Fibroblast growth factor 5 protects against spinal cord injury through activating AMPK pathway.

Excessive productions of inflammatory cytokines and free radicals are involved in spinal cord injury (SCI). Fibroblast growth factor 5 (FGF5) is associated with inflammatory response and oxidative damage, and we herein intend to determine its function in SCI. Lentivirus was instilled to overexpress or knockdown FGF5 expression in mice. Compound C or H89 2HCl were used to suppress AMP-activated protein kinase (AMPK) or protein kinase A (PKA), respectively. FGF5 level was significantly decreased during SCI. FGF5 overexpression mitigated, while FGF5 silence further facilitated inflammatory response, oxidative damage and SCI. Mechanically, FGF5 activated AMPK to attenuate SCI in a cAMP/PKA-dependent manner, while inhibiting AMPK or PKA with pharmacological methods significantly abolished the neuroprotective effects of FGF5 against SCI. More importantly, serum FGF5 level was decreased in SCI patients, and elevated serum FGF5 level often indicate better prognosis. Our study identifies FGF5 as an effective therapeutic and prognostic target for SCI.

Large Optical Asymmetry in Silver Nanoparticle Assemblies Enabled by CH-π Interaction-Mediated Chirality Transfer.

Transfer of asymmetry from the molecular system to the other distinct system requires appropriate chemical interactions. Here, we show how the CH-π interaction, one of the weakest hydrogen bonds, can be applied to transfer the asymmetry from π-conjugated chiral molecules to the assemblies of plasmonic Ag nanoparticles, where the aliphatic chains of chiral molecules and the polystyrene chains grafted on Ag nanoparticles are served as the hydrogen donor and acceptor, respectively. The optical asymmetry g-factor of the chiral assemblies of plasmonic nanoparticles is strongly dependent on the molecular weight of the polystyrene ligand, the core structure of the molecule, and the aliphatic chain length of the chiral molecule. Importantly, we explore a molecular mixing strategy to enhance the asymmetry g-factor of chiral molecular assemblies, which consequently promotes the g-factor of chiral plasmonics efficiently, reaching a high value of ∼0.05 under optimal conditions. Overall, we rationalize the chirality transfer from chiral molecules to inorganic nanoparticles, providing the guidance for structural design of chiral nanocomposites with a high g-factor.

Controlled Hierarchical Self-Assembly of Nanoparticles and Chiral Molecules into Tubular Nanocomposites.

In this work, we show how the kinetics of molecular self-assembly can be coupled with the kinetics of the colloidal self-assembly of inorganic nanoparticles, which in turn drives the formation of several distinct hierarchically assembled tubular nanocomposites with lengths over tens of micrometers. These colloidal nanoparticles primarily serve as "artificial histones," around which the as-assembled supramolecular fibrils are wound into deeply kinetically trapped single-layered nanotubes, which leads to the formation of tubular nanocomposites that are resistant to supramolecular transformation thermally. Alternatively, when these nanoparticles are aggregated prior to the event of molecular self-assembly, these as-formed nanoparticle "oligomers" would be encapsulated into the thermodynamically favored double-layer supramolecular nanotubes, which enables the non-close-packing of nanoparticles inside the nanotubes and results in the nanoparticle superlattices with an open channel. Furthermore, increasing the amounts of nanoparticles enables the assembly of nanoparticles into pseudohexagonal superlattices at the external surface in a sequential fashion, which ultimately drives the formation of triple-layered hierarchically assembled tubular nanocomposites. Importantly, the sense of helicity transfers from the supramolecular nanotubes to the pseudo nanoparticle superlattices with a chiral vector of (2, 9). Our findings represent a strategy for controlling the hierarchical assembly bridging supramolecular chemistry to the inorganic solids to realize the complexity by design.

Effects of propofol and sevoflurane on social and anxiety-related behaviours in sleep-deprived rats.

