Maresin1 alleviates neuroinflammation by inhibiting caspase-3/ GSDME-mediated pyroptosis in mice cerebral ischemia-reperfusion model.

OBJECTIVE: To explore the mechanism of Maresin1 in reducing cerebral ischemia-reperfusion injury. MATERIALS AND METHODS: Male C57BL/6 mice were randomly divided (n = 5 in each group), and focal middle cerebral artery occlusion (MCAO) model was used to simulate cerebral ischemia/reperfusion injury. TTC and the Longa score were used to detect the degree of neurological deficits. Western blot was used to detect the expression levels of GSDME, GSDME-N, caspase-3 and cleaved caspase-3 in cerebral ischemic penumbra tissue, and immunofluorescence was used to detect the expression levels of GSDME-N. The mRNA expression levels of GSDME and pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) were detected by RT-PCR. RESULTS: Compared with sham group, GSDME mRNA levels in MCAO group were significantly increased at 12 h and 24 h after reperfusion, and GSDME and GSDME-N significantly increased at 6-48 h after reperfusion. Compared with sham group, the percentage of infarct size, the Longa score, the mRNA expression levels of IL-1ß, IL-6 and TNF-α, and GSDME, GSDME-N, caspase-3 and cleaved caspase-3 in MCAO group was significantly increased. Then, the percentage of infarct size and the Longa score significantly decreased after MaR1 administration, the mRNA expression levels of IL-1ß and IL-6 downregulated, and GSDME, GSDME-N, caspase-3 and cleaved caspase-3 were also reduced. After administration of Z-DEVD-FMK(ZDF), the expression of caspase-3, cleaved caspase-3 and GSDME-N was decreased, which in MCAO+MaR1+ZDF group was not statistically significant compared with MCAO+ ZDF group. CONCLUSION: Maresin1 alleviates cerebral ischemia/reperfusion injury by inhibiting pyroptosis mediated by caspase-3/GSDME pathway and alleviating neuroinflammation.

Application of ultrasound-guided single femoral triangle and adductor canal block in arthroscopic knee surgery: a prospective, double-blind, randomized clinical study.

PURPOSE: To compare the difference in analgesic effect between femoral triangle block (FTB) and adductor canal block (ACB) during arthroscopic knee surgery. METHODS: Patients who underwent arthroscopic knee surgery were randomized preoperatively to FTB group or ACB group. For each group, 20 mL of 0.1% ropivacaine was injected. PRIMARY OUTCOMES: The numeric rating score (NRS) at 12 h after surgery at rest and during movement. SECONDARY OUTCOME: (1) The NRS at post anesthesia care unit (PACU) and 2, 24 h after surgery at rest and during movement; (2) The quadriceps muscle strength at PACU and 2, 12, 24 h after surgery; (3) Consumption of Rescue analgesia; (4) Incidence of adverse reactions. RESULTS: The NRS at 12 h after surgery at rest and during movement of ACB group were higher than FTB group. Among secondary outcomes, the NRS at PACU at rest and during movement, 2 h after surgery during movement of FTB group lower than ACB group; the quadriceps muscle strength at 2 h after surgery of FTB group stronger than ACB group. After multiple linear regression model analysis, the data showed additional statistically significant reduction NRS at 24 h after surgery at rest (0.757, p = 0.037) in FTB group. Other outcomes were similar between two groups. CONCLUSIONS: The FTB appears to provide superior pain control after knee arthroscopy than ACB, the FTB is superior to the ACB in quadriceps muscle strength at 2 h after surgery. TRIAL REGISTRATION: The trial was registered in the Chinese Clinical Trial Registry (ChiCTR2300068765). Registration date: 28/02/2023.

Comparison of Analgesic Effects of Continuous Femoral Nerve Block, Femoral Triangle Block, and Adductor Block After Total Knee Arthroplasty: A Randomized Clinical Trial.

