis. These results reveal a novel insight into the role of the ICT1/STAT3/BCL-2 axis in OS and therefore may represent a novel molecular target for novel treatments

The cerebral circulation and cerebrovascular disease III: Stroke

In this paper, our review series on cerebrovascular disease anatomy, physiology, and pathology ends with a thorough discussion of the most significant cerebrovascular pathology: stroke. This discussion proceeds through two layers of organization. First, stroke is divided up into its main etiologic categories (ischemic stroke/transient ischemic attack, hemorrhagic stroke, and ischemic to hemorrhagic transformation). Then, the epidemiological, pathophysiological, clinical, and therapeutic (employed currently as well as emerging) aspects of each etiology are explored; emphasis is placed upon the therapeutic aspects. Finally, once we have covered all aspects of each etiologic category, we end our review with a defense of the thesis that there is much hope for the future of stroke treatment to be derived from familiarity with the literature on emerging therapies

Neuroprotective Effects of Pharmacological Hypothermia on Hyperglycolysis and Gluconeogenesis in Rats after Ischemic Stroke

Stroke is a leading threat to human life. Metabolic dysfunction of glucose may play a key role in stroke pathophysiology. Pharmacological hypothermia (PH) is a potential neuroprotective strategy for stroke, in which the temperature is decreased safely. The present study determined whether neuroprotective PH with chlorpromazine and promethazine (C + P), plus dihydrocapsaicin (DHC) improved glucose metabolism in acute ischemic stroke. A total of 208 adult male Sprague Dawley rats were randomly divided into the following groups: sham, stroke, and stroke with various treatments including C + P, DHC, C + P + DHC, phloretin (glucose transporter (GLUT)-1 inhibitor), cytochalasin B (GLUT-3 inhibitor), TZD (thiazolidinedione, phosphoenolpyruvate carboxykinase (PCK) inhibitor), and apocynin (nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor). Stroke was induced by middle cerebral artery occlusion (MCAO) for 2 h followed by 6 or 24 h of reperfusion. Rectal temperature was monitored before, during, and after PH. Infarct volume and neurological deficits were measured to assess the neuroprotective effects. Reactive oxygen species (ROS), NOX activity, lactate, apoptotic cell death, glucose, and ATP levels were measured. Protein expression of GLUT-1, GLUT-3, phosphofructokinase (PFK), lactate dehydrogenase (LDH), PCK1, PCK2, and NOX subunit gp91 was measured with Western blotting. PH with a combination of C + P and DHC induced faster, longer, and deeper hypothermia, as compared to each alone. PH significantly improved every measured outcome as compared to stroke and monotherapy. PH reduced brain infarction, neurological deficits, protein levels of glycolytic enzymes (GLUT-1, GLUT-3, PFK and LDH), gluconeogenic enzymes (PCK1 and PCK2), NOX activity and its subunit gp91, ROS, apoptotic cell death, glucose, and lactate, while raising ATP levels. In conclusion, stroke impaired glucose metabolism by enhancing hyperglycolysis and gluconeogenesis, which led to ischemic injury, all of which were reversed by PH induced by a combination of C + P and DHC

Efficient photothermochemical dry reforming of methane over Ni supported on ZrO2 with CeO2 incorporation

Solar-driven photothermochemical dry reforming of methane (PTC-DRM) has attracted increasing attention to address global climate issues yet still faces challenges of poor stability, especially for Ni-based catalysts. Herein, we developed a strategy to improve PTC-DRM activity and stability of Ni-based catalysts by supporting Ni nanoparticles on CeO2 incorporated ZrO2. At 700 °C under 30 suns light irradiation, the resulting Ni-CeO2/ZrO2 exhibited elevated and stable PTC-DRM with H2 and CO production rates of 713 and 693 mmol g−1 h−1 during a continuous 48 h test, respectively, much higher than those of Ce-free Ni/ZrO2 (542 mmol g−1 h−1 for H2 and 534 mmol g−1 h−1 for CO in a 24 h test). The comparisons between photothermochemical and thermochemical performance at the same temperatures indicate that introducing a small amount of CeO2 lowers the activation energies of CH4 and CO2 conversions from 68.6 and 62.9 kJ mol−1 in the dark to 54.7 and 57.7 kJ mol−1 under light, respectively. Mechanism investigation was performed through in situ DRIFTS and catalysts characterization before and after the PTC-DRM reaction, revealing that the plasmonic effect from Ni mitigates coke deposition and benefits the DRM activities and stability under light illumination. CeO2, serving as a promoter, enhances metal-support interaction, which also plays beneficial effects in continuously generating oxygen vacancies, facilitating the dissociation of carbonate intermediates, and mitigating coke deposition under light irradiation, thus boosting PTC-DRM activity and stability. This study is essential for designing cost-effective Ni-based catalysts and reaction systems for greenhouse gases conversion to produce syngas using sustainable solar energy