Bispectral Index versus the University of Michigan Sedation Scale in assessing sedation depth during pediatric drug-induced sleep endoscopy.

BACKGROUND AND PURPOSE: Bispectral Index (BIS) and University of Michigan Sedation Scale (UMSS) were two commonly used methods of monitoring the sedation depth, but their correlation was not clear. The purpose of this study is to ascertain if BIS correlates with UMSS in determining the sedation level during pediatric drug-induced sleep endoscopy (DISE). METHODS: One-hundred children, aged 36-143 months, with ASA I~II grade, were enrolled. They were subject to general anesthesia for an elective adenotonsillectomy. Two drug regimens were used. After UMSS ≥ 3, the sites of airway obstructions were located by checking the supraglottic airway structures with a fibrous laryngoscope. UMSS scores, BIS values, electromyography (EMG), and signal quality indices (SQIs) were recorded at the pre-medication and pre-DISE baseline (T0), 5 min subsequent to medication administration but prior to DISE initiation (T1), 1 min after DISE was initiated (T2), 1 min after DISE was completed (T3), 1 min subsequent to tracheal intubation (T4), 1 min following extubation (T5), and 30 min past extubation (T6). RESULTS: There were strong correlations between BIS monitor readings and UMSS scores for total and two regimens. Kappa values revealed moderate agreement between BIS and UMSS for total and two regimens. The agreement rates were 67.47% for the total, 61.43% for Regimen 1, and 73.42% for Regimen 2, respectively. CONCLUSION: BIS correlates with UMSS in determining the sedation level during pediatric DISE for two regimens. BIS might serve as an appropriate indicator of sedation intensity when UMSS could not be used.

METTL4 mediated-N6-methyladenosine promotes acute lung injury by activating ferroptosis in alveolar epithelial cells.

Sepsis-induced acute lung injury has been deemed to be an life-threatening pulmonary dysfunction caused by a dysregulated host response to infection. The modification of N6-Methyladenosine (m6A) is implicated in several biological processes, including mitochondrial transcription and ferroptosis. Ferroptosis is an iron-dependent type of programed cell death, which plays a role in sepsis-induced acute lung injury (ALI). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial regulator of intracellular oxidative homeostasis, linked to ferroptosis resistance. This research aims to explore the effect of m6A in ferroptosis in sepsis-induced ALI. First, we found a time-dependent dynamic alteration on pulmonary methylation level during sepsis-induced ALI. We identified METTL4 as a differentially expressed gene in ALI mice using m6A sequencing and RNA-sequencing, and revealed the methylation of several ferroptosis related genes (Nrf2). Thus, we generated METTL4 deficiency mice and found that METTL4 knockdown alleviated ferroptosis, as evidenced by lipid ROS, MDA, Fe2+, as well as alterations in GPX4 and SLC7A11 protein expression. Consistently, we found that METTL4 silencing could decrease ferroptosis sensitivity in LPS-induced TC-1 cells. Furthermore, both the dual-luciferase reporter assay and rescue experiments indicated that METTL4 mediated the N6-methyladenosine of Nrf2 3'UTR, then YTHDF2 binded with the m6A site, promoting the degradation of Nrf2. In conclusion, we revealed that METTL4 promoted alveolar epithelial cells ferroptosis in sepsis-induced lung injury via N6-methyladenosine of Nrf2, which might provide a novel approach to therapeutic strategies for sepsis-induced ALI.

Salidroside postconditioning attenuates ferroptosis-mediated lung ischemia-reperfusion injury by activating the Nrf2/SLC7A11 signaling axis.

BACKGROUND: Ferroptosis, an iron-dependent programmed necrosis, is linked to lung ischemia-reperfusion injury. Salidroside is a glycoside derived from the Rhodiola rosea plant that exhibits anti-inflammatory and antioxidant properties. However, it is uncertain whether salidroside alleviates lung ischemia-reperfusion injury. This investigation explored the function of salidroside in ferroptosis in lung ischemia-reperfusion injury. METHODS: A lung ischemia-reperfusion model was established in wild-type and Nrf2-/- mice, and pulmonary epithelial cells were exposed to hypoxia/regeneration in vitro. We evaluated ferroptosis-related factors by western blotting, transmission electron microscopy, and fluorescence microscopy. To investigate the regulation of Nrf2 by salidroside, coimmunoprecipitation and luciferase reporter assays were used. Transwell assays were used to detect macrophage migration. RESULTS: The data indicated that salidroside postconditioning significantly reduced ferroptosis and alleviated lung ischemia-reperfusion injury in wild-type mice, as evidenced by improved histology and inflammation, reduced lipid peroxides and iron overload, and the induction of Nrf2, SLC7A11, and GPX4 expression. Salidroside activated Nrf2 signaling, resulting in Keap1-Nrf2 dissociation, nuclear translocation, and increased antioxidant-response element reporter activity. Sal consistently inhibited hypoxia/regeneration-induced pulmonary epithelial cell ferroptosis by activating the Nrf2 signaling pathway. Furthermore, ferroptotic cells recruited macrophages via CCL2, whereas salidroside lowered CCL2 expression and inhibited ferroptosis-induced macrophage chemotaxis in lung ischemia-reperfusion injury. Additionally, the antiferroptotic effects of salidroside against lung ischemia-reperfusion injury were eliminated in Nrf2-/- mice. CONCLUSIONS: This study clearly shows that salidroside postconditioning attenuates ferroptosis-mediated lung ischemia-reperfusion injury by activating the Nrf2/SLC7A11 signaling axis.