OBJECTIVES: This study aimed to compare the analgesic effects of continuous femoral nerve block (FNB), femoral triangle block (FTB), and adductor canal block (ACB) following total knee arthroplasty (TKA). The goal was to identify the most effective nerve block technique among these. METHODS: Patients undergoing TKA were randomly assigned to 1 of 3 groups: FNB, FTB, or ACB. Nerve blocks were administered preoperatively, with catheters placed for patient-controlled nerve analgesia (PCNA). The primary end point was the Numeric Rating Scale (NRS) score at movement at 24 hours postsurgery. Secondary end points included NRS scores at rest and movement, quadriceps strength, Timed Up and Go (TUG) test performance, range of motion, effective PCNA utilization, and opioid consumption at various postsurgery time points. RESULTS: Of the 94 valid data sets analyzed (FNB: 31, FTB: 31, ACB: 32), significant differences were observed in the primary end point (H=7.003, P =0.03). Post hoc analysis with Bonferroni correction showed that the FNB group had a significantly lower median pain score (3 [2 to 4]) compared with the ACB group (4 [3 to 5], Bonferroni-adjusted P =0.03). Regarding secondary end points, both the FNB and FTB groups had significantly lower NRS scores than the ACB group at various time points after surgery. Quadriceps strength and TUG completion were better in the FTB and ACB groups. There were no statistically significant differences among the groups for the other end points. DISCUSSION: Continuous FTB provides postoperative analgesia comparable to FNB but with the advantage of significantly less impact on quadriceps muscle strength, a benefit not seen with FNB. Both FTB and ACB are effective in preserving quadriceps strength postoperatively.

Predicting postoperative delirium after hip arthroplasty for elderly patients using machine learning.

BACKGROUND: Postoperative delirium (POD) is a common and severe complication in elderly hip-arthroplasty patients. AIM: This study aims to develop and validate a machine learning (ML) model that determines essential features related to POD and predicts POD for elderly hip-arthroplasty patients. METHODS: The electronic record data of elderly patients who received hip-arthroplasty surgery between January 2017 and April 2021 were enrolled as the dataset. The Confusion Assessment Method (CAM) was administered to the patients during their perioperative period. The feature section method was employed as a filter to determine leading features. The classical machine learning algorithms were trained in cross-validation processing, and the model with the best performance was built in predicting the POD. Metrics of the area under the curve (AUC), accuracy (ACC), sensitivity, specificity, and F1-score were calculated to evaluate the predictive performance. RESULTS: 476 Arthroplasty elderly patients with general anesthesia were included in this study, and the final model combined feature selection method mutual information (MI) and linear binary classifier using logistic regression (LR) achieved an encouraging performance (AUC = 0.94, ACC = 0.88, sensitivity = 0.85, specificity = 0.90, F1-score = 0.87) on a balanced test dataset. CONCLUSION: The model could predict POD with satisfying accuracy and reveal important features of suffering POD such as age, Cystatin C, GFR, CHE, CRP, LDH, monocyte count, history of mental illness or psychotropic drug use and intraoperative blood loss. Proper preoperative interventions for these factors could reduce the incidence of POD among elderly patients.

Transcriptome analysis of the immunomodulatory effects of Salvia miltiorrhiza polysaccharide on hemocyte immune response in Procambarus clarkii.

