ACE2 activation alleviates sepsis-induced cardiomyopathy by promoting MasR-Sirt1-mediated mitochondrial biogenesis.

Sepsis-induced cardiomyopathy (SIC), caused by a dysregulated host response to infection, is a major contributor to high mortality. Angiotensin-converting enzyme 2 (ACE2), a crucial component of the renin-angiotensin system (RAS), has protective effects against several cardiovascular diseases, such as myocardial infarction and heart failure. However, the role of ACE2 in the pathogenesis of SIC and underlying mechanisms remain unknown. The present study was designed to examine the effects of ACE2 activation or inhibition on SIC in C57BL/6 mice. The ACE2 activator diminazene aceturate (DIZE) and ACE2 inhibitor MLN-4760 were applied for treatment. Myocardial function, inflammatory response, oxidative stress, apoptosis and mitochondrial biogenesis were investigated. Major assays were echocardiography, H&E staining, immunofluorescence staining, DHE staining, TUNEL staining, Western blot, qPCR analysis, ELISA and corresponding kits. We confirmed that ACE2 was markedly downregulated in septic heart tissues. Pharmacological activation of ACE2 by DIZE ameliorated cecal ligation puncture (CLP)-induced mortality, cardiac dysfunction, inflammatory response, oxidative stress and the cardiomyocyte apoptosis by promoting MasR-Sirt1-mediated mitochondrial biogenesis. In contrast, SIC was aggravated via inhibiting MasR-Sirt1-mediated mitochondrial biogenesis by the use of ACE2 inhibitor MLN-4760. Consequently, activation of ACE2 may protect against SIC by promoting MasR-Sirt1-mediated mitochondrial biogenesis.

Action mechanism of the potential biocontrol agent Brevibacillus laterosporus SN19-1 against Xanthomonas oryzae pv. oryzae causing rice bacterial leaf blight.

The causal agent of rice bacterial leaf blight (BLB) is Xanthomonas oryzae pv. oryzae (Xoo), which causes serious damage to rice, leading to yield reduction or even crop failure. Brevibacillus laterosporus SN19-1 is a biocontrol strain obtained by long-term screening in our laboratory, which has a good antagonistic effect on a variety of plant pathogenic bacteria. In this study, we investigated the efficacy and bacterial inhibition of B. laterosporus SN19-1 against BLB to lay the theoretical foundation and research technology for the development of SN19-1 as a biopesticide of BLB. It was found that SN19-1 has the ability to fix nitrogen, detoxify organic phosphorus, and produce cellulase, protease, and siderophores, as well as IAA. In a greenhouse pot experiment, the control efficiency of SN19-1 against BLB was as high as 90.92%. Further investigation of the inhibitory mechanism of SN19-1 on Xoo found that the biofilm formation ability of Xoo was inhibited and the pathogenicity was weakened after the action of SN19-1 sterile supernatant on Xoo. The activities of enzymes related to respiration and the energy metabolism of Xoo were significantly inhibited, while the level of intracellular reactive oxygen species was greatly increased. Scanning electron microscopy observations showed folds on the surface of Xoo. A significant increase in cell membrane permeability and outer membrane permeability and a decrease in cell membrane fluidity resulted in the extravasation of intracellular substances and cell death. The results of this study highlight the role of B. laterosporus SN19-1 against the pathogen of BLB and help elucidate the underlying molecular mechanisms.

ACE2 Rescues Sepsis-Associated Encephalopathy by Reducing Inflammation, Oxidative Stress, and Neuronal Apoptosis via the Nrf2/Sestrin2 Signaling Pathway.

