STING Agonist cGAMP Attenuates Sleep Deprivation-Induced Neuroinflammation and Cognitive Deficits via TREM2 Up-Regulation.

Sleep deprivation (SD) has been associated with several adverse effects, including cognitive deficit. Emerging evidence suggests microglia-associated neuroinflammation is a potential trigger of cognitive deficit after SD. Stimulator of interferon genes (STING) constitutes an important factor in host immune response to pathogenic organisms and is found in multiple cells, including microglia. STING is involved in neuroinflammation during neuronal degeneration, although how STING signaling affects SD-induced neuroinflammation remains unexplored. In the present study, the chronic sleep restriction (CSR) model was applied to examine the effects of STING signaling on cognition. The results revealed that cGAMP, a high-affinity and selective STING agonist, significantly improved cognitive deficit, alleviated neural injury, and relieved neuroinflammation in CSR mice by activating the STING-TBK1-IRF3 pathway. Moreover, triggering receptor expressed on myeloid cells 2 (TREM2) was upregulated in CSR mice treated with cGAMP, and this effect was abolished by STING knockout. TREM2 upregulation induced by cGAMP regulated the microglia from pro-inflammatory state to anti-inflammatory state, thereby relieving neuroinflammation in CSR mice. These findings indicate cGAMP-induced STING signaling activation alleviates SD-associated neuroinflammation and cognitive deficit by upregulating TREM2, providing a novel approach for the treatment of SD-related nerve injury.

METTL3 Modulates TXNIP Expression to Affect the Activation of NLRP3 Inflammasome in Hepatic Cells Under Oxygen-Glucose Deprivation/Reperfusion Injury.

Hepatic ischemia-reperfusion (I/R) injury is still a major risk factor and unsolved problem in hepatic surgery. Methyltransferase-like 3 (METTL3), an important m6A-modified methylase, regulates inflammation and cellular stress response. In this study, we demonstrated the special role of METTL3 and its underlying mechanism in hepatic I/R injury. In the mouse model of hepatic I/R and in the oxygen-glucose deprivation and reoxygenation (OGD/R)-induced AML12 and NCTC 1469 cells, the expression of METTL3 was significantly upregulated. Inhibition of METTL3 in OGD/R-induced AML12 and NCTC 1469 cells both increased the cell viability, declined the cell apoptosis, and decreased the reactive oxygen species (ROS) and the release levels of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18), diminishing NLRP3 and Caspase1-p20 expressions. Moreover, METTL3 positively modulated TXNIP expression in an m6A manner. TXNIP overexpression reversed the effects of METTL3 knockdown on OGD/R-induced injury in AML12 cells. Furthermore, inhibition of NLRP3 inflammasome activity contributed to the protective effects of TXNIP knockdown in OGD/R-induced AML12 cells. In conclusion, METTL3 knockdown alleviated OGD/R-induced hepatocyte injury, and the specific mechanism was associated with the inhibition of NLRP3 inflammasome activation, which was attributed to the reduction of TXNIP in an m6A-dependent manner.

Glyceryl triacetate promotes blood-brain barrier recovery after ischemic stroke through lipogenesis-mediated IL-33 in mice.

