Decoding the Neurotoxic Effects of Propofol: Insights into the RARα-Snhg1-Bdnf Regulatory Cascade.

The potential neurotoxic effects of propofol, an extensively utilized anesthetic, underline the urgency to comprehend its influence on neuronal health. Insights into the role of the RARα-Snhg1-Bdnf network can offer significant advancements in minimizing these effects. The study targets the exploration of the RARα and Snhg1 regulatory network's influence on Bdnf expression in the realm of propofol-induced neurotoxicity. Harnessing the GEO database and utilizing JASPAR and RPISeq for projections, the study embarks on an in-depth analysis employing both in vitro and in vivo models. The findings draw a clear link between propofol-induced neurotoxicity and the amplification of RAR signaling pathways, impacting hippocampal development and apoptosis and leading to increased RARα and Snhg1 and decreased Bdnf. Propofol is inferred to accentuate neurotoxicity by heightening RARα and Snhg1 interactions, culminating in Bdnf suppression.

Global trends in research on endothelial cells and sepsis between 2002 and 2022: A systematic bibliometric analysis.

Sepsis is a systemic syndrome involving physiological, pathological, and biochemical abnormalities precipitated by infection and is a major global public health problem. Endothelial cells (ECs) dysfunction is a major contributor to sepsis-induced multiple organ failure. This bibliometric analysis aimed to identify and characterize the status, evolution of the field, and new research trends of ECs and sepsis over the past 20 years. For this analysis, the Web of Science Core Collection database was searched to identify relevant publications on ECs in sepsis published between January 1, 2002, and December 31, 2022. Microsoft Excel 2021, VOSviewer software, CiteSpace software, and the online analysis platform of literature metrology (http://bibliometric.com) were used to visualize the trends of publications' countries/regions, institutions, authors, journals, and keywords. In total, 4200 articles were identified and screened, primarily originating from 86 countries/regions and 3489 institutions. The USA was the leading contributor to this research field, providing 1501 articles (35.74 %). Harvard University's scientists were the most prolific, with 129 articles. Overall, 21,944 authors were identified, among whom Bae Jong Sup was the most prolific, contributing 129 publications. Additionally, Levi Marcel was the most frequently co-cited author, appearing 538 times. The journals that published the most articles were SHOCK, CRITICAL CARE MEDICINE, and PLOS ONE, accounting for 10.79 % of the total. The current emerging hotspots are concentrated on "endothelial glycocalyx," "NLRP3 inflammasome," "extracellular vesicle," "biomarkers," and "COVID-19," among others. In conclusion, this study provides a comprehensive overview of the scientific productivity and emerging research trends in the field of ECs in sepsis. The evidence supporting the significant role of ECs in both physiological and pathological responses to sepsis is continuously growing. More in-depth studies of the molecular mechanisms underlying sepsis-induced endothelial dysfunction and EC-targeted therapies are warranted in the future.

Higher Preoperative Red Blood Cell Distribution Width Increases the Risk of Myocardial Injury After Noncardiac Surgery in Advanced-Age Patients: A Retrospective Cohort Study.

Background: Myocardial injury after noncardiac surgery (MINS) has been associated with worse outcomes. The aim of our study was to investigate the relationship between higher red blood cell distribution width (RDW) and postoperative 30-day MINS among advanced-age patients. Methods: This was a retrospective observational study including advanced-age patients (≥65 years old) who underwent noncardiac surgery between January 2017 and August 2019 at the First Medical Center of the Chinese People's Liberation Army General Hospital. Patients were divided into two groups according to the cutoff value identified the lowest risk using Restricted Cubic Splines (RCS) model. The primary outcome was the incidence of MINS within 30 days after surgery. The relationship between RDW and MINS was investigated by univariable and multi-variable logistic regression analysis. Propensity score (PS) analysis, including propensity score matching (PSM) and inverse probability treatment weighting (IPTW), as well as subgroup analysis were also conducted to identify the effect of RDW. Results: The result of the RCS analysis showed that the risk of MINS in advanced-age patients increases when the baseline RDW is >12.8%. In the univariate analysis, baseline RDW >12.8% was a risk factor for postoperative MINS [odds ratio (OR)=2.11; 95% confidence interval (CI): 1.83-2.44; p<0.001]. After adjustment for all possible components, there was also a high risk of MINS for patients with elevated RDW [Adjusted OR (aOR)=1.43; 95% CI: 1.27-1.61; p<0.001). The relationship remained after PS analysis (aOR=1.24; 95% CI: 1.04-1.47; p=0.016 in PSM; aOR=1.23; 95% CI: 1.05-1.44; p=0.012 in IPTW, respectively). Significant differences between two groups were established in the incidence rate of postoperative cardiac complications and mortality. Conclusion: Elevated preoperative RDW is significantly associated with an increased risk of MINS within postoperative 30 days.

