This study elucidated the mechanism by which lysine-specific demethylase 1 A (KDM1A) promotes colorectal cancer (CRC) progression. We characterized KDM1A expression in CRC cells and tissues and examined its effects on malignant phenotypes, including proliferation, migration, invasion, and glycolysis. Mechanistically, we explored the relationship between KDM1A and hypoxia-inducible factor-1α (HIF-1α)/PDK4 pathway. The tumor-promoting role of KDM1A was further evaluated in a xenograft mouse model. The results showed that KDM1A was overexpressed in CRC cells and tissues. KDM1A knockdown inhibited CRC cell proliferation, migration, and invasion capabilities, and reduced glycolytic activity. Furthermore, KDM1A knockdown shortened the half-life of HIF-1α protein and increased its ubiquitination level, correlating with reduced PDK4 expression. HIF-1α overexpression partially reversed the PDK4 downregulation and glycolysis inhibition caused by KDM1A knockdown. PDK4 knockdown reproduced the metabolic inhibition phenotype of KDM1A deficiency, and KDM1A overexpression reversed the effects of PDK4 deficiency, confirming that KDM1A regulates glycolysis in a PDK4-dependent manner. KDM1A depletion suppressed in vivo tumor growth and decreased Ki-67 and HIF-1α expression levels. In conclusion, KDM1A supports PDK4 expression via HIF-1α stability, promoting glycolytic metabolism and driving CRC growth and metastasis.

The incidence of colorectal cancer (CRC) increases yearly. Ferroptosis, a form of regulated cell death, has gained extensive attention in cancer research. RNA-binding motif single-stranded interacting protein 2 (RBMS2) has been implicated in various cancers, but its role in CRC and its involvement with ferroptosis remains poorly understood. This study explores the involvement of RBMS2 in CRC development and its potential as a therapeutic target. Functional assays, including CCK-8, colony formation, Transwell migration, invasion assays, and EMT-related gene determination, were conducted to evaluate the effects of RBMS2 overexpression and knockdown. Ferroptosis, apoptosis, and autophagy were assessed using specific inhibitors, ferroptosis inducers, and apoptosis and proliferation detection. The interaction between RBMS2 and SLC7A11 was explored during the ferroptosis process. In vivo experiments involved xenograft models in nude mice to observe tumor growth, EMT, and metastasis. Overexpression of RBMS2 inhibited CRC cell proliferation, migration, and epithelial-mesenchymal transition (EMT). Furthermore, RBMS2 promoted ferroptosis by downregulating SLC7A11. Mechanistic studies revealed that RBMS2 destabilizes SLC7A11 at the mRNA level. In vivo, RBMS2 overexpression significantly suppressed tumor growth and lung/liver metastasis. Our findings indicate that RBMS2 inhibits CRC progression by promoting ferroptosis and regulating SLC7A11 mRNA stability. Targeting the RBMS2-SLC7A11 axis could provide a novel therapeutic strategy for CRC.

BACKGROUND AND STUDY AIMS:Ferroptosis and pyroptosis, two forms of cell death, are increasingly reported for their pivotal roles in cancer biology. However, the understanding of the combined ferroptosis-pyroptosis (FPtosis)-related gene signature in colorectal cancer (CRC) remains limited. MATERIAL AND METHODS:We conducted a comprehensive investigation of the FPtosis-related signature in CRC. Data integration from both the training and validation cohorts was performed. The FPtosis-related signature was established. We evaluated the prognostic significance of the signature through Kaplan-Meier analysis, as well as univariate and multivariate Cox regression models. Functional analyses were conducted to explore the underlying biological mechanisms. Additionally, we analyzed the correlations between the FPtosis-related signature, immune infiltration, and immune checkpoint blockade (ICB) immunotherapy. RESULTS:The FPtosis-related signature demonstrated significant prognostic potential and can serve as an independent biomarker for predicting outcomes. The signature showed correlations with advanced tumor stage, invasion depth, lymph node metastasis, and distant metastasis. Subgroup analyses revealed the valuable predictive role of the FPtosis-related signature in predicting survival across different clinical subgroups, including age, gender, tumor stage, invasion depth, lymph node metastasis status, and distant metastasis status. Moreover, the signature exhibited positive associations with inflammation and the infiltration of diverse immune cells, such as neutrophils, M0 and M2 macrophages, and regulatory T cells (Tregs). In microsatellite instable (MSI) CRC, the expression of most ICB genes was higher in the high-FPtosis group compared to the low-FPtosis group. CONCLUSION:The FPtosis signature can effectively predict the prognosis of CRC and had the potential to improve the development of innovative therapeutic strategies.