BACKGROUND: Lipid metabolism has a crucial role in neural repair in neurodegenerative diseases. We recently revealed that lipogenesis-mediated interleukin-33 (IL-33) upregulation lead to blood-brain barrier (BBB) repair after ischemic stroke. However, manipulating the key enzyme fatty acid synthase (FASN) to enhance lipogenesis was very challenging. Glyceryl triacetate (GTA) was used as a donor of acetate and precursor of acetyl coenzyme A, the key substrate for de novo lipogenesis catalyzed by FASN. Therefore, we hypothesized that GTA would promote lipogenesis the peri-infarct after ischemic stroke and contribute to the BBB repair through IL-33. METHODS: Middle cerebral artery occlusion (MCAO) was performed on C57BL mice and GTA was gavage administrated (4 g/kg) on day 2 and 4 after MCAO. Lipogenesis was evaluated by assessment of the protein level of FASN, lipid droplets, and fatty acid products through liquid chromatography-mass spectrometry in the peri-infarct area on day 3 after MCAO, respectively. BBB permeability was determined by extravasation of Evans blue, IgG and dextran, and levels of tight junction proteins in the peri-infarct area on day 7 after MCAO, respectively. Infarct size and neurological defects were assessed on day 7 after MCAO. Brain atrophy on day 30 and long-term sensorimotor abilities after MCAO were analyzed as well. The inhibitor of FASN, C75 and the virus-delivered FASN shRNA were used to evaluate the role of FASN-driven lipogenesis in GTA-improved BBB repair. Finally, the therapeutic potential of recombinant IL-33 on BBB repair and neurological recovery was evaluated. RESULTS: We found that treatment with GTA increased the lipogenesis as evidenced by lipid droplets level and lauric acid content, but not the FASN protein level. Treatment with GTA increased the IL-33 level in the peri-infarct area and decreased the BBB permeability after MCAO. However, infarct size and neurological defect score were unchanged on day 7 after MCAO, while the long-term recovery of sensorimotor function and brain atrophy were improved by GTA. Inhibition of lipogenesis using C75 or FASN shRNA reversed the beneficial effect of GTA. Finally, exogenous IL-33 improved BBB repair and long-term functional recovery after stroke. CONCLUSION: Collectively, we concluded that treatment with GTA improved the BBB repair and functional recovery after ischemic stroke, probably by the enhancement of lipogenesis and IL-33 expression.

Clinical Features and Blood Indicators for Severity and Prognosis in COVID-19 Patients.

BACKGROUND: This study aimed to analyze the clinical manifestations and blood indicators to deepen the understanding of Coronavirus disease 2019 (COVID-19). METHODS: COVID-19 patients admitted to C10 West Ward, Tongji Hospital in Wuhan City ("West Ward") between January 31 and March 28, 2020, were retrospectively analyzed. RESULTS: A total of 61 COVID-19 patients were hospitalized, wherein the non-critical Group had 30 cases, while the critical group had 31 (including 14 survivors and 17 deaths). Age, the proportion of fever cases, white blood cell (WBC), basophils, red blood cell (RBC), hemoglobin, lactate dehydrogenase (LDH), C-reactive protein (CRP), high-sensitivity troponin, pro-BNP (brain natriuretic peptide), prothrombin time (PT), and D-dimer were higher in the critical group while lymphocytes, eosinophils, albumin were lower compared with those of the non-critical group (all p < 0.05). WBC (p = 0.008), basophils (p = 0.034), and LDH (p = 0.005) of the death subgroup climbed remarkably in comparison with those of the survival subgroup. CONCLUSIONS: Advanced age, high fever, increases in indicators such as WBC, basophils, CRP, LDH, high-sensitivity troponin, pro-BNP, and D-dimer, and decreases in indicators, including lymphocytes, eosinophils, and albumin, might forebode a critical condition.

Dual-specificity phosphatase 26-dificient neurons are susceptible to oxygen-glucose deprivation/reoxygenation-evoked apoptosis and proinflammatory response by affecting the TAK1-medaited JNK/P38 MAPK pathway.