Using preoperative N-terminal pro-B-type natriuretic peptide levels for predicting major adverse cardiovascular events and myocardial injury after noncardiac surgery in Chinese advanced-age patients.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is often viewed as an indicator for heart failure. However, the prognostic association and the predictive utility of NT-proBNP for postoperative major adverse cardiovascular events (MACEs) and myocardial injury after noncardiac surgery (MINS) among older patients are unclear. METHODS: In this study, we included 5033 patients aged 65 years or older who underwent noncardiac surgery with preoperative NT-proBNP recorded. Logistic regression was adopted to model the associations between preoperative NT-proBNP and the risk of MACEs and MINS. The receiver operating characteristic curve was used to determine the predictive value of NT-proBNP. RESULTS: A total of 5033 patients were enrolled, 63 patients (1.25%) and 525 patients (10.43%) had incident postoperative MACEs and MINS, respectively. Analysis of the receiver operating characteristic curve indicated that the cutoff values of ln (NT-proBNP) for MACEs and MINS were 5.16 (174 pg/mL) and 5.30 (200 pg/mL), respectively. Adding preoperative ln (NT-proBNP) to the Revised Cardiac Risk Index score and the Cardiac and Stroke Risk Model boosted the area under the receiver operating characteristic curves from 0.682 to 0.726 and 0.787 to 0.804, respectively. The inclusion of preoperative NT-proBNP in the prediction models significantly increased the reclassification and discrimination. CONCLUSIONS: Increased preoperative NT-proBNP was associated with a higher risk of postoperative MACEs and MINS. The inclusion of NT-proBNP enhances the predictive ability of the preexisting models.

Evolution, gene expression, and protein‒protein interaction analyses identify candidate CBL-CIPK signalling networks implicated in stress responses to cold and bacterial infection in citrus.

BACKGROUND: Cold is a major abiotic stress and Huanglongbing and citrus canker disease are two devastating bacterial diseases for citrus. The Ca2+-CBL-CIPK network is known to regulate different types of stress signalling in plants. How do CBL-CIPK signalling networks function in response to cold and infection by CLas or Xcc in citrus? RESULTS: Eight calcineurin B-like proteins (CBLs) and seventeen CBL-interacting protein kinases (CIPKs) were identified from the cold-tolerant satsuma mandarin 'Guijing2501' (Citrus. unshiu) and CLas/Xcc-sensitive sweet orange (C. sinensis). Phylogenetic analysis revealed that both CBL and CIPK family members in citrus were classified into an ancient and a recent clade according to their conserved domain characteristics and/or intron/exon structures. Genome duplication analysis suggested that both tandem and segmental duplications contributed to the amplification of the CBL and CIPK gene families in citrus under intense purifying selection, and the duplication events only existed in the recent clades. Expression comparison of the duplicated gene pairs indicated that the duplicated CBL and CIPK genes underwent functional differentiation. Further expression analysis identified that CBL1, 5, 6, and 8 and CIPK2, 8, 12, 15, 16, and 17 were significantly regulated by multiple stresses, including cold, Xcc infection and/or CLas infection, in citrus, whereas CBL2/7 and CIPK1/4/5/11/13/14 were independently highly regulated by cold and CIPK3 was uniquely responsive to Xcc infection. The combination analyses of targeted Y2H assay and expression analysis revealed that CBL6-CIPK8 was the common signalling network in response to cold and Xcc infection, while CBL6/CBL8-CIPK14 was uniquely responsive to cold in citrus. Further stable transformation and cold tolerance assay indicated that overexpression of CuCIPK16 enhanced the cold tolerance of transgenic Arabidopsis with higher POD activity and lower MDA content. CONCLUSIONS: In this study, evolution, gene expression and protein‒protein interaction analyses of citrus CBLs and CIPKs were comprehensively conducted over a genome-wide range. The results will facilitate future functional characterization of individual citrus CBLs and CIPKs under specific stresses and provide clues for the clarification of cold tolerance and disease susceptibility mechanisms in corresponding citrus cultivars.