BACKGROUND: Sleep disorders can profoundly affect neurological function. We investigated changes in social and anxiety-related brain functional connectivity induced by sleep deprivation, and the potential therapeutic effects of the general anaesthetics propofol and sevoflurane in rats. METHODS: Twelve-week-old male Sprague-Dawley rats were subjected to sleep deprivation for 20 h per day (from 14:00 to 10:00 the next day) for 4 consecutive weeks. They were free from sleep deprivation for the remaining 4 h during which they received propofol (40 mg kg-1 i.p.) or sevoflurane (2% for 2 h) per day or no treatment. These cohorts were instrumented for EEG/EMG recordings on days 2, 14, and 28. Different cohorts were used for open field and three-chambered social behavioural tests, functional MRI, nuclear magnetic resonance spectroscopy, and positron emission tomography imaging 48 h after 4 weeks of sleep deprivation. RESULTS: Propofol protected against sleep deprivation-induced anxiety behaviours with more time (44.7 [8.9] s vs 24.2 [4.1] s for the sleep-deprivation controls; P<0.001) spent in the central area of the open field test and improved social preference index by 30% (all P<0.01). Compared with the sleep-deprived rats, propofol treatment enhanced overall functional connectivity by 74% (P<0.05) and overall glucose metabolism by 30% (P<0.01), and improved glutamate kinetics by 20% (P<0.05). In contrast, these effects were not found after sevoflurane treatment. CONCLUSIONS: Unlike sevoflurane, propofol reduced sleep deprivation-induced social and anxiety-related behaviours. Propofol might be superior to sevoflurane for patients with sleep disorders who receive anaesthesia, which should be studied in clinical studies.

Adenosine 2 receptor regulates autophagy and apoptosis to alleviate ischemia reperfusion injury in type 2 diabetes via IRE-1 signaling.

PURPOSE: This study aimed to determine the effect and mechanism of action of adenosine 2 receptor (A2R) activation on myocardial ischemia reperfusion injury (MIRI) under diabetic conditions. METHODS: MIRI type 2 diabetic rats and H9C2 cardiomyocytes were treated with A2R agonist and then subjected to hypoxia for 6 h and reoxygenation for 18 h. Myocardial damage, and infarct size were determined by cardiac ultrasound. Indicators of cardiomyocyte injury, creatine kinase-MB and cardiac troponin I were detected by Enzyme Linked Immunosorbent Assay. Endoplasmic reticulum stress (ERS) was determined through measuring the expression levels of ERS related genes GRP78, p-IRE1/IRE1, and p-JNKJNK. The mechanism of A2R cardio protection in MIRI through regulating ERS induced autophagy was determined by investigating the ER resident protein IRE-1. The ER-stress inducer Tunicamycin, and the IRE-1 inhibitor STF in combination with the A2R agonist NECA were used, and the cellular responses were assessed through autophagy proteins expression Beclin-1, p62, LC3 and apoptosis. RESULTS: NECA improved left ventricular function post MIRI, limited myocardial infarct size, reduced myocardial damage, decreased cardiomyocytes apoptosis, and attenuated ERS induced autophagy through regulating the IRE-XBP1s-CHOP pathway. These actions resulted into overall protection of the myocardium against MIRI. CONCLUSION: In summary, A2R activation by NECA prior to ischemia attenuates apoptosis, reduces ERS induced autophagy and restores left ventricular function. This protective effect occurs through regulating the IRE1-XBPs-CHOP related mechanisms. NECA is thus a potential target for the treatment of MIRI in patient with type 2 diabetes.

Erbin protects against sepsis-associated encephalopathy by attenuating microglia pyroptosis via IRE1α/Xbp1s-Ca2+ axis.

