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As a general anesthetic widely used in surgical, sevoflurane has been shown to cause cognitive and memory deficits in the elderly. It's important to find out agents that can counteract sevoflurane-induced cognitive dysfunction. This study is aimed to investigate the effect of lovastatin on sevoflurane-induced cognitive impairment in aged rats and reveal the potential mechanisms. BV-2 cells, rat hippocampal neurons or male aged rats were exposed to 2% sevoflurane for 5 h. The cells were pretreated with 10 μM lovastatin. The rats were intraperitoneally injected with 5 mg/kg/day lovastatin for three days. The results showed that lovastatin enhanced exosomal IDE secretion from sevoflurane-exposed BV-2 cells and promoted Aβ degradation. Lovastatin treatment also inhibited the increased expressions of β-secretase 1 (BACE1) and γ-secretase in hippocampal neurons under sevoflurane exposure in vitro. In animal experiments, the discrimination index in novel object recognition test and percentage of spontaneous alternation in Y-maze test were significantly elevated after lovastatin administration. In addition, Aβ plaque area and contents of soluble Aβ 1-40 and Aβ 1-42 in the hippocampal tissues were decreased upon lovastatin treatment. Furthermore, lovastatin reversed sevoflurane-induced Aβ accumulation via up-regulating IDE expression, and down-regulating amyloid precursor protein (APP)-related protein expression (β-C-terminal fragment (CTF), BACE1 and γ-secretase). In conclusion, lovastatin alleviates sevoflurane-induced cognitive deficient in aged rats via promoting Aβ degradation and reducing Aβ production. Lovastatin may be beneficial in preventing anesthetic-induced cognitive impairment. • Lovastatin promoted Aβ degradation in vitro and in vivo. • Lovastatin improved sevoflurane-induced cognitive disorder. • Lovastatin increased IDE secretion from BV-2 cells via an exosome secretory pathway. [ABSTRACT FROM AUTHOR]

Abstract: Propagation properties of electromagnetic waves in a one-dimension random system containing left-handed-material are studied by the transfer matrix method. The statistics of the Lyapunov exponent and its variance of the transmitted waves are also analyzed. The nonlocalized modes are not only found in such a disordered system, the Anderson localization states with short localization length can also be easily realized due to the existence of low frequency resonant gap. Furthermore, our results also show that a single-parameter scaling is generally inadequate even for the complete random system with negative-n materials when the frequency we consider is located in a gap. [Copyright &y& Elsevier]

Reducing serum low-density lipoprotein cholesterol (LDL-C) in hyperlipemia is recognized as an effective strategy to minimize the risk of atherosclerotic cardiovascular disease (ASCVD). MiR-337-3p has already been discovered to play regulatory roles in tumor proliferation and metastasis, adipocyte browning and ischemic brain injury, etc. However, the association between miR-337-3p and LDL-C is unknown. Gene Expression Omnibus (GEO) dataset and two hyperlipidemic murine models were used to analyze the potential relationship between miR-337-3p and LDL-C. AAV-mediated liver-directed miRNA overexpression in high fat diet (HFD)-fed mouse model was used to examine the effect of miR-337-3p on LDL-C and WB/RT-PCR/ELISA/luciferase assays were used to investigate the underlying mechanism. The expressions of miR-337-3p were obviously lower in multiple hyperlipidemic mouse models and had a negative correlation with serum LDL-C levels. After confirming the effect of miR-337-3p on the improvement of serum LDL-C in vivo, we discovered PCSK9 might be a possible target of miR-337-3p, which was further proved by in vitro experiments. MiR-337-3p could directly interact with both the PCSK9 3′UTR and promoter to inhibit PCSK9 translation and transcription. Furthermore, the result from DiI-LDL uptake assay under the knockdown of PCSK9 demonstrated that miR-337-3p promoting the absorption of LDL-C in HepG2 cells was dependent on PCSK9, and the result from LDLR−/− mouse model indicated that miR-337-3p regulating LDL-C was dependent on PCSK9/LDLR pathway. We discovered a new function of miR-337-3p in regulating PCSK9 expression and LDL-C absorption, suggesting miR-337-3p might be a new therapeutic target for the development of antihyperlipidemic drug. • There is a negative correlation between hepatic miR-337-3p and LDL-C in mice. • Overexpression of miR-337-3p in the liver could remit the increase of LDL-C in the HFD mouse model. • MiR-337-3p inhibited the protein and mRNA of PCSK9 in HepG2 cells via translational and transcriptional regulation. [ABSTRACT FROM AUTHOR]