Dual-specificity phosphatase 26 (DUSP26) is linked to a broad range of human disorders as it affects numerous signaling cascades. However, the involvement of DUSP26 in ischemic stroke has not been explored. Here, we investigated DUSP26 as a key mediator of oxygen-glucose deprivation/reoxygenation (OGD/R)-associated neuronal injury, an in vitro model for investigating ischemic stroke. A decline in DUSP26 occurred in neurons suffering from OGD/R. A deficiency in DUSP26 rendered neurons more susceptible to OGD/R by aggravating neuronal apoptosis and inflammation, while the overexpression of DUSP26 blocked OGD/R-evoked neuronal apoptosis and inflammation. Mechanistically, enhanced phosphorylation of transforming growth factor-ß-activated kinase 1 (TAK1), c-Jun N-terminal kinase (JNK) and P38 mitogen-activated protein kinase (MAPK) was evidenced in DUSP26-deficient neurons suffering from OGD/R, whereas the opposite effects were observed in DUSP26-overexpressed neurons. Moreover, the inhibition of TAK1 abolished the DUSP26-deficiency-elicited activation of JNK and P38 MAPK and exhibited anti-OGD/R injury effects in DUSP26-deficiency neurons. Results from these experiments show that DUSP26 is essential for neurons in defending against OGD/R insult, while neuroprotection is achieved by restraining the TAK1-mediated JNK/P38 MAPK pathway. Therefore, DUSP26 may serve as a therapeutic target for the management of ischemic stroke.

Effect of goal-directed fluid therapy based on plasma colloid osmotic pressure on the postoperative pulmonary complications of older patients undergoing major abdominal surgery.

BACKGROUND: As an important component of accelerated rehabilitation surgery, goal-directed fluid therapy (GDT) is one of the optimized fluid therapy strategies and is closely related to perioperative complications and mortality. This article aimed to study the effect of combining plasma colloid osmotic pressure (COP) with stroke volume variation (SVV) as a target for intraoperative GDT for postoperative pulmonary complications in older patients undergoing major abdominal surgery. METHODS: In this study, older patients (n = 100) undergoing radical resection of gastroenteric tumors were randomized to three groups: Group C (n1 = 31) received a conventional infusion regimen, Group S1 (n2 = 34) received GDT based on SVV, and Group S2 (n3 = 35) received GDT based on SVV and COP. The results were recorded, including the lung injury score (LIS); PaO2/FiO2 ratio; lactic acid value at the times of beginning (T0) and 1 h (T1), 2 h (T2), and 3 h (T3) after liquid infusion in the operation room; the total liquid infusion volume; infusion volumes of crystalline and colloidal liquids; urine production rate; pulmonary complications 7 days after surgery; and the severity grading of postoperative pulmonary complications. RESULTS: The patients in the S2 group had fewer postoperative pulmonary complications than those in the C group (P < 0.05) and the proportion of pulmonary complications of grade 1 and higher than grade 2 in S2 group was significantly lower than that in C group (P <0.05); the patients in the S2 group had a higher PaO2/FiO2 ratio than those in the C group (P < 0.05), lower LIS than those in the S1 and C groups (P < 0.05), less total liquid infusion than those in the C group (P < 0.05), and more colloidal fluid infusion than those in the S1 and C groups (P < 0.05). CONCLUSION: The findings of our study show that intraoperative GDT based on COP and SVV can reduce the incidence of pulmonary complications and conducive to shortening the hospital stay in older patients after gastrointestinal surgery. TRIAL REGISTRATION: Chinese Clinical Trial. no. ChiCTR2100045671. Registry at www.chictr.org.cn on April 20, 2021.

A combination of supraglottic airway and bronchial blocker for one-lung ventilation in infants undergoing thoracoscopic surgery.

