Translator's note:
The translation team of "Pearl River Vision" of the Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, screens out the recent high-quality SCI literature and research results published in domestic anesthesiology through keyword search every month, from PubMed and Web of Science and other search engines.
This issue of Pearl River Vision - Good Monthly Essay excerpts from some articles published from September 2023 to October 2023, from Fudan University Cancer Hospital, Peking University Third Hospital, Zhujiang Hospital of Southern Medical University, Xuzhou Medical University Affiliated Hospital, etc., covering neuroinflammation and oxidative stress, melatonin to improve postoperative sleep disorders and delirium, the application of hTERT-UCMSC immortalized cell lines in liver failure, and the impact of sarcopenia and frailty on postoperative rehabilitation in elderly patients.
Monthly good articles (2023.09-2023.10).
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1. Ji Che, Hui Wang, Jing Dong, Yuanyuan Wu, Haichao Zhang, Lei Fu, Jun Zhang. Human umbilical cord mesenchymal stem cell-derived exosomes attenuate neuroinflammation and oxidative stress through the NRF2/NF-κB/NLRP3 pathway. CNS Neurosci Ther. 2023 Sep 12. PMID: 37697971
【Title】
Human umbilical cord mesenchymal stem cell-derived exosomes attenuate neuroinflammation and oxidative stress through the NRF2/NF-κB/NLRP3 pathway
【Corresponding Author】
Jun Zhang, Department of Anesthesiology, Fudan University Cancer Hospital; Lei Fu Shanghai Key Laboratory of Geriatric Clinical Medicine, East China Hospital, Fudan University
【First Author】
Ji Che, Hui Wang, Jing Dong, Department of Anesthesiology, Fudan University Cancer Hospital
【Abstract】
Objective: To investigate whether human umbilical cord mesenchymal stem cell (hUC-MSC)-derived exosomes have therapeutic potential against lipopolysaccharide (LPS)-induced neuroinflammation.
Methods: Exosomes were isolated from hUC-MSC supernatant by ultracentrifugation and characterized by transmission electron microscopy and western blotting. LPS induces an inflammatory response in BV-2 cells, primary microglia cultures, and C57BL/6J mice. H2O2 has also been used to induce inflammation and oxidative stress in BV-2 cells. The effects of hUC-MSC-derived exosomes on inflammatory cytokine expression, oxidative stress and microglial polarization were investigated by immunofluorescence and western blotting.
Results: In vitro, treatment with hUC-MS-derived exosomes significantly reduced the expression of LPS or H2O2-induced oxidative stress and pro-inflammatory cytokines (IL-6 and TNF-α) and promoted the anti-inflammatory (classical M2) phenotype in LPS-treated mouse models. Mechanistically, exosomes upregulate NRF2 levels and inhibit LPS-induced phosphorylation of NF-κB p65 and NLRP3 inflammasome activation. In contrast, the reactive oxygen species scavenger NAC and the NF-κB inhibitor BAY 11-7082 also inhibited LPS-induced NLRP3 inflammasome activation and transitioned to the classical M2 phenotype. The anti-inflammatory and antioxidant effects of exosomes were eliminated after treatment with the NRF2 inhibitor ML385.
Conclusion: hUC-MS-derived exosomes can ameliorate LPS/H2O2-induced neuroinflammation and oxidative stress by inhibiting microglia NRF2/NF-κB/NLRP3 signaling pathway.
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2. Xixi Jia, Yanan Song, Zhengqian Li, Ning Yang, Taotao Liu, Dengyang Han, Zhuonan Sun, Chengmei Shi, Yang Zhou, Jie Shi, Yajie Liu, Xiangyang Guo. Melatonin regulates the circadian rhythm to ameliorate postoperative sleep disorder and neurobehavioral abnormalities in aged mice. CNS Neurosci Ther. 2023 Sep 22. PMID: 37736695
【Title】
Melatonin modulates circadian rhythm to ameliorate postoperative sleep disturbances and neurobehavioral abnormalities in aged mice
【Corresponding Author】
Xiangyang Guo, Yajie Liu, Department of Anesthesiology, Peking University Third Hospital; Jie Shi Beijing Key Laboratory of Drug Dependence Research, China Institute of Drug Dependence, Peking University
【First Author】
Xixi Jia, Yanan Song, Department of Anesthesiology, Peking University Third Hospital
【Abstract】
Background: Postoperative sleep disturbance (PSD) and delirium may be associated with surgery and inhalation anesthetics, with adverse effects in older patients. Emerging evidence suggests that circadian rhythms are associated with various neuropathological disorders, including Alzheimer's disease. Therefore, this study analyzed the potential role of circadian rhythm in PSD and delirium-like behavior in aged mice, aiming to determine whether exogenous melatonin can promote the regulation of circadian rhythm after laparotomy under sevoflurane anesthesia.
Methods: In this study, aged C57BL/6J mice who underwent laparotomy/sevoflurane anesthesia were selected as model animals. Buried food, open field, and Y-maze tests were used to assess delirium-like behavior, and electroencephalography/electromyography (EEG/EMG) was used to study sleep changes. We analyzed the transcriptional rhythms of clock genes in crossover sunuclear clusters (SCNs) to explore the effects of surgery and melatonin pretreatment on circadian rhythms. Thereafter, we tested the levels of melatonin receptors in SCNs and ERK/CREB pathway-associated proteins in the hippocampus and prefrontal cortex to assess their role in PSD and delirium-like behavior.