Neuroinflammation and oxidative stress contribute to the progression of sepsis-associated encephalopathy (SAE). Angiotensin-converting enzyme 2 (ACE2) is considered to be a neuroprotective factor due to its anti-inflammatory and antioxidant properties. However, the role of ACE2 on myeloid cells in regulating SAE and the underlying mechanism warrants further exploration. SAE was induced in ACE2 transgenic (TG), knockout (KO), and bone marrow (BM) chimeric mice by cecal ligation and puncture (CLP). The expression levels of apoptosis-, oxidation- and neuroinflammation-associated mediators and morphological changes were monitored by quantitative real-time PCR analyses and histological examinations in the cortex of septic mice. The contents of angiotensin (Ang) II and Ang-(1-7) along with the activity of ACE2 were examined with commercial kits. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Sestrin2 was detected by immunoblotting analysis. Our results indicated that the expression of cortical ACE2 was significantly reduced in the early phase of CLP-induced sepsis. Moreover, ACE2 overexpression in TG mice conferred neuroprotection against sepsis, as evidenced by alleviated neuronal apoptosis, oxidative stress, and proinflammatory M1-like microglial polarization, accompanied by upregulation of the Ang-(1-7), Nrf2, and Sestrin2 protein levels. Conversely, ACE2 deficiency in KO mice exacerbated SAE. The neuroprotective effects of ACE2 were further confirmed in wild-type mice transplanted with ACE2-TG and KO BM cells. Therefore, our data suggest that myeloid ACE2 exerts a protective role in the pathogenesis of SAE, potentially by activating Ang-(1-7)-Nrf2/sestrin2 signaling pathway, and highlight that upregulating ACE2 expression and activity may represent a promising approach for the treatment of SAE in patients with sepsis.

ACE2 Expressed on Myeloid Cells Alleviates Sepsis-Induced Acute Liver Injury via the Ang-(1-7)-Mas Receptor Axis.

Sepsis-induced acute liver injury (ALI) is common in intensive care units. Angiotensin-converting enzyme 2 (ACE2) plays a vital role in hepatic fibrosis and steatosis; however, its role in sepsis-induced ALI remains unclear. This study found that hepatic ACE2 expression in cecal ligation and puncture (CLP)-treated mice significantly decreased 24 h after CLP. ACE2-transgenic (TG) mice exhibited a significant improvement in CLP-induced ALI, accompanied by the inhibition of hepatocyte apoptosis, oxidative stress, and inflammation, while ACE2-knockout mice demonstrated an opposite trend. During sepsis-induced ALI, ACE2-TG could also elevate the Ang-(1-7) and Mas receptor (MasR) levels in liver tissues. Interestingly, the MasR inhibitor A779 abrogated the favorable effects of ACE2 on CLP-induced ALI. In a bone marrow transplantation experiment, the ACE2-TG transplantation group showed significantly improved inflammation and liver dysfunction, less hepatocyte apoptosis, and reduced oxidative stress after CLP compared with the wild-type transplantation group. In contrast, the ACE2-knockout group showed poor inflammatory response and liver dysfunction, significantly more hepatocyte apoptosis, and elevated oxidative stress than the wild-type transplantation group after CLP. ACE2 protects against sepsis-induced ALI by inhibiting hepatocyte apoptosis, oxidative stress, and inflammation via the Ang-(1-7)-Mas receptor axis. Thus, targeting ACE2 may be a promising novel strategy for preventing and treating sepsis-induced ALI.

Blockage of S100A8/A9 ameliorates septic nephropathy in mice.

Septic acute kidney injury (AKI) is the commonest cause of complication of sepsis in intensive care units, but its pathophysiology remains unclear. Calprotectin (S100A8/A9), which is a damage-associated molecular patterns (DAMPs) molecule, exerts a critical role in modulating leukocyte recruitment and inflammatory response during various diseases. However, role of S100A8/A9 in septic AKI is largely unknown. In this research, Septic AKI was triggered by cecal ligation and puncture (CLP) operation in wild-type mice, which treated with or without an S100A9 inhibitor, Paquinimod (Paq, 10 mg/kg) that prevents S100A8/A9 to bind to Toll-like receptor 4 (TLR4). Renal function, pathological changes, cell death, and oxidative stress were evaluated. Our research indicated that the mRNA and protein expression of S100A9 are time-dependently elevated in the kidney following CLP. Moreover, the administration of Paq for 24 h significantly improved CLP-induced renal dysfunction and pathological alterations compared with vehicle treatment in mice. These beneficial effects were associated with the inhibition of CLP-triggered renal tubular epithelial cell apoptosis, inflammation, superoxide production, and mitochondrial dynamic imbalance. What's more, we further confirmed the above findings by cell co-culture experiments. Our study demonstrates that S100A9 is a prominent protein to lead to septic AKI, and the selective inhibition of S100A9 could represent a new therapeutic approach which can treat septic AKI.

