103 research outputs found
Anesthetic Isoflurane Increases Phosphorylated Tau Levels Mediated by Caspase Activation and AĪ² Generation
Anesthetic isoflurane has been shown to promote Alzheimerās disease (AD) neuropathogenesis by inducing caspase activation and accumulation of Ī²-amyloid (AĪ²). Phosphorylation of tau protein is another important feature of AD neuropathogenesis. However, the effects of isoflurane on phosphorylated tau levels remain largely to be determined. We therefore set out to determine whether isoflurane can increase phosphorylated tau levels. 5 to 8 month-old wild-type and AD transgenic mice [B6.Cg-Tg (APPswe, PSEN1dE9)85Dbo/J] were treated with 1.4% isoflurane for two hours. The mice brain tissues were harvested at six, 12 and 24 hours after the anesthesia. For the in vitro studies, primary neurons from wild-type and the AD transgenic mice were exposed to 2% isoflurane for six hours, and were harvested at the end of anesthesia. The harvested brain tissues and neurons were subjected to Western blot analysis by which the levels of phosphorylated tau protein at Serine 262 (Tau-PS262) were determined. Here we show that the isoflurane anesthesia increased Tau-PS262 levels in brain tissues and primary neurons from the wild-type and AD transgenic mice. Moreover, the isoflurane anesthesia may induce a greater increase in Tau-PS262 levels in primary neurons and brain tissues from the AD transgenic mice. Finally, caspase activation inhibitor Z-VAD and AĪ² generation inhibitor L-685,458 attenuated the isoflurane-induced increases in Tau-PS262 levels. In conclusion, clinically relevant isoflurane anesthesia increases phosphorylated tau levels, which may result from the isoflurane-induced caspase activation and AĪ² generation. These findings will promote more studies to determine the effects of anesthetics on tau phosphorylation
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Time-Dependent Effects of Anesthetic Isoflurane on Reactive Oxygen Species Levels in HEK-293 Cells
The inhalation anesthetic isoflurane has been reported to induce caspase activation and apoptosis, which may lead to learning and memory impairment. However, the underlying mechanisms of these effects are largely unknown. Isoflurane has been shown to induce elevation of cytosol calcium levels, accumulation of reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore, reduction in mitochondria membrane potential, and release of cytochrome c. The time course of these effects, however, remains to be determined. Therefore, we performed a pilot study to determine the effects of treatment with isoflurane for various times on ROS levels in HEK-293 cells. The cells were treated with 2% isoflurane plus 21% O2 and 5% CO2 for 15, 30, 60, or 90 min. We then used fluorescence imaging and microplate fluorometer to detect ROS levels. We show that 2% isoflurane for 60 or 90 min, but not 15 or 30 min, induced ROS accumulation in the cells. These data illustrated that isoflurane could cause time-dependent effects on ROS levels. These findings have established a system to further determine the time course effects of isoflurane on cellular and mitochondria function. Ultimately, the studies would elucidate, at least partially, the underlying mechanisms of isoflurane-induced cellular toxicity
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The potential dual effects of sevoflurane on AKT/GSK3Ī² signaling pathway
Background: Anesthesia with multiple exposures of commonly used inhalation anesthetic sevoflurane induces neuroinflammation and cognitive impairment in young mice, but anesthesia with a single exposure to sevoflurane does not. AKT/glycogen synthase kinase 3Ī² (GSK3Ī²) signaling pathway is involved in neurotoxicity and neurobehavioral deficits. However, whether sevoflurane can induce a dual effect (increase versus decrease) on the activation of AKT/GSK3Ī² signaling pathway remains to be determined. We therefore set out to assess the effects of sevoflurane on AKT/GSK3Ī² signaling pathway in vivo and in vitro. Methods: Six day-old wild-type mice were exposed to 3% sevoflurane two hours daily for one or three days. In the in vitro studies, H4 human neuroglioma cells were treated with 4% sevoflurane for two or six hours. We then determined the effects of different sevoflurane treatments on the levels of phosphorylated (P)-GSK3Ī²(ser9) and P-AKT(ser473) by using Western blot analysis. Results: Here we show that anesthesia with 3% sevoflurane two hours daily for one day increased the levels of P-GSK3Ī²(ser9) and P-AKT(ser473), but the anesthesia with 3% sevoflurane daily for three days decreased them in the mice. The treatment with 4% sevoflurane for two hours increased, but the treatment with 4% sevoflurane for six hours decreased, the levels of P-GSK3Ī²(ser9) and P-AKT(ser473) in the H4 human neuroglioma cells. Conclusions: Anesthetic sevoflurane might induce a dual effect (increase versus decrease) on the activation of the AKT/GSK3Ī² signaling pathway. These studies have established a system to perform further studies to determine the effects of sevoflurane on brain function
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Chronic treatment with anesthetic propofol attenuates Ī²-amyloid protein levels in brain tissues of aged mice
