Propofol EC50 for inducing loss of consciousness in patients under combined epidural-general anesthesia or general anesthesia alone: a randomized double-blind study.

Background: Combined epidural-general anesthesia (GA + EA) has been recommended as a preferred technique for both thoracic and abdominal surgery. The epidural anesthesia on the general anesthetic (GA) requirements has not been well investigated. Therefore, we conducted the present study to explore the predicted effect-site concentration of propofol (Ceprop) required for achieving the loss of consciousness (LOC) in 50% of patients (EC50) with or without epidural anesthesia. Methods: Sixty patients scheduled for gastrectomy were randomized into the GA + EA group or GA alone group to receive general anesthesia alone. Ropivacaine 0.375% was used for epidural anesthesia to achieve a sensory level of T4 or above prior to the induction of general anesthesia. The EC50 of predicted Ceprop for LOC was determined by the up-down sequential method. The consumption of anesthetics, emergence time from anesthesia, and postoperative outcomes were also recorded and compared. Results: The EC50 of predicted Ceprop for LOC was lower in the GA + EA group than in the GA alone group [2.97 (95% CI: 2.63-3.31) vs. 3.36 (95% CI: 3.19-3.53) µg mL-1, (p = 0.036)]. The consumption of anesthetics was lower in the GA + EA group than in the GA alone group (propofol: 0.11 ± 0.02 vs. 0.13 ± 0.02 mg kg-1 min-1, p = 0.014; remifentanil: 0.08 ± 0.03 vs. 0.14 ± 0.04 µg kg-1 min-1, p < 0.001). The emergence time was shorter in the GA + EA group than in the GA alone group (16.0 vs. 20.5 min, p = 0.013). Conclusion: Concomitant epidural anesthesia reduced by 15% the EC50 of predicted Ceprop for LOC, decreased the consumptions of propofol and remifentanil during maintenance of anesthesia, and fastened recovery from anesthesia. Clinical trial registration: ClinicalTrials.gov, identifier: NCT05124704.

High-dose remifentanil exacerbates myocardial ischemia-reperfusion injury through activation of calcium-sensing receptor-mediated pyroptosis.

Background: The aim of this study was to investigate whether calcium-sensing receptor (CaSR) was involved in HRF-mediated exacerbation of MI/R injury through NLRP3 inflammasome activation and pyroptosis. Methods: In vivo, a rat MI/R model was established by ligating the left coronary artery, and short-term HRF exposure was induced during reoxygenation. Then, TUNEL, H&E, Masson staining, immunohistochemical (IHC) and serum levels of lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK), as well as the expression levels of CaSR and pyroptosis-related proteins in heart tissues, were measured. H9c2 cells were cultured to create a hypoxia/reoxygenation (H/R) model and exposed to different concentrations of RF. After pretreatment with the CaSR activator gadolinium chloride (GdCl3) and inhibitor NPS2143 in the H/R model and treatment with HRF, we compared cellular viability, TUNEL, cytosolic [Ca2+]i, the levels of LDH and CK, pyroptosis-related proteins and CaSR in H9c2 cells. We further researched the mechanisms of CaSR-mediated pyroptosis in the H/R+HRF model by CaSR-shRNA, Ac-YVAD-CMK, MCC950 and NAC. Results: We found that HRF significantly increased CaSR expression, rate of cell death, levels of CK and LDH, and exacerbated pyroptosis in MI/R model. In vitro, HRF increased CaSR expression, decreased viability, enhanced cytosolic [Ca2+]i and exacerbated pyroptosis in H/R cells. Pretreated with GdCl3 worsen these changes, and NPS2143, MCC950, Ac-YVAD-CMK, NAC and sh-CaSR can reversed these effects. Conclusion: Exposure to HRF for a short time exacerbates MI/R-induced injury by targeting CaSR to increase cytosolic [Ca2+]i and ROS levels, which mediate the NLRP3 inflammasome and pyroptosis.

Trabectedin induces ferroptosis via regulation of HIF-1α/IRP1/TFR1 and Keap1/Nrf2/GPX4 axis in non-small cell lung cancer cells.