Exposure to general anesthesia in early childhood may lead to adverse effects on adolescent neurocognition. This study investigated the effects of multiple inhalations of sevoflurane on long-term learning and memory in developing rats, and explored the mechanistic role of the tissue plasminogen activator (tPA)/plasminogen activator inhibitor-1 (PAI-1) fibrinolysis system and its regulatory relationship with the brain derived neurotrophic factor (BDNF) by activation of tropomysin related kinase B (TrkB). After rats were inhaled with sevoflurane for 2 h/d for three days, the expression levels of tPA, PAI-1, BDNF, its precursor(proBDNF), TrkB and phosphorylation of TrkB (p-TrkB) were detected at different time points. After 28 d, Morris water maze was used to examine learning and memory function; Golgi staining was used to investigate synaptic plasticity and synaptic-related proteins, such as Synapsin I(SYN1), growth associated protein 43(GAP-43), and postsynaptic density protein 95(PSD-95). Rats were given exogenous tPA and an inhibitor of PAI-1, TM5275. The results showed multiple inhalation of sevoflurane led to learning and memory dysfunction, downregulated the expression of the synaptic-related proteins, decreased dendritic spine density in the hippocampus, increased the expression level of proBDNF and PAI-1, and reduced expression of BDNF, tPA, and p-TrkB. Interestingly, tPA or TM5275 partially reversed the learning and memory dysfunction and the reduction of synaptic plasticity induced by sevoflurane exposure. Furthermore, they blocked the upregulation of proBDNF and PAI-1 protein expression and increased the expression of BDNF, tPA, and p-TrkB. The protective effect of tPA or TM5275 on rats following multiple sevoflurane inhalation was blocked by a TrkB inhibitor. Multiple inhalation of sevoflurane in rats inhibited the cleavage of proBDNF by disrupting the balance of the tPA/PAI-1 fibrinolysis system. This blocked the activation of the downstream TrkB signaling pathway and reduced hippocampal synaptic plasticity, leading to long-term learning and memory dysfunction. Therefore, Sevoflurane exposure could lead to learning and memory dysfunction by inhibiting BDNF cleavage via breaking the balance of tPA/PAI-1. • Learning and memory dysfunction after multiple sevoflurane exposure was caused by decreased tPA activity in hippocampus. • Sevoflurane can elevate PAI-1 expression. • Sevoflurane can inhibite the conversion of proBDNF to mature BDNF as well as the activation of TrkB. • TM5275 and tPA can be used to treat the brain injury caused by sevoflurane. [ABSTRACT FROM AUTHOR]