Alzheimerās disease (AD) is the most common form of dementia. At the present time, however, AD still lacks effective treatments. Our recent studies showed that chronic treatment with anesthetic propofol attenuated brain caspase-3 activation and improved cognitive function in aged mice. Accumulation of Ī²-amyloid protein (AĪ²) is a major component of the neuropathogenesis of AD dementia and cognitive impairment. We therefore set out to determine the effects of chronic treatment with propofol on AĪ² levels in brain tissues of aged mice. Propofol (50 mg/kg) was administrated to aged (18 month-old) wild-type mice once a week for 8 weeks. The brain tissues of mice were harvested one day after the final propofol treatment. The harvested brain tissues were then subjected to enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Here we report that the propofol treatment reduced AĪ² (AĪ²40 and AĪ²42) levels in the brain tissues of the aged mice. Moreover, the propofol treatment decreased the levels of Ī²-site amyloid precursor protein cleaving enzyme (the enzyme for AĪ² generation), and increased the levels of neprilysin (the enzyme for AĪ² degradation) in the brain tissues of the aged mice. These results suggested that the chronic treatment with propofol might reduce brain AĪ² levels potentially via decreasing brain levels of Ī²-site amyloid precursor protein cleaving enzyme, thus decreasing AĪ² generation; and via increasing brain neprilysin levels, thus increasing AĪ² degradation. These preliminary findings from our pilot studies have established a system and postulated a new hypothesis for future research
RNA interference-mediated silencing of BACE and APP attenuates the isoflurane-induced caspase activation
<p>Abstract</p> <p>Background</p> <p>Ī²-Amyloid protein (AĪ²) has been shown to potentiate the caspase-3 activation induced by the commonly used inhalation anesthetic isoflurane. However, it is unknown whether reduction in AĪ² levels can attenuate the isoflurane-induced caspase-3 activation. We therefore set out to determine the effects of RNA interference-mediated silencing of amyloid precursor protein (APP) and Ī²-site APP-cleaving enzyme (BACE) on the levels of AĪ² and the isoflurane-induced caspase-3 activation.</p> <p>Methods</p> <p>H4 human neuroglioma cells stably transfected to express full-length human APP (H4-APP cells) were treated with small interference RNAs (siRNAs) targeted at silencing BACE and APP for 48 hours. The cells were then treated with 2% isoflurane for six hours. The levels of BACE, APP, and caspase-3 were determined using Western blot analysis. Sandwich Enzyme-linked immunosorbent assay (ELISA) was used to determine the extracellular AĪ² levels in the conditioned cell culture media.</p> <p>Results</p> <p>Here we show for the first time that treatment with BACE and APP siRNAs can decrease levels of BACE, full-length APP, and APP c-terminal fragments. Moreover, the treatment attenuates the AĪ² levels and the isoflurane-induced caspase-3 activation. These results further suggest a potential role of AĪ² in the isoflurane-induced caspase-3 activation such that the reduction in AĪ² levels attenuates the isoflurane-induced caspase-3 activation.</p> <p>Conclusion</p> <p>These findings will lead to more studies which aim at illustrating the underlying mechanism by which isoflurane and other anesthetics may affect Alzheimer's disease neuropathogenesis.</p
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Mild Hypothermia Attenuates the Anesthetic Isoflurane-Induced Cytotoxicity
The commonly used inhalation anesthetic isoflurane has been reported to induce DNA damage and cytotoxicity. However, the methods to attenuate these effects remain largely to be determined. Mild hypothermia has neuroprotective effects. We therefore set out to assess whether mild hypothermia could protect the isoflurane-induced DNA damage and cytotoxicity. Moreover, we investigated the underlying mechanisms by assessing the effects of mild hypothermia on the isoflurane-induced changes in ATP levels. H4 human neuroglioma cells were treated with 2% isoflurane for 3 or 6 h with and without mild hypothermia (35Ā°C). We assessed the cell viability by using 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) and lactate dehydrogenase (LDH) assay. We determined DNA damage by measuring levels of phosphorylation of the histone protein H2A variant X at Ser139 (Ī³H2A.X), the marker of DNA damage. We also measured ATP levels in the cells. Here we showed that the treatment with 2% isoflurane for 6 h induced cytotoxicity and DNA damage in the cells. Moreover, the treatment with 2% isoflurane for 3 h decreased ATP levels without inducing cytotoxicity. Mild hypothermia attenuated the isoflurane-induced cytotoxicity, DNA damage, and ATP reduction in the cells. Taken together, these data suggest that the isoflurane-induced reduction in ATP levels occurred before the isoflurane-induced cytotoxicity. Isoflurane may induce DNA damage and cause cytotoxicity through reducing ATP levels. Mild hypothermia would ameliorate isoflurane-induced DNA damage and cytotoxicity by attenuating the isoflurane-induced reduction in ATP levels. These pilot studies have established a system and will promote the future investigations of anesthesia neurotoxicity
An Oil Spill Spatial Data Model for Qinzhou Bay Based on the KML
Qinzhou Bay is an important channel of Chinese southwest goes to sea. The Qinzhou Bay was chosen as the study area in this paper. Using the international advanced model Oilmap, Analysis of oil spill on the initial oil membrane formation factors, exclude some of initial oil film effects are not important factors, Find suitable for oil spill earlier an oil spill force model. Combined with the natural condition of Qinzhou Bay, The transport process of oil membrane in the condition of different wind and current was observed in Qinzhou Bay by means of experiments. This paper analyzes the main factors, such as the shape of oil membrane and migration directions, which leads to the oil spill, and got a suitable model of oil spill to Qinzhou Bay. In order to achieve its visual in the software of geographic information system, the model of oil spill was defined through the KML
