Introduction Delirium is a common complication in elderly patients after major surgeries and can lead to poor outcomes such as neurocognitive decline. Acetaminophen is one of the most widely used adjuvants for perioperative multimodal analgesia. Previous studies showed that it can effectively alleviate postoperative pain, promote opioid sparing and exert anti-neuroinflammatory response, showing strong potential for preventing postoperative delirium. We, thus, propose to test the primary hypothesis that postoperative intravenous acetaminophen would reduce delirium over 5 postoperative days in older patients following major non-cardiac surgery. Methods and analysis We propose a multicentre, randomised, placebo-controlled, parallel-group trial in patients aged>65 years old scheduled for non-cardiac major surgery with general anaesthesia expected to last at least 2 hours. A total of 1930 elderly patients will be enrolled and randomised at 1:1 ratio to acetaminophen or saline placebo groups, stratified by age, education level and trial site with randomsised blocking. Acetaminophen or saline will be given when the surgical suture begins at the end of surgery and, thereafter, a total of seven doses within 48 hours after surgery. Our primary outcome will be the incidence of delirium, assessed two times per day, through the fifth postoperative day. Secondary and exploratory outcomes will include pain scores with movement, total opioid consumption, severity of delirium, intensive care unit and hospital lengths of stay. Ethics and dissemination This study has been approved by the Ethics Committee of Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine (LY2023-239-C) and approved by each participating centre. This report follows the Consolidated Standards of Reporting Trials reporting guideline for randomised studies. The findings will be shared in academic meetings and peer-reviewed academic journals. Trial registration number NCT06653465.

Calorie restriction (CR) mimetic, resveratrol (RSV), has the capacity of promoting phagocytosis. However, its role in hepatic ischemia and reperfusion injury (HIRI) remains poorly understood. This study aimed to investigate the effect of RSV on alleviating HIRI and explore the underlying mechanisms. RSV was intraperitoneally injected in mice HIRI model, while RSV was co-incubated with culture medium for 24 h in RAW 264.7 cells and kupffer cells. Macrophage efferocytosis was assessed by immunostaining of PI and F4/80. The clearance of apoptotic neutrophils in the liver was determined by immunostaining of Ly6-G and cleaved-caspase-3. HE staining, Suzuki's score, serum levels of ALT, AST, TNF-α and IL-1β were analyzed to evaluate HIRI. The efferocytosis inhibitor, Cytochalasin D, was utilized to investigate the effect of RSV on HIRI. Western blot was employed to measure the levels of AMPKα, phospho-AMPKα, STAT3, phospho-STAT3 and S1PR1. SiSTAT3 and inhibitors targeting AMPK, STAT3 and S1PR1, respectively, were used to confirm the involvement of AMPK/STAT3/S1PR1 pathway in RSV-mediated efferocytosis and HIRI. RSV facilitated the clearance of apoptotic neutrophils and attenuated HIRI, which was impeded by Cytochalasin D. RSV boosted macrophage efferocytosis by upregulating the levels of phospho-AMPKα, phospho-STAT3 and S1PR1, which was reversed by AMPK, STAT3 and S1PR1 inhibitors, respectively. Inhibition of STAT3 suppressed RSV-induced clearance of apoptotic neutrophils and exacerbated HIRI. CR mimetic, RSV, alleviates HIRI by promoting macrophages efferocytosis through AMPK/STAT3/S1PR1 pathway, providing valuable insights into the mechanisms underlying the protective effects of CR on attenuating HIRI.

The strategy of enhancing molecular recognition by improving the binding affinity of drug molecules against targets has generated a lot of successful therapeutic applications. However, one critical consequence of such affinity improvement, generally called "on-target, off-tumor" toxicity, emerged as a major obstacle limiting their clinical usage. Herein, we provide a modular assembly strategy that affords affinity-tunable DNA nanostructures allowing for immobilizing multiple aptamers that bind to the example antigen of EpCAM with different affinities. We develop a theoretical model proving that the apparent affinity of aptamer assemblies to target cells varies with antigen density as well as aptamer valency. More importantly, we demonstrate experimentally that the theoretical model can be used to predict the least valency required for discrimination between EpCAMhigh and EpCAMlow cells in vitro and in vivo. We believe that our strategy will have broad applications in an engineering nucleic acid-based delivery platform for targeted and cell therapy.