Objectives: One-lung ventilation (OLV) for children under the age of two years is difficult. The authors hypothesize that a combination of a supraglottic airway (SGA) device and intraluminal placement of a bronchial blocker (BB) may provide an appropriate choice. Design: A prospective method-comparison study. Setting: Second Affiliated Hospital of Xi'an Jiaotong University, China. Participants: 120 patients under the age of two years undergoing thoracoscopic surgery with OLV. Interventions: Participants were randomly assigned to receive intraluminal placement of BB with SGA (n = 60) or extraluminal placement of BB with endotracheal tube (ETT) (n = 60) for OLV. Measurements and main results: The primary outcome was the length of postoperative hospitalization stay. The secondary outcomes were the basic parameters of OLV and investigator-defined severe adverse events. The postoperative hospitalization stay was 6 days (interquartile range, IQR 4-9) in SGA plus BB group compared with 9 days (IQR 6-13) in ETT plus BB group (P = 0.034). The placement and positioning duration of SGA plus BB was 64 s (IQR 51-75) compared with 132 s (IQR 117-152) of ETT plus BB (P = 0.001). The values of leukocyte (WBC) and C-reactive protein (CRP) of SGA plus BB group on the first day of post-operation were 9.8 × 109/L (IQR 7.4-14.5) and 15.1 mg/L (IQR 12.5-17.3) compared with 13.6 × 109/L (IQR 10.8-17.1) and 19.6 mg/L (IQR 15.0-23.5) of ETT plus BB group (P = 0.022 and P = 0.014). Conclusion: There were few if any significant adverse events in the intervention group (SGA plus BB) for OLV in children under the age of two years, and this method seems worthy of clinical application. Meanwhile, the mechanism for this novel technique to shorten the length of postoperative hospitalization stay needs to be further explored.

MicroRNA-137-mediated lysine demethylase 4A regulates the recovery of spinal cord injury via the SFRP4-Wnt/ß-Catenin axis.

OBJECTIVE: Spinal cord injury (SCI) causes great harm to the normal life of patients. Histone demethylase is involved in many biological processes, including SCI. Hence, this study explored the role and mechanism of histone lysine demethylase 4A (KDM4A) in SCI. METHODS: The acute SCI (ASCI) rat model was established after spinal compression and the SCI neuronal model was induced via treating PC12 cells with lipopolysaccharide (LPS). KDM4A expression during SCI was detected. The microRNA (miRNA) targeting KDM4A was predicted and verified. The miRNA and KDM4A expression patterns were intervened in LPS-stimulated PC12 cells to evaluate their combined effects on neuronal cells in SCI. The downstream pathways of KDM4A were predicted, and SFRP4 and H3K9me3 expressions were determined. After the intervention of SFRP4 in LPS-treated cells, ß-Catenin expression and the effect of SFRP4 on neuronal cells in SCI were detected. Finally, the effectiveness of the miR-137/KDM4A/SFRP4/Wnt/ß-Catenin axis was verified in vivo. RESULTS: KDM4A was abnormally elevated in SCI. miR-137 targeted KDM4A. miR-137 effectively inhibited the apoptosis of LPS-challenged PC12 cells, which could be reversed after overexpressing KDM4A. KDM4A promoted SFRP4 expression through demethylation of H3K9me3. Overexpression of SFRP4 blocked the Wnt/ß-Catenin pathway and promoted apoptosis of LPS-stimulated cells. In vivo, miR-137 overexpression remarkably improved SCI symptoms, accompanied by obviously increased ß-Catenin expression and notably decreased KDM4A and SFRP4 expressions, while overexpressed KDM4A treatment showed the opposite trend in the presence of miR-137. CONCLUSION: We demonstrated that miR-137 targeted KDM4A and then downregulated SFRP4 to ameliorate SCI in a Wnt/ß-Catenin-dependent manner.

Influence of Sevoflurane Inhalation Anesthesia on Clinical Outcomes of Morbidly Obese Patients Undergoing Laparoscopic Bariatric Surgery.