BACKGROUND: Microglia pyroptosis-mediated neuroinflammation is thought to be the crucial pathogenesis of sepsis-associated encephalopathy (SAE). Erbin has been reported to be associated with various inflammatory diseases. However, the role of Erbin in SAE and the relationship between Erbin and microglia pyroptosis are unknown. In this study, we investigated the promising role and underlying molecular mechanism of Erbin in the regulation of microglia pyroptosis. METHODS: WT and Erbin knockout mice underwent cecum ligation perforation (CLP) to induce SAE. Primary mouse microglia and BV2 cells were treated with LPS/nigericin in vitro. Behavioral tests were performed to evaluate cognitive function. Nissl staining and transmission electron microscopy were used to assess histological and structural lesions. ELISA and qPCR were carried out to detect neuroinflammation. Western blot and immunofluorescence were used to analyze protein expression. Flow cytometry and confocal microscopy were utilized to observe the Ca2+ changes in the cytoplasm and endoplasmic reticulum (ER). To further explore the underlying mechanism, STF083010 was administered to block the IRE1α/Xbp1s pathway. RESULTS: Erbin deletion resulted in more pronounced neuronal damage and cognitive impairment in mice that underwent CLP. Erbin knockout promoted microglial pyroptosis and inflammatory cytokines secretion in vivo and in vitro, which was mediated by activation of the IRE1α/Xbp1s. Treatment with the selective inhibitor STF083010 significantly inhibited IRE1α/Xbp1s pathway activity, decreased intracytoplasmic Ca2+, attenuated microglial pyroptosis, reduced pro-inflammatory cytokine secretion, lessened neuronal damage, and improved cognitive function. CONCLUSIONS: In SAE, Erbin inhibits IRE1/Xbp1s pathway activity and reduces the ER Ca2+ influx to the cytoplasm, reducing microglial pyroptosis.

A review on the anesthetic management of obese patients undergoing surgery.

There has been an observed increase in theprevalence of obesity over the past few decades. The prevalence of anesthesiology related complications is also observed more frequently in obese patients as compared to patients that are not obese. Due to the increased complications that accompany obesity, obese patients are now more often requiring surgical interventions. Therefore, it is important that anesthesiologists be aware of this development and is equipped to manage these patients effectively and appropriately. As a result, this review highlights the effective management of obese patients undergoing surgery focusing on the preoperative, perioperative and postoperative care of these patients.

Functional Droplets Stabilized by Interfacially Self-Assembled Chiral Nanocomposites.

Here, we show that aqueous dispersions of inorganic nanoparticles bearing negative surface charges would trigger the chiral assembly of organic radical cations solubilized in organic solvent at the liquid-liquid interface, which consequently produces stable droplets covered by a layer of inorganic/organic chiral nanocomposites. We demonstrate that chirality transfer across the liquid-liquid interface from the chiral organic monomers to the nanoparticle assemblies is realized. Surprisingly, opposite handedness between molecular assemblies and nanoparticle assemblies is determined from both CD and CPL measurements. Moreover, the functionalities of these "chiral" droplets could be further engineered through either a simple mixing or a droplet merging strategy, which enables to produce fluorescent emissive-tunable, magnetic, as well as magnetofluorescent dual-functional droplets.

Chirality Inversion in Self-Assembled Nanocomposites Directed by Curvature-Mediated Interactions.

Nanoscale curvature-dependent interactions are of paramount importance in biological systems. Here, we report that nanoscale curvature plays an important role in regulating the chirality of self-assembled nanocomposites from chiral organic molecules and achiral nanoparticles. Specifically, we show that the supramolecular chirality of the nanocomposites markedly depends on the nanoparticle curvature, where small-sized nanoparticles of high curvature and large-sized nanoparticles of low curvature lead to nanocomposites with opposite chirality. Quantitative kinetic experiments and molecular dynamics simulations reveal that nanoparticle curvature plays a key role in promoting the pre-nucleation oligomerization of chiral molecules, which consequently regulates the supramolecular chirality of the nanocomposites. We anticipate that this study will aid in rational design of an artificial cooperative system giving rise to emergent assembling phenomena that can be surprisingly rich and often cannot be understood by studying the conventional noncooperative systems.

The adenosine A2A receptor alleviates postoperative delirium-like behaviors by restoring blood cerebrospinal barrier permeability in rats.