Liver fibrosis (LF) is a progressive pathological process driven by hepatic stellate cell (HSC) activation. This study aimed to explore the effect of remazolam (RE), a benzodiazepine anesthetic, on HSC activation and its underlying mechanisms. LX-2 cells were stimulated with lipopolysaccharide (LPS) and treated with various RE concentrations. Cell viability was assessed by CCK-8 assay, and the expression of fibronectin, collagen I, and α-SMA was analyzed via western blot. Pyroptosis was evaluated by morphological observation, LDH release, ELISA for IL-1β/IL-18, and protein expression in the NLRP3/Caspase-1/GSDMD pathway. Rescue experiments were performed by overexpressing NLRP3. RE dose-dependently reduced LX-2 cell viability and downregulated fibronectin, collagen I, and α-SMA expression. RE also significantly inhibited pyroptosis, evidenced by reduced LDH release, decreased IL-1β/IL-18 levels, and suppression of NLRP3, ASC, cleaved caspase-1, GSDMD-N, and IL-1β. Overexpression of NLRP3 reversed the inhibitory effects of RE on pyroptosis and HSC activation. These findings indicate that RE alleviates LF by inhibiting HSC activation and pyroptosis through suppression of the NLRP3/Caspase-1/GSDMD pathway, highlighting its potential as a therapeutic agent for LF.

Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has been established as an effective treatment for peritoneal cancer (PC). However, this kind of combination therapy is associated with a high lactate level. Moreover, studies have suggested that the rate of complications early after surgery directly increased with elevated lactate levels. Glucose-insulin-potassium (GIP), a potent cardioprotective intervention, has been demonstrated to adjust blood glucose (BG) levels and reduce lactate levels. However, the insulin-glucose ratio should be adjusted according to the surgery performed. Here, we aimed to evaluate the advantages of using modified GIP during CRS/HIPEC to reduce the lactate level at the end of surgery and further reduce the incidence of early postoperative complications. The modified GIP versus conventional management during surgery study is a single-center, randomized, single-blinded outcome assessment clinical trial of 80 patients with PC who are between 18 and 64 years old and undergoing CRS/HIPEC. Participants will be randomly allocated to receive modified GIP or conventional treatment (1:1). The primary outcome will be the plasma lactate level at the end of surgery. The secondary outcomes will include the highest levels and fluctuation ranges of lactate and BG during surgery, extubation time, APACHE-II score 24 h after surgery, postoperative defecation and exhaust time, postoperative lactate clearance time, postoperative liver and kidney function, incidence of complications within 7 days after surgery, length of intensive care unit stay (LIS), length of hospital stay (LHS), and total cost of hospitalization. The trial protocol was approved by the Scientific Research Ethics Committee of Beijing Shijitan Hospital Affiliated with Capital Medical University, approval number sjtky11-1x-2022(118). The results will be published in international peer-reviewed journals. ChiCTR2200057258. Registered on March 5, 2022.