Results: Laparotomy under sevoflurane anesthesia had a greater impact than sevoflurane alone, resulting in sleep disturbances, altered sleep-wake rhythms, and delirium-like behavior. One day after laparotomy, the mRNA expression of Bmal1, Clock and Cry1 in aged mice showed peak shifts, the expression level of MT1 melatonin receptor in SCN increased, and p-ERK/ERK and p-CREB/CREB decreased in hippocampus and prefrontal cortex. Melatonin has significant efficacy in improving PSD and delirium-like behavior, restoring circadian rhythms, and reversing the abnormal expression of melatonin receptors and ERK/CREB pathways. In addition, most of the beneficial effects of melatonin are antagonized by the melatonin receptor antagonist Luzindole.
Conclusion: Melatonin receptors, circadian rhythm and ERK/CREB signaling pathways in SCN are involved in the pathophysiological process of PSD and delirium-like behavior. Melatonin interventions may be potential therapies for the prevention of PSD and delirium.
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3. Xia Shen, Huiqian Yu, Kaizheng Chen, Qineng Xue, Jin Lu, Zhongcong Xie. Association between severe preoperative hearing impairment and postoperative emergence agitation among elderly patients undergoing middle ear surgery . J Clin Anesth. 2023 Sep 7;91:111254. PMID: 37689025
【Title】
Correlation between severe preoperative hearing impairment and postoperative awakening agitation in elderly patients undergoing middle ear surgery
【Corresponding Author】
Chung Chung Tse, Division of Geriatric Anesthesia in the Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital and Harvard Medical School
【First Author】
Department of Anesthesiology, Eye and Otolaryngology Hospital, Fudan University; Huiqian Yu, Department of Otolaryngology, Eye and Otolaryngology Hospital, Fudan University
【Abstract】
Background: Hearing impairment is an independent risk factor for delirium. It is unclear whether preoperative hearing impairment in older patients is associated with postoperative awakening agitation (POEA). This study aims to explore the relationship between the two in older patients undergoing ear surgery.
Methods: This study was a prospective observational study conducted from July 15, 2020 to February 28, 2021 in an ear center of a tertiary hospital. The data of 417 elderly patients who underwent microscopic and endoscopic middle ear surgery were analyzed. Hearing function was assessed using a pure-tone mean preoperatively, and a PTA ≥50dB indicated severe hearing impairment. The POEA was scored using the Richmond agitation-sedation scale. Multivariate logistic regression analysis was used to determine the relationship between preoperative hearing function and POEA.
Results: A total of 417 patients were enrolled, of whom 45.8% were male, with a median age of 64 years (interquartile range: 62-67 years). There were 113 cases (27.1%) with severe hearing impairment and 42 cases (10.1%) with POEA before surgery. Multivariate logistic regression analysis showed that severe preoperative hearing impairment was associated with an increased risk of POEA (OR: 2.031; 95% confidence interval: 1.044-3.954, P= 0.037).
Conclusion: The results of this study suggest that severe hearing impairment before surgery may be an independent predictor of POEA in elderly patients undergoing middle ear surgery, but confirmatory studies are still needed. It also highlights the need for further research to better understand the biomarkers and pathogenesis of POEA, so as to identify targeted interventions for POEA and improve patient outcomes.
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4. Qi Chen, Mei-xian Jin, Si-min Wang, Ke-xin Wang, Li-qin Chen, Xiao-juan Zhu, Ying Zhang, Yi Wang, Yang Li, Shao Li, You-min Zeng, Lei Feng, Wan-ren Yang, Yi Gao, Shu-qin Zhou, Qing Peng. Establishing an hTERT-driven immortalized umbilical cord-derived mesenchymal stem cell line and its therapeutic application in mice with liver failure. J Tissue Eng, 2023 Sep 19; 14. PMID: 37736245
【Title】
Establishment of hTERT-driven immortalized umbilical cord mesenchymal stem cell lines and their therapeutic applications in mice with liver failure
【Corresponding Author】
Peng Qing, Institute of Regenerative Medicine, General Surgery Center, Second Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver; Shuqin Zhou, Department of Anesthesiology, Zhujiang Hospital, Southern Medical University
【First Author】
Qi Chen, Meixian Jin, Simin Wang, Department of Anesthesiology, Zhujiang Hospital, Southern Medical University;
【Abstract】
Acute liver failure (ALF) is characterized by rapid destruction of liver cells. It is a multietiological fulminant complication with a clinical mortality rate of more than 80%. Treatment with mesenchymal stem cells (MSCs) or MSCs-derived exosomes can alleviate acute liver injury, which has been demonstrated in animal experiments and clinical applications. However, similar to other stem cells, factors such as different cell sources, poor stability, and cell senescence limit the clinical application of mesenchymal stem cells. In order to achieve large-scale production and quality control of stem cells and their exosomes, umbilical cord mesenchymal stem cells (UCMSC) overexpressing human telomerase reverse transcriptase (hTERT) gene were transfected with lentivirus, and the hTERT-UCMSC immortalized cell line was constructed. Compared to the early passaged primary UCMSC (P3) and the immortalized cell line hTERT-UCMSC (P10), hTERT-UCMSCs retained key morphological and physiological features of UCMSCs at passage 35 (P35) and showed no signs of carcinogenicity and toxicity in mice. There was no difference in exosome production and exosome characterization in the culture of P3 primary cells, P10 and P35 immortalized hTERT-UCMSCs. Inoculation with hTERT-UCMSC (P35) or its exosomes improves survival and liver function in thioacetamide (TAA)-induced ALF mice. Our findings suggest that this immortalized cell line can retain its properties over long-term cultures. Inoculation with hTERT-UCMSCs and their exosomes may be used in the clinical treatment of liver failure in the future.
