Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis

Background: Acute lung injury (ALI) is a common and serious complication of sepsis with high mortality. Ferroptosis, categorized as programmed cell death, contributes to the development of lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is an endogenous lipid mediator that exerts protective effects against multiorgan injury. However, the role of PCTR1 in the ferroptosis of sepsis-related ALI remains unknown. Methods: A pulmonary epithelial cell line and a mouse model of ALI stimulated with lipopolysaccharide (LPS) were established in vitro and in vivo. Ferroptosis biomarkers, including ferrous (Fe2+), glutathione (GSH), malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE), were assessed by relevant assay kits. Glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) protein levels were determined by western blotting. Lipid peroxides were examined by fluorescence microscopy and flow cytometry. Cell viability was determined by a CCK-8 assay kit. The ultrastructure of mitochondria was observed with transmission electron microscopy. Morphology and inflammatory cytokine levels predicted the severity of lung injury. Afterward, related inhibitors were used to explore the potential mechanism by which PCTR1 regulates ferroptosis. Results: PCTR1 treatment protected mice from LPS-induced lung injury, which was consistent with the effect of the ferroptosis inhibitor ferrostatin-1. PCTR1 treatment decreased Fe2+, PTGS2 and lipid reactive oxygen species (ROS) contents, increased GSH and GPX4 levels and ameliorated mitochondrial ultrastructural injury. Administration of LPS or the ferroptosis agonist RSL3 resulted in reduced cell viability, which was rescued by PCTR1. Mechanistically, inhibition of the PCTR1 receptor lipoxin A4 (ALX), protein kinase A (PKA) and transcription factor cAMP-response element binding protein (CREB) partly decreased PCTR1 upregulated GPX4 expression and a CREB inhibitor blocked the effects ofPCTR1 on ferroptosis inhibition and lung protection. Conclusion: This study suggests that PCTR1 suppresses LPS-induced ferroptosis via the ALX/PKA/CREB signaling pathway, which may offer promising therapeutic prospects in sepsis-related ALI

Inhibition the ubiquitination of ENaC and Na,K-ATPase with erythropoietin promotes alveolar fluid clearance in sepsis-induced acute respiratory distress syndrome

Sepsis-induced acute respiratory distress syndrome (ARDS) causes significant fatalities worldwide and lacks pharmacological intervention. Alveolar fluid clearance (AFC) plays a pivotal role in the remission of ARDS and is markedly impaired in the pathogenesis of ARDS. Here, we demonstrated that erythropoietin could effectively ameliorate lung injury manifestations and lethality, restore lung function and promote AFC in a rat model of lipopolysaccharide (LPS)-induced ARDS. Moreover, it was proven that EPO-induced restoration of AFC occurs through triggering the total protein expression of ENaC and Na,K-ATPase channels, enhancing their protein abundance in the membrane, and suppressing their ubiquitination for degeneration. Mechanistically, the data indicated the possible involvement of EPOR/JAK2/STAT3/SGK1/Nedd4–2 signaling in this process, and the pharmacological inhibition of the pathway markedly eliminated the stimulating effects of EPO on ENaC and Na,K-ATPase, and subsequently reversed the augmentation of AFC by EPO. Consistently, in vitro studies of alveolar epithelial cells paralleled with that EPO upregulated the expression of ENaC and Na,K-ATPase, and patch-clamp studies further demonstrated that EPO substantially strengthened sodium ion currents. Collectively, EPO could effectively promote AFC by improving ENaC and Na,K-ATPase protein expression and abundance in the membrane, dependent on inhibition of ENaC and Na,K-ATPase ubiquitination, and resulting in diminishing LPS-associated lung injuries

Corrigendum to: The TianQin project: current progress on science and technology

In the originally published version, this manuscript included an error related to indicating the corresponding author within the author list. This has now been corrected online to reflect the fact that author Jun Luo is the corresponding author of the article

PigBiobank: a valuable resource for understanding genetic and biological mechanisms of diverse complex traits in pigs

© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] fully unlock the potential of pigs as both agricultural species for animal-based protein food and biomedical models for human biology and disease, a comprehensive understanding of molecular and cellular mechanisms underlying various complex phenotypes in pigs and how the findings can be translated to other species, especially humans, are urgently needed. Here, within the Farm animal Genotype-Tissue Expression (FarmGTEx) project, we build the PigBiobank (http://pigbiobank.farmgtex.org) to systematically investigate the relationships among genomic variants, regulatory elements, genes, molecular networks, tissues and complex traits in pigs. This first version of the PigBiobank curates 71 885 pigs with both genotypes and phenotypes from over 100 pig breeds worldwide, covering 264 distinct complex traits. The PigBiobank has the following functions: (i) imputed sequence-based genotype-phenotype associations via a standardized and uniform pipeline, (ii) molecular and cellular mechanisms underlying trait-associations via integrating multi-omics data, (iii) cross-species gene mapping of complex traits via transcriptome-wide association studies, and (iv) high-quality results display and visualization. The PigBiobank will be updated timely with the development of the FarmGTEx-PigGTEx project, serving as an open-access and easy-to-use resource for genetically and biologically dissecting complex traits in pigs and translating the findings to other species.National Natural Science Foundation of China [32022078]; National Key R&D Program of China [2022YFF1000900]; Local Innovative and Research Teams Project of Guangdong Province [2019BT02N630]; China Agriculture Research System [CARS-35]. Funding for open access charge: National Natural Science Foundation of China [32022078].Peer reviewe

Relation between Red Cell Distribution Width and Mortality in Critically Ill Patients with Acute Respiratory Distress Syndrome

Background. Currently, evidence regarding the predictive significance of red blood cell distribution width (RDW) among patients with acute respiratory distress syndrome (ARDS) remains scarce. The aim of this study was to determine the prognostic value of RDW for critically ill patients with ARDS. Methods. We studied all patients with ARDS from the Multiparameter Intelligent Monitoring in Intensive Care Database III (MIMIC-III) for whom RDW was available. The clinical outcomes were 30-day and 90-day mortality. Analyses included logistic multivariate regression model, Receiver Operating Characteristic (ROC) analysis, and subgroup analysis. Results. A total of 404 eligible ARDS patients were included. After adjustment for several clinical characteristics related to 30-day mortality, the adjusted OR (95% CIs) for RDW levels ≥14.5% was 1.91 (1.08, 3.39). A similar trend was observed for 90-day mortality. The RDW levels ≥14.5% were also an independent predictor of 90-day mortality (OR, 2.56; 95% CI, 1.50 to 4.37; P = 0.0006) compared with the low RDW levels (<14.5%). In subgroup analyses, RDW showed no significant interactions with other relevant risk factors for 30-day mortality. Conclusions. RDW appeared to be a novel, independent predictor of mortality in critically ill patients with ARDS

Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery: An Update Meta-Analysis and Trial Sequential Analysis

Background. Recent studies suggest that levosimendan does not provide mortality benefit in patients with low cardiac output syndrome undergoing cardiac surgery. These results conflict with previous findings. The aim of the current study is to assess whether levosimendan reduces postoperative mortality in patients with impaired left ventricular function (mean EF ≤ 40%) undergoing cardiac surgery. Methods. We conducted a comprehensive search of PubMed, EMBASE, and Cochrane Library Database through November 20, 2017. Inclusion criteria were random allocation to treatment with at least one group receiving levosimendan and another group receiving placebo or other treatments and cardiac surgery patients with a left ventricular ejection fraction of 40% or less. The primary endpoint was postoperative mortality. Secondary outcomes were cardiac index, pulmonary capillary wedge pressure (PCWP), length of intensive care unit (ICU) stay, postoperative atrial fibrillation, and postoperative renal replacement therapy. We performed trial sequential analysis (TSA) to evaluate the reliability of the primary endpoint. Results. Data from 2,152 patients in 15 randomized clinical trials were analyzed. Pooled results demonstrated a reduction in postoperative mortality in the levosimendan group [RR = 0.53, 95% CI (0.38–0.73), I2=0]. However, the result of TSA showed that the conclusion may be a false positive. Secondary outcomes demonstrated that PCWP, postoperative renal replacement therapy, and length of ICU stay were significantly reduced. Cardiac index was greater in the levosimendan group. No difference was found in the rate of postoperative atrial fibrillation. Conclusions. Levosimendan reduces the rate of death and other adverse outcomes in patients with low ejection fraction who were undergoing cardiac surgery, but results remain inconclusive. More large-volume randomized clinical trials (RCTs) are warranted