BACKGROUND:Hypobaric hypoxia exposure leads to brain edema, followed by neuropsychological disorders. However, the related mechanism and effective treatments are still unclear. The study aimed to discuss the neuroprotective effects of Cordycepin on hypobaric hypoxia-induced cognitive impairment.METHODS:The study contained two parts. In the first part, rats underwent hypobaric hypoxia (HH) exposure for 7 days, with or without Cordycepin (10 mg/kg) or lipopolysaccharide (LPS,10 mg/kg) treatment once a day. In the second part, rats underwent HH exposure for 7 days, with or without TAK242 (3 mg/kg) and Cordycepin (10 mg/kg) once a day. Open field and Morris water maze test were performed one day after the 7days treatment. The BBB permeability was detected by the uptake of NaF. Western bloting was used to detect the levels of TLR4/MyD88/NF-κB pathway related proteins in the hippocampus. The hippocampal and serous levels of cytokines were detected by ELISA. The structure of tight junctions in the hippocampus was observed under the transmission electron microscopy.RESULTS:Both acute HH and LPS exposure could activate the TLR4 pathway and neuroinflammation, further induced BBB disruption and cognitive injury. Cordycepin could inhibit the activation of theTLR-4/NF-κB/MMP-9 pathway, which further attenuated cognitive dysfunction, and disruption of the blood-brain barrier (BBB) in HH and LPS exposed rats. Furthermore, TAK242, a TLR4 antagonist, also inhibited the activation of theTLR-4/NF-κB/MMP-9 pathway and BBB disruption, as well as attenuated HH induced cognitive impairment.CONCLUSIONS:Cordycepin could ameliorate HH-induced neuroinflammation, BBB disruption, and cognitive damage partly by inhibiting the TLR-4/NF-κB/MMP-9 pathway.

Delirium and cognition impairment are common complications in elderly patients after anesthesia and surgery. However, it remains unclear how to prevent these complications. Based on acupuncture theory, transcutaneous electrical stimulation (TES) improves brain function, which may be a preventive strategy. Therefore, we aimed to find whether TES could prevent surgery-induced delirium and cognitive dysfunction in elderly patients after surgery.

In clinic, perioperative neurocognitive disorder is becoming a common complication of surgery in old patients. Neuroinflammation and blood-brain barrier (BBB) disruption are important contributors for cognitive impairment. Atorvastatin, as a strong HMG-CoA reductase inhibitor, has been widely used in clinic. However, it remains unclear whether atorvastatin could prevent anesthesia and surgery-induced BBB disruption and cognitive injury by its anti-inflammatory property. In this study, aged C57BL/6J mice were used to address this question. Initially, the mice were subject to atorvastatin treatment for 7 days (10 mg/kg). After a simple laparotomy under 1.5% isoflurane anesthesia, Morris water maze was performed to assess spatial learning and memory. Western blot analysis, immunohistochemistry, and enzyme-linked immunosorbent assay were used to examine the inflammatory response, BBB integrity, and cell apoptosis. Terminal-deoxynucleotidyl transferase mediated nick end labeling assay was used to assess cell apoptosis. The fluorescein sodium and transmission electron microscopy were used to detect the permeability and structure of BBB. The results showed that anesthesia and surgery significantly injured hippocampal-dependent learning and memory, which was ameliorated by atorvastatin. Atorvastatin could also reverse the surgery-induced increase of systemic and hippocampal cytokines, including IL-1β, TNF-α, and IL-6, accompanied by inhibiting the nuclear factor kappa-B (NF-κB) pathway and Nucleotide-Binding Oligomerization Domain, or Leucine Rich Repeat and Pyrin Domain Containing 3 (NLRP3) inflammasome activation, as well as hippocampal neuronal apoptosis. In addition, surgery triggered an increase of BBB permeability, paralleled by a decrease of the ZO-1, occludin, and Claudin 5 proteins in the hippocampus. However, atorvastatin treatment could protect the BBB integrity from the impact of surgery, by up-regulating the expressions of ZO-1, occludin, and Claudin 5. These findings suggest that atorvastatin exhibits neuroprotective effects on cognition in aged mice undergoing surgery.