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5. Yong-chen Cui, Xiao-feng Wang, Yang Xu, Yue Cao, Gang Luo, Zhe Zhao, Jun-feng Zhang. Ropivacaine promotes axon regeneration by regulating Nav1.8-mediated macrophage signaling after sciatic nerve injury in rats. Anesthesiology, 2023 Sep 5. PMID: 37669448
【Title】
Ropivacaine promotes axon regeneration after sciatic nerve injury in rats by modulating Nav1.8-mediated macrophage signaling
【Corresponding Author】
Junfeng Zhang, Department of Anesthesiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine
【First Author】
Yong-chen Cui, Xiao-feng Wang, Yang Xu, Department of Anesthesiology, Shanghai Jiao Tong University School of Medicine, Sixth People's Hospital
【Abstract】
Background: Ropivacaine continuous nerve block is a commonly used method after surgery to repair traumatic peripheral nerve injury. Tetrodotoxin-insensitive voltage-gated sodium channel Nav1.8 was upregulated after peripheral nerve injury and was involved in macrophage inflammatory response. We investigated whether ropivacaine promotes peripheral nerve regeneration through NAV1.8-mediated macrophage signaling.
Methods: A sciatic nerve transection repair (SNT) model was established in adult SD rats. Rats are injected with 0.2% ropivacaine or 10 μM Nav1.8 selective inhibitor A-803467 around the injury site or near the sacrum for 3 days. Neuroregeneration was assessed by behavioral, electrophysiological, and morphological examinations. In addition, myelin debris clearance, macrophage phenotype, Nav1.8 expression, and neuropeptide expression were assessed using immunostaining, enzyme-linked immunosorbent assay, and western blotting.
Results: Compared with the SNT+ control group, the sensory, motor and sensorimotor coordination functions were significantly improved in the ropivacaine group in both groups. Electrophysiology (mean± SD: amplitude recovery index, control 0.43±0.17 vs ropivacaine 0.83±0.25, n = 11, P<0.001) and histological analysis showed that ropivacaine significantly promoted axon regeneration (percentage of NF-200 positive area: control 19.88± 2.81 vs ropivacaine 31.07±2.62, n = 6, P<0.001). We also found that the SNT+ropivacaine group had a faster clearance of myelin fragments, a significant increase in macrophage infiltration, and a transition from the M1 to M2 phenotypes compared to the SNT+ control group. In addition, ropivacaine significantly attenuated the upregulation of Nav1.8 on day 9 after sciatic nerve transection (4.12±0.30-fold for control and 2.75±0.36-fold for ropivacaine, n=5, P<0.001), which was consistent with increased expression of chemokine ligand 2 and substance P.
Conclusion: Continuous nerve block with ropivacaine may promote structural and functional recovery of injured sciatic nerves by modulating Nav1.8-mediated macrophage signaling.
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6. Yong-jun Liu, Zhi-yong Peng, Song-qiao Liu, Xiang-you Yu, Du-ming Zhu, Lin-lin Zhang, Jian-li Wen, You-zhong An, Li-ying Zhan, Xiao-chuang Wang, Yan Kang, Ai-jun Pan, Jing Yan, Li-na Zhang, Feng-ming Liu, Jun Zeng, Qin-han Lin, Ren-hua Sun, Jiang-quan Yu, Hua-xue Wang, Li Yao, Chuan-xi Chen, Ning Liu, Yao Nie, Jie Lyu, Kun Wu, Jian-feng Wu, Xiao Liu, Xiang-dong Guan. Efficacy and Safety of Ciprofol Sedation in ICU Patients Undergoing Mechanical Ventilation: A Multicenter, Single-Blind, Randomized, Noninferiority Trial . Crit Care Med, 2023, 51(10): 1318-1327. PMID: 37272947
【Title】
Efficacy and Safety of Cyclopofol Sedation in Mechanically Ventilated Patients in the ICU: A Multicenter, Single-blind, Randomized, Non-inferiority Trial
【Corresponding Author】
Guan Xiangdong, Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University
【First Author】
Liu Yongjun, Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University; Peng Zhiyong, Department of Critical Care Medicine, Zhongnan Hospital, Wuhan University; Songqiao Liu, Department of Critical Care Medicine, Zhongda Hospital, Southeast University; Yu Xiangyou, Department of Critical Care Medicine, First Affiliated Hospital of Xinjiang Medical University
【Abstract】
Objective: To investigate the efficacy and safety of cyclopofol in sedated patients requiring mechanical ventilation (MV) in the ICU.
Design: A multicenter, single-blind, randomized, non-inferiority trial.
Units: From December 2020 to June 2021, there were 21 centers nationwide.
Patients: A total of 135 ICU patients aged 18 to 80 years undergoing endotracheal intubation and MV are expected to require sedation for 6-24 hours.
Intervention: A total of 135 ICU patients were randomly divided into cyclopofol group (n=90) and propofol group (n=45) in a 2:1 ratio. Depending on the patient's physical condition, intravenous infusion of cyclopofol or propofol at a loading dose of 0.1 mg/kg or 0.5 mg/kg, respectively, for 4 minutes ± 30 seconds. Immediately thereafter, an initial maintenance dose of 0.3 mg/kg/hr or 1.5 mg/kg/hr of cyclopofol or propofol was given to achieve the target sedation range (+1 ~ -2) of the Richmond agitation-sedation score. At the same time, remifentanil was given continuous intravenous analgesia (loading dose 0.5 ~ 1 μg/kg, maintenance dose 0.02 ~ 0.15 μg/kg/min).