BACKGROUND AND OBJECTIVES: Non-small cell lung cancer (NSCLC) is a global health concern. NSCLC treatment outcomes are generally poor due to treatment resistance or toxicity. Ferroptosis is a novel cell death triggered by iron accumulation, reactive oxygen species (ROS), and lipid peroxidation. Ferroptosis may kill cancer cells, particularly those resistant to apoptosis. MATERIALS AND METHODS: The Cell Counting Kit-8 assay assessed NSCLC cell viability after trabectedin treatment. Flow cytometry with Annexin V-FITC staining evaluated cell death. ROS, iron, lipid peroxidation, and GSH levels were measured using commercial kits. qRT-PCR and western blots evaluated messenger RNA and protein levels. Proteins were inhibited using short interfering RNA transfection and specific inhibitors. RESULTS: Trabectedin was cytotoxic to NSCLC cells regardless of p53 status. Trabectedin upregulated iron, ROS, and lipid peroxidation in NSCLC cells, causing ferroptosis. Trabectedin increases iron and ROS levels by upregulating transferrin receptor 1 and the HIF-1/IRP1 axis. In NSCLC cells, trabectedin suppresses glutathione peroxidase 4, followed by the Keap1/Nrf2 axis. CONCLUSIONS: Our findings imply that trabectedin may treat NSCLC effectively.

Incidence of oxygen desaturation using a high-flow nasal cannula versus a facemask during flexible bronchoscopy in patients at risk of hypoxemia: a randomised controlled trial.

BACKGROUND: Patients with obstructive sleep apnoea (OSA), male sex, obesity, older age or hypertension are prone to hypoxemia during flexible bronchoscopy. This study investigated whether using a high-flow nasal cannula (HFNC) could reduce the incidence of oxygen desaturation during bronchoscopy under deep sedation in patients at risk of hypoxemia. METHODS: A total of 176 patients at risk of hypoxemia who underwent flexible bronchoscopy under deep sedation were randomly assigned to two groups: the HFNC group (humidified oxygen was supplied via a high-flow nasal cannula at a rate of 60 L/min and a concentration of 100%, n = 87) and the facemask group (oxygen was supplied via a tight-fitting facemask at a rate of 6 L/min and a concentration of 100%, n = 89). RESULTS: Oxygen desaturation occurred in 4 (4.6%) patients in the HFNC group and 26 (29.2%) patients in the facemask group (P < 0.001). The facemask group required more jaw thrust manoeuvres than the HFNC group (43[48.3%] vs. 5[5.7%], P < 0.001). 8 patients (9.0%) in the facemask group and none in the HFNC group required bag-mask ventilation (P = 0.012). CONCLUSION: The use of an HFNC can reduce the incidence of oxygen desaturation and the requirement for airway intervention in patients at risk of hypoxemia during flexible bronchoscopy under deep sedation. TRIAL REGISTRATION: www.chiCTR.org.cn Identifier: ChiCTR2100044105. Registered 11/03/2021.

Dexmedetomidine protects cardiomyocytes against hypoxia/reoxygenation injury via multiple mechanisms.

BACKGROUND: Myocardial infarction (MI) is a serious cardiovascular disease associated with myocardial ischemia/reperfusion (I/R) injury. Dexmedetomidine (Dex), an α2-adrenoceptor agonist, has been reported to protect against I/R injury. We examined the cardioprotective effects of Dex on cardiomyocytes under hypoxia/reoxygenation (H/R) conditions and explored the underlying mechanisms. MATERIALS AND METHODS: A H/R model was established to mimic the MI injury. The CCK-8 assay was performed to measure cell viability. Cellular apoptosis was measured using the Annexin V fluorescein isothiocyanate (FITC)-propidium iodide (PI) staining. The levels of interleukin (IL)-1α and tumor necrosis factor (TNF)-α, and the activity of lactate dehydrogenase (LDH) were measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit. Reactive oxygen species (ROS) were measured using the 2'-7' dichlorofluorescein diacetate (DCFH-DA) staining assay. In addition, the levels of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD), catalase (CAT), and caspase-3 were measured using a commercial kit. siRNA was used to silence Bcl-2, catalase, or STAT3. Western blotting was used to measure the change in the levels of proteins. RESULTS: Dex improved the cell viability and inhibited the inflammatory response in H9c2 cells exposed to H/R treatment. In addition, Dex inhibited apoptosis and alleviated the endoplasmic reticulum (ER) stress and oxidative stress in H9c2 cells under the H/R treatment. Mechanism investigation showed that Dex inhibited the intrinsic pathway of apoptosis. Moreover, Dex enhanced the activation of the JAK2/STAT3 signaling pathway in H/R-treated H9c2 cells. CONCLUSION: Altogether, our findings suggested Dex as a promising therapeutic agent for myocardial I/R.

SIRT6 silencing overcomes resistance to sorafenib by promoting ferroptosis in gastric cancer.