Background: Morbid obesity is one of the fastest-growing subgroups of obesity and is associated with high mortality, with an estimated 2.8 million people dying from obesity each year. Objective: This research sets out to elucidate the impact of sevoflurane (Sevo) inhalation anesthesia on the clinical outcome of morbidly obese (MO) patients undergoing laparoscopic bariatric surgery (LBS). Methods: A retrospective study was conducted on 150 MO patients undergoing LBS in the Second Affiliated Hospital of Xi'an Jiaotong University from November 2019 to November 2021. According to the difference of anesthesia methods, 100 patients with Sevo anesthesia were set as group A, and 50 patients with propofol (P) anesthesia were set as group B. Intergroup comparisons were performed in terms of eye-opening time, tracheal intubation removal time, directional force recovery, heart rate (HR), mean arterial pressure (MAP), peak airway pressure (Ppeak), plateau pressure (Pplat), standard time out of PACU, postoperative food intake (FI), length of stay (LOS), and complication rate. Results: Group A had a shorter time to open eyes, remove tracheal intubation, and restore directional force than Group B, with better recovery of HR, MAP, Ppeak, and Pplat. Group A was also superior to Group B in the standard time out of PACU, postoperative FI, and LOS, with a lower complication rate. Conclusions: Sevo inhalation anesthesia is more effective and safer for MO patients undergoing LBS.

De novo Lipogenesis in Astrocytes Promotes the Repair of Blood-Brain Barrier after Transient Cerebral Ischemia Through Interleukin-33.

Astrocytes experience significant metabolic shifts in the "sensitive period" of neurological function recovery following cerebral ischemia. However, the changes in astrocyte lipid metabolism and their implications for neurological recovery remain unknown. In the present study, we employed a mouse middle cerebral artery occlusion model to investigate the changes in de novo lipogenesis and interleukin-33 (IL-33) production in astrocytes and elucidate their role in blood-brain barrier (BBB) repair in the subacute phase of cerebral ischemia. Neurological behavior evaluation was used to assess functional changes in mice. Pharmacological inhibition and astrocyte-specific downregulation of fatty acid synthase (FASN) were used to evaluate the role of de novo lipogenesis in brain injury. Intracerebroventricular administration of recombinant IL-33 was performed to study the contribution of IL-33 to BBB disruption. Extravasation of Evans blue dye, dextran and IgG were used to assess BBB integrity. Western blotting of tight junction proteins ZO-1, Occludin, and Claudin-5 were performed at defined time points to evaluate changes in BBB. It was found that de novo lipogenesis was activated, and IL-33 production increased in astrocytes at the subacute stage of cerebral ischemia injury. Inhibition of lipogenesis in astrocytes decreased IL-33 production in the peri-infarct area, deteriorated BBB damage and interfered with neurological recovery. In addition, supplementation of IL-33 alleviated BBB destruction and improved neurological recovery worsened by lipogenesis inhibition. These findings indicate that astrocyte lipogenesis increases the production of IL-33 in the peri-infarct area, which promotes BBB repair in the subacute phase of cerebral ischemia injury and improves long-term functional recovery.

Glycopyrrolate versus atropine for preventing bradycardia induced by neostigmine injection after general anesthesia surgery: a randomized open, parallel-controlled multicenter clinical trial.

OBJECTIVE: With atropine as a positive control, randomized controlled clinical trials were conducted to verify the efficacy of glycopyrrolate injection in preventing bradycardia caused by neostigmine. METHOD: Patients undergoing elective general anesthesia and non-cardiac surgery were randomly divided into an experimental group (129 cases) and control group (127 cases) (ChiCTR2100046022, http://www.chictr.org.cn/showproj.aspx?proj=126075). At the end of the operation, the test group was given glycopyrrolate 6 ug/kg + neostigmine 0.04 mg/kg, and the control group was given atropine 0.016 mg/kg + neostigmine 0.04 mg/kg, bolus time 1 min, to antagonize muscle residual effects of relaxants. We compared the area under the time curve (AUC) of the difference between heart rate and baseline heart rate within 15 minutes of administration, the measured value of heart rate per minute, and the change in heart rate compared with baseline. We verified the safety of glycopyrrolate injection through laboratory tests, clinical symptoms, signs, and adverse events/serious adverse events. RESULTS: The AUC of the experimental group's heart rate within 15 minutes after the administration was lower than the baseline heart rate change value, (P<005). The measured value of the heart rate at each time changed less than the control group; the experimental group's heart rate remained at the baseline level for longer than the control group (P<005). There was no significant difference in the incidence of adverse reactions between the two groups of patients (P>005). CONCLUSION: Glycopyrrolate and atropine are safe to prevent heart rate slowing induced by the non-depolarizing muscle relaxant antagonist neostigmine, and glycopyrrolate is more conducive to maintaining a stable heart rate in patients.