Measurements and main results: Of the 135 patients enrolled, 129 completed the study. The primary endpoint sedation success rate was 97.7% and 97.8% in the full analysis set (FAS) and 100% in the per-protocol set (PPS) for both cyclopofol and propofol arms. The non-inferiority cut-off was set at 8%, and the difference between FAS and PPS groups was -5.98% and -4.32%, and was confirmed with a bilateral lower 95% CI limit. Patients treated with cyclopofol had a longer recovery time (P = 0.003), but there was no difference in the other secondary endpoints (all P>0.05). There was no significant difference in the incidence of treatment-emergent adverse events (TEAEs) or drug-related TEAEs between the two groups (all P>0.05).
Conclusions: Among patients who received MV for 6-24 hours in the ICU in China, cyclopofol was well tolerated, and the sedative effect was not inferior to that of propofol.
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7. Kedi Guo, Xinghe Wang, Xian Lu, Yuping Yang, Wensi Lu, Shuting Wang, Xihui Tang, Yan Wu, Yuqing Xu, Qingsong Chen, and Su Liu. Effects of sarcopenia and frailty on postoperative recovery in elderly patients: A prospective cohort study. Journal of Cachexia, Sarcopenia and Muscle, 2023, Sep 19. PMID: 37724506
【Title】Effect of sarcopenia and frailty on postoperative rehabilitation in elderly patients: a prospective cohort study
【Corresponding Author】LIU Su, Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University;
【First Author】Kedi Guo, Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Jiangsu Provincial Key Laboratory of Anesthesiology, Xuzhou Medical University; Xinghe Wang, Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Jiangsu Provincial Key Laboratory of Anesthesiology, Xuzhou Central Hospital, Xuzhou Medical University; Xian Lu, Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Jiangsu Provincial Key Laboratory of Anesthesiology, Xuzhou Medical University
Background: Both sarcopenia and frailty are age-related declines in functional reserve and are associated with adverse health outcomes. It is important to understand the prognosis for a combination of these conditions. The aim of this study was to investigate the effects of sarcopenia and frailty on postoperative rehabilitation and risk factors in elderly patients.
Methods: This prospective cohort study enrolled 608 patients aged ≥ 60 years, ASA class I-III, and scheduled to undergo thoracic (non-cardiac) and abdominal surgery from March 1, 2022 to October 31, 2022. The degree of frailty was measured by the 28-item frailty index, while sarcopenia was assessed by the skeletal muscle index on computed tomography, hand grip strength, and 6-meter walking. Participants were divided into the following four groups: Group A: sarcopenia with frailty; Group B: sarcopenia only; Group C: debilitating only; Group D: neither sarcopenia nor asthenia. The primary outcome was morbidity at 90 days postoperatively. A multivariate logistic regression model was used to assess the association of sarcopenia, frailty, and morbidity at 90 days postoperatively.
Results: The median age (interquartile range) of participants was 68 (64-72) years, of which 62.7% were male. The prevalence of sarcopenia and frailty was 32.8% and 47.6%, respectively. The incidence rate at 90 days after surgery was 58.5% in group A, 46.2% in group B, 42.0% in group C, and 28.8% in group D (P < 0.001). In multivariate analysis, sarcopenia with frailty (odds ratio 2.21, 95% CI 1.26-3.89), sarcopenia only (odds ratio 1.84, 95% CI 1.01-3.36), frailty only (odds ratio 1.77, 95% CI 1.03-3.03), women (odds ratio 0.67, 95% CI 0.45-0.99), body mass index (odds ratio 0.94, 95% CI 0.88-0.99), and preoperative albumin (odds ratio 0.96, 95% CI 0.91-1.00) and surgical stress score (OSS) [OSS 3 (odds ratio 2.09, 95% CI 1.21-3.67); OSS 4 to 5 (odds ratio 3.81, 95% CI 2.31-6.42)] was strongly associated with incidence at 90 days postoperatively. In a multivariate analysis adjusted for inverse probability weighting, sarcopenia and frailty were also significantly associated with morbidity at 90 days postoperatively.
Conclusions: Sarcopenia and frailty in elderly patients, either alone or at the same time, are associated with an increased risk of morbidity 90 days after surgery. Sex, body mass index, preoperative albumin, and surgical stress are also independent factors for morbidity within 90 days of surgery.
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8. Xiao-Dong Wu, Qian Wang, Yu-Xiang Song, Xian-Yang Chen, Teng Xue, Li-Bin Ma, Yun-Gen Luo, Hao Li,Jing-Sheng Lou,Yan-Hong Liu, Di-Fen Wang, Qing-Ping Wu, Yu-Ming Peng, Wei-Dong Mi, and Jiang-Bei Cao. Risk factors prediction of 6-month mortality after non-cardiac surgery of older patients in China: A multicentre retrospective cohort study. International Journal of Surgery, 2023 Sep 22. PMID: 37738004
【Title】Risk factors for mortality at 6 months after noncardiac surgery in elderly Chinese patients: a multicenter retrospective cohort study
【Corresponding author】Cao Jiangbei, Mi Weidong, Department of Anesthesiology, First Medical Center, Chinese People's Liberation Army General Hospital, National Geriatric Clinical Research Center, Chinese People's Liberation Army General Hospital
【First author】Department of Anesthesiology, First Medical Center, Chinese People's Liberation Army General Hospital; Qian Wang Chinese Department of Anesthesiology, First Medical Center, People's Liberation Army General Hospital, Chinese People's Liberation Army Medical College; Yu-Xiang Song Chinese Department of Anesthesiology, First Medical Center, General Hospital of the People's Liberation Army
Background: It is crucial to identify risk factors associated with perioperative mortality, especially in older patients. Predicting the 6-month mortality risk of elderly patients based on large datasets can help patients and surgeons make perioperative clinical decisions. The purpose of this study was to use the clinical data of 11,894 elderly patients in China to establish a risk prediction model for death within 6 months after noncardiac surgery.