目的 探讨右美托咪定联合罗哌卡因双侧竖脊肌平面阻滞(ESPB)对老年患者腰椎间孔镜镇痛效果及术后恢复质量的影响.方法 选取2018年11月至2020年11月在北京世纪坛医院择期行腰椎间孔镜手术的老年患者(≥65岁)120例.随机分为对照组、右美托咪定组、ESPB组、联合组.对照组选择0.375％罗哌卡因20 ml局部浸润麻醉;右美托咪定组术前予右美托咪定0.5μg/(kg·h)泵注10 min,术中以0.3μg/(kg·h)维持;ESPB组术前俯卧位行超声引导下双侧ESPB,每侧注入0.375％罗哌卡因20 ml;联合组术前予右美托咪定0.5μg/(kg·h)泵注10 min,术中以0.3μg/(kg·h)维持.同时俯卧位行超声引导下双侧竖脊肌平面阻滞,每侧注入0.375％罗哌卡因20 ml.记录患者手术时间,入室后(T0)、切皮时(T1)、分离肌肉期间(T2)、椎间孔成形时(T3)、脊神经根减压(T4)、手术结束时(T5)时的平均动脉压(MAP)、心率(HR)、血氧饱和度(SpO2)、视觉模拟评分法(VAS)评分、Ramsay评分,术中地佐辛用量,术中及术后24 h内各种不良事件及术后24 h患者恢复质量评分(QoR-15评分)和患者满意度.结果 T1、T2时点,ESPB组与对照组MAP、HR及SpO2无统计学差异(P>0.05);联合组、右美托咪定组MAP、HR明显低于ESPB组和对照组(P<0.05);T3、T4及T5时点,右美托咪定组、ESPB组及联合组MAP、HR明显低于对照组(P<0.05).T0、T1及T2时,4组VAS评分无统计学差异(P>0.05).T3、T4及T5时,联合组、ESPB组及右美托咪定组VAS评分明显低于对照组(P<0.05).T1～T5时,右美托咪定组及联合组Ramsay评分明显低于对照组和ESPB组(P<0.05).右美托咪定组、ESPB组及联合组术中地佐辛用量明显低于对照组(P<0.05).右美托咪定组、ESPB组及联合组术中出现疼痛、恶心呕吐、高血压的老龄患者明显少于对照组(P<0.05);右美托咪定组及联合组出现嗜睡的例数明显高于对照组和ESPB组(P<0.05).右美托咪定组、ESPB组及联合组术后24 h内出现疼痛、恶心呕吐的老龄患者及地佐辛用量明显少于对照组(P<0.05);而术后24 h内的恢复质量评分及满意度明显高于对照组(P<0.05).结论 右美托咪定联合罗哌卡因双侧竖脊肌平面阻滞能够提供充分的镇静镇痛效果,降低围术期应激反应,减少不良事件的发生,促进术后快速康复.

目的 探讨通心络胶囊对急性低压缺氧暴露大鼠认知功能损伤的神经保护作用及其相关机制.方法 64只雄性Sprague-Dawley大鼠随机均分为四组,包括正常组(C),通心络组(TXL),低压低氧组(HH),和低压低氧+通心络组(TXL+HH).在低压低氧暴露前,所有大鼠进行5 d水迷宫训练.然后在低压低氧环境下暴露7 d.7 d后,采用旷场实验,水迷宫实验测定认知功能,然后处死取海马组织,Western blot检测海马组织TLR-4、MyD88、IκB-α,NF-κB p65,AQP4,MMP-9的表达,ELISA检测血清和海马组织中IL-1β、TNF-α、IL-6的水平,HE染色观察海马组织病理学变化,并测定大鼠的脑水含量.结果(1)行为学实验:四组大鼠旷场实验结果无统计学差异(P>0.05);但在水迷宫空间探索实验中发现,与C组比较,HH组大鼠原平台所在象限停留时间及穿越平台次数明显降低(P<0.05);TXL干预后,大鼠原平台所在象限停留时间及穿越平台次数较低压低氧组明显升高,(P<0.05);(2)炎症指标比较:与C组比较,HH组大鼠血清及海马组织IL-1β、TNF-α、IL-6水平,海马TLR-4、MyD88、NF-κB p65蛋白水平明显升高(P<0.05),TXL干预后,炎症指标相关蛋白水平均下降(P<0.05);(3)海马组织损伤比较:HH组大鼠海马AQP4及MMP-9表达及脑水含量明显高于C组(P<0.05),海马区细胞排列紊乱,肿胀明显,边界模糊;而TXL干预后,AQP4,MMP-9表达及脑水含量均明显下降(P<0.05).结论 急性低压缺氧暴露可导致认知功能障碍和脑组织水肿,通心络干预可通过抑制TLR4/MyD88/NF-κB信号通路活化,减轻海马炎症,改善认知损伤和脑组织水肿.