Postoperative delirium (POD) is a common post-operative complication in elderly patients that is associated with increased morbidity and mortality. However, the neuropathogenesis of this complication remains unknown. The blood-cerebrospinal fluid barrier (BCB) and brain-blood barrier (BBB) are composed of tight junctions between cells that form physical barriers, and BBB damage plays an important role in the neuropathogenesis of POD. Nevertheless, the role of BCB in POD remains to be elucidated. Herein, we investigated the effect of adenosine A2A receptor (A2A R), a key regulator of the permeability of barriers, on surgery-induced increased permeability of BCB and POD-like behaviors. Open field, buried food, and Y maze tests were used to evaluate behavioral changes in rats after surgery. Levels of tight junction proteins, adherens junction proteins, A2A R, GTP-RhoA, and ROCK2 in the choroid plexus were assessed by western blotting. The concentrations of NaFI and FITC-dextran in the cerebrospinal fluid (CSF) were detected by fluorescence spectrophotometry. Transmission electron microscopy was applied to observe the ultrastructure of the choroid plexus. Surgery/anesthesia decreased the levels of tight junction (e.g., ZO-1, occludin, and claudin1) proteins, increased concentrations of NaFI and FITC-dextran in CSF, damaged the ultrastructure of choroid plexus, and induced POD-like behaviors in rats. An A2A R antagonist alleviated POD-like behaviors in rats. Furthermore, the A2A R antagonist increased the levels of tight junction proteins and restored the permeability of BCB in rats with POD. Fasudil, a selective Rho-associated protein kinase 2 (ROCK2) inhibitor, ameliorated POD-like behaviors induced by A2A R activation. Moreover, fasudil also abolished the increased levels of GTP-RhoA/ROCK2, decreased levels of tight junction proteins, and increased permeability of BCB caused by A2A R activation. Our findings demonstrate that A2A R might participate in regulating BCB permeability in rats with POD via the RhoA/ROCK2 signaling pathway, which suggests the potential of A2A R as a therapeutic target for POD.

Neuronal mechanisms of adenosine A2A receptors in the loss of consciousness induced by propofol general anesthesia with functional magnetic resonance imaging.

Propofol is the most common intravenous anesthetic agent for induction and maintenance of anesthesia, and has been used clinically for more than 30 years. However, the mechanism by which propofol induces loss of consciousness (LOC) remains largely unknown. The adenosine A2A receptor (A2A R) has been extensively proven to have an effect on physiological sleep. It is, therefore, important to investigate the role of A2A R in the induction of LOC using propofol. In the present study, the administration of the highly selective A2A R agonist (CGS21680) and antagonist (SCH58261) was utilized to investigate the function of A2A R under general anesthesia induced by propofol by means of animal behavior studies, resting-state magnetic resonance imaging and c-Fos immunofluorescence staining approaches. Our results show that CGS21680 significantly prolonged the duration of LOC induced by propofol, increased the c-Fos expression in nucleus accumbens (NAc) and suppressed the functional connectivity of NAc-dorsal raphe nucleus (DR) and NAc-cingulate cortex (CG). However, SCH58261 significantly shortened the duration of LOC induced by propofol, decreased the c-Fos expression in NAc, increased the c-Fos expression in DR, and elevated the functional connectivity of NAc-DR and NAc-CG. Collectively, our findings demonstrate the important roles played by A2A R in the LOC induced by propofol and suggest that the neural circuit between NAc-DR maybe controlled by A2A R in the mechanism of anesthesia induced by propofol.

Oxycodone attenuates vascular leak and lung inflammation in a clinically relevant two-hit rat model of acute lung injury.

BACKGROUND: Oxycodone is a synthetic opioid receptor agonist that exerts antinociceptive activity via κ-, µ- and δ-opioid receptors (KOR, MOR and DOR, respectively). Activation of MOR has been reported to provide protection against acute lung injury (ALI). We hypothesized that pretreatment with oxycodone would attenuate lung injury at the level of alveolar tight junctions (TJs) and aquaporins (AQPs) and investigated this possibility in a two-hit model of ALI induced by lipopolysaccharide (LPS) and mechanical ventilation (MV). METHOD: Male Sprague Dawley rats and A59 cells were divided into 6 groups: the control group, ALI group, oxycodone-pretreated group, and oxycodone/κ-, µ-, or δ-opioid receptor antagonist-pretreated groups. The rats were pretreated with oxycodone 30 min before intravenous injection of LPS and then allowed to recover for 24 h prior to MV, establishing a two-hit model of ALI. The cells were similarly treated with oxycodone (with or without antagonists) 30 min after exposure to lipopolysaccharide. The cells were cyclically stretched 24 h later to mirror the in vivo MV protocol. RESULTS: Oxycodone alleviated the histological lung changes in the rats with ALI and decreased pulmonary microvascular permeability both in vivo and in vitro. Oxycodone upregulated the expression of claudin-5, ZO-1, AQP1, and AQP5 but downregulated the expression of TNF-α, IL-1ß, TLR4, NF-κB, MMP9, and caspase-3 and suppressed endothelial apoptosis in vivo and in vitro. These protective effects of oxycodone were partly eliminated by KOR and MOR antagonists but not by DOR antagonists. CONCLUSION: Oxycodone pretreatment appears to act via κ- and µ-opioid receptors to ameliorate LPS- and MV-induced lung injury by suppressing inflammation and apoptosis, and this protective effect might be mediated through the inhibition of the TLR4/NF-κB pathways.