Sorafenib is a tyrosine kinase inhibitor that shows anti-tumour effects against various cancers including gastric cancer (GC). However, the clinical application of sorafenib is often hampered by drug resistance. Sirtuins 6 (SIRT6) is a member of the Sirtuin family of NAD (+)-dependent enzymes that are critically involved in various biological activities. This study presents that SIRT6 silencing overcomes sorafenib resistance by promoting ferroptosis, which is a novel form of cell death. Mechanistically, SIRT6 inhibition led to the inactivation of the Keap1/Nrf2 signalling pathway and downregulation of GPX4. The overexpression of GPX4 or activation of Keap1/Nrf2 reverses the effects of the downregulation of SIRT6 on sorafenib-induced ferroptosis. Thus, targeting the SIRT6/Keap1/Nrf2/GPX4 signalling pathway may be a potential strategy for overcoming sorafenib resistance in GC.

The Postoperative Lymphocyte to Monocyte Ratio Change Predicts Poor Clinical Outcome in Patients with Esophageal Squamous Cell Carcinoma Undergoing Curative Resection.

BACKGROUND: Postoperative lymphocyte to monocyte ratio (post-LMR) change (LMRc) reflects the dynamic change of balance between inflammatory reaction and immune reaction after curative operation. An elevated preoperative LMR (pre-LMR) has been shown to be a prognostic factor in patients with esophageal squamous cell carcinoma (ESCC), but the clinical value of the LMRc remains unknown. METHODS: 674 patients in ESCC undergoing curative operation were enrolled in this study. LMRc (LMRc = pre-LMR-post-LMR) was counted on the basis of data within one week before and after operation. The median of LMRc was chosen to be the optimal cut-off value to evaluate the prognostic value of LMRc. RESULTS: Kaplan-Meier curves revealed that LMRc ≤ 1.59 was significantly associated with worse overall survival (OS) (P = 0.003) and disease-free survival (DFS) (P = 0.008). Multivariate analysis suggested that LMRc could serve as an independent prognostic predictor for both OS (P = 0.006, HR = 0.687, 95% CI 0.526-0.898) and DFS (P = 0.003, HR = 0.640, 95% CI 0.476-0.859). CONCLUSIONS: LMRc is a promising prognostic predictor for predicting the worse clinical outcome in patients with ESCC undergoing curative operation.

Effect of anesthetic methods on postoperative CD3+, CD4+ and CD4+CD25+ in patients with lung cancer undergoing radical operation.

Effects of anesthesia methods on immune function in patients with lung cancer undergoing radical operation were investigated. A total of 122 patients undergoing radical resection of lung cancer who were treated in Zhejiang Cancer Hospital from September 2013 to April 2016 were randomly divided into the combined anesthesia group and the intravenous anesthesia group, with 61 cases in each group. The patients in the combined anesthesia group were given intravenous combined epidural anesthesia. Patients in the intravenous anesthesia group were given intravenous anesthesia. The change of CD3+, CD4+ and CD4+CD25+ at time-point T0 (before anesthesia), T1 (the time of anesthesia), T2 (after operation), T3 (24 h after operation), T4 (72 h after operation) were compared between the two groups. The levels of CD3+, CD4+ and CD4+CD25+ at T1, T2, T3 and T4 in the combined anesthesia group were higher than that in the intravenous anesthesia group (P<0.05). Αfter starting anesthesia, the levels of CD3+, CD4+ and CD4+CD25+ began to decrease in both groups. The levels of CD3+, CD4+ and CD4+CD25+ at T2 and T1 were lower than those at T0 (P<0.05). The levels of CD3+, CD4+ and CD4+CD25+ at T2 were lower than T1 (P<0.05). After T3, the levels of CD3+, CD4+ and CD4+CD25+ began to increase in both groups. Τhe levels of CD3+, CD4+ and CD4+CD25+ at T3 and T4 were higher in both groups than those at T2 and T1 (P<0.05), and the levels of CD3+, CD4+ and CD4+CD25+ at T4 were higher in both groups than those at T3, but the levels of CD3+, CD4+ and CD4+CD25+ at T3 and T4 were lower than those at T0 (P<0.05). Intravenous combined epidural anesthesia can maintain a relatively stable immune function compared with simple intravenous anesthesia patients.

Breviscapine suppresses the growth of non-small cell lung cancer by enhancing microRNA-7 expression.