lncRNA BDNF-AS Attenuates Propofol-Induced Apoptosis in HT22 Cells by Modulating the BDNF/TrkB Pathway.

Propofol is widely used as an intravenous anesthetic in clinical practice. Previous studies have indicated that propofol induces apoptosis in neurons. Brain-derived neurotrophic factor (BDNF), a neurotrophic factor, is associated with neuronal apoptosis. BDNF-AS, a relatively conserved long non-coding RNA, can reverse the transcription of BDNF. This study aimed to investigate the involvement of BDNF-AS in propofol-induced apoptosis in HT22 cells. HT22 cells were treated with various concentrations of propofol at different time points. BDNF-AS was silenced using BDNF-AS-targeting siRNA. TrkB was antagonized by the TrkB inhibitor, ANA-12. Flow cytometry, quantitative reverse-transcription PCR, and western blotting were performed to analyze apoptosis and the expression of genes and proteins, respectively. In propofol-treated HT22 cells, BDNF-AS was upregulated, and BDNF was downregulated in a time- and dose-dependent manner. BDNF-AS downregulation mediated by siRNA mitigated apoptosis, upregulated the expression of Bcl-2, and downregulated the expression of Bax and caspase-3, 7, and 9. ANA-12 downregulated the expression of Bcl-2, upregulated the expression of Bax and caspase-3, 7, and 9, and increased apoptosis. Our study implied that inhibition of BDNF-AS can decrease propofol-induced apoptosis by activating the BDNF/TrkB pathway. Thus, the BDNF-AS-BDNF/TrkB signaling pathway may be a valuable target for treating propofol-induced neurotoxicity.

Efficacy of Erector Spinae Nerve Block for Pain Control After Spinal Surgeries: An Updated Systematic Review and Meta-Analysis.

Background: Erector spinae plane block (ESPB), as a regional anesthesia modality, is gaining interest and has been used in abdominal, thoracic and breast surgeries. The evidence on the efficacy of this block in spinal surgeries is equivocal. Recently published reviews on this issue have concerning limitations in methodology. Methods: A systematic search was conducted using the PubMed, Scopus, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). Randomized controlled trials (RCTs) that were done in patients undergoing spinal surgery and had compared outcomes of interest among those that received ESPB and those with no block/placebo were considered for inclusion. Statistical analysis was performed using STATA software. GRADE assessment was done for the quality of pooled evidence. Results: A total of 13 studies were included. Patients receiving ESPB had significantly reduced total opioid use (Standardized mean difference, SMD -2.76, 95% CI: -3.69, -1.82), need for rescue analgesia (Relative risk, RR 0.38, 95% CI: 0.22, 0.66) and amount of rescue analgesia (SMD -5.08, 95% CI: -7.95, -2.21). Patients receiving ESPB reported comparatively lesser pain score at 1 h (WMD -1.62, 95% CI: -2.55, -0.69), 6 h (WMD -1.10, 95% CI: -1.45, -0.75), 12 h (WMD -0.78, 95% CI: -1.23, -0.32) and 24 h (WMD -0.54, 95% CI: -0.83, -0.25) post-operatively. The risk of postoperative nausea and vomiting (PONV) (RR 0.32, 95% CI: 0.19, 0.54) was lower in those receiving ESPB. There were no differences in the duration of surgery, intra-operative blood loss and length of hospital stay between the two groups. The quality of pooled findings was judged to be low to moderate. Conclusions: ESPB may be effective in patients with spinal surgery in reducing post-operative pain as well as need for rescue analgesic and total opioid use. In view of the low to moderate quality of evidence, more trials are needed to confirm these findings.Systematic Review Registration: http://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42021278133.