GTS-21 ameliorates polymicrobial sepsis-induced hepatic injury by modulating autophagy through α7nAchRs in mice.

BACKGROUND: Previous studies showed that GTS-21, a selective alpha 7 nAchR agonist, can trigger anti-inflammatory effects and improve the survival of septic animals. However, whether GTS-21 affects autophagy responses remains unclear. Here, we tested the hypothesis that GTS-21 ameliorates sepsis-induced hepatic injury by modulating autophagy in mice. METHOD: C57BL/6 male mice were randomly separated and categorized into four groups: the sham group, and CLP group subjected to caecal ligation and puncture (CLP, a model of polymicrobial sepsis). The CLP + GTS-21 group was administered GTS-21 immediately after CLP challenge. α-Bungarotoxin (an alpha 7 nAchR antagonist) was injected before CLP was performed, and then, after CLP challenge, GTS-21 was administered to α-BGT + CLP + GTS-21 group. The hepatic tissue and blood samples were harvested 6 h after the operation. RESULTS: CLP challenge increased TNF-α and IL-6 production, and hepatic enzyme alanine aminotransferase and aspartate transaminase levels. CLP also elevated the expression of hepatic LC3-II, sequestosome-1/p62, Atg7 and Atg5. The administration of GTS-21 inhibited pro-inflammatory cytokine production and hepatic enzymatic marker expression, promoted the expression of LC3-II, Atg7, Atg5, and decreased the expression of p62, which could be reversed by α-BGT treatment. CONCLUSION: Our findings suggested that α7nAchR is involved in diminishing hepatic damage by inhibiting inflammatory responses and improving autophagy in mice with polymicrobial sepsis.

Sevoflurane Induces Learning and Memory Impairment in Young Mice Through a Reduction in Neuronal Glucose Transporter 3.

Sevoflurane, which is widely used in paediatric anaesthesia, induces neural apoptosis in the developing brain and cognitive impairment in young mammals. Glucose hypometabolism is the key pathophysiological modulator of cognitive dysfunction. However, the effects and mechanism of sevoflurane on cerebral glucose metabolism after its use as an anaesthetic and its complete elimination are still unknown. We therefore investigated the influence of sevoflurane on neuronal glucose transporter isoform 3 (GLUT3) expression, glucose metabolism and apoptosis in vivo and in vitro and on neurocognitive function in young mice 24 h after the third exposure to sevoflurane. Postnatal day 14 (P14) mice and neural cells were exposed to 3% sevoflurane 2 h daily for three days. We found that sevoflurane anaesthesia decreased GLUT3 gene and protein expression in the hippocampus and temporal lobe, consistent with a decrease in glucose metabolism in the hippocampus and temporal lobe observed by [18F] fluorodeoxyglucose positron emission tomography (18F-FDG PET). Moreover, sevoflurane anaesthesia increased the number of TUNEL-positive cells and the levels of Bax, cleaved caspase 3 and cleaved PARP and reduced Bcl-2 levels in the hippocampus and temporal lobe. Young mice exposed to sevoflurane multiple times also showed learning and memory impairment. In addition, sevoflurane inhibited GLUT3 expression in primary hippocampal neurons and PC12 cells. GLUT3 overexpression in cultured neurons ameliorated the sevoflurane-induced decrease in glucose utilization and increase in the apoptosis rate. These data indicate that GLUT3 deficiency may contribute to sevoflurane-induced learning and memory deficits in young mice.