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Age-dependent postoperative cognitive impairment and Alzheimer-related neuropathology in mice
Post-operative cognitive dysfunction (POCD) is associated with increased cost of care, morbidity, and mortality. However, its pathogenesis remains largely to be determined. Specifically, it is unknown why elderly patients are more likely to develop POCD and whether POCD is dependent on general anesthesia. We therefore set out to investigate the effects of peripheral surgery on the cognition and Alzheimer-related neuropathology in mice with different ages. Abdominal surgery under local anesthesia was established in the mice. The surgery induced post-operative elevation in brain Ī²-amyloid (AĪ²) levels and cognitive impairment in the 18 month-old wild-type and 9 month-old Alzheimer's disease transgenic mice, but not the 9 month-old wild-type mice. The AĪ² accumulation likely resulted from elevation of beta-site amyloid precursor protein cleaving enzyme and phosphorylated eukaryotic translation initiation factor 2Ī±. Ī³-Secretase inhibitor compound E ameliorated the surgery-induced brain AĪ² accumulation and cognitive impairment in the 18 month-old mice. These data suggested that the peripheral surgery was able to induce cognitive impairment independent of general anesthesia, and that the combination of peripheral surgery with aging- or Alzheimer gene mutation-associated AĪ² accumulation was needed for the POCD to occur. These findings would likely promote more research to investigate the pathogenesis of POCD
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Peripheral Surgical Wounding and Age-Dependent Neuroinflammation in Mice
Post-operative cognitive dysfunction is associated with morbidity and mortality. However, its neuropathogenesis remains largely to be determined. Neuroinflammation and accumulation of Ī²-amyloid (AĪ²) have been reported to contribute to cognitive dysfunction in humans and cognitive impairment in animals. Our recent studies have established a pre-clinical model in mice, and have found that the peripheral surgical wounding without the influence of general anesthesia induces an age-dependent AĪ² accumulation and cognitive impairment in mice. We therefore set out to assess the effects of peripheral surgical wounding, in the absence of general anesthesia, on neuroinflammation in mice with different ages. Abdominal surgery under local anesthesia was established in 9 and 18 month-old mice. The levels of tumor necrosis factor-Ī± (TNF-Ī±), interleukin-6 (IL-6), Iba1 positive cells (the marker of microglia activation), CD33, and cognitive function in mice were determined. The peripheral surgical wounding increased the levels of TNF-Ī±, IL-6, and Iba1 positive cells in the hippocampus of both 9 and 18 month-old mice, and age potentiated these effects. The peripheral surgical wounding increased the levels of CD33 in the hippocampus of 18, but not 9, month-old mice. Finally, anti-inflammatory drug ibuprofen ameliorated the peripheral surgical wounding-induced cognitive impairment in 18 month-old mice. These data suggested that the peripheral surgical wounding could induce an age-dependent neuroinflammation and elevation of CD33 levels in the hippocampus of mice, which could lead to cognitive impairment in aged mice. Pending further studies, anti-inflammatory therapies may reduce the risk of postoperative cognitive dysfunction in elderly patients
Robust Representation Learning for Unified Online Top-K Recommendation
In large-scale industrial e-commerce, the efficiency of an online
recommendation system is crucial in delivering highly relevant item/content
advertising that caters to diverse business scenarios. However, most existing
studies focus solely on item advertising, neglecting the significance of
content advertising. This oversight results in inconsistencies within the
multi-entity structure and unfair retrieval. Furthermore, the challenge of
retrieving top-k advertisements from multi-entity advertisements across
different domains adds to the complexity. Recent research proves that
user-entity behaviors within different domains exhibit characteristics of
differentiation and homogeneity. Therefore, the multi-domain matching models
typically rely on the hybrid-experts framework with domain-invariant and
domain-specific representations. Unfortunately, most approaches primarily focus
on optimizing the combination mode of different experts, failing to address the
inherent difficulty in optimizing the expert modules themselves. The existence
of redundant information across different domains introduces interference and
competition among experts, while the distinct learning objectives of each
domain lead to varying optimization challenges among experts. To tackle these
issues, we propose robust representation learning for the unified online top-k
recommendation. Our approach constructs unified modeling in entity space to
ensure data fairness. The robust representation learning employs domain
adversarial learning and multi-view wasserstein distribution learning to learn
robust representations. Moreover, the proposed method balances conflicting
objectives through the homoscedastic uncertainty weights and orthogonality
constraints. Various experiments validate the effectiveness and rationality of
our proposed method, which has been successfully deployed online to serve real
business scenarios.Comment: 14 pages, 6 figures, submitted to ICD
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