Bioinformatics-driven identification and validation of diagnostic biomarkers for cerebral ischemia reperfusion injury.

Objective: This article aims to identify genetic features associated with immune cell infiltration in cerebral ischemia-reperfusion injury (CIRI) development through bioinformatics, with the goal of discovering diagnostic biomarkers and potential therapeutic targets. Methods: We obtained two datasets from the Gene Expression Omnibus (GEO) database to identify immune-related differentially expressed genes (IRDEGs). These genes' functions were analyzed via Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Tools such as CIBERSORT and ssGSEA assessed immune cell infiltration. The Starbase and miRDB databases predicted miRNAs interacting with hub genes, and Cytoscape software mapped mRNA-miRNA interaction networks. The ENCORI database was employed to predict RNA binding proteins interacting with hub genes. Key genes were identified using a random forest algorithm and constructing a Support Vector Machine (SVM) model. LASSO regression analysis constructed a diagnostic model for hub genes to determine their diagnostic value, and PCR analysis validated their expression in cerebral ischemia-reperfusion. Results: We identified 10 IRDEGs (C1qa, Ccl4, Cd74, Cd8a, Cxcl10, Gmfg, Grp, Lgals3bp, Timp1, Vim). The random forest algorithm, and SVM model intersection revealed three key genes (Ccl4, Gmfg, C1qa) as diagnostic biomarkers for CIRI. LASSO regression analysis, further refined this to two key genes (Ccl4 and C1qa), With ROC curve, analysis confirming their diagnostic efficacy (C1qa AUC = 0.75, Ccl4 AUC = 0.939). PCR analysis corroborated these findings. Conclusions: Our study elucidates immune and metabolic response mechanisms in CIRI, identifying two immune-related genes as key biomarkers and potential therapeutic targets in response to cerebral ischemia-reperfusion injury.

Proteomic analysis of Biliverdin protected cerebral ischemia-reperfusion injury in rats.

Biliverdin, a heme metabolite, has been previously reported to alleviate cerebral ischemic reperfusion injury (CIRI). However, the alterations of brain proteome profiles underlying this treatment remain elusive. The objective of this study is to analyze the differential protein expression profile in cerebral cortex of rats involved in anti-CIRI effects of Biliverdin, providing experimental foundation for searching specific marker proteins. Rat model of MCAO/R was established, HE staining, TTC staining, TUNEL staining, and neurological behavioral examination, corner turning test, adhesive removal test, were performed to validate the effects of Biliverdin, and the results indicated that Biliverdin plays a significant role in alleviating CIRI. Furthermore, proteomic analysis of brain tissues of rats subjected to CIRI following Biliverdin treatment was performed using an integrated TMT-based quantitative proteomic approach coupled with LC-MS/MS technology to clarify the comprehensive mechanisms of Biliverdin in CIRI. First, we conducted strict quality control data for TMT experiments. Finally, a total of 7366 proteins were identified, of which 95 proteins were differentially expressed (DEPs) between the CIRI group and the Sham group and 52 between the CIRI and BV groups. In addition, two overlapping proteins among the 147 DEPs, Atg4c and Camlg, were validated by RT-qPCR and western blotting, and their levels were consistent with the results of TMT analysis. Taken together, the current findings firstly mapped comprehensive proteomic changes after CIRI treated with Biliverdin, providing a foundation for developing potentially therapeutic targets of anti-CIRI of Biliverdin and clinically prognostic biomarkers of stroke.

Direct Synthesis of Elastic and Stretchable Hierarchical Structured Fiber and Graphene-Based Sponges for Noise Reduction.

Noise pollution, as one of the three major pollutants in the world, has become a great burden on people's health and the global economy. Most present noise absorbers suffer large weight and inevitable compromise between good low-frequency (usually <1000 Hz) and high-frequency (typically >1000 Hz) noise reduction performance. This study presents a scalable strategy to directly synthesize ultrafine fiber sponges with ultrathin graphene-based vibrators by the synchronous occurrence of humidity-assisted electrospinning and electrospraying. The unique physical entanglements between reduced graphene oxide (rGO) nanosheets and ultrafine fibers endow hierarchical vibration structured fiber sponges (VSFSs) with excellent mechanical properties, which could withstand large shear strain (60%) and tensile stress (6000 times its weight) without damage and almost have no plastic deformation after 1000 compressions. Attribute to the vibration effect of ultrathin graphene-based vibrators and the viscous friction effect of porous fiber networks, the VSFSs achieve both good low-frequency (absorption coefficient of 0.98 in 680 Hz) and high-frequency sound absorption (absorption coefficients above 0.8 in 2000-6300 Hz) simultaneously. Furthermore, the noise reduction coefficient (NRC) of lightweight VSFSs (thickness of 30 mm) reaches 0.63, which could reduce high decibel noise by 24.4 dB, providing potential solutions for developing ideal noise-absorbing materials.