The efficiency and safety of high-dose vitamin C in patients with COVID-19: a retrospective cohort study.

BACKGROUND: The inflammatory reaction is the main cause of acute respiratory distress syndrome and multiple organ failure in patients with Coronavirus disease 2019, especially those with severe and critical illness. Several studies suggested that high-dose vitamin C reduced inflammatory reaction associated with sepsis and acute respiratory distress syndrome. This study aimed to determine the efficacy and safety of high-dose vitamin C in Coronavirus disease 2019. METHODS: We included 76 patients with Coronavirus disease 2019, classified into the high-dose vitamin C group (loading dose of 6g intravenous infusion per 12 hr on the first day, and 6g once for the following 4 days, n=46) and the standard therapy group (standard therapy alone, n=30). RESULTS: The risk of 28-day mortality was reduced for the high-dose vitamin C versus the standard therapy group (HR=0.14, 95% CI, 0.03-0.72). Oxygen support status was improved more with high-dose vitamin C than standard therapy (63.9% vs 36.1%). No safety events were associated with high-dose vitamin C therapy. CONCLUSION: High-dose vitamin C may reduce the mortality and improve oxygen support status in patients with Coronavirus disease 2019 without adverse events.

Remimazolam tosilate in upper gastrointestinal endoscopy: A multicenter, randomized, non-inferiority, phase III trial.

BACKGROUND AND AIM: Remimazolam tosilate (RT) is a new short-acting GABA(A) receptor agonist, having potential to be an effective option for procedural sedation. Here, we aimed to compare the efficacy and safety of RT with propofol in patients undergoing upper gastrointestinal endoscopy. METHODS: This positive-controlled, non-inferiority, phase III trial recruited patients at 17 centers, between September 2017 and November 2017. A total of 384 patients scheduled to undergo upper gastrointestinal endoscopy were randomly assigned to receive RT or propofol. Primary endpoint was the success rate of sedation. Adverse events (AEs) were recorded to evaluate safety. RESULTS: The success rate of sedation in the RT group was non-inferior to that in the propofol group (97.34% vs 100.00%; difference in rate -2.66%, 95% CI -4.96 to -0.36, meeting criteria for non-inferiority). Patients in the RT group had longer time to adequate sedation (P < 0.0001) but shorter time to fully alert (P < 0.0001) than that in the propofol group. The incidences of hypotension (13.04% vs 42.86%, P < 0.0001), treatment-related hypotension (0.54% vs 5.82%, P < 0.0001), and respiratory depression (1.09% vs 6.88%, P = 0.0064) were significantly lower in the RT group. AEs were reported in 74 (39.15%) patients in the RT group and 114 (60.32%) patients in the propofol group, with significant difference (P < 0.0001). CONCLUSION: This trial established non-inferior sedation success rate of RT compared with propofol. RT allows faster recovery from sedation compared with propofol. The safety profile is favorable and appears to be superior to propofol, indicating that it was feasible and well tolerated for patients.

Anesthesia and protection in an emergency cesarean section for pregnant woman infected with a novel coronavirus: case report and literature review.