Natural plant polysaccharide as immune modulator is considered an effective strategy for healthy aquaculture to reduce medicine treatment. Salvia miltiorrhiza polysaccharides (SMP) had applications to regulate immune activity and enhance antioxidant in vertebrates, but the potential function has been rarely reported in crustaceans. In this study, the immunological effects of SMP on hemocytes of Procambarus clarkii were analyzed. Results showed that total superoxide dismutase (T-SOD), phenoloxidase (PO) activity and respiratory burst were up-regulated after SMP treatment. After high-throughput sequencing, 2170 differentially expressed genes (DEGs) including 1294 up-regulated and 876 down-regulated genes were identified. KEGG function enrichment analysis indicated that DEGs are involved in crustaceans cellular immune-related signaling pathways, including lysosome, phagosome and endocytosis. Transcriptome mining and qRT-PCR showed that SMP up-regulated humoral immunity factors gene expression. Diets supplemented with 0.8% SMP significantly up-regulated the total number of hemocytes (THC), T-SOD and PO activity, improved the survival of crayfish after Citrobacter freundii infection. This study suggested that SMP could improve the cellular and humoral immunity of P. clarkii. Furthermore, this finding supplied a molecular foundation for further comprehending the immunopotentiator effects of plant polysaccharides in crustaceans.

Shared genetic architecture between the two neurodegenerative diseases: Alzheimer's disease and glaucoma.

Background: Considered as the representatives of neurodegenerative diseases, Alzheimer's disease (AD) and glaucoma are complex progressive neuropathies affected by both genetic and environmental risk factors and cause irreversible damages. Current research indicates that there are common features between AD and glaucoma in terms of epidemiology and pathophysiology. However, the understandings and explanations of their comorbidity and potential genetic overlaps are still limited and insufficient. Method: Genetic pleiotropy analysis was performed using large genome-wide association studies summary statistics of AD and glaucoma, with an independent cohort of glaucoma for replication. Conditional and conjunctional false discovery rate methods were applied to identify the shared loci. Biological function and network analysis, as well as the expression level analysis were performed to investigate the significance of the shared genes. Results: A significant positive genetic correlation between AD and glaucoma was identified, indicating that there were significant polygenetic overlaps. Forty-nine shared loci were identified and mapped to 11 shared protein-coding genes. Functional genomic analyses of the shared genes indicate their modulation of critical physiological processes in human cells, including those occurring in the mitochondria, nucleus, and cellular membranes. Most of the shared genes indicated a potential modulation of metabolic processes in human cells and tissues. Furthermore, human protein-protein interaction network analyses revealed that some of the shared genes, especially MTCH2, NDUFS3, and PTPMT1, as well as SPI1 and MYBPC3, may function concordantly. The modulation of their expressions may be related to metabolic dysfunction and pathogenic processes. Conclusion: Our study identified a shared genetic architecture between AD and glaucoma, which may explain their shared features in epidemiology and pathophysiology. The potential involvement of these shared genes in molecular and cellular processes reflects the "inter-organ crosstalk" between AD and glaucoma. These results may serve as a genetic basis for the development of innovative and effective therapeutics for AD, glaucoma, and other neurodegenerative diseases.

Salvia miltiorrhiza polysaccharide activated macrophages and improved the disease resistance of sturgeon against Aeromonas hydrophila.

The use of plant polysaccharides in aquaculture is recognized as a healthy strategy to enhance disease resistance and reduce medication use. Salvia miltiorrhiza polysaccharide (SMP) can regulate the immune function of higher vertebrates. However, the effects of SMP on fish have not been fully investigated. In this study, the ability of SMP to activate the macrophages of Siberian sturgeon (Acipenser bareii) was analyzed in vitro. The effects of SMP on immune cell activity of hybrid sturgeon (A. baerii ♀ × Acipenser schrenckii ♂) and resistance to Aeromonas hydrophila were further detected in vivo. The in vitro results showed that SMP up-regulated phagocytosis, respiratory burst, inducible nitric oxide synthase activity, nitric oxide (NO) concentration, and cytokine mRNA expression of macrophages. The in vivo results showed that dietary supplementation with SMP enhanced the respiratory burst of macrophages and proliferative activity of lymphocytes. Dietary supplementation with SMP increased serum concentrations of lysozyme and NO, and improved the survival rate of hybrid sturgeon challenged with A. hydrophila. Collectively, these results suggest that SMP can improve the immune function and disease resistance of sturgeon. This study provides a theoretical basis for the application of SMP for healthy farming of sturgeon.