Methylene Blue Protects Against Sevoflurane-Induced Cognitive Dysfunction by Suppressing Drp1 deSUMOylation in Aged Mice.

Exposure to sevoflurane and other inhalational anesthetics can induce cognitive impairment in elderly patients. Studies have indicated that methylene blue (MB) has beneficial effects on multiple neurodegenerative diseases and the mechanism involves mitochondrial function preservation. However, whether MB can attenuate the cognitive decline induced by sevoflurane in aged mice requires further investigation. Forty-five 18-month-old C57/BL mice were used to establish a model of sevoflurane-induced cognitive impairment in which the mice were exposed to 3% sevoflurane for 2 h. Mice in the MB group were intraperitoneally injected with MB at a dose of 5 mg/kg before sevoflurane inhalation. The Morris water maze test was used to evaluate the learning and memory performances. We also examined changes in mitochondrial morphology as well as the expression and interaction of related proteins in the aged hippocampus. Parkin, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), mitochondrial dynamin-related protein 1 (Drp1), small ubiquitin-like modifier (SUMO2/3), SUMO-specific proteases 3 (SENP3), and ubiquitin-like conjugating enzyme 9 expression in the mouse hippocampus was detected by western blotting, and SUMO2/3-Drp1 was examined by coimmunoprecipitation. Exposure to sevoflurane increased SENP3 expression and Drp1 deSUMOylation in the aged hippocampus and resulted in cognitive deficiency. MB attenuated sevoflurane-induced memory loss and mitochondrial fragmentation and decreased Drp1 deSUMOylation in the aged hippocampus. This neuroprotective effect provides a mechanistic explanation for how the SUMOylation status of Drp1 acts as a key switch in the cognitive dysfunction induced by sevoflurane.

Pyruvate Protects Against Intestinal Injury by Inhibiting the JAK/STAT Signaling Pathway in Rats With Hemorrhagic Shock.

BACKGROUND: This study aimed to investigate the role of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway in protection by peritoneal resuscitation (PR) using pyruvate-peritoneal dialysis solution (PY-PDS) against intestinal injury from hemorrhagic shock (HS) in rats. MATERIALS AND METHODS: Sixty-four rats were assigned to eight groups: group SHAM; group intravenous resuscitation (VR); groups NS, LA, and PY in which the rats were subjected to HS and PR with normal saline (NS), lactate-peritoneal dialysis solution (LA-PDS), and PY-PDS, respectively, combined with VR; and groups DMSO, RPM, and AG490 in which the rats were subjected to HS and VR with pretreatment of dimethyl sulfoxide (DMSO), rapamycin (RPM), and tyrphostin B42 (AG490). RESULTS: At 2 h after HS and resuscitation, the levels of diamine oxidase, 15-F2t-isoprostane, thromboxane B2, and endothelin-1, in the blood and the intestinal mucosal apoptotic index and caspase-3 were lower in groups PY, RPM, and AG490 than in groups VR, NS, LA, and DMSO. Group PY showed lower levels of malondialdehyde and myeloperoxidase and a higher level of superoxide dismutase than groups VR, NS, and LA. Phosphorylated JAK2 and phosphorylated STAT3 levels were lower in groups PY, RPM, AG490, and LA than in groups VR, NS, and DMSO. CONCLUSIONS: The protection mechanism of PR with PY-PDS combined with VR was related to the inhibition of the JAK/STAT signaling pathway during HS and resuscitation. The process might include suppression of oxidative stress, reduction of neutrophil infiltration, regulation of microcirculation, and inhibition of apoptosis.

