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[Display omitted] • BHB reduced infarct volume, increased muscle mass and muscle fiber CSA of tMCAO mice. • Delayed administration of BHB after tMCAO, when the infarct volume was stable, improved the balance beam score and time of rotarod and increased muscle mass and muscle fiber CSA. • BHB increased the total contents of H3K9bhb and enhanced the endogenous binding of H3K9bhb with FOXO3a promoter in response to the transcription inhibition of FOXO3a. • BHB promoted protein synthesis, muscle regeneration and proliferation to maintain protein metabolic homeostasis and ultimately ameliorated SRS. Stroke-related sarcopenia (SRS) is characterized by progressive systemic muscle loss and decreased function and is thought to be primarily affected by catabolic-anabolic imbalance, but there is a lack of specific treatment. Our study evaluated whether β-hydroxybutyrate (BHB) improves SRS through regulation in protein synthesis and proteolysis. BHB reduced infarct volume, increased muscle mass and muscle fiber cross-sectional area. Delayed administration of BHB, when the infarct volume was stable, improved the balance beam score and time of rotarod and the above SRS indicators. Mechanistically, BHB increased the total contents of H3K9bhb in gastrocnemius muscles of tMCAO mice and enhanced the endogenous binding of H3K9bhb with Foxo3a promoter in response to the transcription inhibition of Foxo3a. Our study indicated BHB alleviated SRS, which was partly mediated by H3K9bhb, and then inhibited FOXO3a. BHB also promoted protein synthesis, muscle regeneration and proliferation to maintain protein metabolic homeostasis and ultimately ameliorated SRS. [ABSTRACT FROM AUTHOR]

Neurocritically ill patients are more likely to be comatose and suffer from dysphagia, conditions that inevitably require nutritional support. Inappropriate nutritional support may lead to refeeding syndrome (RFS). This study aimed to explore the incidence and outcome of RFS in neurocritically ill patients. We conducted a retrospective study among neurocritically ill patients who received total enteral nutrition for >72 h in a university-affiliated hospital. RFS was defined as the occurrence of new-onset hypophosphatemia (<0.65 mmol/L) within 72 h of the commencement of nutritional support. The primary outcome was 6-month mortality. The secondary outcomes included 30-day mortality, neurocritical care unit (NCU) stay, and hospital length of stay. A total of 328 patients were enrolled, and 56 (17.1%) of them developed RFS within 72 h of nutrition support. Significantly, we found that patients with high malnutrition universal screening tool (MUST) and sequential organ failure assessment (SOFA) scores were more likely to develop RFS. The occurrence of RFS was associated with a longer NCU stay, higher 30-day mortality and 6-month mortality, and poorer 6-month functional outcome. Moreover, RFS was identified as an independent risk factor for 6-month mortality. RFS is not rare in neurocritically ill patients and is more likely to occur in patients with nutritional risk and more severe conditions. RFS is an independent risk factor for 6-month mortality in neurocritically ill patients. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the meaning of immunostaining of rat hippocampus with respect to clinical manifestations, Status epilepticus(SE)severity, treatment, and prognosis of New-Onset Refractory Status Epilepticus(NORSE) patients.Methods: Consecutive patients with cryptogenic NORSE admitted to the neuro-intensive care unit (NICU) between January 2015 and October 2018 were screened, and those who had serum and cerebrospinal fluid (CSF) immunostaining were included. Subsequently, the patients were classified into positive and negative immunostain groups. Immunotherapy was initiated in patients who progressed to super-RSE (SRSE). The demographic, and clinical, and immunostaining data were collected. The prognosis was evaluated by modified Rankin scale (mRS) at discharge (short-term prognosis) and 6 months (long-term prognosis), with mRS score ≤2 defined as the favorable outcome. The clinical manifestations, treatment response, and prognosis were compared between the patients with positive and negative immunostains.Results: 4/18 patients had positive immunostaining on both CSF and serum, 8 (had positive immunostaining on serum only, while 6 had negative immunostaining on serum and CSF. Twelve (66.7 %) patients progressed to SRSE, with no difference between the positive and negative immunostaining groups (P = 1.000). 7/18 patients had a favorable outcome at discharge and 11/18 after 6 months. No significant difference on the prognosis was detected between patients with positive and negative serum/CSF immunostaining and between the patients with or without immunotherapy at discharge or 6-month follow-up (P = 0.657/P = 0.502, P = 0.445/P = 0.829, P = 0.622, P = 0.567, respectively).Conclusions: The immunostaining on serum and/or CSF from NORSE patients did not indicate the progression to SRSE and clinical outcomes. [ABSTRACT FROM AUTHOR]