Biliverdin modulates the Nrf2/A20/eEF1A2 axis to alleviate cerebral ischemia-reperfusion injury by inhibiting pyroptosis.

This study aimed to examine whether Biliverdin, which is a common metabolite of haem, can alleviate cerebral ischemia reperfusion injury (CIRI) by inhibiting pyroptosis. Here, CIRI was induced by middle cerebral artery occlusion-reperfusion (MCAO/R) in C57BL/6 J mice and modelled by oxygen and glucose deprivation/reoxygenation (OGD/R) in HT22 cells, it was treated with or without Biliverdin. The spatiotemporal expression of GSDMD-N and infarction volumes were assessed by immunofluorescence staining and triphenyltetrazolium chloride (TTC), respectively. The NLRP3/Caspase-1/GSDMD pathway, which is central to the pyroptosis process, as well as the expression of Nrf2, A20, and eEF1A2 were determined by Western-blots. Nrf2, A20, and eEF1A2 interactions were verified using dual-luciferase reporter assays, chromatin immunoprecipitation, or co-immunoprecipitation. Additionally, the role of Nrf2/A20/eEF1A2 axis in modulating the neuroprotective properties of Biliverdin was investigated using A20 or eEF1A2 gene interference (overexpression and/or silencing). 40 mg/kg of Biliverdin could significantly alleviate CIRI both in vivo and in vitro, promoted the activation of Nrf2, elevated A20 expression, but decreased eEF1A2 expression. Nrf2 can bind to the promoter of A20, thereby transcriptionally regulating the expression of A20. A20 can furthermore interacted with eEF1A2 through its ZnF4 domain to ubiquitinate and degrade it, leading to the downregulation of eEF1A2. Our studies have also demonstrated that either the knock-down of A20 or over-expression of eEF1A2 blunted the protective effect of Biliverdin. Rescue experiments further confirmed that Biliverdin could regulate the NF-κB pathway via the Nrf2/A20/eEF1A2 axis. In summary, our study demonstrates that Biliverdin ameliorates CIRI by inhibiting the NF-κB pathway via the Nrf2/A20/eEF1A2 axis. Our findings can help identify novel therapeutic targets for the treatment of CIRI.

Effects of Subchronic Propofol Administration on the Proliferation and Differentiation of Neural Stem Cells in Rat Hippocampus.

Background: Although controversial, experimental data suggest the use of propofol may be associated with neurotoxicity. The mechanisms responsible for propofol neurotoxicity in animals are not yet clear. Objective: This study aimed to determine the effects of propofol on the proliferation of neural stem cells in rat hippocampus and the mechanisms underlying these effects. Methods: Forty-five adult male Sprague-Dawley rats were randomly divided into 5 groups: Control (N group), intralipid (V group), 30 mg/kg propofol (Prop30 group), 60 mg/kg propofol (Prop60 group), and 120 mg/kg propofol (Prop120 group). The rats in all groups received 5, once daily intraperitoneal injections. For each of the 5 days, the N group received 6 mL/kg normal saline, the V group received 6 mL/kg fat emulsion, the Prop30 group received 30 mg/kg propofol, the Prop60 group received 60 mg/kg propofol, and the Prop120 group received 120 mg/kg propofol. Memory function was scored daily using the Morris water maze test. Immunofluorescence staining was used to histologically monitor the proliferation and differentiation of the rats' hippocampal neural stem cells, and real time quantitative polymerase chain reaction and Western blotting were used to determine the expression of Notch3, Hes1, and Hes5. Results: Compared with the N group, the Prop120 group exhibited reduced learning and memory, whereas there were no significant differences for the Prop60 group. The number of ß-tubulin III+ cells increased in the Prop60 group, but decreased in the Prop120 group. Compared with the N group, the relative expression of Notch3 and Hes5 increased significantly in the Prop60 group, whereas this expression decreased in the Prop120 group. Conclusions: These data demonstrate that repeated, subchronic (5 days) intraperitoneal injections of 60 mg/kg propofol can effectively promote rat hippocampal neural stem cells proliferation and differentiation, and that this is likely mediated by its effects on the Notch3-Hes5 pathway.