Background The prevalence of metabolic associated fatty liver disease (MAFLD) presented a booming growth over recent years in the whole world. MAFLD was associated with a higher risk of end-stage liver disease, hepatocellular carcinoma and liver transplantation. Accumulating evidence indicated that gut microbiota and MAFLD were interrelated and interacted with each other. However, to the knowledge of the authors, no bibliometric quantitative analysis has been carried out to evaluate the links between the gut microbiota and MAFLD. This study aimed to use bibliometric analysis to evaluate current publication trends and hotspots in the links between the gut microbiota and MAFLD, in order to advance research in this field. Methods The articles regarding the links between gut microbiota and MAFLD from 2002 to 2021 were identified from the Science Citation Index-Expanded of Web of Science Core Collection. CiteSpace software, Vosviewer, the R package “bibliometrix” and the Online Analysis Platform of Literature Metrology were used to analyze current publication trends and hotspots in this field. Results A total of 707 articles were retrieved regarding the links between gut microbiota and MAFLD from 2002 to 2021. The USA occupied the leading role until 2015 and the dominance of China started in 2016. The USA was the most frequently involved country in international cooperation. Shanghai Jiao Tong University was the most productive institution. Ina Bergheim was the most productive author, publishing 14 articles. The co-citation keywords cluster label displayed ten main clusters: probiotics, bile acid, immune function, adolescents, nutritional genomics, high fat diet, systems biology, lipopolysaccharides, phosphatidylcholine, and oxidative stress. Keyword bursts analysis indicated that diet induced obesity, metabolic syndrome, ppar alpha, and lactobacillus were the research hotspots with high strength. Conclusion The number of publications covering the links of gut microbiota and MAFLD increased dramatically in the past decade and especially became exponential growth in the last 3 years. Probiotics and bile acid will be the research direction of great importance in the etiology and novel treatment for MAFLD. This study provided systematic information and instructive assistance for future research work, that helped to discover the mechanisms and new treatments of MAFLD.

Background and aims:The gut microbiota is involved in the regulation of pain, which is proved by plenty of evidence. Although a substantial quantity of research on the link between the gut microbiota and pain has emerged, no study has focused on the bibliometric analysis of this topic. We aim to present a bibliometric review of publications over the past 20 years and predict research hot spots.Methods:Relevant publications between 2002 and 2021 were extracted from the Science Citation Index-Expanded (SCI-EXPANDED) of the Web of Science Core Collection (WoSCC) database on April 22, 2022. CiteSpace (version 5.8 R3c), VOSviewer, the Online Analysis Platform of Literature Metrology, and the R package bibliometrix were used to analyze and visualize.Results:A total of 233 articles have been published between 2002 and 2021. The number of publication outputs increased rapidly since 2016. The collaboration network revealed that the USA, Baylor College of Medicine, and Vassilia Theodorou were the most influential country, institute, and scholar, respectively. Alimentary pharmacology and therapeutics and Gut were the most co-cited journal and Neurogastroenterology and Motility was the most productive journal. Visceral sensitivity, fibromyalgia, gastrointestinal, chronic pain, stress, gut microbiome, LGG, brain-gut axis, SLAB51, and sequencing were the top 10 clusters in co-occurrence cluster analysis. Keyword burst detection indicated that the brain-gut axis and short-chain fatty acid were the current research hot spots.Conclusion:Research on the links between the gut microbiota and pain has increased rapidly since 2016. The current research focused on the brain-gut axis and short-chain fatty acid. Accordingly, the SCFAs-mediated mechanism of pain regulation will be a research direction of great importance on the links between the gut microbiota and pain. This study provided instructive assistance to direct future research efforts on the links between the gut microbiota and pain.