Risk Factors and a Nomogram Model Establishment for Postoperative Delirium in Elderly Patients Undergoing Arthroplasty Surgery: A Single-Center Retrospective Study.

OBJECTIVE: To explore the related risk factors of postoperative delirium (POD) after hip or knee arthroplasty in elderly orthopedic patients and the predictive value of related risk factors. Material and Methods. In total, 309 patients (≥60 years) who received knee and hip arthroplasty between January 2017 and May 2020 were consecutively selected into the POD and nonpostoperative delirium (NPOD) groups. Group bias was eliminated through propensity score matching. Univariate and multivariable logistic analysis was used to determine the risk factors for POD. The nomogram was made by R. RESULTS: 58 patients were included in each group after propensity score matching; multivariable analysis demonstrated that LDH (OR = 4.364, P = 0.017), CHE (OR = 4.640, P = 0.004), Cystatin C (OR = 5.283, P = 0.006), arrhythmia (OR = 5.253, P = 0.002), and operation duration (OR = 1.017, P = 0.050) were independent risk factors of POD. LDH, CHE, Cystatin C, and arrhythmia were used to construct a nomogram to predict the POD. The nomogram was well calibrated and had moderate discriminative ability (AUC = 0.821, 95% CI: 0.760~0.883). Decision curve analysis demonstrated that the nomogram was clinically useful. CONCLUSIONS: Our study revealed that arrhythmia, operation duration, the increase of lactate dehydrogenase and Cystatin C, and the decrease of cholinesterase were reliable factors for predicting postoperative delirium after elderly hip and knee arthroplasty. Meanwhile, the nomogram we developed can assist the clinician to filtrate potential patients with postoperative delirium.

CXCR3 alleviates renal ischemia­reperfusion injury via increase of Tregs.

Increasing evidence has demonstrated that regulatory T cells (Tregs) suppress innate immunity, as well as protect the kidneys from ischemia­reperfusion injury (IRI) and offer a potentially effective strategy to prevent or alleviate renal IRI. The present study explored whether C­X­C motif chemokine receptor 3 (CXCR3) alleviated renal IRI by increasing Tregs. Male C57BL/6J mice were divided into sham­surgery, IRI, CXCR3 overexpression (OE­CXCR3)+IRI, PC61+IRI and OE­CXCR3+PC61+IRI groups. Histopathological examination of the kidney was carried out using hematoxylin­eosin and Masson staining. The levels of serum creatinine (Scr) and blood urea nitrogen (BUN) were measured. Blood and kidney levels of IL­6, TNF­α, C­C motif chemokine ligand (CCL)­2 and IL­10 were detected by ELISA and western blotting. The levels of superoxide dismutase (SOD), glutathione peroxidase (GSH­Px) and malondialdehyde (MDA) in kidney tissues were also measured to assess oxidative stress. The population of Tregs in the kidney was assessed using flow cytometry. The results demonstrated that administration of OE­CXCR3 to IRI mice significantly decreased the levels of Scr, BUN, IL­6, TNF­α, CCL­2 and MDA, increased the levels of IL­10, SOD and GSH­Px, and mitigated the morphologic injury and fibrosis induced by IR compared with the IRI group. In addition, administration of OE­CXCR3 induced significant reductions in the expression levels of fibrosis­related markers, including fibronectin and type IV collagen, and increased the number of Tregs. These roles of OE­CXCR3 were significantly neutralized following deletion of Tregs with PC61 (anti­CD25 antibody). Together, the present study demonstrated that injection of OE­CXCR3 lentiviral vectors into animal models can alleviate renal IRI by increasing the number of Tregs. The results may be a promising approach for the treatment of renal IRI.

Genomic structure and molecular characterization of NLRC3-like from Siberian sturgeon (Acipenser baerii) and expression response to Streptococcus iniae and pathogen-associated molecular patterns.