Materials and Methods:A multicenter, retrospective cohort study was conducted in 20 tertiary hospitals. A review of 11,894 patients aged ≥ 65 years who underwent noncardiac surgery between April 2020 and April 2022 was included. The minimum absolute contraction and selection operator model based on linear regression was used to analyze and select the risk factors, and various machine learning methods were used to construct the prediction model of 6-month death.
Results: We predicted 12 preoperative risk factors associated with mortality at six months after noncardiac surgery, including laboratory-related risk factors such as monocyte proportion and total blood cholesterol level, as well as medical history-related risk factors such as stroke, chronic disease history, etc. Using the random forest model, we constructed a prediction model with satisfactory accuracy (area under the ROC curve = 0.97).
Conclusions: Twelve preoperative risk factors associated with 6-month mortality in elderly patients undergoing noncardiac surgery have been identified. These preoperative risk factors provide evidence for a comprehensive preoperative anesthetic evaluation and provide the necessary information for anesthesiologist clinical decision-making.
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9. Wenjuan Zhang, Bowei Zhou, Xiao Yang, Jin Zhao, Jingjuan Hu, Yuqi Ding, Shuteng Zhan, Yifeng Yang, Jun Chen, Fu Zhang, Bingcheng Zhao, Fan Deng, Zebin Lin, Qishun Sun, Fangling Zhang, Zhiwen Yao, Weifeng Liu, Cai Li, and Ke-Xuan Liu. Exosomal circEZH2_005, an intestinal injury biomarker, alleviates intestinal ischemia/reperfusion injury by mediating Gprc5a signaling. Nat Commun, 2023; 14: 5437. PMID: 37673874
【Title】
Intestinal injury biomarker exosomes circEZH2_005 attenuate intestinal ischemia/reperfusion injury by mediating Gprc5a signaling
【Corresponding Author】
Kexuan Liu, Si Li, Department of Anesthesiology, Nanfang Hospital, Southern Medical University
【First Author】
Wenjuan Zhang, Baiwei Zhou, Department of Anesthesiology, Nanfang Hospital, Southern Medical University
【Abstract】
Intestinal ischemia/reperfusion (I/R) injury is a serious clinical condition with no optimal diagnostic markers and no clear molecular etiology. Plasma exosomal circular RNAs (circRNAs) are valuable biomarkers and therapeutic targets for various diseases, but their role in intestinal I/R damage is unclear. In this study, the expression profile of circRNAs in intestinal tissue exosomes collected from intestinal I/R mice was screened and the circEZH2_005 was identified as a significantly downregulated exosomal circRNA. At the same time, patients who developed intestinal I/R injury after clinical cardiac surgery also experienced a reduction in plasma circEZH2_005. Exosome circEZH2_005 has significant diagnostic value for I/R-induced intestinal injury. Mechanistically, circEZH2_005 is highly expressed in intestinal crypt cells. Upregulation of circEZH2_005 promotes the proliferation of Lgr5+ stem cells through direct interaction with hnRNPA1 and enhances the stability of Gprc5a, thereby attenuating I/R-induced intestinal mucosal injury. Therefore, exosome circEZH2_005 can be used as biomarkers of intestinal I/R injury, and targeting the circEZH2_005/hnRNPA1/Gprc5a axis may be a potential therapeutic strategy for intestinal I/R injury.
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10.Ting Li, Ying Yue, Yan Ma, Ziwen Zhong, Miaomiao Guo, Jie Zhang, Zhiping Wang, Changhong Miao. Fasting-mimicking diet alleviates inflammatory pain by inhibiting neutrophil extracellular traps formation and neuroinflammation in the spinal cord. Cell Commun Signal, 2023, 21: 250. PMID: 37735678
【Title】
A simulated fasting diet relieves inflammatory pain by inhibiting the formation of neutrophil extracellular traps and neuroinflammation in the spinal cord
【Corresponding Author】
Miao Changhong, Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Perioperative Stress and Protection; Zhiping Wang, Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University; Zhang Jie, Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Perioperative Stress and Protection
【First Author】
Li Ting, Yue Ying, Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Perioperative Stress and Protection
【Abstract】
Background: Neutrophil extracellular traps (NETs) promote neuroinflammation and thus central nervous system (CNS) disease progression. However, it is unclear whether CNS-related NETs affect pain outcomes. A simulated fasting diet (FMD) alleviates neurological disorders by reducing neuroinflammation and promoting nerve regeneration. Therefore, in this study, we explored the role of NETs in the CNS during acute pain and investigated the role of FMD in inhibiting NETs and relieving pain.
Methods: Complete Freund's adjuvant (CFA) was injected into the hindpaws of mice to establish an inflammatory pain model. The FMD diet regimen was used in the perioperative period. PAD4 siRNA or CI-amidine (PAD4 inhibitor) is used to inhibit the formation of NETs. Monoamine oxidase-B (MAO-B) knockdown can be inhibited by AAV-GFAP-shRNA or AAV-hSyn-shRNA, or by selegiline, a MAO-B inhibitor. Western blotting, immunofluorescence, ELISA, and flow cytometry were used to detect NETs, neuroinflammation, and changes in related signaling pathways.