(5 R)-5-hydroxytriptolide (LLDT-8) is a triptolide analog with excellent capability against cancers, cerebral ischemic injury and rheumatoid arthritis. Here, we discovered its hepatoprotective effects in a mouse model of non-alcoholic fatty liver disease (NAFLD) by ameliorating liver lipid accumulation. Male C57BL/6J mice were fed with a high-fat/high-fructose (HFHFr) diet for 29 weeks to induce the pathological phenomena of NAFLD. Then the mice were treated with LLDT-8 (0.5mg/kg and 1mg/kg) or Vehicle for 8 weeks. Finally, the serum biochemical indexes, liver histological features, fatty acids (FAs) profile and related gene expression in liver were detected to investigate the effect of LLDT-8 on lipid accumulation and its possible mechanism. LLDT-8 treatment significantly inhibited hepatic injury featured by the decrease of serum alanine aminotransferase (ALT) and aspartate transaminase (AST), the lessening of hepatic ballooning and macrovesicular steatosis. Moreover, LLDT-8 could downregulate the expression of stearoyl-CoA desaturase 1 (SCD1), which further led to the lower ratios of C16:1/C16:0 and C18:1/C18:0 and thus inhibited lipid synthesis. LLDT-8 treatment also could upregulate liver peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase 1a (Cpt1a), peroxisomal acyl-CoA oxidase 1 (Acox1), long-chain acyl-CoA dehydrogenase (Acadl) and medium-chain acyl-CoA dehydrogenase (Acadm) expression levels involved in fatty acids oxidation (FAO) and markedly promoted lipolysis. Our results provide a novel application of LLDT-8 in improving NAFLD. [ABSTRACT FROM AUTHOR]

• EAAT2 expression in hippocampus reduced after H/R injury. • Midazolam alleviated H/R-induced apoptosis and learning and memory impairment. • Midazolam reversed the decreased expression of EAAT2 induced by H/R injury. • Involvement of EAAT2 in the neuroprotective effect of midazolam on H/R injury. Excitotoxicity is one of the main mechanisms related to hypoxia/reoxygenation (H/R) injury. Excitatory amino acid transporter (EAAT)2 mainly distributes on astrocytes and plays an important role on glutamate reuptake and glutamate homeostasis. Midazolam has a neuroprotective effect in some neuropathological conditions. The present study aimed to detect the role of EAAT2 in the neuroprotective effect of midazolam in neonatal rat brain subjected to H/R. Pretreatment with midazolam reversed H/R-induced apoptosis and downregulation of EAAT2 mRNA and protein expression in the hippocampus. Pretreatment with dihydrokainic acid (a selective inhibitor of EAAT2) exacerbated apoptosis, and thus inhibited the neuroprotective effect of midazolam against H/R injury. We demonstrated for the first time that dysregulation of EAAT2 expression may be related to the neural injury induced by H/R in rat pups, and pretreatment with midazolam attenuated apoptosis and improved learning and memory partly due to regulating EAAT2 expression. [ABSTRACT FROM AUTHOR]

The nuclear location of miRNAs has been known for more than a decade, but the exact function of miRNAs in the nucleus has not been fully elucidated. We previously discovered that intranuclear miR-552-3p has an inhibitory role on gene transcription and contains a particular AGGTCA-like sequence, the cis-elements of the NR1 subfamily of nuclear receptors. Here, we aim to explore the potential effect of miR-552-3p and its AGGTCA-like sequence on NR1s and its possible application in improving hepatic glycolipid metabolism. RNA-seq, mass spectrometry, and bioinformatics analysis were used to reveal the possible pathways influenced by miR-552-3p. High fat-high fructose diet-fed mice and db/db mice transfected with AAV2/8-miR-552-3p were established to investigate the in vivo effects of miR-552-3p on hepatic glycolipid metabolism. Fluorescence resonance energy transfer, pull-down, electrophoretic mobility shift, and chromatin immunoprecipitation assays were performed to explore the mechanism by which miR-552-3p regulates NR1s. RT-PCR was conducted to analyse miR-552-3p levels in liver biopsies from patients with NAFLD and normal controls. MiR-552-3p could inhibit metabolic gene expression in vitro and displayed beneficial effects on glycolipid metabolism in vivo. Intranuclear miR-552-3p primarily regulated the LXRα and FXR pathways; this was achieved by its binding to the complementary sequence of AGGTCA to modulate the transcriptional activities of LXRα and FXR. Moreover, LXRα and FXR ligands could restore the effects of miR-552-3p on gene expression and glycolipid metabolism. Additionally, the hepatic miR-552-3p level was significantly decreased in liver samples from patients with NAFLD compared to normal controls. The mechanism by which miR-552-3p modulates LXRα and FXR has revealed a new method of miRNA-mediated gene regulation. In addition, the beneficial effects in vivo and clinical relevance of miR-552-3p suggest that it might be a potential therapeutic target for the treatment of glycolipid metabolic disease. Glycolipid metabolic diseases, which have become a major public health concern worldwide, are triggered by abnormalities in lipid and glucose metabolism. Herein, we show that miR-552-3p has the ability to ameliorate hepatic glycolipid metabolic diseases by modulating the transcriptional activities of LXRα and FXR in the nucleus. These findings provide evidence that miR-552-3p may serve as a potential therapeutic target. • MiR-552-3p inhibits metabolism-related gene expression by modulating the transcriptional activities of LXRα and FXR in the nucleus. • MiR-552-3p ameliorates glycolipid metabolism disorder in mouse models. • MiR-552-3p levels are reduced in the livers of patients with NAFLD. • MiR-552-3p may serve as a potential target for treatment of glycolipid metabolic disease. [ABSTRACT FROM AUTHOR]