Isoflurane, a widely used volatile anesthetic, induces neuronal apoptosis and memory impairments in various animal models. However, the potential mechanisms and effective pharmacologic agents are still not fully understood. The p38MAPK/ATF-2 pathway has been proved to regulate neuronal cell survival and inflammation. Besides, atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, exerts neuroprotective effects. Thus, this study aimed to explore the influence of atorvastatin on isoflurane-induced neurodegeneration and underlying mechanisms. Aged C57BL/6 mice (20 months old) were exposed to isoflurane (1.5%) anesthesia for 6 h. Atorvastatin (5, 10, or 20 mg/kg body weight) was administered to the mice for 7 days. Atorvastatin attenuated the isoflurane-induced generation of ROS and apoptosis. Western blotting revealed a decrease in cleaved caspase-9 and caspase-3 expression in line with ROS levels. Furthermore, atorvastatin ameliorated the isoflurane-induced activation of p38MAPK/ATF-2 signaling. In a cellular study, we proved that isoflurane could induce oxidative stress and inflammation by activating the p38MAPK/ATF-2 pathway in BV-2 microglia cells. In addition, SB203580, a selected p38MAPK inhibitor, inhibited the isoflurane-induced inflammation, oxidative stress, and apoptosis. The results implied that p38MAPK/ATF-2 was a potential target for the treatment of postoperative cognitive dysfunction.

In this study, we synthesised the zinc oxide nanoparticles from Vernonia amygdalina and evaluated its anti-inflammatory and antinociceptive potentials against the different inflammation and pain induced mice model. The synthesised zinc oxide nanoparticles were characterised by UV, SEM, XRD and FTIR techniques. The anti-nociceptive effects of V. amygdalina were examined by different stimuli e.g. acetic acid, glutamate, capsaicin, and formalin-induced nociception in mice. The anti-inflammatory effects of synthesised zinc oxide nanoparticles were assessed by air sack assessment and the level of inflammatory cytokines were studied. The muscle tension of animals were studied through open field assessment. The present study exhibited proficient antinociceptive and anti-inflammatory actions of the synthesised Zinc oxide nanoparticles from V. amygdalina. The sormulated zinc oxide nanoparticles were appreciably reduced the acetic acid, glutamate, capsaicin, and formalin-induced nociceptive responses in mice. Further the zinc nanoparticles were exhibited the potent anti-inflammatory actions via reducing the inflammatory response and pro-inflammatory cytokines level in the mice. In conclusion, the findings of this study proved the beneficial effects of zinc oxide nanoparticles from V. amygdalina against the different pain and inflammation-induced mice. Hence, it was clear that the zinc nanoparticles from V. amygdalina could be promising antinociceptive and anti-inflammatory agent in the future.

超声可视化技术在麻醉学科的应用引导了麻醉领域新一轮的改革;这项变革为实施精准化麻醉、提高麻醉质量、减少麻醉并发症提供了现实基础与依据.目前超声教学方案与实践培训还不够完善,为提高麻醉超声教学质量,介绍以超声引导下穿刺技术基础教育、模拟教育、实践培训为体系的教学方案,使麻醉医师在培训结束后可以掌握超声引导下穿刺技术,满足临床麻醉需求.

With the development of aging society,postoperative cognitive dysfunction(POCD)has become one of the main complications in elderly patients after surgery,influencing the rehabilitation of patients greatly.In recent years,there are a lot of domestic and foreign research on the exploration of postoperative cognitive dysfunction.The occurrence of cogni-tive dysfunction may be related to inflammatory reaction,oxidative stress and so on.It is caused by multiple factors.But, there is no clear conclusion on its pathogenesis and diagnostic criteria at present.There are many ways to evaluate cognitive function.Chinese medicine,as a traditional medicine in China,has long studied the recovery of nerve function.POCD can be reduced by Chinese medicine Shenmai injection,ligustrazine,ginkgo leaf injection,electroacupuncture stimulation and per-cutaneous acupoint electrical stimulation.But the influence of compound electroacupuncture on POCD needs to be further explored in the future.