NLRs are important intracellular pattern recognition receptors and play an essential role in innate immunity for vertebrates. However, research on sturgeon NLRs is still scarce. In this study, the NLRC3-like gene from Siberian sturgeon (Acipenser baerii) (AbNLRC3-like) was cloned and characterized. The AbNLRC3-like full-length cDNA was composed of 3310 bp with a 166 bp of 5'-UTR, 2838 bp open reading frame (ORF) and 306 bp 3'-UTR, encoding 945 amino acids. Structural analysis of AbNLRC3-like showed the typical NLRs structure, including a central NACHT domain and a C-terminal 12 LRR motifs. Quantitative real-time PCR (qRT-PCR) analysis revealed that AbNLRC3-like was widely distributed in all tested tissues with a relatively high expression level in the mid-kidney, head-kidney and spleen. After Streptococcus iniae infection, the mRNA expression of AbNLRC3-like was significantly up-regulated at the pre-mortality period and the recovering period in valvula intestine, but it was significantly down-regulated around the mortality period in the duodenum and spleen. In splenic leukocyte, the mRNA expression of AbNLRC3-like was significantly induced by LPS, PGN and Poly(I:C). These results suggested that AbNLRC3-like may play a critical role in the immune response of Siberian sturgeon during pathogen challenge. To our best knowledge, this is the first report of the NLRC3 gene in sturgeon.

Mechanisms underlying CD19-positive ALL relapse after anti-CD19 CAR T cell therapy and associated strategies.

Chimeric antigen receptor (CAR) T cell therapy, especially anti-CD19 CAR T cell therapy, has shown remarkable anticancer activity in patients with relapsed/refractory acute lymphoblastic leukemia, demonstrating an inspiring complete remission rate. However, with extension of the follow-up period, the limitations of this therapy have gradually emerged. Patients are at a high risk of early relapse after achieving complete remission. Although there are many studies with a primary focus on the mechanisms underlying CD19- relapse related to immune escape, early CD19+ relapse owing to poor in vivo persistence and impaired efficacy accounts for a larger proportion of the high relapse rate. However, the mechanisms underlying CD19+ relapse are still poorly understood. Herein, we discuss factors that could become obstacles to improved persistence and efficacy of CAR T cells during production, preinfusion processing, and in vivo interactions in detail. Furthermore, we propose potential strategies to overcome these barriers to achieve a reduced CD19+ relapse rate and produce prolonged survival in patients after CAR T cell therapy.

Low lethal doses of Streptococcus iniae caused enteritis in Siberian sturgeon (Acipenser baerii).

In aquaculture, the incidence of enteritis due to Streptococcus iniae infection in Siberian sturgeon (Acipenser baerii) has increased in recent years. The pathogenesis of S. iniae is largely unknown due to the paucity of experimental studies on fish intestinal inflammation. In this study, S. iniae infection of A. baerii juveniles was induced by anal intubation of 0.15 mL at a low lethal dose (2 × 107 CFU/mL). Intestinal pathology and gene expression studies were conducted within 10 days of the experiment. Histopathological examination showed severe intestinal lesions, inflammatory cell infiltration, intestinal submucosa edema, epithelial cell shedding and necrosis. Predominant symptoms of exudative inflammation, metamorphic inflammation and proliferative inflammation on days 1-3, 4-6, and 7-10 post infection were shown, respectively. Ultrastructural observations also revealed fractured microvilli and shedding on days 4-6. Intestinal villi gradually repaired during the subsequent 7-10 days post infection. Expression of the pro-inflammatory cytokines, tumor necrosis factor and interleukin 1ß were up-regulated on days 1-3 followed by a significant decrease on day 5, ultimately reaching control levels on day 10 post infection. A similar pattern was shown in mucus cells, involving mucin secretion and expression of the mucin encoding gene, Mucin-2. These results showed the cellular response to S. iniae infection associated with inflammatory genes expression in the Siberian sturgeon.