Aims Critically ill old patients sometimes require repeated surgical interventions, and thus it is important to determine the influence of repeated exposure to anesthetics on learning and memory. Sevoflurane, a widely used inhalation anesthetic, has few neurological adverse effects and offers a rapid return to consciousness. But the long-term influence of sevoflurane exposure and the effect of repeated sevoflurane exposure on cognition have rarely been reported, and available studies are contradictory. Materials and methods In the present study, the Morris water maze test was employed to investigate the long-term influence of single (4 h) or repeated (2 h daily for 5 consecutive days) exposure to 1.5% or 2.5% sevoflurane on the learning ability and memory of old (16–18 months old) male rats. Testing was performed from 1 day to 4 weeks after the last exposure. In the hippocampus, brain derived neurotrophic factor (BDNF), NF-κB mRNA, and apoptosis rate were also examined to determine whether cellular biochemical changes related to cognition and memory occurred after single or repeated exposure to sevoflurane. Key findings Repeated exposure to 2.5% sevoflurane decreased hippocampal levels of BDNF protein, enhanced hippocampal levels of NF-κB mRNA, and increased the apoptosis rate of pyramidal cells. Single exposure to 2.5% sevoflurane, and repeated exposure to either 1.5% or 2.5% sevoflurane significantly compromised learning and memory of old male rats. Significance Repeated exposure to sevoflurane impaired the learning and memory of old male rats, an impairment that was accompanied by cognition-related biochemical changes in the hippocampus. [ABSTRACT FROM AUTHOR]

To observe the effect of dexmedetomidine (DEX) on mitochondrial apoptosis of hippocampal neurons in hypoxia/reoxygenation (H/R) brain injury in developing rats, and to investigate its regulatory mechanism on HIF-1α/p53 signaling pathway. Hypoxia/reoxygenation model was used in this study. TUNEL assay was performed to detect cell apoptosis. Immunohistochemical analysis and Western-blotting analysis were conducted to detect Cytochrome-C (Cyt-c), APAF-1, Caspase-3, Neuroglobin (Ngb), HIF-1α and p53 expression. After 28 days, Morris water maze (MWM) was performed. 50 μg/kg DEX improved H/R-induced brain injury and inhibited mitochondrial apoptosis in rats. Western-blotting and Immunohistochemical results demonstrated that DEX could up-regulate Ngb through α 2 receptor to inhibit H/R-induced mitochondrial apoptosis. In addition, by adding inhibitors yohimbine and 2-methoxyestradiol (2ME2), we found that DEX could activate HIF-1α/p53 signaling pathway. MWM test showed that DEX could enhance long-term learning and memory of H/R brain injury rats. DEX alleviates H/R-induced brain injury and mitochondrial apoptosis in developing rats through α 2 receptor, which may be related to activation of HIF-1α/p53 signaling pathway to up-regulate the expression of Ngb. [ABSTRACT FROM AUTHOR]