Biliverdin modulates the long non-coding RNA H19/microRNA-181b-5p/endothelial cell specific molecule 1 axis to alleviate cerebral ischemia reperfusion injury.

Injuries caused by cerebral ischemia reperfusion (CIR) can worsen neurological outcomes, Biliverdin (BV) is an antioxidant and anti-apoptotic agent that was shown to affect CIR, although the underlying mechanisms remain unclear. In this study, we investigated the role of BV and its potential underlying mechanism in CIR injury. CIR rat models and primary cortical neurons were established and treated with and without BV. Additionally, adenovirus vectors that could overexpress LncRNA H19 and overexpress or knock-down miR-181b-5p and Esm1 were created to investigate their regulation of molecular expression. Our findings showed that BV could significantly improve CIR injury, both in vivo and in vitro, decrease LncRNA H19 and Esm1 expression, and increase miR-181b-5p expression. Overexpression of LncRNA H19 inhibited the anti-injury effects of BV. Further, the down-regulation of miR-181b-5p or up-regulation of Esm1 expression weakened the in vitro protective effect of BV. RNA immunoprecipitation assay and dual luciferase reporter gene assay further confirmed that LncRNA H19 could sponge miR-181b-5p, and Esm1 was the target of miR-181b-5p. Rescue experiments confirmed that BV could regulate the LncRNA H19/miR-181b-5p/Esm1 molecular axis. Lastly, proteomic and bioinformatic analyzes revealed that Esm1 upregulation in BV-treated neurons resulted in the differential expression of 16 proteins, including 9 upregulated and 7 downregulated proteins. In conclusion, this study found that BV could ameliorate CIR injury by regulating the LncRNA H19/miR-181b-5p/Esm1 axis.

Bubble Templated Flexible Ceramic Nanofiber Aerogels with Cascaded Resonant Cavities for High-Temperature Noise Absorption.

Aviation noise pollution has become a significant public health problem, especially with the endless improvement of flight speed and loading capacity. Existing aviation noise absorbers have fatal defects of large weight, weak high-temperature stability, and difficulty to achieve both good low-frequency (<1000 Hz) and high-frequency (up to 6000 Hz) noise absorption simultaneously. Herein, we report a robust strategy to create flexible ceramic nanofiber aerogels with cascaded resonant cavities by the air bubbles-assisted freeze-casting technology. The stable hinged resonance cavity structures coassembled by flexible ceramic nanofibers, soft montmorillonite nanosheets, and silica sol glue endow the aerogels with temperature-invariant compressibility (from -196 to 1100 °C) and bendability. Moreover, the comprehensive advantages of cascaded resonance cavities and interconnected fibrous networks enable flexible ceramic nanofiber aerogels to have temperature-invariant full-frequency noise absorption performance (noise reduction coefficient up to 0.66 in 63-6300 Hz). The synthesis of this flexible ceramic nanofiber aerogel provides a versatile platform for the design of high-efficiency noise-absorbing material for various fields.

Advances in the Study of the Ubiquitin-Editing Enzyme A20.

Ubiquitin modification is a common post-translational protein modification and an important mechanism whereby the body regulates protein levels and functions. As a common enzyme associated with ubiquitin modification, the ubiquitin-editing enzyme A20 may be closely associated with the development of numerous pathological processes through its different structural domains. The aim of this paper is to provide an overview of the following: advances in ubiquitination research, the structure and function of A20, and the relationships between A20 and immune inflammatory response, apoptosis, necroptosis, pyroptosis, and autophagy.

Exploration in the Therapeutic and Multi-Target Mechanism of Ketamine on Cerebral Ischemia Based on Network Pharmacology and Molecular Docking.

Background: Ketamine is famous for its dissociative anesthetic properties. It is also analgesic, anti-inflammatory and anti-depressant, and even has a cerebral protective effect. We searched the evidence of the correlation between ketamine target and clinical efficacy and utilized network pharmacology to gather information about the multi-target mechanism of ketamine against cerebral ischemia (CI). We found that ketamine's clinical significance may be more extensive than previously thought. Methods: The drug target of ketamine and CI-related genes were predicted by SwissTargetPrediction, DrugBank, PubChem, GeneCards and DisGeNET databases. The intersection of ketamine's drug-targets and CI-related genes was analyzed by using GO and KEGG. We predicted the molecular docking between the potential target and ketamine. Results: The results indicated that the effect of ketamine on CI was primarily associated with the target of α-synuclein (SNCA), muscarinic acetylcholine receptor M1 (CHRM1) and nitric oxide synthase 1 (NOS1). It principally regulates the signal pathways of circadian transmission, calcium signaling pathway, dopaminergic synapse, cholinergic synapse and glutamatergic synapse. Molecular docking analysis exhibited that hydrogen bond and Pi-Pi interaction were the predominant modes of interaction. Conclusion: There are protein targets affected by ketamine in the treatment of CI. Three pivotal targets involving 298 proteins, SNCA, CHRM1 and NOS1, have emerged as multi-target mechanisms for ketamine in CI therapy. Similarly, this study also provides a new idea for introducing network pharmacology into the evaluation of multi-targeted drugs for CI and cerebral protection.