An outbreak of novel coronavirus pneumonia occurred worldwide since December 2019, which had been named COVID-19 subsequently. It is extremely transmissive that infection in pregnant women were unavoidable. The delivery process will produce large amount of contaminated media, leaving a challenge for medical personnel to ensure both the safety of the mother and infant and good self-protection. Only rare cases of pregnant women with COVID-19 are available for reference. Here, we report a 30-year-old woman had reverse transcription polymerase chain reaction-confirmed COVID-19 at 36 weeks 2 days of gestation. Significant low and high variability of fetal heart rate baseline and severe variable decelerations were repeated after admission. An emergency cesarean section at 37 weeks 1 day of gestation under combined spinal and epidural anesthesia was performed with strict protection for all personnel. Anesthesia and operation went uneventfully. None of the participants were infected. We can conclude that when confronted with cesarean section in parturient with COVID-19, careful planning and detailed preparation can improve the safety of the mother and infant and reduce the risk of infection for medical staff to help preventing and controlling the epidemic.

Theanine attenuates hippocampus damage of rat cerebral ischemia-reperfusion injury by inhibiting HO-1 expression and activating ERK1/2 pathway.

AIMS: Theanine, as a naturally occurring component in tea, has been shown to deliver benefits against various diseases. However, the exact molecular mechanisms underlying theanine's protective actions against cerebral ischemia/reperfusion (IR) injury still remains largely unknown. MAIN METHODS: In this study, rat cerebral IR injury model was established and were randomly divided into the following five groups: Sham (SH), IR, IR + Theanine (TH), IR + TH+ heme oxygenase-1 (HO-1) inducer cobalt protoporphyrin (Copp), and IR + Copp groups. KEY FINDINGS: We found that theanine significantly inhibited neuron damage and apoptosis in the hippocampus during the 48 h detection period, as detected by hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Meanwhile, reduced levels of malondialdehyde (MDA) and elevated activities of superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-PX) were observed in the theanine-treated group. Enzyme-linked immunosorbent (ELISA) assay also revealed that theanine markedly decreased the levels of inflammatory cytokines, such as IL-6, IL-1ß, and TNF-α, in IR rats. The anti-apoptotic effect of theanine on IR injury was further verified by flow cytometry assay. Besides, theanine dramatically inhibited HO-1 expression and activity but increased extracellular signal-regulated kinase 1/2 (ERK1/2) activity in hippocampal tissue from rats with cerebral IR injury. However, co-treatment with Copp remarkably abolished the protective effects of theanine on cerebral IR injury. SIGNIFICANCE: These findings demonstrated that the neuroprotective role of theanine was associated with its anti-oxidative, anti-inflammatory, and anti-apoptotic properties, which might be through regulation of HO-1 activation in rats with cerebral IR injury.

Inhibition of microRNA-148b-3p alleviates oxygen-glucose deprivation/reoxygenation-induced apoptosis and oxidative stress in HT22 hippocampal neuron via reinforcing Sestrin2/Nrf2 signalling.

MicroRNAs (miRNAs) have emerged as crucial regulators of neuronal injury during cerebral ischaemia/reperfusion injury. Various miRNAs are dysregulated during this pathological process; however, the precise role of these miRNAs in regulating neuronal injury remains largely unknown. In the current study, we explored the potential function of microRNA-148b-3p (miR-148b-3p) in regulating neuronal injury induced by oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro, a cellular model for mimicking cerebral ischaemia/reperfusion injury. We found that miR-148b-3p expression was significantly decreased in neurons in response to OGD/R exposure. Importantly, miR-148b-3p overexpression decreased cell viability and exacerbated apoptosis and reactive oxygen species (ROS) production in OGD/R-exposed neurons. By contrast, miR-148b-3p inhibition improved cell viability and decreased apoptosis and ROS production in OGD/R-exposed neurons. Notably, Sestrin2, a cytoprotective gene, was identified as a miR-148b-3p target gene. miR-148b-3p inhibition markedly increased Sestrin2 expression as well as the activation of nuclear factor erythroid-2-related factor 2 (Nrf2) antioxidant signalling. Moreover, silencing of Sestrin2 or Nrf2 significantly reversed the miR-148-3p-inhibition-mediated protective effect in OGD/R-injured neurons. Overall, these results demonstrate that miR-148b-3p inhibition protects neurons from OGD/R-induced apoptosis and ROS production through reinforcing Nrf2 antioxidant signalling via upregulation of Sestrin2. Our study indicates that the miR-148b-3p/Sestrin2/Nrf2 axis plays an important role in regulating neuronal injury and may serve as a potential therapeutic target for providing neuroprotection during cerebral ischaemia/reperfusion injury.