ß-Patchoulene Preconditioning Protects Mice Against Hepatic Ischemia-Reperfusion Injury by Regulating Nrf2/HO-1 Signaling Pathway.

INTRODUCTION: Hepatic ischemia-reperfusion (I/R) injury is one of the main causes of liver dysfunction after the liver resection and transplantation. Hepatic I/R was characterized by the tissue hypoxia during ischemia phase and oxidative stress and immune response during hypoxia-reoxygenation. The objectives of the present study were to determine the protective effects of ß-patchoulene (ß-PAE), a novel bioactive agent, in a mice model of hepatic I/R injury and to explore its potential mechanisms. METHODS: A segmental liver warm I/R injury model was performed by occluding the portal vessels for 1 h followed by 6-h reperfusion. Twenty-four mice were randomly divided into three groups: Sham, I/R, and I/R + ß-PAE, with eight mice in each group. Mice were intravenously injected with ß-PAE (10 mg/kg) or saline 2 h before surgery, and parameters were measured 6 h after designated treatment. Serum aminotransferase, histologic changes, cytokines expression, and apoptosis were determined. The potential effects of ß-PAE on macrophage activation and apoptosis were further evaluated in a hypoxia and reperfusion (H/R) model in vitro. Oxidative stress markers (reactive oxygen species production and malondialdehyde) and cytokines expression were measured by commercial kits. Nrf2/HO-1 and NF-ƘB signaling pathways were determined by Western blotting. Finally, blockade of nuclear factor erythroid 2-related factor 2 (Nrf2) with ML385 was used to confirm the involvement of Nrf2/HO-1 pathway in H/R injury. RESULTS: Hepatic I/R induced apparent tissue injury as evidenced by the increased expression of serum aminotransferase, pro-inflammatory mediators production, hepatocellular apoptosis, and necrosis. ß-PAE pretreatment protected mice against I/R-induced injury, which was proved by decreased serum aminotransferase and cytokines production, reduced TUNEL-positive cells, and alleviated histopathological lesion. Immunofluorescence staining showed that ß-PAE suppressed the M1 polarization of Kupffer cell induced by I/R injury. Moreover, pretreatment with ß-PAE suppressed H/R-induced cytokines expression and apoptosis in cultured macrophage. The mechanistic study demonstrated that ß-PAE significantly promoted the nuclear Nrf2 translocation and upregulation of HO-1 while downregulating the NF-ƘB signaling pathway in both in vivo and in vitro experiments. Furthermore, blockade of Nrf2 abolished the protective effects of ß-PAE on the inhibition of H/R-mediated oxidative stress, inflammatory response, and apoptosis in vitro. CONCLUSIONS: ß-PAE preconditioning protects mice against hepatic I/R, which was at least in part through the reversing disequilibrium between Nrf2/HO-1 and NF-ƘB pathways. ß-PAE might serve as a promising therapeutic agent in the treatment of hepatic I/R injury.

Exploration of Exosomal miRNAs from Serum and Synovial Fluid in Arthritis Patients.