Results: During the acute phase of inflammatory pain, NETs accumulated in the spinal cord of mice. This is associated with increased neuroinflammation. At the same time, inhibition of the formation of NETs can alleviate ectopic pain and neuroinflammation in CFA mice. FMD inhibits NETs production and reduces inflammatory pain, NETs inhibitor CI-amidine treatment enhances inflammatory pain, and NETs inducer phorbol 13-acetate (PMA) reverses this effect. Mechanistically, the neutrophil recruitment pathways MAO-B/5-hydroxyindoleacetic acid (5-HIAA)/G protein-coupled receptor 35 (GPR35) and the NET-inducible pathway MAO-B/reactive oxygen species (ROS) are significantly upregulated during the development of inflammatory pain. MAO-B is predominantly expressed in astrocytes and neurons of the spinal cord of CFA mice. However, knockdown or inhibition of MAO-B is effective in reducing CFA-induced inflammatory pain, NETs formation, and neuroinflammation of the spinal cord. In addition, in salvage experiments, MAO-B inhibitors synergistically enhanced FMD-induced pain relief, NETs inhibition, and neuroinflammation attenuation, while supplementation with MAO-B downstream molecules (i.e., 5-HIAA and PMA) eliminated this effect.
Conclusion: NETs released by neutrophils in the spinal cord are involved in the development of pain. FMD inhibits the formation of NETs and NETs-induced neuroinflammation by inhibiting the MAO-B/5-HIAA/GPR35 and MAO-B/ROS pathways in astrocytes and neurons, thereby alleviating pain progression.
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11.Huijing Xie, Ju Li, Nan Lian, Min Xie, Minming Wu, Kuo Tang, Yi Kang, Peilin Lu,Tao Li. Defective branched-chain amino acid catabolism in dorsal root ganglia contributes to mechanical pain. EMBO Rep. 2023 Sep18. PMID: 37721527
【Title】Defects in the catabolism of branched-chain amino acids in the dorsal root ganglia lead to mechanical pain
【Corresponding Author】LI Tao, Peilin Lu, Anesthesia Surgery Center, West China Hospital, Sichuan University
【First Author】Huijing Xie,Ju Li, National Clinical Research Center for Geriatrics, Anesthesiology and Surgery Center, West China Hospital, Sichuan University, Laboratory of Mitochondria and Metabolism, National and Local Joint Engineering Research Center for Anesthesiology and Translational Medicine, West China Hospital, Sichuan University; Nan Lian, Anesthesia Surgery Center, West China Hospital, Sichuan University, National Clinical Research Center for Geriatrics, Laboratory of Mitochondria and Metabolism, National and Local Joint Engineering Research Center for Anesthesiology, West China Hospital, Sichuan University, MR Research Center for Radiology, West China Hospital, Sichuan University, Key Laboratory of Functional and Molecular Imaging, Sichuan Province
Impaired catabolism of branched-chain amino acids (BCAAs) has recently been thought to be involved in the development of mechanical pain, but the underlying molecular mechanisms are still unclear. Here, we report BCAA catabolic defects in dorsal root ganglion (DRG) neurons that sensitize mice to mechanical pain by increasing lactate production and expression of the mechanical transduction channel Piezo2. In obese mice fed with a high-fat diet, we observed downregulation of PP2Cm, a key regulator of the BCAA catabolic pathway, in DRG neurons. Condition: DRG neuron mice with PP2Cm knockout exhibit mechanical allodynia under normal or SNI-induced neuropathic injury conditions. In addition, VAS scores in patients with peripheral neuropathic pain were positively correlated with BCAA levels in plasma. Mechanistically, BCAA catabolic defects in DRG neurons promote lactate production through glycolysis, thereby increasing H3K18la modification and driving Piezo2 expression. Inhibition of lactate production or Piezo2 silencing attenuates the painful phenotype of mechanical stimulation in knockout mice. Therefore, our study demonstrates the causal role of BCAA catabolic defects in mechanical pain by enhancing metabolite-mediated epigenetic regulation.
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12. Penghui Wei, Min Jia, Xiangyi Kong, Wenyuan Lyu, HaoFeng, Xinyi Sun, Jianjun Li , Jian-jun Yang. Human umbilical cord-derived mesenchymal stem cells ameliorate perioperative neurocognitive disorder by inhibiting inflammatory responses and activating BDNF/TrkB/CREB signaling pathway in aged mice. Stem Cell Res 2023 Ther 14. PMID: 37735415
【Title】Human umbilical cord-derived mesenchymal stem cells can improve perioperative neurocognitive impairment in elderly mice by inhibiting inflammatory response and activating BDNF/TrkB/CREB signaling pathway【Corresponding Author】Jianjun Yang, Department of Anesthesiology and Perioperative Medicine, First Affiliated Hospital of Zhengzhou University, Institute of Neurology, Academy of Medical Sciences, Zhengzhou University, Henan International Joint Laboratory for Pain Cognition and Emotion Research
【First Author】Penghui Wei, Department of Anesthesiology and Perioperative Medicine, First Affiliated Hospital of Zhengzhou University, Department of Anesthesiology, Qilu Hospital, Shandong University, Institute of Neurology, Academy of Medical Sciences, Zhengzhou University, Henan International Joint Laboratory of Pain Cognition and Emotion Research
Background: Perioperative neurocognitive impairment (PND) is a key complication affecting the elderly after anesthesia and surgery. If multiple drug treatments for PND are not translated from preclinical studies to clinical settings, new therapeutic strategies need to be explored. Human umbilical cord mesenchymal stem cells (hUC-MSCs) therapy has emerged as a promising therapeutic strategy for the treatment of neurodegenerative diseases and has the potential to translate basic science into clinical practice. This study investigated the effect and potential mechanism of hUC-MSCs on PND in aged mice.