MicroRNA-181b-5p attenuates early postoperative cognitive dysfunction by suppressing hippocampal neuroinflammation in mice.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after surgery and its occurrence is associated with increased morbidity and mortality. However, the pathophysiology of this complication remains largely unknown. Efforts to identify causes of POCD have focused on the hippocampal neuroinflammation. Recently, accumulated evidence indicates that NeurimmiRs, a subset of microRNAs (miRNAs), which modulate both neuronal and immune processes, play an important role in neuroinflammation. However, the impact of NeurimmiRs on POCD has not been investigated. We hypothesized that NeurimmiRs is involved in surgery-induced cognitive impairment in adult mice via mediating hippocampal neuroinflammation. METHODS: MicroRNA(miR)-181b-5p was found to be downregulated in the hippocampi of mice with POCD using microRNA array, which was also verified in vivo in the mouse model of POCD by Quantitative real-time polymerase chain reaction (qPCR). Subsequently, the expression of miR-181b-5p was measured in lipopolysaccharide (LPS) stimulated BV-2 microglial cells and hippocampal tissues of the mice with POCD. Then, loss of function and overexpression studies were performed by transfection with miR-181b-5p mimic/ inhibitor in cultured BV-2 cell lines and intrahippocampal injection of miR-181b-5p agomir before Surgery/Anesthesia, to identify the role of miR-181b-5p in neuroinflammation and cognitive impairments. QPCR, western blot and ELISA were used to determine the expression of proinflammatory mediators. Immunofluorescence staining was applied to evaluate the activation of microglia. Furthermore, we used bioinformatics analysis and dual-luciferase assay to predict and verify the potential target of miR-181b-5p. RESULTS: The results indicated that miR-181b-5p mimic could repress the mRNA and protein expression of proinflammatory mediators, including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and monocyte chemoattractant protein (MCP)-1 in LPS-stimulated BV-2 microglial cells, while the miR-181b-5p inhibitor induced upregulation of the above-mentioned proinflammatory factors. Further bioinformatics analysis showed that miR-181b-5p was predicted to potentially target the 3'-untranslated region (UTR) of TNF-α, and binding sites of miR-181b-5p in the 3'-UTR of TNF-α were identified by dual-luciferase assay. Importantly, injecting miR-181b-5p agomir into the hippocampus of mice before surgery, ameliorated the hippocampus-dependent memory, and was accompanied by downregulation of proinflammatory factors expression and reduced microglial activation in the hippocampus of POCD mice. CONCLUSIONS: Collectively, these findings suggest that miR-181b-5p attenuates early POCD by suppressing hippocampal neuroinflammation in mice. They also highlight the importance of studying miRNAs in the context of POCD and identify miR-181b-5p as a novel potential therapeutic target for improving POCD.

MicroRNA-146a protects against cognitive decline induced by surgical trauma by suppressing hippocampal neuroinflammation in mice.

Postoperative cognitive dysfunction (POCD) is a common postoperative complication that is associated with increased morbidity and mortality. However, the neuropathogenesis of this complication remains largely unknown. Neuroinflammation, in particular hippocampal inflammation, contributes to POCD. Recently, increasing evidence has supported the involvement of microRNAs (miRNAs) in the regulation of neuroinflammation in human neurological disorders. In the present study, we investigated the role of miR-146a, a key regulator of the innate immune response, in surgery-induced hippocampal inflammation and cognitive impairment. The expression of miR-146a was measured in BV-2 microglial cells stimulated with lipopolysaccharide (LPS) and hippocampal tissues of mice with POCD. Loss of function and overexpression studies were performed via transfection with miR-146a mimic/inhibitor in cultured BV-2 cell lines and intrahippocampal injection of miR-146a agomir/antagomir before surgery/anesthesia to identify the role of miR-146a in neuroinflammation and cognitive impairment. QPCR, Western blot and ELISA were used to determine the expression levels of downstream adaptor proteins and proinflammatory cytokines. Immunofluorescence staining was applied to evaluate the activation of microglia. Increased expression of miR-146a was observed in BV-2 microglial cells stimulated with LPS and hippocampal tissues of mice with POCD. Modulation of miR-146a expression via transfection of microglia with miR-146a mimic or inhibitor regulated the mRNA and protein expression levels of downstream targets of miR-146a (IRAK1 and TRAF6) as well as the release of proinflammatory cytokines (TNF-α, IL-1ß and IL-6). In addition, overexpression of miR-146a attenuated hippocampus-dependent learning and memory impairment in mice with POCD, which was accompanied by decreased expression of the IRAK1/TRAF6/nuclear factor (NF)-κB pathway and downregulation of microglial activation in the hippocampus. Conversely, knockdown of miR-146a expression may exacerbate hippocampus-dependent learning and memory deficiency and hippocampal inflammation in mice with POCD. Collectively, our findings demonstrate the important role of miR-146a in the neuropathogenesis of POCD and suggest that miR-146a may be a potential therapeutic target for POCD.