Remifentanil is a potent, short-acting opioid analgesic drug that can protect tissues from ischemia and reperfusion injury though anti-inflammatory effects. However, the utility of remifentanil in liver regeneration after hepatectomy is not known. Using a 70% hepatectomy mouse model (PHx), we found that preconditioning animals with 4 mu g/kg remifentanil enhanced liver regeneration through supporting hepatocyte proliferation but not through anti-inflammatory effects. These effects were also phenocopied in vitro where 40 mM remifentanil promoted the proliferation of primary mouse hepatocyte cultures. We further identified that remifentanil treatment increased the expression of beta-promote liver regeneration in liver-specific beta-arrestin 2 knockout (CKO) mice subjected to PHx. While remifentanil increased the expression of activated (phosphorylated)-ERK and cyclin D1 in PHx livers, their levels were not signifi-cantly changed in remifentanil-treated CKO mice nor in WT mice pretreated with the ERK inhibitor U0126. Our findings suggest that remifentanil promotes liver regeneration via upregulation of a beta-arrestin 2/ERK/cyclin D1 axis, with implications for improving regeneration process after hepatectomy. (C) 2021 Elsevier Inc. All rights reserved.

The ability to regulate membrane protein abundance offers great opportunities for developing therapeutic sites for various diseases. Herein, we describe a platform for the targeted degradation of membrane-associated proteins using bispecific aptamer chimeras that bind both the cell-surface lysosome-shuttling receptor (IGFIIR) and the targeted membrane-bound proteins of interest. We demonstrate that the aptamer chimeras can efficiently and quickly shuttle the therapeutically relevant membrane proteins of Met and PTK-7 to lysosomes and degrade them through the lysosomal protein degradation machinery. We anticipate that our method will provide a universal platform for the use of readily synthesized aptamer materials for biochemical research and potential therapeutics.

目的·探讨类风湿关节炎(rhumatoid arthritis,RA)患者B细胞亚群特点及表没食子儿茶素没食子酸酯(epigallocatechingallate,EGCG)对RA患者B细胞亚群的调节作用.方法·纳入年龄、性别匹配的RA患者和健康对照各29例,运用配对t检验分析2组外周血中B细胞亚群的差异;根据28关节疾病活动评分(disease activity score in 28 joints,DAS28)的值将RA患者分为活动组(2.6≤DAS28<5.1)和高度活动组(DAS28≥5.1),运用t检验分析2组外周血中B细胞亚群的差异.在0、10、100μmol/L EGCG和2.5μg/L葡萄球菌A蛋白共刺激条件下,体外培养RA患者外周血单个核细胞,24 h后应用实时聚合酶链反应检测B细胞活化因子受体(B-cell-activating factor receptor,BAFF-R)的表达水平,48 h后用流式细胞术检测B细胞亚群.结果 ·RA患者的总B细胞、未分化B细胞、记忆B细胞和浆母细胞占淋巴细胞比例和数量均高于健康对照(P<0.05),而CD19+IL-10+调节性B细胞(regulatory B cell,Breg)占淋巴细胞比例和数量与健康对照相比差异无统计学意义(P>0.05).10例活动组与19例高度活动组RA患者的总B细胞及各B细胞亚群(除CD19+IL-10+Breg外)占淋巴细胞比例和数量的差异无统计学意义(P>0.05),6例活动组与12例高度活动组RA患者CD19+IL-10+Breg占淋巴细胞比例和数量的差异也无统计学意义(P>0.05).RA患者外周血总B细胞所占比例与IgG型类风湿因子呈弱正相关(r=0.308).EGCG能显著提高CD19+IL-10+Breg占淋巴细胞比例(P<0.05),且100μmol/L EGCG能显著降低总B细胞中BAFF-R mRNA的表达水平(P=0.000);但其对未分化B细胞、记忆B细胞和浆母细胞占淋巴细胞比例无显著影响(P>0.05).结论 ·B细胞可能在RA发病中发挥辅助作用,RA患者CD19+IL-10+Breg数量反馈性增加,EGCG可促进Breg增殖,降低BAFF-R mRNA表达水平.

自身免疫病(autoimmune disease,AID)是机体对自身抗原产生免疫反应,进而导致体内组织器官损害的疾病.作为一种具有独特表型和功能的T淋巴细胞亚群,γδT细胞与AID的发生发展密切相关.故文章就γδT细胞与多种免疫细胞的相互作用在AID中的作用、机制研究作一综述.