Methods: hUC-MSCs were isolated from the umbilical cord of infants and identified using flow cytometry and differentiation assays. We used 18-month-old male C57BL/6 mice under isoflurane anesthesia for aseptic laparotomy to maintain spontaneous ventilation and establish a PND model. Before anesthesia, hUC-MSCs were slowly injected into mice via the tail vein. Cognitive function, systemic and neuroinflammatory responses, neuroplasticity, endogenous neurogenesis, and brain-derived neurotrophic factor (BDNF) are assessed. To determine the brain mechanism by which hUC-MSCs mediate their neuroprotective effects in PND, the BDNF receptor antagonist K252a is intraperitoneally injected preoperatively. The hippocampal BDNF/TrkB/CREB signaling pathway and metabolomic characteristics were evaluated.
Results: hUC-MSC treatment improved learning and memory impairment in aged PND mice. Its downstream effects are inhibition of systemic and hippocampal inflammation and restoration of neurogenesis and neuroplastic dysregulation. Interestingly, after hUC-MSC treatment, the levels of mature BDNF in the hippocampus increased, but the levels of proBDNF did not. Further analysis showed that the improvement in cognitive recovery, neurogenesis, and neuroplastic dysregulation caused by exposure to hUC-MSCs was at least partially mediated by activation of the BDNF/TrkB/CREB signaling pathway. Non-targeted metabolomics further suggests that lipid metabolism dysfunction may be downstream of the BDNF/TrkB/CREB signaling pathway in hUC-MSC-mediated neuroprotection of PND.
Conclusions: Our study highlights the beneficial effects of hUC-MSC treatment on PND and provides a basis for considering the potential use of hUC-MSCs in the perioperative period.
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13. Yumiao Shi, Yiqi Zhang, Suyang Yu, Jiamei Luo, Zhiying Pan, Xiaoqiang Wang, Jie Tian. Activation of kappa opioid receptor (KOR) inhibits estrogen receptor
(ER)-positive breast cancer through the KOR-ER-XBP1 pathway. Biomedicine & Pharmacotherapy, 167 (2023) 115462. PMID: 37708692
【Title】Activation of kappa opioid receptor (KOR) inhibits estrogen receptor (ER)-positive breast cancer through the KOR-ER-XBP1 pathway
【Corresponding Author】Xiaoqiang Wang, Jie Tian, Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine
【First Author】Yumiao Shi,Yiqi ZhangDepartment of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Opioids are commonly used in breast cancer (BC) patients, both for perioperative analgesia and for chronic cancer pain. Studies suggest that opioid receptors (ORs) may be associated with the prognosis of patients with BC. However, the exact role of different opioid receptors is still poorly understood. In the present study, we found that κ opioid receptor (KOR) was the only OR among the four OR types that was significantly reduced in BC tumor tissue compared to peritumoral normal tissue. In addition, in estrogen receptor (ER)-positive BC patients, reduced KOR expression was associated with poor clinical prognosis. In vitro studies confirmed the anti-tumor effects of KOR agonists on ER-positive MCF-7 and T47D cells, suggesting that activation of KOR significantly inhibited cell proliferation and promoted apoptosis. Using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein Interaction Network (PPI) analysis, we found that KOR-ER-XBP1 is a potential downstream signaling pathway that mediates the antitumor effects of KOR agonists. Finally, the effect of XBP1 was confirmed, and both the increase in ER-positive BC cell proliferation and monoclonal formation capacity induced by KOR activation were significantly eliminated after XBP1 silencing. These findings allow us to better understand the role of different ORs in BC, determining that KOR agonists provide analgesia better than traditional μ opioid receptor (MOR) agonists in patients with ER-positive BC because they are associated with better prognosis.
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14. Zhihao Sheng, Qidong Liu, Rong Lin, Yan Zhao, Weiqing Liu, Zhendong Xu, Zhiqiang Liu. Potential CSF biomarkers of postpartum depression following delivery via caesarian section. Journal of Affective Disorders, 342(2023)177-181. PMID: 37730149
【Title】
Potential cerebrospinal fluid biomarkers of postpartum depression after cesarean section
【Corresponding Author】
Zhiqiang Liu, Zhendong Xu, Department of Anesthesiology, First Maternity and Infant Health Hospital, Shanghai Tongji University School of Medicine, and Translational Medicine Research Center, Shanghai First Maternity and Infant Health Hospital
【First Author】
Zhihao Sheng, Department of Anesthesiology, The First Maternity and Infant Health Hospital, Shanghai Tongji University School of Medicine, and Translational Medicine Research Center, Shanghai First Maternity and Infant Health Hospital; Qidong Liu, Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital, Tongji University, Key Laboratory of Spinal Cord Injury Regeneration and Repair, Ministry of Education (Tongji University)
【Abstract】
Background: Postpartum depression (PPD), a depressive episode after childbirth, is a serious and common psychiatric disorder. While there are many screening tools for depressive episodes, such as the Edinburgh Postnatal Depression Scale (EPDS), there are no objective biological indicators to predict PPD. Although some studies have been conducted to identify biomarkers in PPD, there is limited exploration of cerebrospinal fluid (CSF) in direct contact with the brain. Therefore, there is a need to explore new potential cerebrospinal fluid biomarkers to predict PPD and develop specific preventive interventions.