Biliverdin Protects Against Cerebral Ischemia/Reperfusion Injury by Regulating the miR-27a-3p/Rgs1 Axis.

BACKGROUND: We have previously demonstrated that biliverdin has neuroprotective effects that ameliorate cerebral ischemia/reperfusion (I/R) injury in rats. However, the underlying mechanism is unknown. This study aimed at elucidating on the modulatory role of miR-27a-3p on Rgs1 as a mechanism by which biliverdin affects cerebral I/R injury. METHODS: Middle cerebral artery occlusion/reperfusion (MCAO/R) was used to establish I/R rat models while oxygen glucose deprivation/reoxygenation (OGD/R) was used to induce hippocampal neurons to establish I/R models in vitro. Infarct volume was assessed by TTC staining. Apoptotic analyses of ischemic cortical neurons and cells were performed by TUNEL staining and flow cytometry, respectively. Cell viability was assessed by the CCK-8 assay while the target of miR-27a-3p was determined by double luciferase reporter assay. Relative expression levels of miR-27a-3p and Rgs1 (in vivo and in vitro) as well as markers of inflammation and apoptosis (in vitro) were detected by RT-qPCR. Then, Elisa and western blot were used to assess protein expression levels of inflammatory and apoptotic markers in vitro. RESULTS: Biliverdin suppressed inflammation and apoptosis in hippocampal neurons upon OGD/R, and reduced cerebral infarction volume as well as apoptosis in the MCAO/R rat model. Furthermore, biliverdin upregulated miR-27a-3p and downregulated hippocampal neuron Rgs1 after OGD/R as well as in rat brain tissues after cerebral I/R. Bioinformatic analysis revealed an miR-27a-3p docking site in the 3'-UTR region of Rgs1. Luciferase reporter assays showed that Rgs1 is an miR-27a-3p target. Moreover, miR-27a-3p upregulation inhibited OGD/R-triggered inflammation and suppressed neuronal apoptosis. Rgs1 knockdown suppressed OGD/R-triggered inflammation and decreased neuronal apoptosis while miR-27a-3p downregulation reversed the protective effect of Rgs1 knockdown. Moreover, miR-27a-3p overexpression and Rgs1 silencing suppressed NF-κB (p65) expression. CONCLUSION: Biliverdin protects against cerebral I/R injury by regulating the miR-27a-3p/Rgs1 axis, thereby inhibiting inflammation and apoptosis.

Pulmonary protection of transcutaneous electrical acupoint stimulation in gynecological laparoscopic surgery: A randomized controlled trial.

Laparoscopy is performed worldwide due to its limited side effects and optimal treatment efficacy. However, it also has adverse effects, including atelectasis and ischemia-reperfusion injury, due to CO2 accumulation during ventilation in a head-down position, which may result in severe disorders and adversely affecting postoperative recovery, prolonging hospitalization. The present study was performed to assess whether transcutaneous electrical acupoint stimulation (TEAS) protects against lung injury occurring during gynecological laparoscopic surgery. Patients were randomly allocated to two groups: Control group (received no stimulation) and TEAS group (patients treated with TEAS on BL13, LI4 and LU5). The mean arterial pressure, heart rate and oxygen saturation were recorded at the time-points of arriving in the operating room (T0), immediately prior to induction of the pneumoperitoneum (T1), immediately after the end of pneumoperitoneum (T2) and on leaving the operating room (T3). Arterial blood gas analysis was performed to record the pH, determine the partial pressure of carbon dioxide and calculate the oxygenation index (OI) at T0-3. Blood samples were taken from the peripheral vein for determination of the serum concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß at T0 and T3. Post-operative pulmonary complications occurring during the first five days after surgery were also recorded. A total of 100 patients were initially enrolled and 80 patients were analysed. The results indicated that the OI in the control group was significantly lower than that in the TEAS group at the T2 and T3 time-points. The serum concentrations of TNF-α and IL-1ß were significantly increased following surgery, while the extent of these increases was lower in the TEAS group compared with that in the control group. The incidence of post-operative pulmonary complications was significantly lower in the TEAS group. It was therefore indicated that TEAS protect against lung injury as a complication of gynecological laparoscopic surgery. The present study was registered at http://www.clinicaltrials.gov prior to enrollment of the patients (no. NCT02850471).