Downregulation of microRNA-302b-3p relieves oxygen-glucose deprivation/re-oxygenation induced injury in murine hippocampal neurons through up-regulating Nrf2 signaling by targeting fibroblast growth factor 15/19.

MicroRNAs have emerged as critical mediators of cerebral ischaemia/reperfusion injury. Recent studies have demonstrated that microRNA-302b-3p (miR-302b-3p) plays an important role in regulating apoptosis and oxidative stress in various cells. However, whether miR-302b-3p is involved in regulating cerebral ischaemia/reperfusion injury-induced neuronal apoptosis and oxidative stress remains unknown. In the present study, we explored the potential function and molecular mechanism of miR-302b-3p in oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced neuronal injury, using an in vitro model of cerebral ischaemia/reperfusion injury. We found that miR-302b-3p expression was up-regulated by OGD/R treatment in neurons. The inhibition of miR-302b-3p improved cell viability, and reduced apoptosis and the production of reactive oxygen species, showing a protective effect against OGD/R-induced injury. Interestingly, miR-302b-3p was shown to target and modulate murine fibroblast growth factor 15 (FGF15). Moreover, our results showed that miR-302b-3p down-regulation contributed to the promotion of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE)-mediated antioxidant signaling associated with the inactivation of glycogen synthase kinase-3ß. However, the knockdown of FGF15 significantly reversed the miR-302b-3p inhibition-mediated protective effect in OGD/R-treated neurons. Overall, these results demonstrated that miR-302b-3p inhibition confers a neuroprotective effect in OGD/R-treated neurons by up-regulating Nrf2/ARE antioxidant signaling via targeting FGF15, providing a novel target for neuroprotection in cerebral ischaemia/reperfusion injury.

LncRNA MALAT1 cessation antagonizes hypoxia/reoxygenation injury in hepatocytes by inhibiting apoptosis and inflammation via the HMGB1-TLR4 axis.

Hepatic ischemia-reperfusion (I/R) injury frequently occurs after liver transplantation, stroke, and trauma, resulting in organ dysfunction and failure. Hepatocyte apoptosis and inflammation are identified as the hallmarks of liver I/R injury. Long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is induced following hypoxia or ischemic stimulation, and exerts the contradictory roles in various injury progression. However, its role and mechanism lying beneath hepatic I/R remains ill defined. In this study, elevation of MALAT1 expression was corroborated in human hepatocytes under hypoxia/reoxygenation (H/R)H/R condition. Of interest, depression of MALAT1 blunted H/R-inhibited cell viability, and counteracted lactate dehydrogenase (LDH) and malondialdehyde release. Additionally, MALAT1 cessation antagonized H/R-evoked cell apoptosis and caspase-3 activity. Simultaneously, the increased inflammatory reaction triggered by H/R stimulation was also abrogated following MALAT1 suppression by reducing pro-inflammatory cytokine transcripts and productions including IL-1ß and TNF-α. Mechanistically, H/R exposure activated the pathway of high-mobility group box1 (HMGB1)-TLR4, which was muted after MALAT1 inhibition. More importantly, elevation of HMGB1 reversed MALAT1 down-regulation-mediated inhibition in cell injury and inflammation. Moreover, blocking the TLR4 signaling also ameliorated H/R-evoked hepatocyte apoptosis and inflammatory response. Consequently, these data suggest that MALAT1 may aggravate hepatic I/R injury by regulating the HMGB1-TLR4-triggered cell apoptosis and inflammation, implying a promising therapeutic strategy to fight liver I/R injury.