Methods: Cerebrospinal fluid (CSF) was collected from 75 women with cesarean section. Among the 28 healthy women who did not meet the exclusion criteria, 10 were pregnant with an EPDS (6-wpp) score of < 5 at 6 weeks postpartum and 10 were pregnant with a postpartum 6-wpp score of ≥13. Gas chromatography-mass spectrometry (GC-MS) analysis was used to analyze cerebrospinal fluid.
Results: We found that capric acid, dodecanoic acid, arachidonic acid, and docaneic acid in cerebrospinal fluid were significantly negatively correlated with PPD symptoms, while L-tryptophan was significantly positively associated with PPD symptoms. In addition, these five biomarkers can be used as effective predictive biomarkers for PPD.
Limitations: the main limitations were the inclusion of women who had cesarean section and the small sample size.
Conclusion: This study innovatively studied the potential predictive biomarkers of PPD before the onset of PPD through intrapartum maternal cerebrospinal fluid metabolomics, which provided a more objective method for predicting and diagnosing PPD, which was helpful to identify high-risk mothers, carry out early secondary prevention, and reduce the global burden of PPD.
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15. Yan Dong, Chunyu Ai, Ying Chen, Zaili Zhang, Dong Zhang, Sidan Liu, Xiangyi Tong, Hong Ma. Eph receptor A4 regulates motor neuron ferroptosis in spinal cord ischemia/reperfusion injury in rats. Neural Regen Research, 18(10):2219-2228. PMID: 37056141
【Title】Eph receptor A4 regulates motor neuron ferroptosis in rat spinal cord ischemia-reperfusion injury [Corresponding Author] Ma Hong, Department of Anesthesiology, The First Affiliated Hospital of China Medical University
【First Author】Yan Dong, Department of Anesthesiology, The First Affiliated Hospital of China Medical University【Abstract】Previous studies have shown that the receptor tyrosine kinase Eph receptor A4 (EphA4) is abundantly expressed in the nervous system. The EphA4 signaling pathway plays an important role in regulating motor neuron ferroptosis in motor neuron disease. In order to investigate whether the EphA4 signaling pathway is involved in ferroptosis in spinal cord ischemia-reperfusion injury, a rat model of spinal cord ischemia-reperfusion injury was established by clamping the left carotid artery and the left subclavian artery. We found that after spinal cord ischemia-reperfusion injury, EphA4 expression in anterior horn neurons increased, ferroptosis-related indicators deteriorated significantly, the number of mitochondria consistent with ferroptosis characteristics increased substantially, motor nerve function deteriorated, blood-spinal cord barrier permeability increased, and motor neuron mortality increased. Inhibition of EphA4 largely restores these effects. However, intrathecal administration of the ferroptosis-inducing agent Erastin counteracted the beneficial effects of treatment with EphA4 inhibitors. Proteins that interact with EphA4 were identified by mass spectrometry analysis and PubMed search, most notably Beclin1 and Erk1/2. Our results suggest that inhibition of EphA4 expression reduces binding to Beclin1, significantly decreases p-Beclin1, and reduces the formation of the Beclin1-XCT complex. Inhibition of EphA4 also reduces binding to p-Erk1/2 and significantly reduces the expression of c-Myc, transferrin receptor 1, and p-Erk1/2. In addition, we observed the colocalization of EphA4 and p-Beclin1 and EphA4 and p-ERK1/2 in anterior horn neurons. In summary, EphA4 is involved in the regulation of ferroptosis in the anterior horn of spinal cord motor neuron by promoting the formation of the Beclin1-XCT complex and activating the Erk1/2/c-Myc/transferrin receptor 1 axis.
Retrieved: Sun Yao, Wang Yimin
Translation: Xie Yixin, Xiao Tong
Proofreading: Liu Minyu, Zhao Wei
Instructor Profile:
Li Le
Deputy Chief Physician of the Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, M.D., double postdoctoral fellow of Stanford Medical School and Baylor School of Medicine, academic master's supervisor. She is currently a member of the Youth Committee of the Anesthesiology Branch of the Guangdong Medical Association, a member of the Perioperative Basic and Translational Medicine Branch, and a member of the Anesthesiology and Perioperative Medicine Professional Committee of the Guangdong Women Physicians Association. He has presided over 1 National Natural Science Foundation Youth Fund, 2 general funds, and 2 Guangdong Natural Science Foundations, and published more than 10 papers as the first author or corresponding author, with the highest impact factor of 23.653 points. His main research interests are perioperative nerve injury and myocardial injury.
【Pearl River Vision-Introduction to the Translation Team】
Since its establishment in May 2020, the translation team of the "Pearl River Vision" of the Department of Anesthesiology of Zhujiang Hospital of Southern Medical University has mainly been engaged in the translation and promotion of the latest progress in the field of anesthesiology and related disciplines. The translation team searches the latest literature for the first time every month, organizes the research groups of graduate supervisors to translate and proofread, and publishes it in the "Pearl River Vision" column of the official account of the "New Youth Anesthesia Forum" after reviewing and collectively discussing the finalized draft through the division of labor among the team members. So far, with the support and joint efforts of all graduate tutors and research groups of the Department of Anesthesiology of Zhujiang Hospital of Southern Medical University, the literature push column of "Pearl River Vision" has gone through more than 700 days and nights. In the future, we will continue to share the academic achievements related to anesthesiology at home and abroad, and welcome colleagues at home and abroad to put forward constructive comments on the content of this column.
"Pearl River Vision", pay attention to professionalism, pursue excellence, and walk with the world!
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