Arthritis is caused by inflammation, infection, degeneration, trauma, or other factors that affect approximately 250 million people all over the world. Early diagnosis and prediction are essential for treatment. Exosomes are nanoscale vesicles that participate in the process of joint disease. Serum is the mainly used sources in the study of arthritis-related exosomes, while whether serum exosomes can reflect the contents of synovial fluid exosomes is still unknown. In this work, we separated exosomes from serum and the synovial fluid of osteoarthritis patients and compared their miRNA expression utilizing miRNA sequencing. The results revealed that 31 upregulated and 33 downregulated miRNAs were found in synovial fluid compared to serum. Transcriptome analysis showed that these differentially expressed miRNAs were mainly associated with intercellular processes and metabolic pathways. Our results show that serum-derived exosomes cannot fully represent the exosomes of synovial fluid, which may be helpful for the study of joint diseases and the discovery of early diagnostic biomarkers of arthritis.

Advances of Exosomal miRNAs in Breast Cancer Progression and Diagnosis.

Breast cancer is one of the most commonly diagnosed malignancies and the leading cause of cancer death in women worldwide. Although many factors associated with breast cancer have been identified, the definite etiology of breast cancer is still unclear. In addition, early diagnosis of breast cancer remains challenging. Exosomes are membrane-bound nanovesicles secreted by most types of cells and contain a series of biologically important molecules, such as lipids, proteins, and miRNAs, etc. Emerging evidence shows that exosomes can affect the status of cells by transmitting substances and messages among cells and are involved in various physiological and pathological processes. In breast cancer, exosomes play a significant role in breast tumorigenesis and progression through transfer miRNAs which can be potential biomarkers for early diagnosis of breast cancer. This review discusses the potential utility of exosomal miRNAs in breast cancer progression such as tumorigenesis, metastasis, immune regulation and drug resistance, and further in breast cancer diagnosis.

Access to gem-Dibromoenones Enabled by Carbon-Centered Radical Addition to Terminal Alkynes in Water Solution.

We herein report a novel and more practical approach to prepare gem-dibromoenones from terminal alkynes, tetrabromomethane (CBr4), and water in a single step. Mechanistic studies reveal that the generation of a tribromomethyl radical with the assistance of a persulfate salt (K2S2O8) is essential to this transformation. The reaction features readily available chemicals, a broad substrate scope, a green solvent, and mild reaction conditions, providing an efficient alternative for construction of halogen-substituted enones.

A Portable Device for Simple Exosome Separation from Biological Samples.

Exosomes are membrane-bound nanovesicles secreted by most types of cells, which contain a series of biologically important molecules, such as miRNAs, proteins, and lipids, etc. Emerging evidence show that exosomes can affect the physiological status of cells and are involved in various pathological processes. However, due to their small size and density close to body fluids, it is challenging to separate exosomes from a small volume of biological samples in a simple manner. Herein, we propose a new strategy for isolating circulating exosomes from biological samples in a portable device. This method synergistically integrates chitosan electrostatic-adsorption, scaffold substrates, and shuttle flow to enable the highly effective capture of circulating exosomes with a recovery rate of over 80% within 20 min, which is much better than the performance of traditional ultracentrifugation (5-25%, 3 h). Besides, the isolated exosomes from samples could be lysed in situ and further subjected to RNA concentration detection and protein analysis. In particular, all the necessary procedures for exosome separation could be integrated into a single device without the need for bulky equipment. This established device is portable and easy to operate, which provides a promising platform for the study of exosome biology and clinical diagnosis.

High-Affinity Anti-VISTA Antibody Protects against Sepsis by Inhibition of T Lymphocyte Apoptosis and Suppression of the Inflammatory Response.