Quercetin attenuates sepsis-induced acute lung injury via suppressing oxidative stress-mediated ER stress through activation of SIRT1/AMPK pathways.

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction play a pivotal role in the pathological process of sepsis-induced acute lung injury (ALI). Quercetin has been proved to exert anti-inflammation in ALI. This study aimed to explore the protection mechanism of quercetin against sepsis-induced ALI via suppressing ER stress and mitochondrial dysfunction. Cecal ligation and puncture (CLP) mouse model was established to mimic sepsis, and LPS was used to stimulate murine lung epithelial (MLE-12) cells. We observed that quercetin ameliorated pulmonary pathological lesion and oxidative damage in sepsis-induced mice. In LPS-stimulated MLE-12 cells, quercetin could inhibit the level of ER stress as evidenced by decreased mRNA expression of PDI, CHOP, GRP78, ATF6, PERK, IRE1α and improve mitochondrial function, as presented by increased MMP, SOD level and reduced production of ROS, MDA. Meanwhile, transcriptome analysis revealed that quercetin upregulated SIRT1/AMPK mRNA expression. Furthermore, we used siRNA to knockdown SIRT1 in MLE-12 cells, and we found that SIRT1 knockdown could abrogate the quercetin-elicited antioxidation in vitro. Therefore, quercetin could protect against sepsis-induced ALI by suppressing oxidative stress-mediated ER stress and mitochondrial dysfunction via induction of the SIRT1/AMPK pathways.

YAP1 alleviates sepsis-induced acute lung injury via inhibiting ferritinophagy-mediated ferroptosis.

Ferroptosis is a phospholipid peroxidation-mediated and iron-dependent cell death form, involved in sepsis-induced organ injury and other lung diseases. Yes-associated protein 1 (YAP1), a key regulator of the Hippo signaling pathway, could target multiple ferroptosis regulators. Herein, this study aimed to explore the involvement of ferroptosis in the etiopathogenesis of sepsis-induced acute lung injury (ALI) and demonstrate that YAP1 could disrupt ferritinophagy and moderate sepsis-induced ALI. Cecal ligation and puncture (CLP) models were constructed in wild-type (WT) and pulmonary epithelium-conditional knockout (YAP1f/f) mice to induce ALI, while MLE-12 cells with or without YAP1 overexpression were stimulated by lipopolysaccharide (LPS) in vitro. In-vivo modes showed that YAP1 knockout aggravated CLP-induced ALI and also accelerated pulmonary ferroptosis, as presented by the downregulated expression of GPX4, FTH1, and SLC7A11, along with the upregulated expression of SFXN1 and NCOA4. Transcriptome research identified these key genes and ferroptosis pathways involved in sepsis-induced ALI. In-vitro modes consistently verified that YAP1 deficiency boosted the ferrous iron accumulation and mitochondrial dysfunction in response to LPS. Furthermore, the co-IP assay revealed that YAP1 overexpression could prevent the degradation of ferritin to a mass of Fe2+ (ferritinophagy) via disrupting the NCOA4-FTH1 interaction, which blocked the transport of cytoplasmic Fe2+ into the mitochondria via the mitochondrial membrane protein (SFXN1), further reducing the generation of mitochondrial ROS. Therefore, these findings revealed that YAP1 could inhibit ferroptosis in a ferritinophagy-mediated manner, thus alleviating sepsis-induced ALI, which may provide a new approach to the therapeutic orientation for sepsis-induced ALI.

Nrf2 Deficiency Exacerbated CLP-Induced Pulmonary Injury and Inflammation through Autophagy- and NF-κB/PPARγ-Mediated Macrophage Polarization.