Genome-Wide Identification and Functional Analysis of the Calcineurin B-like Protein and Calcineurin B-like Protein-Interacting Protein Kinase Gene Families in Chinese Cabbage (Brassica rapa ssp. pekinensis)

In plants, calcineurin B-like proteins (CBL) are a unique set of calcium sensors that decode calcium signals by activating a plant-specific protein kinase family called CBL-interacting protein kinases (CIPKs). The CBL&ndash;CIPK family and its interacting complexes regulate plant responses to various environmental stimuli. Chinese cabbage (Brassica rapa ssp. pekinensis) is an important vegetable crop in Asia; however, there are no reports on the role of the CBLs&ndash;CIPKs&rsquo; signaling system in response to abiotic stress during cabbage growth. In this study, 18 CBL genes and 47 CIPK genes were identified from the Chinese cabbage genome. Expansion of the gene families was mainly due to tandem repeats and segmental duplication. An analysis of gene expression patterns showed that different duplicate genes exhibited different expression patterns in response to treatment with Mg2+, K+, and low temperature. In addition, differences in the structural domain sequences of NAF/FISL and interaction profiles in yeast two-hybrid assays suggested a functional divergence of the duplicate genes during the long-term evolution of Chinese cabbage, a result further validated by potassium deficiency treatment using trans-BraCIPK23.1/23.2/23.3 Arabidopsis thaliana. Our results provide a basis for studies related to the functional divergence of duplicate genes and in-depth studies of BraCBL&ndash;BraCIPK functions in Chinese cabbage

Serum Anion Gap Predicts All-Cause Mortality in Critically Ill Patients with Acute Kidney Injury: Analysis of the MIMIC-III Database

Background. No epidemiological study has investigated the effect of anion gap (AG) on the prognosis of critically ill patients with acute kidney injury (AKI). Therefore, we aimed to determine the association between serum AG and all-cause mortality in these patients. Methods. From MIMIC III, we extracted demographics, vital signs, laboratory tests, comorbidities, and scoring systems from the first 24 h after patient ICU admission. A generalized additive model was used to identify a nonlinear association between anion gap and 30-day all-cause mortality. We also used the Cox proportional hazards models to measure the association between AG levels and 30-day, 90-day, and 365-day mortality in patients with AKI. Results. A total of 11,573 eligible subjects were extracted from the MIMIC-III. The relationship between AG levels and 30-day all-cause mortality in patients with AKI was nonlinear, with a U-shaped curve. In multivariate analysis, after adjusting for potential confounders, higher AG was a significant predictor of 30-day, 90-day, and 365-day all-cause mortality compared with lower AG (HR, 95% CI: 1.54, 1.33–1.75; 1.55, 1.38–1.73; 1.46, 1.31–1.60). Conclusions. The relationship between AG levels and 30-day all-cause mortality described a U-shaped curve. High-AG levels were associated with increased risk 30-day, 90-day, and 365-day all-cause mortality in critically ill patients with AKI

The Neutrophil Percentage-to-Albumin Ratio Is Associated with All-Cause Mortality in Critically Ill Patients with Acute Kidney Injury

Background. There is no evidence to suggest the predictive power of neutrophil percentage-to-albumin ratio (NPAR) in patients with acute kidney injury (AKI). We hypothesized that NPAR would correlate with all-cause mortality in critically ill patients with AKI. Methods. From the MIMIC-III V1.4 database, we extracted demographics, vital signs, comorbidities, laboratory tests, and other clinical data. The clinical endpoints were 30-, 90- and 365-day all-cause mortality in critically ill patients with AKI. Cox proportional hazards models were used to evaluate the prognostic values of NPAR, and subgroup analyses were performed to measure mortality across various subgroups. Results. A total of 7,481 eligible subjects were enrolled. In multivariate analysis, after adjustments for age, ethnicity, gender, and other confounding factors, higher NPARs were associated with an increased risk of 30-, 90- and 365-day all-cause mortality in critically ill patients with AKI (tertile 3 versus tertile 1: adjusted HR, 95% CI: 1.48, 1.30–1.69; 1.47, 1.31–1.66; 1.46, 1.32–1.62, respectively; P trend <0.01). A similar trend was observed in the NPAR group division by quintiles. Subgroup analysis revealed no significant interactions in most strata. Conclusions. Increased NPAR correlates with increased risk of all-cause mortality in critically ill patients with AKI