Excessive inflammatory response produced after cardiac arrest and cardiopulmonary resuscitation (CA/CPR) is one of major causes of cerebral injury. High mobility group box 1 (HMGB1) is a pro-inflammatory cytokine and its role in brain injury after CA/CPR is unclear. Herein we investigated whether blocking HMGB1 signaling could ease brain injury after CA/CPR. Male Sprague–Dawley rats (n = 181) were subjected to 8-min Asphyxia CA model or Sham operation. The ELISA data revealed both resuscitated patients and animals had elevated HMGB1 level in sera, compared with the healthy volunteers or Sham operative rats, respectively ( P < 0.01). Rats successfully resuscitated from CA were then randomly treated with either membrane permeable (TAT-fused) HMGB1 binding heptamer peptide (HBHP) or Scramble peptide. Results showed that HBHP treatment markedly improved 7-day survival rate, reduced neurological deficit scores, and prevented neuronal and dendrite loss in hippocampal CA1 region. Moreover, HBHP inhibited the activation of microglia and astrocytes and downregulated the mRNA and protein expressions of proinflammatory factors. We finally blocked toll-like receptor-4 (TLR4, one of HMGB1 receptors) with a specific antagonist TAK-242 before CA induction to confirm the detrimental effect of HMGB1 signaling and found blocking TLR4 could also attenuate the neuronal degeneration, as well as reduce NF-κB-mediated inflammatory signaling. Our findings indicate that CA/CPR can induce HMGB1 release to serum, while blocking HMGB1 signaling with peptide may improve the survival and attenuate post-resuscitation brain injury in the rat model of CA/CPR. TLR4 antagonist may also offer neuroprotective effects through weakening HMGB1-mediated proinflammatory reactions. [ABSTRACT FROM AUTHOR]

• The h-CeO 2 shows great catalytic performance and long term stability. • The h-CeO 2 has great heat transfer property in the light off stage. • The h-CeO 2 has great mass transfer property in thermodynamic and homogeneous region. In this work, hollow CeO 2 microspheres were synthesized and the catalytic performance of lean-CH 4 combustion and stability were conducted. The structure property of the hollow CeO 2 microspheres was characterized for tentatively exploring the catalytic advancement of hollow CeO 2 microspheres. Further, the heat and mass transfer property of hollow CeO 2 microspheres was calculated to investigate the mechanism of reactants/products and heat transfer property on hollow structure. The hollow CeO 2 microspheres show greater catalytic performance and long term stability than the solid CeO 2. The numerical results indicate that the hollow structure could increase the heat and mass transfer property, which could improve the reaction rate in the light off stage, thermodynamic region and homogeneous reaction region of the methane combustion process. This work provides a sight for increasing the heat and mass transfer property of catalyst for heterogeneous catalysis reaction. [ABSTRACT FROM AUTHOR]

Glibenclamide (GBC), a sulfonylurea receptor 1 blocker, emerges recently as a promising neuron protectant in various neurological disorders. This study aimed to determine whether GBC improves survival and neurological outcome of status epilepticus (SE). Male Sprague-Dawley rats successfully undergoing SE for 2.5 h (n = 134) were randomly assigned to GBC or vehicle group. Rats in the GBC group received a loading dose of 10 μg/kg of GBC, followed by 1.2 μg/6 h for 3 days, while same dose of vehicle was used as control. The 28-day survival rate in the GBC group (11/23) was significantly higher than that in the vehicle group (8/36). In addition, the frequency and duration of spontaneous recurrent seizures in SE rats were profoundly reduced by GBC but not by vehicle treatment. Moreover, cognitive impairment was observed in the SE rats at day 28, which was reversed by GBC treatment. Meanwhile, cerebral edema, as well as neuronal loss, was decreased in several brain areas in the GBC group. Additionally, on the molecular basis, the subunits of sulfonylurea receptor 1/transient receptor potential M4 (SUR1-TRPM4) heterodimer were both strongly upregulated after SE but partly suppressed by GBC treatment. Furthermore, gene knockdown of Trpm4 in SE rats reduced BBB disruption and neuronal loss, similar to the inhibitory effects with GBC treatment. Taken together, GBC treatment markedly improved survival and neurologic outcomes after SE. The salutary effects of GBC were correlated to the alleviation of cerebral edema and reduction in neurological injury via down-regulation of SUR1-TRPM4 channel. [ABSTRACT FROM AUTHOR]