The balance between M1 and M2 macrophage polarization is involved in the regulation of pulmonary inflammation. Nuclear factor erythroid-derived 2-like 2 (Nfe2l2, also known as Nrf2), a nuclear transcription factor, is reported to play protective roles in acute lung injury (ALI) and inflammation, and increasing evidence indicates that the protective effects of Nrf2 are closely related to autophagy. This study aimed to explore whether Nrf2 is involved in sepsis-induced acute pulmonary injury and inflammation and in the role of macrophage polarization in the process. In the present study, sepsis patients, an Nrf2 knockout mouse that underwent cecal ligation and puncture (CLP), and lipopolysaccharide (LPS)-treated macrophage cell lines were employed to investigate the potential functions of Nrf2 in sepsis-induced lung injury and the underlying mechanisms. Clinical studies showed that the NRF2 mRNA level was inversely correlated with pulmonary inflammation and disease severity in patients with sepsis. Analyses in a CLP-treated Nrf2 knockout mouse model indicated that an Nrf2 deficiency promoted a CLP-induced increase in M1 macrophage polarization and apoptosis and inhibited CLP-induced upregulation of the autophagy level in lung tissues. Experiments in RAW264.7 cells revealed that Nrf2 overexpression inhibited M1 macrophage polarization but promoted M2 macrophage polarization by improving the autophagy, and Nrf2 overexpression promoted PPARγ but inhibited NF-κB nuclear translocation. In conclusion, these results indicate that Nrf2 plays a protective role in sepsis-induced pulmonary injury and inflammation through the regulation of autophagy- and NF-κB/PPARγ-mediated macrophage polarization.

Irisin Rescues Blood-Brain Barrier Permeability following Traumatic Brain Injury and Contributes to the Neuroprotection of Exercise in Traumatic Brain Injury.

Traumatic brain injury (TBI) has a high incidence, mortality, and morbidity all over the world. One important reason for its poor clinical prognosis is brain edema caused by blood-brain barrier (BBB) dysfunction after TBI. The mechanism may be related to the disorder of mitochondrial morphology and function of neurons in damaged brain tissue, the decrease of uncoupling protein 2 (UCP2) activity, and the increase of inflammatory reaction and oxidative stress. In this study, we aimed to investigate the effects of exogenous irisin on BBB dysfunction after TBI and its role in the neuroprotective effects of endurance exercise (EE) in mice. The concentrations of irisin in cerebrospinal fluid (CSF) and plasma of patients with mild to severe TBI were measured by ELISA. Then, male C57BL/6J mice and UCP2 knockout mice with C57BL/6J background were used to establish the TBI model. The BBB structure and permeability were examined by transmission electron microscopy and Evans blue extravasation, respectively. The protein expressions of irisin, occludin, claudin-5, zonula occludens-1 (ZO-1), nuclear factor E2-related factor 2(Nrf2), quinine oxidoreductase (NQO-1), hemeoxygenase-1 (HO-1), cytochrome C (Cyt-C), cytochrome C oxidase (COX IV), BCL2-associated X protein (Bax), cleaved caspase-3, and UCP2 were detected by western blot. The production of reactive oxygen species (ROS) was evaluated by the dihydroethidium (DHE) staining. The levels of inflammatory factors were detected by ELISA. In this study, we found that the CSF irisin levels were positively correlated with the severity of disease in patients with TBI and both EE and exogenous irisin could reduce BBB damage in a mouse model of TBI. In addition, we used UCP2-/- mice and further found that irisin could improve the dysfunction of BBB after TBI by promoting the expression of UCP2 on the mitochondrial membrane of neurons, reducing the damage of mitochondrial structure and function, thus alleviating the inflammatory response and oxidative stress. In conclusion, the results of this study suggested that irisin might alleviate brain edema after TBI by promoting the expression of UCP2 on the mitochondrial membrane of neurons and contribute to the neuroprotection of EE against TBI.

Identification of the Risk Factors of Postoperative Pulmonary Complications in Elderly Patients Undergoing Elective Colorectal Surgery.

OBJECTIVE: This study was to identify the perioperative related risk factors of postoperative pulmonary complications (PPCs) in elderly patients undergoing elective colorectal surgery, which will provide new insight for better prevention and intervention of PPCs in elderly patients. METHODS: A retrospective study involving 445 patients (age ≥65), who registered in Shengjing Hospital affiliated to China Medical University for elective colorectal surgery from October 2014 to March 2017, was conducted. Clinical data, including demographic information, medical history, preoperative examination, and surgery-related factors, were analyzed and compared between the patient group with PPCs and the group without PPCs. t-test or χ2 test was performed for statistical analysis between the 2 groups. Binary logistic regression analysis was further employed to identify the potential independent risk factors of PPCs. RESULTS: Among the 445 patients enrolled in the study, 49 (11%) had PPCs, while 396 (89%) did not. The main risk factors of PPC occurrence in the elderly patients undergoing elective colorectal surgery included older age (age ≥75 years), ASA >II, hypertension, myocardial ischemia, basic pulmonary diseases, laparotomy, blood transfusion, preoperative hemoglobin <100 g/L, and albumin <35 g/L. Laparotomy (compared with laparoscope) and ASA >II were independent risk factors for the increased incidence of PPCs. CONCLUSION: More attention should be paid to patients with older age and ASA >II in elective colorectal surgery. Choice of laparoscopic operation, proper treatment of hypertension, myocardial ischemia, basic pulmonary diseases, and correction of anemia and nutritional status can effectively reduce the incidence of PPCs. An adequate and comprehensive evaluation of the potential risk factors related to PPCs is required before surgery.