Use of pre-operative anxiety score to determine the precise dose of butorphanol for intra-operative sedation under regional anesthesia: A double-blinded randomized trial.

A randomized double-blinded controlled trial was performed to explore the association between pre-operative anxiety and intra-operative butorphanol requirement to evaluate the precise sedative requirement and to confirm the sedative effect of butorphanol in patients receiving lower-limb orthopedic surgery. The Amsterdam pre-operative anxiety and information scale and the Ramsay sedation score (RSS) were used to assess the patients' pre-operative anxiety score and sedation state during surgery. Patients were divided into two groups according to their pre-operative anxiety score prior to administration of pre-medication. Patients in each group were randomly divided into a butorphanol group and a 0.9% saline group. A total of 142 patients were enrolled and 131 patients were analyzed. The sedation scores of patients with high pre-operative anxiety in the 0.9% saline group were lower than those in the butorphanol group at each time-point after infusion. An increased pre-operative anxiety score predicted an increased duration to reach an RSS of 4 for an acceptable level of sedation (r2=0.887, P<0.0001). In conclusion, butorphanol had a good sedative effect on patients with pre-operative anxiety. The following formula was proposed: Precise dose of butorphanol (µg/kg)=15.26 + (0.14× pre-operative anxiety score), which may provide an improvement for patients exhibiting a high level of pre-operative anxiety. The trial was registered prior to patient enrollment at clinicaltrials.gov on 20.01.2018 (trial registration no. NCT03429179).

Effect of physical exercise on young anesthesiologists with on-call-related fatigue.

To explore whether exercise can effectively relieve the fatigue state of overnight shift anesthesiologists with chronic fatigue. 78 anesthesiologists between 30 and 40 years of age at four hospitals in China were analyzed in the investigation. The Profile of Mood States (POMS) and Chalder Fatigue Scale (CFS) were used to assess psychological symptoms and fatigue respectively, and data regarding demographics, health, exercise and work-related variables were also collected. The total and physical fatigue score were highest among those who seldom do exercise compared to those who always do exercise (p < .05, respectively). Moreover, anesthesiologists who exercised 30-60 min everyday had the lowest total and physical fatigue score. When exercise for more than 60 min, the total and physical fatigue scores then increased. After completing a night shift, the post-on-call total Profile of Mood States scores of those who seldom do exercise was significantly increased (t = -4.9, p < .001). These study findings suggested that regular exercise 30-60 min everyday could effectively reduce anesthesiologists' physical fatigue and decrease their negative psychological state, and anesthesiologists should positively adjust working and exercise time.

Effects of Transcutaneous Electrical Acupoint Stimulation on the Stress Response During Extubation After General Anesthesia in Elderly Patients Undergoing Elective Supratentorial Craniotomy: A Prospective Randomized Controlled Trial.

BACKGROUND: Elderly patients have an increased risk of a stress response during extubation after general anesthesia. In this study, we aimed to investigate whether transcutaneous electrical acupoint stimulation (TEAS) might decrease the stress response and improve the quality of recovery in elderly patients after elective supratentorial craniotomy. MATERIALS AND METHODS: In this prospective randomized controlled study, patients were randomly assigned to either a TEAS group (n=37) or a control group (n=38). The primary outcomes were the hemodynamic parameters and plasma concentrations of epinephrine, norepinephrine, and cortisol. The secondary outcome included the consumption of remifentanil and propofol, time to extubation and reorientation, extubation quality score, postoperative quality of recovery, and postoperative complications. RESULTS: Compared with the control group, hemodynamic parameters and plasma concentrations of epinephrine, norepinephrine, and cortisol during extubation were decreased in the TEAS group. TEAS reduced the consumption of remifentanil (P<0.01), as well as incidence of postoperative complications. The extubation quality score was lower (P<0.01) and the quality of recovery score was higher (P<0.01) in the TEAS group than in the control group. However, the time to extubation and reorientation, and the consumption of propofol were not significantly different between the 2 groups. CONCLUSIONS: TEAS may decrease the stress response during extubation, improve quality of postoperative recovery, and decrease incidence of postoperative complications in elderly patients undergoing elective supratentorial craniotomy.