Background and purpose Low dose glibenclamide exhibits pleiotropic protective effects in different central nervous system diseases. Previously, we have shown that mild hypothermia enhanced the efficacy of glibenclamide in the cultured cortical neuronal cells. This study aims to evaluate the impact of mild hypothermia on the pharmacokinetics of low dose glibenclamide in rats via its cytochrome P450 2C9 (CYP2C9) metabolic pathway. Methods Male Sprague-Dawley rats were maintained at 37 °C (normothermic group) or cooled to 33 °C (hypothermic group). Glibenclamide (33 μg/kg) or diclofenac (10 mg/kg, a probe drug for assessing the activity of CYP2C9 which involves in glibenclamide and diclofenac metabolism in liver) were intravenously administered at 10 min after stabilization of temperature. Plasma samples were collected at 9 different time points. Glibenclamide and diclofenac in sera were separated by liquid chromatography and quantified with tandem mass spectrometry. Results Compared with normothermia, mild hypothermia significantly decreased the total clearance of glibenclamide (16.00 ± 4.1–6.72 ± 2.1 mL/min/kg; p < 0.01), and there was a non-significant trend in a slightly higher half-life, (1.64 ± 0.34–2.71 ± 1.7 h, p = 0.157). Area under the plasma concentration versus time curve (AUC last ) in the hypothermic group was increased (33.2 ± 11–77.8 ± 18 h ng/mL, p < 0.01). Moreover, mild hypothermia reduced the total clearance of diclofenac (10.33 ± 1.53–7.20 ± 1.66 mL/min/kg, p < 0.01), indicating that the CYP2C9 activity was compromised in reduced temperature. Conclusion Mild hypothermia reduced the total clearance of glibenclamide, probably via mediating the activity of CYP2C9. The impact of hypothermia in clinical application of glibenclamide should be considered. [ABSTRACT FROM AUTHOR]

Glibenclamide protects against ischemic injury in both preclinical and clinical studies, presumably by blocking the de novo assembled sulfonylurea receptor 1-transient receptor potential M4 (Sur1-Trpm4) channel induced by ischemia. However, glibenclamide may cause unexpected serious hypoglycemia. Here, we tested whether glimepiride, another sulfonylurea with better safety, has comparable efficacy with glibenclamide and whether gene deletion of Trpm4 (Trpm4 −/− ) exerts similar effect. Wild-type (WT) mice subjected to temporary middle cerebral artery occlusion (tMCAO) were randomized to receive glibenclamide (an initial dose of 10 μg/kg and additional doses of 1.2 μg every 8 h), three different doses of glimepiride (10 μg/kg, 100 μg/kg and 1 mg/kg) or vehicle after ischemia, while tMCAO-treated Trpm4 −/− mice were randomized to receive vehicle or glimepiride. Neurological function, infarct volume, edema formation, the integrity of blood-brain barrier and inflammatory reaction were evaluated at 24 h after ischemia. In tMCAO-treated WT mice, 10 μg/kg and 100 μg/kg glimepiride had comparable efficacy with glibenclamide in improving longa score and grip test score, reducing infarct volume, mitigating brain edema, lessening extravasation of Evans blue dye and IgG, restoring tight junction protein expression as well as suppressing inflammatory cytokines. Compared with WT mice, Trpm4 −/− mice showed less neurological deficit, smaller cerebral infarction, lighter brain edema and more integrity of blood-brain barrier. As expected, glimepiride did not provide additional neuroprotection compared with vehicle in the tMCAO-treated Trpm4 −/− mice. Glimepiride shows comparable efficacy with glibenclamide in alleviating brain injury after ischemic stroke in mice, possibly via targeting the Sur1-Trpm4 channel. • Glimepiride is safer than glibenclamide, especially in serious hypoglycemia. • Glimepiride was similar to glibenclamide in protecting against ischemic stroke. • Neurological function and blood-brain barrier were protected. • Infarct volume, cerebral edema and inflammatory reaction were lightened. • Gene deletion of Trpm4 protected against ischemic stroke. [ABSTRACT FROM AUTHOR]