A detection of benzimidazole resistance-associated SNPs in the isotype-1 ß-tubulin gene in Haemonchus contortus from wild blue sheep (Pseudois nayaur) sympatric with sheep in Helan Mountains, China.

BACKGROUND: Benzimidazole (BZ) resistance is an increasingly serious problem due to the excessive use of this anthelmintic for controlling Haemonchus contortus, which is one of the major gastrointestinal nematodes infecting small ruminants worldwide. Three known single nucleotide polymorphisms (SNPs), F167Y (TAC), E198A (GCA) and F200Y (TAC), in the isotype-1 ß-tubulin gene of H. contortus are associated with BZ resistance. Comprehending the spread and origins of BZ resistance-associated SNPs has important implications for the control of this nematode. RESULTS: Twenty-seven adult H. contortus were harvested from wild blue sheep (Pseudois nayaur), small wild ruminants sympatric with domestic ruminants, inhabiting the Helan Mountains, China, to monitor the status of BZ resistance. In addition, 20 adult H. contortus from domestic sheep sympatric with this wild ruminant and 36 isotype-1 ß-tubulin haplotype sequences of H. contortus (two of these haplotypes, E198A3 and E198A4, possessed resistance-associated SNP E198A (GCA) from domestic ruminants in eight other geographical regions of China were used to further define the origins of BZ resistance-associated SNPs within the worms collected from blue sheep. The BZ resistance-associated SNP E198A was detected, whereas SNPs F167Y (TAC) and F200Y (TAC) were not found within the worms collected from blue sheep, and the frequency of homozygous resistant E198A (GCA) was 7.40%. The evolutionary tree and network showed consistent topologies for which there was no obvious boundary among the worms from the wild and domestic hosts, and two haplotypes (E198A1 and E198A2) possessing E198A from the wild blue sheep had two different independent origins. E198A1 had the same origin with E198A3 but E198A2 had a different origin with them. Population genetic analyses revealed a low level of Fst values (ranging from 0 to 0.19749) between all H. contortus worm groups in China. CONCLUSIONS: Results of the current study of the three BZ resistance-associated SNPs of H. contortus from wild blue sheep suggested that only E198A (GCA) was present within the worms collected from the wild ruminants and had multiple independent origins.

A comparison of effects of scalp nerve block and local anesthetic infiltration on inflammatory response, hemodynamic response, and postoperative pain in patients undergoing craniotomy for cerebral aneurysms: a randomized controlled trial.

BACKGROUND: The purpose of this study was to compare the effects of scalp nerve block (SNB) and local anesthetic infiltration (LA) with 0.75% ropivacaine on postoperative inflammatory response, intraoperative hemodynamic response, and postoperative pain control in patients undergoing craniotomy. METHODS: Fifty-seven patients were admitted for elective craniotomy for surgical clipping of a cerebral aneurysm. They were randomly divided into three groups: Group S (SNB with 15 mL of 0.75% ropivacaine), group I (LA with 15 mL of 0.75% ropivacaine) and group C (that only received routine intravenous analgesia). Pro-inflammatory cytokine levels in plasma for 72 h postoperatively, hemodynamic response to skin incision, and postoperative pain intensity were measured. RESULTS: The SNB with 0.75% ropivacaine not only decreased IL-6 levels in plasma 6 h after craniotomy but also decreased plasma CRP levels and increased plasma IL-10 levels 12 and 24 h after surgery compared to LA and routine analgesia. There were significant increases in mean arterial pressure 2 and 5 mins after the incision and during dura opening in Groups I and C compared with Group S. Group S had lower postoperative pain intensity, longer duration before the first dose of oxycodone, less consumption of oxycodone and lower incidence of PONV through 48 h postoperatively than Groups I and C. CONCLUSION: Preoperative SNB attenuated inflammatory response to craniotomy for cerebral aneurysms, blunted the hemodynamic response to scalp incision, and controlled postoperative pain better than LA or routine analgesia. TRIAL REGISTRATION: Clinicaltrials.gov NCT03073889 (PI:Xi Yang; date of registration:08/03/2017).