Breviscapine (BVP) has previously been shown to inhibit the proliferation of hepatocellular carcinoma cells. However, little is known about the effects of BVP on non-small cell lung cancer (NSCLC) growth. Here, we aimed to study the effects of BVP on human NSCLC growth. We employed A549, NCL-H460 and A549 cells transfected with microRNA-7 (miR-7) mimic and inhibitor to investigate the effect of BVP on cell proliferation, apoptosis and apoptosis-associated molecules. The results showed that BVP significantly reduced the growth of A549 and NCLH460 cells in a concentration-dependent and time-dependent manner, accompanied by a significant elevation of apoptosis. Additionally, the present study also confirmed that BVP-treated A549 cells showed increased levels of Bax and microRNA-7 (miR-7) and a decreased level of Bcl-2. The up-regulation of miR-7 enhanced the BVP sensitivity of NSCLC cells by suppressing cell proliferation and promoting cell apoptosis, while the inhibition of miR-7 reversed the anti-proliferative pro-apoptotic effects of BVP. Pre-treatment with miR-7 mimics enhanced the BVP-mediated down-regulation of Bax/Bcl-2 in NSCLC cells, while pre-treatment with the miR-7 inhibitor blocked the BVPmediated down-regulation of Bax/Bcl. Taken together, these results confirm that BVP effectively inhibits NSCLC proliferation and that miR-7, as a novel target, is likely involved in BVP-induced growth suppression and the apoptosis of NSCLC cells.

Epigenetic modulation of neuronal apoptosis and cognitive functions in sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE), which associates with neuronal apoptosis and cognitive disorders, is a common complication of systemic sepsis. However, the mechanism involving its modulation remains to be elucidated. Recent studies showed that histone deacetylases (HDACs) were implicated in neurodegeneration and cognitive functions. The current study was designed to investigate whether septic brain is epigenetically modulated by HDACs, using cecal ligation and peroration (CLP) rats and primary hippocampal neuronal cultures. We found that hippocampal acetylated histone 3 (AcH3), acetylated histone 4 (AcH4), cytoplasmic HDAC4 and Bcl-XL were inhibited in septic brain. Hippocampal Bax and nuclear HDAC4 expressions were enhanced in CLP rats. Administration of HDACs inhibitor, trichostatin A (TSA) or suberoylanilide hydroxamic acid (SAHA) rescued the changes of Bcl-XL and Bax in vivo, and decreased apoptotic cells in vitro. In addition, HDAC4 shRNA transfection significantly enhanced AcH3, AcH4 and Bcl-XL, but suppressed Bax. Neuronal apoptosis was also reduced by transfection of HDAC4 shRNA. Furthermore, CLP rats exhibited significant spatial learning and memory deficits, which could be ameliorated by application of TSA or SAHA without influence on locomotive activity. These results reveal that epigenetic modulation is involved in septic brain, and the inhibition of HDACs may serve as a potential therapeutic approach for SAE treatment.

[Effect of chemotherapy preoperatively upon early postoperative cognitive dysfunction in eldly tumor patients].

OBJECTIVE: To investigate whether preoperative chemotherapy history could influence the incidence of early postoperative cognitive dysfunction (POCD) in elderly tumor patients. METHODS: A total of 107 tumor patients (> or = 60 years old, tumor TNM stages T2 - T3, N0 - N3, ASA I -III class) undergoing elective radical surgery of gastric or colorectal cancer were selected and assigned into two groups according to preoperative chemotherapy history: with preoperative chemotherapy history group (C group, n = 52) and without preoperative chemotherapy history group (N group, n = 55). Patients in two groups received radical surgery under intravenous-inhalation general anesthesia combined with epidural anesthesia. Cognitive function was assessed using a battery of neuropsychological tests from five aspects including memory, verbal intelligence, visual-motor, executive function and motor function at 1 day preoperatively and 3 days postoperatively. RESULTS: There was no significant difference in general state of patient preoperatively health including sex ratio, body mass index, complications, cancer types and stages, ASA classification between two groups (P > 0.05). Neither significant difference was found in duration of anesthesia and surgery, intra-operative bleeding volume and transfusion volume between two groups (P > 0.05). There was no significant difference in ICU admission rate, ICU stay, incidence of complications, hospitalization duration and mortality rate between two groups (P > 0.05). Preoperative neuropsychological test score in group C was slightly lower than that in group N, but the difference was not significant (P > 0.05). Impaired incidence rate of digit-symbol substitution test, controlled oral word association test, grooved pegboard non-dominant hand test and semantic fluency test at 3 days postoperation in group C were significantly higher than those in N group (P < 0.05). Incidence of POCD at 3 days postoperation in group C was significantly higher than that in group N (42.3% vs 15.4% , P < 0.05). CONCLUSION: Chemotherapy preoperatively could increase the incidence of early postoperative cognitive dysfunction in elderly with tumor.