Objective To evaluate the effect of atorvastatin preconditioning on cognitive function in isoflurane-anaesthetized mice.Methods Forty-eight healthy male C57BL/6 mice,aged 3 months,weighing 27-41 g,were divided into 3 groups (n =16 each) using a random number table:control group (group C),isoflurane anesthesia group (group Ⅰ) and atorvastatin preconditioning plus isoflurane anesthesia group (group AI).Atorvastatin 10 mg/kg was given through a gastric tube into the stomach at the same time every day for 7 consecutive days in group AI.In Ⅰ and AI groups,1.5％ isoflurane was inhaled for 6 h with fresh gas flow of 2 L/min at 1 day after the end of administration.Open field test and Morris water maze test were performed at 1 day after the end of anesthesia.The mice were sacrificed at 1 day after the end of Morris water maze test,and hippocampi were isolated for determination of caspase-3,Bax and Bcl-2 expression (by Western blot) and contents of interleukin-1beta (IL-1β),tumor necrosis factor-alpha (TNF-α) and soluble Aβ1-42 in hippocampal tissues (by enzyme-linked immunosorbent assay).Results There was no significant difference in the parameters of open field test among the three groups (P＞0.05).Compared with group C,the escape latency was significantly prolonged at each time point,the time of staying at the original platform quadrant was shortened,the frequency of crossing the original platform was decreased,the contents of IL-1β,TNF-α and soluble Aβ1-42 were increased,the expression of caspase-3 and Bax was up-regulated,and Bcl-2 expression was down-regulated in Ⅰ and AI groups (P＜0.05).Compared with group Ⅰ,the escape latency was significantly shortened at each time point,the time of staying at the original platform quadrant was prolonged,the frequency of crossing the original platform was increased,the contents of IL-1β,TNF-α and soluble Aβ1-42 were decreased,the expression of caspase-3 and Bax was downregulated,and Bcl-2 expression was up-regulated in group AI (P＜0.05).Conclusion Atorvastatin preconditioning can improve cognitive function in isoflurane-anaesthetized mice,and the mechanism may be association with attenuating hippocampal inflammatory responses,inhibiting over-expression of Aβ1-42 and inhibiting neuronal apoptosis.

The risk calculator of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) has been shown to be useful in predicting postoperative complications. In this study, we aimed to evaluate the predictive value of the ACS-NSQIP calculator in geriatric patients undergoing lumbar surgery.A total of 242 geriatric patients who underwent lumbar surgery between January 2014 and December 2016 were included. Preoperative clinical information was retrospectively reviewed and entered into the ACS-NSQIP calculator. The predictive value of the ACS-NSQIP model was assessed using the Hosmer-Lemeshow test, Brier score (B), and receiver operating characteristics (ROC, also referred C-statistic) curve analysis. Additional risk factors were calculated as surgeon-adjusted risk including previous cardiac event and cerebrovascular disease.Preoperative risk factors including age (P=.004), functional independence (P=0), American Society of Anesthesiologists class (ASA class, P=0), dyspnea (P=0), dialysis (P=.049), previous cardiac event (P=.001), and history of cerebrovascular disease (P=0) were significantly associated with a greater incidence of postoperative complications. Observed and predicted incidence of postoperative complications was 43.8% and 13.7% (5.9%) (P<.01), respectively. The Hosmer-Lemeshow test demonstrated adequate predictive accuracy of the ACS-NSQIP model for all complications. However, Brier score showed that the ACS-NSQIP model could not accurately predict risk of all (B=0.321) or serious (B=0.241) complications, although it accurately predicted the risk of death (B=0.0072); this was supported by ROC curve analysis. The ROC curve also showed that the model had high sensitivity and specificity for predicting renal failure and readmission.The ACS-NSQIP surgical risk calculator is not an accurate tool for the prediction of postoperative complications in geriatric Chinese patients undergoing lumbar surgery.