BACKGROUND: B7 family members and ligands have been identified as critical checkpoints in orchestrating the immune response during sepsis. V-domain Ig suppressor of T cell activation (VISTA) is a new inhibitory immune checkpoint involved in restraining T cell response. Previous studies demonstrated that VISTA engagement on T cells and myeloid cells could transmit inhibitory signals, resulting in reduced activation and function. The current study was designed to determine the potential therapeutic effects of a high-affinity anti-VISTA antibody (clone MH5A) in a murine model of sepsis. METHODS: Polymicrobial sepsis was induced in male C57BL/6 mice via cecal ligation and puncture. Expression profiles of VISTA on T lymphocytes and macrophage were examined at 24 and 72 h postsurgery. The effects of anti-VISTA mAb on the 7-day survival, lymphocyte apoptosis, cytokine expression, bacterial burden, and vital organ damage were determined. Furthermore, the effects of anti-VISTA mAb on CD3+ T cell apoptosis and macrophage activation were determined in vitro. RESULTS: VISTA was substantially expressed on T cells and macrophages in sham-operated mice; septic peritonitis did not induce significant changes in the expression profiles. Treatment with MH5A improved the survival of septic mice, accompanied by reduced lymphocyte apoptosis, decreased cytokine expression, and enhanced bacterial clearance. Engagement of VISTA receptor with MH5A mitigated CD3+ T cell apoptosis cultured from CLP mice and suppressed LPS-induced cytokine production by macrophage in vitro. CONCLUSION: The present study identified VISTA as a novel immune checkpoint in the regulation of T cell and macrophage response during sepsis. Modulation of the VISTA pathway might offer a promising opportunity in the immunotherapy for sepsis.

Simple and fast isolation of circulating exosomes with a chitosan modified shuttle flow microchip for breast cancer diagnosis.

Tumor-derived exosomes have been recognized as promising biomarkers for early-stage cancer diagnosis, tumor prognosis monitoring and individual medical treatment. However, it is a huge challenge to separate exosomes from trace biological samples in clinics for disease diagnosis. Herein, we propose a simple, quick, and label-free method for isolating circulating exosomes from serum of patients. The strategy synergistically integrates chitosan electrostatic-adsorption, micro-patterned substrates, and microfluidic shuttle flow control to enable the capture/release of circulating exosomes in a simple manner. Using this microchip, we can isolate exosomes from trace samples (10 µl) with relative purity over 90% and high RNA recovery ratio over 84% within 15 minutes, which is impossible for traditional ultracentrifugation methods. We then validate the application of the microchip using 24 serum samples from clinical breast cancer and breast fibroma patients. The isolated exosomes are subjected to miRNA sequencing and RT-PCR, followed by pathway prediction analysis. The results showed that exosomes were relevant to the invasion and metastasis of breast cancer cells and hsa-miR-18a-3p might have the potential to become a new biomarker for distinguishing breast cancer from breast fibroma (AUC = 0.83, P value = 0.019). This established method is simple, quick and easy to operate with integration. And it may pave a new way for clinical research on exosomes and tumor relevant diagnosis.

Sonic Hedgehog Signaling Contributes to Chronic Post-Thoracotomy Pain via Activating BDNF/TrkB Pathway in Rats.

PURPOSE: Some patients undergoing thoracotomy may suffer from chronic post-thoracotomy pain (CPTP). Treatment of CPTP has been a clinical challenge and the underlying mechanisms of CPTP remain elusive. Recently, sonic hedgehog (Shh) signaling has been shown to be associated with various pain states but its role in the pathogenesis of CPTP is still unclear. METHODS: CPTP was induced in rats by thoracotomy. Rats were divided into CPTP group and non-CPTP group based on the mechanical withdrawal threshold (MWT). Rats were administered with Shh signaling inhibitor cyclopamine and activator smoothened agonist (SAG), and then evaluated by MWT and cold allodynia testing. The expressions of Shh signaling (Shh ligand, patched and smoothened receptor, Gli transcription factors), brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase receptor B (Trk-B), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) in rat T4-5 spinal cord dorsal horn (SDH) were detected by Western blotting and immunohistochemistry. RESULTS: The expression of Shh signaling significantly increased and the BDNF/TrkB pathway was activated in T4-5 SDH of CPTP rats. Cyclopamine attenuated hyperalgesia and down-regulated the expressions of Gil1, BDNF, p-TrkB, p-PI3K and p-Akt in CPTP rats. SAG induced hyperalgesia in non-CPTP rats and elevated the expressions of Gil1, BDNF, p-TrkB, p-PI3K and p-Akt. CONCLUSION: Shh signaling may contribute to CPTP via activating BDNF/TrkB signaling pathway, and inhibition of Shh signaling may effectively alleviate CPTP.