Impact of propofol versus sevoflurane on the incidence of postoperative delirium in elderly patients after spine surgery: study protocol of a randomized controlled trial.

BACKGROUND: Postoperative delirium in elderly patients is a common and costly complication after surgery. Propofol and sevoflurane are commonly used anesthetics during general anesthesia, and the sedative and anti-inflammatory mechanisms of the two medications are different. The aim of this trial is to compare the impact of propofol with sevoflurane on the incidence of postoperative delirium in elderly patients after spine surgery. METHODS: A single-center randomized controlled trial will be performed at First Affiliated Hospital of Shandong First Medical University, China. A total of 298 participants will be enrolled in the study and randomized to propofol infusion or sevoflurane inhalation groups. The primary outcome is the incidence of delirium within 7 days after surgery. Secondary outcomes include the day of postoperative delirium onset, duration (time from first to last delirium-positive day), and total delirium-positive days among patients who developed delirium; tracheal intubation time in PACU; the length of stay in PACU; the rate of postoperative shivering; the rate of postoperative nausea and vomiting; the rate of emergence agitation; pain severity; QoR40 at the first day after surgery; the length of stay in hospital after surgery; and the incidence of non-delirium complications within 30 days after surgery. DISCUSSION: The primary objective of this study is to compare the impact of propofol and sevoflurane on the incidence of postoperative delirium for elderly patients undergoing spine surgery. The results may help inform strategies to the optimal selection of maintenance drugs for general anesthesia in elderly patients undergoing spine surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT05158998 . Registered on 14 December 2021.

Outcome prediction using the Mortality in Emergency Department Sepsis score combined with procalcitonin for influenza patients.

BACKGROUND: Severe influenza is often associated with bacterial coinfection and can trigger sepsis, which increases the severity, complexity and mortality of the disease. To determine an effective method for predicting 28-day mortality of emergency department (ED) patients with influenza, we investigated the Mortality in Emergency Department Sepsis (MEDS) score, procalcitonin (PCT) and other relevant biomarkers. METHODS: We conducted a retrospective, observational, monocentric study, and the endpoint was 28-day mortality. Independent predictors were identified and a new combination predictive model was created both by logistic regression, and the model was evaluated by a receiver operating characteristic (ROC) curve. RESULTS: A total of 364 consecutive ED admitted patients with influenza were enrolled and 45 patients died within 28 days. For predicting 28-day mortality, the MEDS score and PCT were independent predictors with adjusted odds ratio of 1.318 (95% CI 1.206-1.439) and 1.038 (95% CI 1.010-1.065), and with AUCs of 0.817 (95% CI 0.756-0.878) and 0.793 (95% CI 0.725-0.861), respectively. The new combination of the MEDS score with PCT significantly improved the efficacy for predicting 28-day mortality with an AUC of 0.857 (95% CI 0.809-0.905), and was superior to the SOFA score with an AUC of 0.837 (95% CI 0.779-0.894). CONCLUSION: The MEDS score and PCT, especially when combined, perform well for predicting mortality of ED admitted patients with influenza.

[Effects of Organic Carbon Content on the Residue and Migration of Polycyclic Aromatic Hydrocarbons in Soil Profiles].

The effects of total organic carbon content (TOC) on the migration of polycyclic aromatic hydrocarbons (PAHs) in the soil were investigated. This study analyzed the vertical properties of the concentrations and distributions of PAHs and TOC at various soil profiles from functionally different environmental regions including nature reserves, ploughs, orchards, farmlands, metropolitan areas, and industrial parks. The vertical migration properties of PAHs in soils were examined by conducting leaching experiments in soil columns. The concentrations of PAHs varied from region to region and showed strong, positive correlations with TOC in the same region. Furthermore, based on the leaching experiments, the transport abilities of PAHs were significantly influenced by TOC, although they could all be transported to the deep layers by TOC in soil columns. The downward migration of PAHs decreased with the increase in TOC and vice versa. The properties of the composition and structure of PAHs also had an obvious influence on their residues and migration in soil profiles at the same TOC conditions. In addition, the transport of PAHs was related to the amount of leaching water, the leaching time, and the additional PAHs.